CN104119339A - Compounds reducing intraocular pressure, and preparation method and application thereof - Google Patents

Compounds reducing intraocular pressure, and preparation method and application thereof Download PDF

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Publication number
CN104119339A
CN104119339A CN201310032188.3A CN201310032188A CN104119339A CN 104119339 A CN104119339 A CN 104119339A CN 201310032188 A CN201310032188 A CN 201310032188A CN 104119339 A CN104119339 A CN 104119339A
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compound
propyl
preparation
ethyl
intraocular pressure
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CN104119339B (en
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韩冰
王爽
王斓
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    • 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
    • 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)
  • Organic Chemistry (AREA)
  • 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 compounds reducing intraocular pressure, and a preparation method and application thereof. The application is application to prepare medicines for reducing intraocular pressure. The above compounds have extremely substantial effect on reducing intraocular pressure.

Description

One class reduces compound of intraocular pressure and its production and use
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, so 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 effective 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 preparation and the new purposes in the medicine of preparation reduction intraocular pressure thereof of one group of compound and similar compound or its pharmacologically acceptable salt.
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:
R wherein 1be selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy; R2 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, propoxy-; R3 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy; R4 is selected from ethynyl, vinyl, ethyl.
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:
R wherein 1be selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy; R2 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, propoxy-; R3 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy; R4 is selected from ethynyl, vinyl, ethyl.
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 the powder injection through 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.Painful for removing sufferer, the quality of life that improves patient is significant.
Accompanying drawing explanation
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 compd A 9)
Compd A 1 generates A2 under tert-Butyl dicarbonate catalysis, under oxalyl chloride and diisopropylethylamine catalysis, under condition of ultralow temperature, in the mixed solution of dimethyl sulfoxide (DMSO) and methylene dichloride, reaction generates A3, then under the catalysis of a1 and a2, in the ethanolic soln of hydrochloric acid, reflux and generate A4, A4 normal temperature in the aqueous ethanolic solution of sodium hydroxide generates A5, in the ethanolic soln of sodium borohydride, normal temperature refluxes and generates A6, in methylene dichloride, a3, I-hydroxybenzotriazole, under 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide catalysis, generate A7, in the methylene dichloride of trifluoroacetic acid, generate A8, under a4 catalysis, in methylene dichloride, generate A9.
Preparation Example 2 (compd B is the preparation of compd B 9)
Compound B-11 generates B2 under tert-Butyl dicarbonate catalysis, under oxalyl chloride and diisopropylethylamine catalysis, under condition of ultralow temperature, in the mixed solution of dimethyl sulfoxide (DMSO) and methylene dichloride, reaction generates B3, then under the catalysis of b1 and b2, in the ethanolic soln of hydrochloric acid, reflux and generate B4, B4 normal temperature in the aqueous ethanolic solution of sodium hydroxide generates B5, in the ethanolic soln of sodium borohydride, normal temperature refluxes and generates B6, in methylene dichloride, b3, I-hydroxybenzotriazole, under 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide catalysis, generate B7, in the methylene dichloride of trifluoroacetic acid, generate B8, under b4 catalysis, in methylene dichloride, generate B9.
Preparation Example 3 (Compound C is the preparation of Compound C 9)
Compound C 1 generates C2 under tert-Butyl dicarbonate catalysis, under oxalyl chloride and diisopropylethylamine catalysis, under condition of ultralow temperature, in the mixed solution of dimethyl sulfoxide (DMSO) and methylene dichloride, reaction generates C3, then under the catalysis of c1 and c2, in the ethanolic soln of hydrochloric acid, reflux and generate C4, C4 normal temperature in the aqueous ethanolic solution of sodium hydroxide generates C5, in the ethanolic soln of sodium borohydride, normal temperature refluxes and generates C6, in methylene dichloride, c3, I-hydroxybenzotriazole, under 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide catalysis, generate C7, in the methylene dichloride of trifluoroacetic acid, generate C8, under c4 catalysis, in methylene dichloride, generate C9.
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 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 400mg 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.
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 injecting 0.2 milliliter of state that makes animal continuous narcosis of 4% Chloral Hydrate every film half an hour chamber.Adopt pulley-suture system that rat right eye intraocular pressure is raise, left side eyeball contrasts simultaneously.By surgical sutures two ends, be respectively an identical heavy counterweight, 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
Table 1 is respectively organized the intraocular pressure result (mmHg, n=10) of the rat under drug treatment
Compare * P < 0.05**P < 0.01 with 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.
The lagophthalmos that table 2 is respectively organized under drug treatment is pressed result (n=10)
Compare * P < 0.05**P < 0.01 with 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 (7)

1. a compounds or its pharmacologically acceptable salt and analogue thereof, the structure of described compound is as follows:
R wherein 1be selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy; R2 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, propoxy-; R3 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy; R4 is selected from ethynyl, vinyl, ethyl.
2. compound or pharmaceutically acceptable salt thereof claimed in claim 1 and analogue thereof, it is selected 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:
r wherein 1be selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy; R2 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, propoxy-; R3 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy; R4 is selected from ethynyl, vinyl, ethyl.
4. described in claim 1-3 any one, compound or pharmaceutically acceptable salt thereof and analogue thereof reduce the purposes in the medicine of intraocular pressure in preparation.
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.
7. the pharmaceutical composition of claim 6, described compound and pharmacologically acceptable salt thereof and its analogue are prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.
CN201310032188.3A 2013-01-22 2013-01-22 One kind reduces compound of intraocular pressure and its production and use Active CN104119339B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104119341A (en) * 2013-01-22 2014-10-29 韩冰 Protease inhibitors, preparation method and application thereof

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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
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