CN104370882A - Intraocular tension reducing compound and preparation method and use thereof - Google Patents

Intraocular tension reducing compound and preparation method and use thereof Download PDF

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Publication number
CN104370882A
CN104370882A CN201410034523.8A CN201410034523A CN104370882A CN 104370882 A CN104370882 A CN 104370882A CN 201410034523 A CN201410034523 A CN 201410034523A CN 104370882 A CN104370882 A CN 104370882A
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compound
ethanoyl
represent hydrogen
preparation
ethyl
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CN201410034523.8A
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Chinese (zh)
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韩冰
邢瑞娟
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses an intraocular tension reducing compound, a pharmaceutically acceptable salt and an analogue thereof, a pharmaceutical composition prepared from the intraocular tension reducing compound, the pharmaceutically acceptable salt and the analogue, and use of the intraocular tension reducing compound, the pharmaceutically acceptable salt and the analogue in preparation of intraocular tension reducing drugs, the invention discloses a preparation method and use of the intraocular tension reducing compound and the pharmaceutical composition, the intraocular tension reducing animal experiment of the intraocular tension reducing compound is performed, 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 1represent hydrogen, methyl; R 2represent hydrogen, methyl; R represent hydrogen, 2-methysulfonylethyl, 2-morpholinyl ethyl, 2-hydroxyethyl, 2-amino-ethyl, 2-cyano ethyl, carbamoyhnethyl, 2-picolyl, carboxymethyl, formamyl, 2-picolinoyl, 3-picolinoyl, 4-picolinoyl, ethanoyl, 2-dimethylamino acetyl, 2-hydroxyethylamino ethanoyl, 2-( n-hydroxyethyl methylamino-) ethanoyl, 2-(2-imidazolyl) ethanoyl, 2,3-dihydroxyl propionyls.
Work as R 1, R 2represent hydrogen, R is when representing 2-dimethylamino acetyl, the various salt of this compound; Work as R 1, R 2represent hydrogen, R is when representing 2-methysulfonylethyl, the various salt of this compound; Work as R 1, R 2represent hydrogen, R is when representing 2-morpholinyl ethyl, the various salt of this compound.
Be selected from following compound:
Compound (A), 4-cyano group- n-[2-[3-[1-[2-(dimethylamino) ethanoyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1 h-imidazoles-2-methane amide
；
Compound (B), 4-cyano group- n-[2-[3-[1-[2-(methyl sulphonyl) ethyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1 h-imidazoles-2-methane amide;
Compound (C), 4-cyano group- n-[2-[3-[1-[2-morpholinyl ethyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1 h-imidazoles-2-methane amide;
It is characterized by and synthesize according to following route:
Wherein: R 1represent hydrogen, methyl; R 2represent hydrogen, methyl; R represent hydrogen, 2-methysulfonylethyl, 2-morpholinyl ethyl, 2-hydroxyethyl, 2-amino-ethyl, 2-cyano ethyl, carbamoyhnethyl, 2-picolyl, carboxymethyl, formamyl, 2-picolinoyl, 3-picolinoyl, 4-picolinoyl, ethanoyl, 2-dimethylamino acetyl, 2-hydroxyethylamino ethanoyl, 2-( n-hydroxyethyl methylamino-) ethanoyl, 2-(2-imidazolyl) ethanoyl, 2,3-dihydroxyl propionyls.
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 11)
Compd A 1 and A2 chemical combination generate compound A-13; A3 bromination obtains compd A 4; benzene replaces bromine and generates compound A-45; generate compd A 6 after deaminizing, nitro replaces generation compd A 7, and nitro is reduced generation compound A-28; under Boc protection; A8 is not generated compd A 9 by the amino-reactive that Boc protects, and trifluoroacetic acid takes off Boc and generates A10, and naphthene amino activation generates A11.
The preparation of preparation embodiment 2(compd B and compound B-11 1)
Compound B-11 and B2 chemical combination generate compd B 3; B3 bromination obtains compd B 4; benzene replaces bromine and generates compd B 5; generate compound B-26 after deaminizing, nitro replaces generation compd B 7, and nitro is reduced and generates compd B 8; under Boc protection; B8 is not generated compd B 9 by the amino-reactive that Boc protects, and trifluoroacetic acid takes off Boc and generates B10, and naphthene amino activation generates B11.
The preparation of preparation embodiment 3(Compound C and Compound C 11)
Compound C 1 and C2 chemical combination generate Compound C 3; C3 bromination obtains Compound C 4; benzene replaces bromine and generates Compound C 5; generate Compound C 6 after deaminizing, nitro replaces generation Compound C 7, and nitroreduction generates Compound C 8; under Boc protection; C8 is not generated Compound C 9 by the amino-reactive that Boc protects, and trifluoroacetic acid takes off Boc and generates C10, and naphthene amino activation generates C11.
 
preparation containing compd A injection:
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 freeze-drying therapeutical agent and auxiliary materials;
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.
 
Preparation containing compd B injection:
1. get common 50mg and 200mg formula (B) 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 freeze-drying therapeutical agent and auxiliary materials;
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.
 
Preparation containing Compound C injection:
1. get common 50mg and 400mg formula (C) 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 freeze-drying therapeutical agent and auxiliary materials;
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.
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 28.3±1.5 15.9±1.3**
Medicine B group 28.0±1.4 16.0±1.3**
Medicine C group 27.9±1.4 15.0±1.5**
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 36.0±5.2 16.1±4.0**
Medicine B group 36.1±5.3 16.3±4.1**
Medicine C group 36.1±5.1 16.3±4.1**
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 (8)

1. a compounds or its pharmacologically acceptable salt and analogue thereof, the structure of described compound is as follows:
Wherein: R 1represent hydrogen, methyl; R 2represent hydrogen, methyl; R represent hydrogen, 2-methysulfonylethyl, 2-morpholinyl ethyl, 2-hydroxyethyl, 2-amino-ethyl, 2-cyano ethyl, carbamoyhnethyl, 2-picolyl, carboxymethyl, formamyl, 2-picolinoyl, 3-picolinoyl, 4-picolinoyl, ethanoyl, 2-dimethylamino acetyl, 2-hydroxyethylamino ethanoyl, 2-( n-hydroxyethyl methylamino-) ethanoyl, 2-(2-imidazolyl) ethanoyl, 2,3-dihydroxyl propionyls.
2.2. compound or pharmaceutically acceptable salt thereof according to claim 1 and analogue thereof, work as R 1, R 2represent hydrogen, R is when representing 2-dimethylamino acetyl, the various salt of this compound; Work as R 1, R 2represent hydrogen, R is when representing 2-methysulfonylethyl, the various salt of this compound; Work as R 1, R 2represent hydrogen, R is when representing 2-morpholinyl ethyl, the various salt of this compound.
3. compound or pharmaceutically acceptable salt thereof according to claim 1 and analogue thereof, it is selected from following compound:
Compound (A), 4-cyano group- n-[2-[3-[1-[2-(dimethylamino) ethanoyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1 h-imidazoles-2-methane amide
；
Compound (B), 4-cyano group- n-[2-[3-[1-[2-(methyl sulphonyl) ethyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1 h-imidazoles-2-methane amide;
Compound (C), 4-cyano group- n-[2-[3-[1-[2-morpholinyl ethyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1 h-imidazoles-2-methane amide.
4.4. 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 1represent hydrogen, methyl; R 2represent hydrogen, methyl; R represent hydrogen, 2-methysulfonylethyl, 2-morpholinyl ethyl, 2-hydroxyethyl, 2-amino-ethyl, 2-cyano ethyl, carbamoyhnethyl, 2-picolyl, carboxymethyl, formamyl, 2-picolinoyl, 3-picolinoyl, 4-picolinoyl, ethanoyl, 2-dimethylamino acetyl, 2-hydroxyethylamino ethanoyl, 2-( n-hydroxyethyl methylamino-) ethanoyl, 2-(2-imidazolyl) ethanoyl, 2,3-dihydroxyl propionyls.
5.5. 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.
6.6. purposes according to claim 5, is characterized in that the effect of described reduction intraocular pressure is specially the intraocular pressure rising that can reduce and be caused by a variety of causes.
7.7. comprise the pharmaceutical composition of compound or pharmaceutically acceptable salt thereof any one of claim 1-6 and analogue thereof, it is characterized in that this pharmaceutical composition to be prepared into ordinary preparation, controlled release preparation or targeting preparation.
8.8. the pharmaceutical composition of claim 7, described compound and pharmacologically acceptable salt thereof are prepared into through topical with its analogue, gastrointestinal administration or the various preparations of parenteral administration.
CN201410034523.8A 2013-01-24 2014-01-24 Intraocular tension reducing compound and preparation method and use thereof Pending CN104370882A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101437514A (en) * 2004-10-22 2009-05-20 詹森药业有限公司 Inhibidores of C-FMS cinasa
WO2011137219A1 (en) * 2010-04-30 2011-11-03 Schering Corporation Inhibitors of phosphoinositide dependent kinase 1 (pdk1)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101437514A (en) * 2004-10-22 2009-05-20 詹森药业有限公司 Inhibidores of C-FMS cinasa
WO2011137219A1 (en) * 2010-04-30 2011-11-03 Schering Corporation Inhibitors of phosphoinositide dependent kinase 1 (pdk1)

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Application publication date: 20150225