CN104119339B - One kind reduces compound of intraocular pressure and its production and use - Google Patents
One kind reduces compound of intraocular pressure and its production and use Download PDFInfo
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- CN104119339B CN104119339B CN201310032188.3A CN201310032188A CN104119339B CN 104119339 B CN104119339 B CN 104119339B CN 201310032188 A CN201310032188 A CN 201310032188A CN 104119339 B CN104119339 B CN 104119339B
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- 0 CCC(C)(*)C(CC(*)=[*-])=CCC(*C)C(C(C1C)C(*(C2=CCC(*)=C(*)C=C2)=C)=O)[n]2nnc(*)c2*1=C Chemical compound CCC(C)(*)C(CC(*)=[*-])=CCC(*C)C(C(C1C)C(*(C2=CCC(*)=C(*)C=C2)=C)=O)[n]2nnc(*)c2*1=C 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of compound and its pharmaceutical composition and its production and use, the purposes reduces the purposes in the medicine of intraocular pressure for preparation.Above-claimed cpd reduces the action effect highly significant of intraocular pressure.
Description
Technical field
The present invention relates to a kind of compound for reducing intraocular pressure and its officinal salt and its analog, by above-claimed cpd
And its pharmaceutical composition prepared by officinal salt and its analog, and described compound or pharmaceutically acceptable salt thereof and the like exists
Prepare the purposes in the medicine for reducing intraocular pressure.
Background technology
Intraocular pressure (IOP) is a kind of eye disease for endangering whole world human health because a variety of causes raises, patient's
It is mainly shown as that intraocular pressure is short-term or increases for a long time.Because intraocular pressure rise can cause the vision loss of irreversibility, therefore
This is a kind of very serious diseases causing blindness.
Scientific circles there is no final conclusion for reducing the pathogenic factor of intraocular pressure at present, it is recognized that to be caused by many reasons, face at present
It is not very good in the therapeutic effect for the medicine for reducing intraocular pressure on bed.Because PATIENT POPULATION is very big and harm is very big, one is needed badly
The effective medicine of kind is treated.
The present inventor is prepared for one group of compound and its similar compound or its officinal salt, this group of compound and its similar
Compound or pharmaceutically acceptable salt thereof has unexpected outstanding effect on the medicine for reducing intraocular pressure is prepared.
The content of the invention
Reduced the invention provides the preparation of one group of compound and its similar compound or its officinal salt and its preparing
New application in the medicine of intraocular pressure.
Technical scheme is as follows：
A kind of compound or pharmaceutically acceptable salt thereof and the like, the structure of the compound are as follows：
Wherein R1Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxyl group, ethyoxyl, positive propoxy；R2 is selected from hydrogen,
Methyl, ethyl, n-propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group；R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl
Base, methoxyl group, ethyoxyl, positive propoxy；R4 is selected from acetenyl, vinyl, ethyl.
The present invention is specifically prepared for following 3 compounds：
Compound (A)；
Compound (B)；
Compound (C)；
The synthetic route of compound of the present invention is as follows：
Wherein R1Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxyl group, ethyoxyl, positive propoxy；R2 is selected from hydrogen,
Methyl, ethyl, n-propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group；R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl
Base, methoxyl group, ethyoxyl, positive propoxy；R4 is selected from acetenyl, vinyl, ethyl.
Purposes of the compound or pharmaceutically acceptable salt thereof of the present invention and the like in the medicine for reducing intraocular pressure is prepared, specifically
Raised for the intraocular pressure as caused by a variety of causes can be reduced.
Compound of the present invention and the like or its officinal salt can be prepared into through local administration, gastrointestinal administration
Or the various preparations of parenteral administration.The preparation includes ordinary preparation, controlled release preparation, targeting preparation etc..Described office
Portion's drug-delivery preparation is high by the powder-injection of organ administration, liquid drugs injection, microball preparation, nanometer formulation, Liposomal formulation, dendroid
Molecular preparation, implant, polyethyleneglycol modified preparation, aqueogel etc..Described parenterals are suitable quiet
Arteries and veins injection, intramuscular injection, hypodermic injection, marrow injection, cutaneous penetration, the formulation of mucosa delivery and inhalation.
The present inventor, which studies, to be found：Such compound can greatly alleviate Bulbi hypertonia symptom, from the result of pharmacodynamic experiment
See, the effect of the decompression of such compound exceeds the medicine of current clinical practice.The exploitation of this noval chemical compound will be to following high
Very big effect is played in the recovery of intraocular pressure patient.For releasing sufferer pain, improving the quality of life of patient has great meaning
Justice.
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
Prepare embodiment
Prepare embodiment 1 (compound A is compound A9 preparation)
Compound A1 generates A2 under di-tert-butyl dicarbonate catalysis, under oxalyl chloride and diisopropylethylamine catalysis, surpasses
Under cryogenic conditions, reaction generation A3 in the mixed liquor of dimethyl sulfoxide (DMSO) and dichloromethane, then in salt under a1 and a2 catalysis
Backflow generation A4, A4 normal temperature in the ethanol water of sodium hydroxide generates A5 in the ethanol solution of acid, in the second of sodium borohydride
Normal temperature backflow generation A6 in alcoholic solution, in dichloromethane, a3, I-hydroxybenzotriazole, 1- (3- dimethylamino-propyls) -3- second
A7 is generated under base carbodiimide catalyzed, A8 is generated in the dichloromethane of trifluoroacetic acid, under a4 catalysis, is generated in dichloromethane
A9。
Prepare embodiment 2 (compound B is compound B9 preparation)
Compound B-11 generates B2 under di-tert-butyl dicarbonate catalysis, under oxalyl chloride and diisopropylethylamine catalysis, surpasses
Under cryogenic conditions, reaction generation B3 in the mixed liquor of dimethyl sulfoxide (DMSO) and dichloromethane, then in salt under b1 and b2 catalysis
Backflow generation B4, B4 normal temperature in the ethanol water of sodium hydroxide generates B5 in the ethanol solution of acid, in the second of sodium borohydride
Normal temperature backflow generation B6 in alcoholic solution, in dichloromethane, b3, I-hydroxybenzotriazole, 1- (3- dimethylamino-propyls) -3- second
B7 is generated under base carbodiimide catalyzed, B8 is generated in the dichloromethane of trifluoroacetic acid, under b4 catalysis, is generated in dichloromethane
B9。
Prepare embodiment 3 (compound C is compound C9 preparation)
Compound C1 generates C2 under di-tert-butyl dicarbonate catalysis, under oxalyl chloride and diisopropylethylamine catalysis, surpasses
Under cryogenic conditions, reaction generation C3 in the mixed liquor of dimethyl sulfoxide (DMSO) and dichloromethane, then in salt under c1 and c2 catalysis
Backflow generation C4, C4 normal temperature in the ethanol water of sodium hydroxide generates C5 in the ethanol solution of acid, in the second of sodium borohydride
Normal temperature backflow generation C6 in alcoholic solution, in dichloromethane, c3, I-hydroxybenzotriazole, 1- (3- dimethylamino-propyls) -3- second
C7 is generated under base carbodiimide catalyzed, C8 is generated in the dichloromethane of trifluoroacetic acid, under c4 catalysis, is generated in dichloromethane
C9。
The preparation of the injections of A containing compound：
1. take mannitol, phosphatide, glycerine, cyclodextrine derivatives, dimethyl sulfoxide (DMSO) and the common 50mg and 100mg formulas of poloxamer
(A) compound mixes in water for injection and is allowed to dissolve；
2. 0.45um miillpore filter coarse filtration is first used after mixing dissolving after stable, then with 0.2um filtering with microporous membrane；
3. being distributed into small cillin bottle, other lyophilized therapeutic agents and auxiliary material are added；
4. carry out procedural lyophilized；
5. the corresponding inspection such as pyrogen, sterile, visible foreign matters, particulate matter is carried out, it is stand-by after meeting the requirements.
The preparation of the injections of B containing compound：
1. take mannitol, phosphatide, glycerine, cyclodextrine derivatives, dimethyl sulfoxide (DMSO) and the common 50mg and 200mg formulas of poloxamer
(B) compound mixes in water for injection and is allowed to dissolve；
2. 0.45um miillpore filter coarse filtration is first used after mixing dissolving after stable, then with 0.2um filtering with microporous membrane；
3. being distributed into small cillin bottle, other lyophilized therapeutic agents and auxiliary material are added；
4. carry out procedural lyophilized；
5. the corresponding inspection such as pyrogen, sterile, visible foreign matters, particulate matter is carried out, it is stand-by after meeting the requirements.
The preparation of the injections of C containing compound：
1. take mannitol, phosphatide, glycerine, cyclodextrine derivatives, dimethyl sulfoxide (DMSO) and the common 50mg and 400mg formulas of poloxamer
(C) compound mixes in water for injection and is allowed to dissolve；
2. 0.45um miillpore filter coarse filtration is first used after mixing dissolving after stable, then with 0.2um filtering with microporous membrane；
3. being distributed into small cillin bottle, other lyophilized therapeutic agents and auxiliary material are added；
4. carry out procedural lyophilized；
5. the corresponding inspection such as pyrogen, sterile, visible foreign matters, particulate matter is carried out, it is stand-by after meeting the requirements.
Effect example
Experiment on therapy of the compound (A-C) to high intraocular pressure in rats
1.1 experimental animals and packet
Experiment uses Thirty male rats, body weight 220g or so.Before modeling, animal is grouped at random：That is blank
Control group；Model group；Compound (A-C) group, was administered once every 5 days intravitreal injections, dosage 0.1mg injections/kg；Sun
Property medicine group selection pilocarpinum eye drops, be administered once a day, one time one drop.All administrations continue 15 days.
The foundation of 1.2 animal models
Experiment before intraperitoneal injection the chloraldurate of rat 4% (200mg.kg-1), then with 1% lidocaine local anaesthesia
Cornea of rats.During preparing high intraocular pressure model, keep making animal every half an hour membrane cavity 0.2 milliliter of 4% chloraldurate of injection
The state of continuous narcosis.Rat right eye intraocular pressure is raised using pulley-suture system, while left side eyeball compares.Will be outer
Section's suture both ends are respectively an identical heavy counterweight, and a circle is hitched among suture and is used for after the rat canthus limbus of sclera 2 in the least
Rice, the counterweight at both ends is by pulley to the continual and steady pressure of rat eye.Counterweight pressure is 20 grams, continuous 6 hours, is caused
High intraocular pressure in rats model.15 days measure ratholes are raised after administration to press and record.1.3 experimental result
Experimental result is shown in Table 1
The intraocular pressure result (mmHg, n=10) of rat under each group drug treatment of table 1
The * P ＜ 0.05**P ＜ 0.01 compared with model group
Experiment on therapy of the compound A-C to rabbit Bulbi hypertonia
2.1 experimental animals and packet
Healthy regular grade rabbit, male and female half and half, body weight 2.3kg or so, examination with slitlamp microscope is without anterior ocular segment disease
Become.Before non-modeling, experimental rabbit 20 is randomly selected, respectively at daily more point in time measurement rabbit bilateral intraocular pressures and is recorded.It is continuous to see
After examining one week, to determine this group of experimental rabbit normal intraocular tension scope.After modeling 1 week, animal pattern is grouped at random：Animal is random
Packet：That is blank control group；Model group；Compound (A-C) group, is administered once every 5 days intravitreal injections, in every lagophthalmos
0.5mg injections are administered in injection；Positive drug group selection selects VUFB-6453 eye drops, is administered once a day.All administrations continue
15 days.
The foundation of 2.2 animal models
Every group of point position puncture of anterior chamber of 10 rabbit cornea of right eye edge 12, extract 0.2 milliliter of aqueous humor out.0.3% carbomer and
0.025% 0.2 milliliter of dexamethasone is injected to anterior chamber through puncture orifice, and left eye is control eye, and modeling starts to be administered after one week.
2.3 measurement intraocular pressures
After animal administration, with the 15th day intraocular pressure after tonometer measurement administration and record.
2.4 experimental result
Intraocular pressure raises after rabbit modeling, and the intraocular pressure of each medication therapy groups raises, display modeling type success.After administration, respectively
Individual medicine group has inhibitory action to intraocular pressure rise, and wherein compound (A-C) group effect is the most obvious, and medicine (A-C) group
Therapeutic effect is better than positive drug group.
Lagophthalmos pressure result (n=10) under each group drug treatment of table 2
The * P ＜ 0.05**P ＜ 0.01 compared with model group
Summary experimental result is drawn a conclusion：Compound (A), (B), medicine prepared by (C) play preferable reduction
The effect of intraocular pressure.
Claims (2)
1. purposes of a kind of compound or pharmaceutically acceptable salt thereof in the medicine for reducing intraocular pressure is prepared, the structure of the compound are as follows：
Wherein R1Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxyl group, ethyoxyl, positive propoxy；R2Selected from hydrogen, methyl,
Ethyl, n-propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group；R3Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy
Base, ethyoxyl, positive propoxy；R4Selected from acetenyl, vinyl, ethyl.
2. the purposes described in claim 1, to prepare the purposes reduced in the elevated medicine of the intraocular pressure as caused by a variety of causes.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310032188.3A CN104119339B (en) | 2013-01-22 | 2013-01-22 | One kind reduces compound of intraocular pressure and its production and use |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310032188.3A CN104119339B (en) | 2013-01-22 | 2013-01-22 | One kind reduces compound of intraocular pressure and its production and use |
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| CN104119339A CN104119339A (en) | 2014-10-29 |
| CN104119339B true CN104119339B (en) | 2018-03-13 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104119341B (en) * | 2013-01-22 | 2018-03-13 | 韩冰 | A kind of protease inhibitors and its production and use |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101437824A (en) * | 2006-05-04 | 2009-05-20 | 肝炎与病毒研究所 | Inhibitors of secretion of hepatitis B virus antigens for treatment of a chronic hepatitis virus |
| CN104119341A (en) * | 2013-01-22 | 2014-10-29 | 韩冰 | Protease inhibitors, preparation method and application thereof |
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2013
- 2013-01-22 CN CN201310032188.3A patent/CN104119339B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101437824A (en) * | 2006-05-04 | 2009-05-20 | 肝炎与病毒研究所 | Inhibitors of secretion of hepatitis B virus antigens for treatment of a chronic hepatitis virus |
| CN104119341A (en) * | 2013-01-22 | 2014-10-29 | 韩冰 | Protease inhibitors, preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| "A three-dimensional pharmacophore modelling of ITK inhibitors and virtual screening for novel inhibitors";V.Bagga et al.,;《SAR and QSAR in Environmental Research》;20110309;第22卷(第1-2期);第171-190页 * |
| "Synthesis of 6-acyl-7-aryl-4,7-dihydrotetrazolo[1,5-α]pyrimidine-5-carboxylic acids and their methyl esters";V.L.Gein et al.;《Russian Journal of Organic Chemistry》;20071231;第43卷(第9期);第1382-1386页 * |
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