CN104370824A - Intraocular tension reducing compound and preparation method and use thereof - Google Patents

Abstract

The invention discloses a compound and a pharmaceutical composition and a 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

One class reduces compound of intraocular pressure and its production and use

Technical field

The present invention relates to a class and reduce compound of intraocular pressure and its production and use, the pharmaceutical composition 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 endangering whole world human health because a variety of causes raises, and the main manifestations of patient 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.

Current scientific circles there is no final conclusion for the pathogenic factor reducing intraocular pressure, are known as and are caused by many reasons, not very good in the result for the treatment of of the medicine reducing intraocular pressure clinically at present.Because PATIENT POPULATION is very large and harm is very large, need a kind of effective medicine badly and treat.

The present inventor has prepared one group of compound and similar compound thereof or its pharmacologically acceptable salt, and this group compound and similar compound thereof or its pharmacologically acceptable salt reduce on the medicine of intraocular pressure in preparation beyond thought outstanding effect.

Summary of the invention

The preparation that the invention provides one group of compound and similar compound or its pharmacologically acceptable salt and the novelty teabag reduced in preparation in the medicine of 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, ethyl, n-propyl; R ₂be selected from methyl, ethyl, n-propyl; Integer between n=2-4; X is haloid element or amino.

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 R ₁, R ₂with n according to any one of claim 1-6, X is F, Cl, Br, I or amino.

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 the intraocular pressure rising that can reduce and be caused by a variety of causes.

Compound of the present invention and analogue thereof or its pharmacologically acceptable salt can be prepared into through topical, gastrointestinal administration or the various preparations of parenteral administration.Described preparation comprises ordinary preparation, controlled release preparation, targeting preparation etc.Described local administration preparation is powder injection, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, implant, polyethyleneglycol modified preparation, aqueogel etc. through organ administration.Described parenterals is the formulation of suitable intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.

The present inventor studies discovery: this compounds can greatly alleviate Bulbi hypertonia symptom, 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 is by for playing very large effect to the recovery of following Bulbi hypertonia patient.Painful for releasing sufferer, the quality of life improving 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 embodiment

The preparation of preparation embodiment 1(compd A and compd A 12)

Compd A 1 is 50 degree of generation compd As 2 in hydrochloric acid soln, compd A 2 is under a1 catalysis, reflux in methanol solution and generate an A3 in, in thionyl chloride and chloroformic solution, backflow generates compd A 4, under a2 catalysis, 120 degree of lower dimethyl formamide catalysis generate compound A-45, and under the catalysis of diamine reductive agent, in ethanolic soln, backflow generation compd A 6 is stand-by.Compd A 7 and compound A-28 normal-temperature reaction in oil of mirbane and aluminum chloride obtains compd A 9 in 2 hours, under the catalysis of diamine reductive agent, in ethanolic soln, backflow generates compd A 10, reflux in n-propyl alcohol solution with compd A 6 and generate compd A 11, in the ethanol solution hydrochloride adding Fe powder, backflow generates compd A 12.

Preparation embodiment 2

compound (A12) is prepared according to the method identical with preparing embodiment 1.Then 0 degree of reaction 2 hours in hydrochloric acid and sodium nitrate solution, adds in the mixing solutions of cuprous chloride and hydrochloric acid after rear drying, 50 degree of reactions are spent the night to obtain compd B.

Preparation embodiment 3

Compound (A12) is prepared according to the method identical with preparing embodiment 1.Then 0 degree of reaction 2 hours in bromic acid and sodium nitrate solution, adds in the mixing solutions of cuprous bromide and bromic acid after rear drying, 50 degree of reactions are spent the night to obtain compd B.

Medicine preparation example 1(is containing the preparation of the lyophilized injection of compd A):

1. get common 50mg and 100mg formula (A) compound of N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer mix in water for injection and make it to dissolve;

2. mixing first uses 0.45um millipore filtration coarse filtration after dissolving after stable, then uses 0.2um filtering with microporous membrane;

3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;

4. procedural freeze-drying is carried out;

5. pyrogen, aseptic, the corresponding inspection such as visible foreign matters, particulate matter is carried out, stand-by after all meeting the requirements.

Medicine preparation example 2-5

By compound (B)-compound (C) alternative compounds (A), and contain the lyophilized injection of compound (B)-compound (C) according to the method preparation of medicine preparation example 1.

effect example

Compound (A-C) is to the Experiment on therapy of high intraocular pressure in rats

1.1 laboratory animal and grouping

Experiment adopts Thirty male rats, about body weight 220g.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, every day is administered once, 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 the lignocaine toponarcosis cornea of rats of 1%.During preparing high intraocular pressure model, keep every half an hour abdominal injection 4% Chloral Hydrate 0.2 milliliter make the state of animal continuous narcosis.Adopt pulley-suture system that rat right eye intraocular pressure is raised, 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 eye 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.Raise after administration and within 15 days, measure rathole pressure and record.

1.3 experimental result

Experimental result is in table 1

The intraocular pressure result (mmHg, n=10) of the rat under drug treatment respectively organized by table 1

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	28.2±1.5	15.8±1.3**
Medicine B group	28.1±1.5	16.2±1.4**
			Medicine C group	28.2±1.6	16.1±1.3**
Positive drug eye drop group	28.0±1.4	21.7±1.3*

* P<0.05**P<0.01 is compared with model group

Compd A-C is to the ocular hypertensive Experiment on therapy of rabbit

2.1 laboratory animal and grouping

Healthy regular grade rabbit, male and female half and half, about body weight 2.3kg, examination with slitlamp microscope is without anterior ocular segment pathology.Before non-modeling, random selecting experimental rabbit 20, respectively at many point in time measurement rabbit bilateral intraocular pressure record every day.Continuous Observation is after one week, to determine this group experimental rabbit normal intraocular tension scope.Modeling is after 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 every day is administered once.All administrations continue 15 days.

The foundation of 2.2 animal models

Often organize 10 rabbit cornea of right eye edge, 12 position puncture of anterior chamber, extract aqueous humor 0.2 milliliter out.0.3% carbomer and 0.025% dexamethasone 0.2 milliliter 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, measure the 15th day intraocular pressure after administration and record with tonometer.

2.4 experimental result

After rabbit modeling, intraocular pressure raises, and the intraocular pressure of each medication therapy groups all raises, the success of display modeling type.After administration, each medicine group raises intraocular pressure all has restraining effect, and wherein to organize effect the most obvious for compound (A-C), and medicine (A-C) is organized result for the treatment of and is all better than positive drug group.

 

Lagophthalmos pressure result (n=10) under drug treatment respectively organized by table 2

Group	Value before medicine	15 days
			Model group	36.0±5.0	28.0±5.1
Medicine A group	36.2±5.2	16.2±4.1**
			Medicine B group	36.2±5.1	16.1±4.2**
Medicine C group	36.1±5.1	16.2±4.3**
			Positive drug eye drop group	36.2±5.4	20.0±4.3*

* P<0.05**P<0.01 is compared with model group

Comprehensive above-mentioned experimental result is reached a conclusion: compound (A), (B), and medicine prepared by (C) all plays the effect reducing intraocular pressure preferably.

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, ethyl, n-propyl; R ₂be selected from methyl, ethyl, n-propyl; Integer between n=2-4; X is haloid element or amino.

2. compound or pharmaceutically acceptable salt thereof according to claim 1 and analogue thereof, wherein halogen is selected from F, Cl, Br, I.

3. compound or pharmaceutically acceptable salt thereof according to claim 1 and analogue thereof, it is selected from following compound:

Compound (A);

Compound (B);

Compound (C).

4. the preparation method of compound described in claim any one of claim 1-3, is characterized by and synthesize according to following route:

Wherein R ₁, R ₂with n according to any one of claim 1-3, X is F, Cl, Br, I or amino.

5. compound or pharmaceutically acceptable salt thereof described in any one of claim 1-4 and analogue thereof reduce the purposes in the medicine of intraocular pressure in preparation.

6. comprise the pharmaceutical composition of compound or pharmaceutically acceptable salt thereof any one of claim 1-5 and analogue thereof, it is characterized in that this pharmaceutical composition to be prepared into ordinary preparation, controlled release preparation or targeting preparation.