CN103896900A - Compound with nerve protection function as well as preparation method and application of compound - Google Patents

Compound with nerve protection function as well as preparation method and application of compound Download PDF

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CN103896900A
CN103896900A CN201210594969.7A CN201210594969A CN103896900A CN 103896900 A CN103896900 A CN 103896900A CN 201210594969 A CN201210594969 A CN 201210594969A CN 103896900 A CN103896900 A CN 103896900A
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compound
preparation
neuroprotective
cch
acceptable salt
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韩冰
王爽
柳怀玉
张海锋
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4

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  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses a compound as well as a pharmaceutical composition, a preparation method and an application thereof. The application refers to the application in preparing a medicine with the nerve protection function. The use effect of the compound for protecting nerve is very remarkable.

Description

One class has compound of neuroprotective and its production and use
Technical field
The present invention relates to compound and pharmacologically acceptable salt and its analogue that a class has neuroprotective; 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 have the purposes in the medicine of neuroprotective in preparation.
Background technology
Scientific circles, actively finding nerve protection medicine, use it for the nerve injury causing due to a variety of causes at present, exploitation nerve protection medicine, and the molecular mechanism of research neuroprotective is to be extensively subject to the hot issue that Chinese scholars is paid close attention at present.The importance of neuroprotective is well imagined; nearly hundred kinds of the medicines that has neuroprotective of reporting at present; conventional neuroprotective comprises calcium-channel antagonists, free-radical scavengers, glutamate antagonist, cell membrane stability agent etc.; but at present because pathogenesis is unintelligible; therefore very good neuroprotective so far does not produce effect; because patient colony is large and harm is large, need to develop a kind of medicine effectively with extraordinary neuroprotective.
The synthetic one group of new compound of the inventor and similar compound thereof or its pharmacologically acceptable salt have in preparation on the medicine of neuroprotective and have an unexpected effect, and have neuroprotective at present there is no report for this compounds.
Summary of the invention
The invention provides the preparation of one group of compound and similar compound or its pharmacologically acceptable salt and the new purposes in the medicine of preparing neuroprotective 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:
Figure BSA00000835163900011
(compound 4)
Wherein R 1be selected from (CH 3) 3cCH 2cH 2-, (CH 3) 3cCH 2-, (CH 3) 3c-, R 2be selected from-OH-Br ,-H ,-CH 3,
Be selected from-CN of R3 ,-CONH 2,-COOC 2h 5.
The present invention has specifically prepared following 5 compounds:
Figure BSA00000835163900021
Compound (A);
Compound (B);
Figure BSA00000835163900023
Compound (C);
Figure BSA00000835163900031
Compound (D);
Figure BSA00000835163900032
Compound (E).
The synthetic route of compound of the present invention is as follows:
Figure BSA00000835163900033
R 1?is?chosen?from(CH 3) 3CCH 2CH 2-，(CH 3) 3CCH 2-，(CH 3) 3C-.
R 2?is?chosen?from-OH，-Br，-H，-Me.
R 3?is?chosen?from-CN，-CONH 2，-COOEt.
Wherein R 1be selected from (CH 3) 3cCH 2cH 2-, (CH 3) 3cCH 2-, (CH 3) 3c-, R 2be selected from-OH-Br ,-H ,-CH 3, be selected from-CN of R3 ,-CONH 2,-COOC 2h 5.
Compound or pharmaceutically acceptable salt thereof of the present invention and analogue thereof the purposes in the medicine of preparing neuroprotective, is specially the provide protection to peripheral nerve and nervus centralis.
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 through the powder injection of organ administration, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, 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 has the effect of extraordinary neuroprotective, and from the result of pharmacodynamic experiment, the effect of the neuroprotective of this compounds exceeds the medicine of current clinical application.The exploitation of this new compound will be for removing sufferer misery, and the quality of life that improves patient contributes.
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).
Fig. 4: the nuclear magnetic spectrum of compound (D).
Fig. 5: the nuclear magnetic spectrum of compound (E).
Embodiment
Preparation Example
Preparation Example 1 (compd A is the preparation of compd A 4)
Compd A 1 and 1-iodo-2,2-dimethylpropane refluxes and generates compd A 2 in salt of wormwood, acetonitrile solution, compd A 2 refluxes and generates compound A-13 with Resorcinol, propane dinitrile in ethanol and triethylamine mixing solutions, and Sold Stannous Chloride Catalyzes compound A-13 normal-temperature reaction in ethanol solution hydrochloride generates compd A 4.
Figure BSA00000835163900051
Preparation Example 2 (compd B is the preparation of compd B 4)
Compound B-11 and 1-iodo-3,3-dimethylbutane refluxes and generates compd B 2 in salt of wormwood, acetonitrile solution, compd B 2 refluxes and generates compd B 3 with p-cresol, propane dinitrile in ethanol and triethylamine mixing solutions, and Sold Stannous Chloride Catalyzes compd B 3 normal-temperature reaction in ethanol solution hydrochloride generates compd B 4.
Figure BSA00000835163900061
Preparation Example 3 (Compound C is the preparation of Compound C 4)
Compound C 1 and 1-iodo-3,3-dimethylbutane refluxes and generates Compound C 2 in salt of wormwood, acetonitrile solution, Compound C 2 refluxes and generates Compound C 3 with phenol, propane dinitrile in ethanol and triethylamine mixing solutions, and Sold Stannous Chloride Catalyzes Compound C 3 normal-temperature reaction in ethanol solution hydrochloride generates Compound C 4.
Figure BSA00000835163900071
Preparation Example 4 (Compound D is the preparation of Compound D 4)
Compound D 1 and 1-iodo-3,3-dimethylbutane refluxes and generates Compound D 2 in salt of wormwood, acetonitrile solution, Compound D 2 refluxes and generates compound d3 with Resorcinol, propane dinitrile in ethanol and triethylamine mixing solutions, and Sold Stannous Chloride Catalyzes compound d3 normal-temperature reaction in ethanol solution hydrochloride generates Compound D 4.
Figure BSA00000835163900081
Preparation Example 5 (compd E is the preparation of compd E 4)
Compd E 1 and 1-iodo-3,3-dimethylbutane refluxes and generates compd E 2 in salt of wormwood, acetonitrile solution, compd E 2 refluxes and generates compd E 3 with Resorcinol, 2-malonamide nitrile in ethanol and triethylamine mixing solutions, and Sold Stannous Chloride Catalyzes compd E 3 normal-temperature reaction in ethanol solution hydrochloride generates compd E 4.
Figure BSA00000835163900091
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 20mg 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.
Preparation containing Compound D injection:
1. altogether 50mg and 50mg formula (D) 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 E injection:
1. get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer 50mg and 80mg altogether
Formula (E) compound in water for injection, mix and make it dissolve;
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
Medicine A-E is to neural provide protection
1 Animal Model and administration
Healthy adult new zealand rabbit, body weight 2kg, male and female half and half.Method according to Luo Wenlong, Zhou Cuiying report is carried out modeling (Initial Experiment of the pHGF opposite repairing of neural injury effect of Chongqing Medical the 32nd the 3rd phase of volume of March in 2003).Preoperative normal raising, postoperative routine gives penicillin 1 abdominal injection every day.Give new zealand rabbit Chloral Hydrate intraperitoneal injection of anesthesia by 500mg/kg body weight, expose and the about 1.5cm of the neural upper buccal branches of surface of separation, cross-section and cut 0.2cm.Two broken ends of fractured bone embed the each 0.2cm of the long silicone tube of 1cm (external diameter 3mm, internal diameter 2mm), merge fixing silicone tube in epineurium along 120 degree clearance gaps with 9-0 silk thread, form the gap of about 6mm between two broken ends of fractured bone, wherein the injection solution (5mg injection) of micro sample adding appliance injection of medicine A-E is used respectively on rabbit right side, every kind of medicine carries out 10 rabbit experiments, every rabbit right nervus lateralis is as medicine group, the physiological saline that equal volume amounts is all injected in left side is as model control group, stroke-physiological saline solution flush operation chamber, 4-0 silk thread layer-by-layer suture otch.
2 experiment calibratings
The detection of 2.1 nerve conduction velocity
Postoperative one month, all rabbit are anaesthetized, and enter along former otch, with the pin electrode dry proximal part that directly excites nerve, on its domination muscle, use concentric needle electrode record, calculate nerve conduction velocity and compound muscle action potential latent period.
The each group of table 1 drug treatment nerve conduction velocity comparative result (m/s, n=10) after month
Figure BSA00000835163900111
With relatively * P < 0.05**P < 0.01 of model control group
The each group of table 2 drug treatment compound muscle action potential comparative result in latent period (s, n=10) after month
Figure BSA00000835163900112
With relatively * P < 0.05**P < 0.01 of model control group
2.2 nervous tissue dyeing are observed
Get the nerve segment of the each 0.5cm of the nearly far-end of previous anastomotic, be fixed with 10% formalin, after dehydration, embedding, section, dyeing, examine under a microscope.According to the method for Luo Wenlong, Zhou Cuiying report, after taking pictures, with ias, Regenerating Axons quantity, diameter, area and myelin thickness etc. are measured.The results are shown in Table 3-5.
The each group of table 3 drug treatment regenerating nerve examine of diameter comparative result (um, n=10) after month
Figure BSA00000835163900113
With relatively * P < 0.05**P < 0.01 of model control group
The each group of table 4 drug treatment after one month regenerating nerve have marrow aixs cylinder Area comparison result (um 2, n=10)
Figure BSA00000835163900121
With relatively * P < 0.05**P < 0.01 of model control group
The each group of table 5 drug treatment after one month regenerating nerve have marrow aixs cylinder counting comparative result (n=10)
Figure BSA00000835163900122
With relatively * P < 0.05**P < 0.01 of model control group
Comprehensive above-mentioned experimental result is reached a conclusion: compound (A), (B), (C), (D), the medicine of (E) preparing all plays extraordinary neuroprotective.

Claims (9)

1. a compounds or its pharmacologically acceptable salt and analogue thereof, the structure of described compound is as follows:
Figure FSA00000835163800011
Wherein R 1be selected from (CH 3) 3cCH 2cH 2-, (CH 3) 3cCH 2-, (CH 3) 3c-, R 2be selected from-OH-Br ,-H ,-CH 3, be selected from-CN of R3 ,-CONH 2,-COOC 2h 5.
2. compound or pharmaceutically acceptable salt thereof claimed in claim 1 and analogue thereof, it is selected from following compound:
Figure FSA00000835163800012
Compound (A);
Figure FSA00000835163800013
Compound (B);
Figure FSA00000835163800021
Compound (C);
Figure FSA00000835163800022
Compound (D);
Figure FSA00000835163800023
Compound (E).
3. the preparation method of compound described in any one claim in claim 1-2, is characterized by according to following route synthetic:
Figure FSA00000835163800031
R 1?is?chosen?from(CH 3) 3CCH 2CH 2-，(CH 3) 3CCH 2-，(CH 3) 3C-.
R 2?is?chosen?from-OH，-Br，-H，-Me.
R 3?is?chosen?from-CN，-CONH 2，-COOEt.
Wherein R 1be selected from (CH 3) 3cCH 2cH 2-, (CH 3) 3cCH 2-, (CH 3) 3c-, R 2be selected from-OH-Br ,-H ,-CH 3, be selected from-CN of R3 ,-CONH 2,-COOC 2h 5.
4. compound or pharmaceutically acceptable salt thereof and the purposes of analogue in the medicine of preparing neuroprotective thereof described in claim 1-3 any one.
5. application described in claim 4, described neuroprotective refers to comprising the unify neuroprotective of peripheral nervous system of central nervous system.
6. application described in claim 5, described neuroprotective refers to the protection neural to facial nerve, auditory nerve, optic nerve, cranial nerve, spinal nerves etc.
As claimed in claim 6 application, described neuroprotective for be people, animal and cell etc.
8. the pharmaceutical composition that comprises any one compound or pharmaceutically acceptable salt thereof in claim 1-7 and analogue thereof, is characterized in that this pharmaceutical composition to be prepared into ordinary preparation, controlled release preparation or targeting preparation.
9. the pharmaceutical composition of claim 8, described compound and pharmacologically acceptable salt thereof and its analogue are prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.
CN201210594969.7A 2012-12-25 2012-12-25 Compound with nerve protection function as well as preparation method and application of compound Pending CN103896900A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006026832A1 (en) * 2004-09-09 2006-03-16 Howard Florey Institute Of Experimental Physiology And Medicine Enzyme inhibitors and uses thereof
WO2009065169A1 (en) * 2007-11-19 2009-05-28 Howard Florey Institute Insulin-regulated aminopeptidase (irap) inhibitors and uses thereof
CN103896899A (en) * 2012-12-25 2014-07-02 韩冰 Compounds for reducing intraocular pressure and preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006026832A1 (en) * 2004-09-09 2006-03-16 Howard Florey Institute Of Experimental Physiology And Medicine Enzyme inhibitors and uses thereof
WO2009065169A1 (en) * 2007-11-19 2009-05-28 Howard Florey Institute Insulin-regulated aminopeptidase (irap) inhibitors and uses thereof
CN103896899A (en) * 2012-12-25 2014-07-02 韩冰 Compounds for reducing intraocular pressure and preparation method and application thereof

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Application publication date: 20140702