CN103845334A - Compound for reducing intraocular pressure and application thereof - Google Patents

Abstract

The invention discloses a compound as well as a drug composition and new application thereof. The compound is applied to preparation of drugs for reducing intraocular pressure. The compound has very obvious effects on reducing intraocular pressure.

Description

One class reduces compound of intraocular pressure and uses thereof

Technical field

The present invention relates to compound and officinal salt and its analog that a class reduces intraocular pressure, the pharmaceutical composition of being prepared by above-claimed cpd and officinal salt thereof and its analog, and described compound or pharmaceutically acceptable salt thereof and analog thereof reduce the purposes in the medicine of intraocular pressure in preparation.

Background technology

Intraocular pressure (IOP) is a kind of ocular 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 irreversibility, 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 at the therapeutic effect 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 is surprised to find that one group of compound and similar compound or its officinal salt thereof have an unexpected effect on the medicine of preparation reduction intraocular pressure, reduce intraocular pressure for this compounds at present and there is no report.

Summary of the invention

The invention provides one group of compound and similar compound thereof or its officinal salt new purposes in the medicine of preparation reduction intraocular pressure.

Technical scheme of the present invention is as follows:

The invention provides one group of compound or pharmaceutically acceptable salt thereof that can reduce intraocular pressure disease, and analog, the structure of described compound is as follows: compound (A); compound (B);

compound (C);

compound (D);

compound (E).

Above formula compound and analog thereof or its officinal 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 injectable powder of dosing eyes, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, polyethyleneglycol modified preparation, aqueogel etc.Described parenteral administration preparation is the dosage form of suitable intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.

The inventor studies and finds that this compounds can greatly reduce intraocular pressure, and from the result of pharmacodynamic experiment, the effect of this compounds exceeds the medicine of current clinical practice.Great role is played in the recovery of the sufferer colony to high intraocular pressure by the exploitation of this noval chemical compound, is significant for the misery of removing sufferer and its family.

Detailed description of the invention

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 compound (A);

compound (B);

compound (C);

compound (D); compound (E).

Preparation containing compd A injection:

1. altogether 50mg and 100mg formula (A) compound mix and make it dissolving in water for injection to get mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;

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

3. be distributed into little cillin bottle, add other lyophilizing therapeutic agent and adjuvants;

4. carry out procedural lyophilizing;

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 300mg formula (B) compound mix and make it dissolving in water for injection to get mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;

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

3. be distributed into little cillin bottle, add other lyophilizing therapeutic agent and adjuvants;

4. carry out procedural lyophilizing;

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 20mg formula (C) compound mix and make it dissolving in water for injection to get mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;

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

3. be distributed into little cillin bottle, add other lyophilizing therapeutic agent and adjuvants;

4. carry out procedural lyophilizing;

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 50mg formula (D) compound mix and make it dissolving in water for injection to get mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;

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

3. be distributed into little cillin bottle, add other lyophilizing therapeutic agent and adjuvants;

4. carry out procedural lyophilizing;

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. altogether 50mg and 500mg formula (E) compound mix and make it dissolving in water for injection to get mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;

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

3. be distributed into little cillin bottle, add other lyophilizing therapeutic agent and adjuvants;

4. carry out procedural lyophilizing;

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 high intraocular pressure in rats

1.1 laboratory animals 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

Lumbar injection rat 4% chloral hydrate (200mg.kg-1) before experiment, then uses 1% lignocaine local anesthesia cornea of rats.During preparing high intraocular pressure model, keep every half an hour 0.2 milliliter of lumbar 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

With relatively * P < 0.05**P < 0.01 of model group

Compd A-E is to the ocular hypertensive treatment experiment of rabbit

2.1 laboratory animals 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 pathological changes., 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 paracentesis 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 inhibitory action intraocular pressure, and wherein compound (A-E) group effect is the most obvious, and medicine (A-E) group therapeutic effect 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 effect of good reduction intraocular pressure.

Claims (6)

1. a compounds or its officinal salt, and analog, the structure of described compound is as follows:

compound (A);

compound (B);

compound (C);

compound (D);

compound (E).

2. a pharmaceutical composition, it comprises compound claimed in claim 1 and officinal salt and its analog.

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 officinal salt thereof and its analog 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 officinal salt thereof and its analog purposes in the medicine of preparation reduction intraocular pressure described in claim 2.