CN106474113B - A kind of pharmaceutical composition and its application for nerve regneration after cerebral arterial thrombosis - Google Patents
A kind of pharmaceutical composition and its application for nerve regneration after cerebral arterial thrombosis Download PDFInfo
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- CN106474113B CN106474113B CN201610782033.5A CN201610782033A CN106474113B CN 106474113 B CN106474113 B CN 106474113B CN 201610782033 A CN201610782033 A CN 201610782033A CN 106474113 B CN106474113 B CN 106474113B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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Abstract
The invention discloses a kind of pharmaceutical compositions and its application for nerve regneration after cerebral arterial thrombosis; the pharmaceutical composition is oral preparation; it is prepared by active constituent and pharmaceutic adjuvant, the active constituent is N '-(2- (1H- indol-3-yl) acetyl group) -2- iodobenzene formylhydrazine.Pharmaceutical composition of the invention can inhibit the expression of nerve growth negative regulators by the expression of increase nerve growth positivity regulatory factor, the nerve regeneration after promoting cerebral arterial thrombosis, and then promote motion function rehabilitation.
Description
Technical field
The invention belongs to pharmaceutical technology fields, specifically, more particularly to it is a kind of for nerve after cerebral arterial thrombosis again
Raw pharmaceutical composition and its application.
Background technique
Cerebral arterial thrombosis be as angiemphraxis outside encephalic or rupture and caused by acute injury of brain function, seriously endanger
The life and health of the middle-aged and the old, and cause that the middle-aged and the old is lethal, one of the main reason for disabling.Ischemic cerebral stroke patients are about
Have 1/3 in morbidity death shortly after, survivor loses work since the sequelae such as hemiplegia, aphasia disable or even energy of taking care of oneself
Power.There are two types of methods for general therapeutic cerebral arterial thrombosis at present: one is improve oxygen and grape in artery by increasing blood flow
It is sugared insufficient；Another kind is protection neuron, reduces brain tissue ischemia possibility, and the exitotoxicity for reducing neuron is dead.For
The Neuroprotective Agents of clinical treatment have calcium ion channel blockor, glutamate receptor antagonists, nmda antagonist etc..With ischemic
High incidence, high lethality rate and the high disability rate of property cerebral apoplexy are compared, the drug currently used for prophylactic treatment cerebral arterial thrombosis
It is of less types, it is far from satisfying clinical needs.
Studies have shown that most of tissues of human body have regeneration and repair ability after injury, but in Adult Mammals
But it is difficult with reparation to there is regeneration after pivot nervous system damage, in cerebral ischemic injury related disease, spinal cord injury and many
In the case where neuropathy, central nervous system function restores very limited, and is easy to happen limb motion and sensory disturbance
Etc. the illness for seriously affecting personal lifestyle quality.Therefore, central nervous system regrowth problem is always medical field and Neuscience
Boundary's great difficult problem urgently to be resolved in theoretical research and clinical practice.Research in the latest 20 years has breakthrough, mesh
Before think that the nerve regneration after central lesion and later period rehabilitation efficacy are closely related, but by internal factor and external rings
The limitation in border.Internal factor includes growth related gene, albumen, and external environment includes neurotrophic factor, nerve growth inhibition
The factor, glial scar etc..Trk-B is the high-affinity receptor of brain-derived nerve growth factor, focuses primarily upon central nervous system
Expression in system is that intracerebral distribution is the most extensive, is also indispensable neurotrophic factor acceptor.Nogo-A is presently found
Nerve fiber regeneration inhibiting substances the strongest inhibit injuring nerve regeneration, the especially long range of regenerated nervous fibers raw
Long, it all shows the effect of inhibition neural axon growth in vivo and in vitro.And nerve obtained after antagonism nogo-A
Regeneration is functional property, and can form the functional synaptic contact of tool.Trk-B and nogo-A has respectively represented nerve again
Two aspects of nerve growth trophic factors and inhibiting factor of raw microenvironment.Therefore, the drug for influencing this expressions of both is found, than
Compared with its active power, it may be appreciated that Chinese medicine Central nervous regenerates the effect of microenvironment, non-to clinical treatment central nervous system injury
It is often important.CN105732468A discloses a kind of N '-(2- (1H- indol-3-yl) acetyl group) aromatic hydrazide kind compound, and drapes over one's shoulders
Revealed such compound to significantly inhibit HCV virus, preparation method include the following steps: the following steps are included:
(1) heteroauxin and C1-C5 alcohol generation esterification obtain ethychlozate ester；(2) ethychlozate ester and hydrazine hydrate shown in Formula II
Reaction obtains indoles acethydrazide；(3) aromatic carboxylic acids as shown in formula IV is reacted with chlorination reagent is prepared aryl-acyl chlorides；(4) by
Indoles acethydrazide shown in formula III reacts to obtain the fragrant hydrazides of N '-(2- (1H- indol-3-yl) acetyl group) with aryl-acyl chlorides shown in Formula V
Class compound.However, the prior art, which does not disclose such compound, can be used for treating the medium Cranial nerve injury as birth trauma of ischemic cerebral apoplexy
Property disease.
Summary of the invention
The purpose of the present invention is to provide a kind of pharmaceutical compositions for promoting the nerve regneration of ischemic ischemic cerebral stroke patients
Object and its application.In order to achieve the object of the present invention, inventor by a large number of experiments research and unremitting effort, be finally obtained as
Lower technical solution:
A kind of pharmaceutical composition for nerve regneration after cerebral arterial thrombosis, the pharmaceutical composition are oral preparation, by
Active constituent and pharmaceutic adjuvant are prepared, and the active constituent includes the (2- (1H- indol-3-yl) of N '-shown in formula (I)
Acetyl group) aromatic hydrazide kind compound (N '-(2- (1H- indol-3-yl) acetyl group) -2- iodobenzene formylhydrazine):
Preferably, the pharmaceutical composition as described above for nerve regneration after cerebral arterial thrombosis, active constituent therein
The N '-shown in the formula (I) (2- (1H- indol-3-yl) acetyl group) aromatic hydrazide kind compound forms.
It is further preferred that the pharmaceutical composition of nerve regneration after cerebral arterial thrombosis is used for as described above, wherein described
Pharmaceutical composition be oral preparation, the oral preparation includes tablet, capsule, granule.
The present invention is by preparing middle cerebral artery occlusion rat model experimental study N '-(2- (1H- indoles-with coagulation method
3- yl) acetyl group) aromatic hydrazide kind compound is to cerebral arterial thrombosis rat model motor function and brain tissue tyrosine kinase receptors
Kinase b (trk-B) and the not influence of filamentous actin A (Nogo-A) expression, as a result, it has been found that the compound can significantly increase trk-B and press down
The expression of Nogo-A processed promotes cerebral arterial thrombosis rat motor functional rehabilitation so as to improve nerve regneration microenvironment.Therefore,
The present invention also provides a kind of pharmaceutical applications, it may be assumed that N '-(2- (1H- indol-3-yl) acetyl group) -2- iodobenzene formylhydrazine is used in preparation
Application after cerebral arterial thrombosis in the drug of nerve regneration；Or: N '-(2- (1H- indol-3-yl) acetyl group) -2- iodine
Application of the benzoyl hydrazine in the drug of preparation prevention or treatment cerebral arterial thrombosis.
Compared with prior art, pharmaceutical composition of the invention can pass through the table of increase nerve growth positivity regulatory factor
It reaches, inhibits the expression of nerve growth negative regulators, give full play to Post stroke to the various repair mechanisms of nervous system injury,
Nerve regeneration after promoting cerebral arterial thrombosis, and then promote motion function rehabilitation.
Specific embodiment
The following is specific embodiments of the present invention, and technical scheme of the present invention is further described, but of the invention
Protection scope be not limited to these examples.It is all to be included in this hair without departing substantially from the change of present inventive concept or equivalent substitute
Within bright protection scope.
The preparation of embodiment 1:N '-(2- (1H- indol-3-yl) acetyl group) -2- iodobenzene formylhydrazine
(1) heteroauxin 8.8g (50mmol) is added in 500 milliliters of round-bottomed flasks, methanol (60mL), the concentrated sulfuric acid
(3mL), 70 DEG C reaction 1-3 hours, TLC is detected after completion of the reaction, steams methanol, is added water (50mL), and organic phase, water phase are separated
It is extracted with ethyl acetate (3 × 20mL), merges organic phase, successively use saturated sodium bicarbonate solution and water washing, anhydrous sodium sulfate
It is dry, heteroauxin methyl esters crude product is obtained after reduced pressure.
(2) heteroauxin methyl esters 9.46g (48mmol) is added in 500 milliliters of round-bottomed flasks, ethylene glycol monomethyl ether (40mL),
Hydrazine hydrate 5mL, 115 DEG C heating reflux reaction about 20 hours, thin-layer chromatography (TLC) detects raw material point and disappears, and stops reaction, cooling
It to room temperature, is added water (50mL), stands and white solid is precipitated, suction filtration obtains crude product, obtains indoles acethydrazide with ethyl alcohol recrystallization
9.2 grams of white solid.
(3) aromatic carboxylic acids 1.6mmol, anhydrous tetrahydro furan 10mL are added in 100 milliliters of round-bottomed flasks, a drop is added dropwise
0.5mL thionyl chloride, oil bath is added in DMF, and 70 DEG C of heating are reacted about 10 hours, and TLC is detected after completion of the reaction, is steamed solvent, is obtained
2- iodobenzoyl chloride crude product is directly used in react in next step.
(4) 3- indoles acethydrazide (300mg, 1.59mmol) is added in 100 milliliters of round-bottomed flasks, anhydrous tetrahydro furan 10
The tetrahydrofuran solution of 2- iodobenzoyl chloride (1.59mmol) is added dropwise in milliliter, Et3N (3mL, 1.59mmol), generates precipitating, after
(25 DEG C) of continuous room temperature stirs 12 hours, and TLC is detected after completion of the reaction, and solvent is removed under reduced pressure and obtains orange/yellow solid, uses acetic acid respectively
Ethyl ester, water washing, suction filtration obtain faint yellow crude product, recrystallize to obtain white solid sterling, yield: 92.5%, mp:188.1~
189.0℃；1H-NMR (500MHz, DMSO-d6), 6 (ppm): 3.68 (s, 2H, CH2), 6.92-6.93 (s, 1H, Ar-H),
6.98-7.24 (m, 4H, Ar-H), 7.32-7.35 (m, 1H, Ar-H), 7.43-7.44 (m, 1H, Ar-H), 7.53-7.55 (m,
1H, Ar-H), 7.80-7.82 (m, 1H, Ar-H), 10.23 (s, 1H, NH), 10.29 (s, 1H, NH), 10.97 (s, 1H, indoles-
NH)；m/z418.0[M+-1]。
Embodiment 2: influence test of the compound to middle cerebral artery occlusion model
Adult SD rats 55, male, healthy cleaning grade, 280~320g of weight, 15 rat conducts of taking-up at random
Sham-operation group, remaining rat make middle cerebral artery occlusion model as follows: with 0.4% yellow Jackets 10mL/kg abdomen
Chamber injecting anesthetic rat, lateral position are fixed on operating table, along right external auditory canal and right eye outer canthus line midpoint, are cut perpendicular to line
Skin about 2cm is opened, then along temporalis middle line under surgical operation microscope, successively cuts off temporalis and masseter, and separate to two sides, exposure
Zygomatic arch out.It is removed with rongeur and zygomatic arch and cuts off fascia along skull, expose temporo precoila, with small Distraction Apparatus by zygomatic arch and mandibular
Distance support it is big, the major part of exposure squamosal bone, the then drilling at united front lower place about 2mm before cheekbone and squamosal bone is opened
One diameter about 2mm microcephalia window, punctures endocranium, and pia mater and spider web membrane tissue around separating blood vessel are allowed to free.Then exist
Tractus olfactorius and arteria cerebri media intersection gently provoke arteria cerebri media, and electric knife is set bipolar coagulation position, 3-4 grades of coagulations is selected to open
Close, coagulation burns in tractus olfactorius 2mm to one section of arteria cerebri media between venae cerebri inferiores, after blood vessel blocking in distal side cut off to prevent
Only re perfusion, layer-by-layer suture wound, postoperative recovery send former cage raising back to.Above procedure is in constant (24-25 DEG C) situation of room temperature
Lower progress, in favor of evaluating cerebral ischemia degree.Anesthesia wake up after for 24 hours in occur left limb pain stimulation shrinkage phenomenon disappear, to the left
It rolls or turn-take, left upper extremity cannot extend straight forward successful for model copy when mentioning tail, and the successful rat of modeling is divided into model pair
According to group (18), compound treatment group (18).Rats in sham-operated group row equally opens cranium art, but does not coagulate and close arteria cerebri media,
The remaining same model control group of operation.
On the basis of rat weight, N '-(2- (1H- indol-3-yl) acetyl group) -2- iodine is given in the stomach-filling of compound treatment group
Same amount of normal saline is given in stomach-filling respectively for benzoyl hydrazine 60mg/kg/ times, model control group and sham-operation group, daily early 9 point points
With evening 6 points each 1 time, totally 2 weeks.6h is administered after modeling success, and solid feed and water freely absorb.Model pair in experimentation
There is 1 death according to a group rat.After the test, using forelimb place detection method (HuaY, SchallertT, KeepRF,
Elal.Behavioral tests after intracerebral hemorrhage in therat [J] .Stroke,
2002,33:2478.) rat motor function is measured.Examiner, which holds rat dorsum skin, keeps four limbs hanging, by side beard brush
Desktop corner edge is touched, tests movable Sui's condition of ipsilateral forelimb, forelimb can be put into rapidly desktop by undamaged person, this is dynamic when cerebral injury
Work has different degrees of damage.Tested 10 times of the every side of rat, the percentage that forelimb touches desktop corner edge number is that the side obtains
Point.Note: grasping rat will softly, and forelimb freely dangles, and the preceding gently moving rats of test allow it to loosen, as rat is earned as far as possible
It pricks, muscular tone or limbs are placed on including experimenter disregards on hand.Respectively at modeling success after for 24 hours, 3d, score within 1,2 week.
In addition, using immunohistochemical method, the expression of hybridization in situ detection trk-B, nogo-A.Test statistics result referring to
Table 1, table 2.
1 each group rat motor function score of table compares
Note: compared with model control group,#P < 0.05；##P < 0.01.
2 each group rat trk-B, nogo-A average gray of table compares
Note: compared with model control group,#P < 0.05；##P < 0.01.
It can be seen that postoperative model control group for 24 hours by the test result of table 1 and the scoring of compound treatment group be significant
Lower than sham-operation group；Later each time point model control group and the scoring of compound treatment group are improved, and compound treatment group
It becomes apparent, there is significant difference (P < 0.05 or P < 0.01) compared with model control group.It can be with by the test result of table 2
Finding out, the trk-B of model control group and compound treatment group dyes average gray and significantly reduces compared with sham-operation group after 2 weeks, but
Compound treatment group reduces and becomes apparent, and has extremely significant difference (P < 0.01) compared with model control group；Model control group
Nogo-A dyes average gray and significantly reduces compared with sham-operation group, and compound treatment group is then close to sham-operation group, with model control group
Comparing has extremely significant difference (P < 0.01).
Claims (2)
1.N '-(2- (1H- indol-3-yl) acetyl group) -2- iodobenzene formylhydrazine is being prepared for nerve after cerebral arterial thrombosis again
Application in raw drug.
2.N '-(2- (1H- indol-3-yl) acetyl group) -2- iodobenzene formylhydrazine is in preparation prevention or treats cerebral arterial thrombosis
Application in drug.
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| RU2714214C1 (en) * | 2019-10-09 | 2020-02-13 | Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр реабилитации и курортологии" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ РК" Минздрава России) | Method of medical rehabilitation of patients of working age in early recovery period of ischemic stroke with accompanying obstructive chronic respiratory system disturbance outside exacerbation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1260345A (en) * | 1998-12-17 | 2000-07-19 | 阿迪尔公司 | Hydrazide compound, its preparing method and medicine compositions thereof |
| WO2008064342A2 (en) * | 2006-11-21 | 2008-05-29 | Omeros Corporation | Pde10 inhibitors and related compositions and methods |
| CN105732468A (en) * | 2016-04-07 | 2016-07-06 | 昆明理工大学 | N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound and preparation method and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1260345A (en) * | 1998-12-17 | 2000-07-19 | 阿迪尔公司 | Hydrazide compound, its preparing method and medicine compositions thereof |
| WO2008064342A2 (en) * | 2006-11-21 | 2008-05-29 | Omeros Corporation | Pde10 inhibitors and related compositions and methods |
| CN105732468A (en) * | 2016-04-07 | 2016-07-06 | 昆明理工大学 | N'-(2-(1H-indole-3-yl)acetyl)arylhydrazide compound and preparation method and application thereof |
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Inventor after: Zhang Yang Inventor after: Bai Qiang Inventor after: Zhang Yi Inventor before: Bai Qiang Inventor before: Zhang Yi |
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Effective date of registration: 20190116 Address after: 221008 Tongshan Road 209, Xuzhou City, Jiangsu Province Applicant after: Xuzhou Medical University Address before: 721013 Tianqi pharmaceutical company 85, high tech Avenue, Weibin District, Baoji, Shaanxi Applicant before: Bai Qiang |
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