CN106474113A - A kind of pharmaceutical composition for neuranagenesis after cerebral infarction and its application - Google Patents
A kind of pharmaceutical composition for neuranagenesis after cerebral infarction and its application Download PDFInfo
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- CN106474113A CN106474113A CN201610782033.5A CN201610782033A CN106474113A CN 106474113 A CN106474113 A CN 106474113A CN 201610782033 A CN201610782033 A CN 201610782033A CN 106474113 A CN106474113 A CN 106474113A
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- pharmaceutical composition
- cerebral infarction
- neuranagenesis
- acetyl group
- indol
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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
Abstract
The invention discloses a kind of pharmaceutical composition for neuranagenesis after cerebral infarction and its application; this pharmaceutical composition is oral formulations; it is prepared from by active component and pharmaceutic adjuvant, described active component is N ' (2 (1H indole 3 base) acetyl group) 2 iodobenzene formylhydrazines.The pharmaceutical composition of the present invention can promote the nerve regeneration after cerebral infarction, and then promote motion function rehabilitation by increasing the expression of nerve growth positivity regulatory factor, the expression of suppression nerve growth negative regulators.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically, more particularly, to a kind of for nerve after cerebral infarction again
Raw pharmaceutical composition and its application.
Background technology
Cerebral infarction is the acute injury of brain function being caused due to the outer angiemphraxises of intracranial or rupture, serious harm
The life and health of middle-aged and elderly people, is also to cause the one of the main reasons that middle-aged and elderly people is lethal, disable.Ischemic cerebral stroke patients are about
Have 1/3 in morbidity death in the near future, survivor loses work or even energy of taking care of oneself because the sequela such as hemiplegia, aphasia disable
Power.General therapeutic cerebral infarction has two methods at present：One kind is to improve oxygen and Fructus Vitis viniferae in tremulous pulse by increasing blood flow
Sugar is not enough；Another kind is protection neuron, reduces brain tissue ischemia probability, and the exitotoxicity reducing neuron is dead.For
The Neuroprotective Agents of clinical treatment have calcium ion channel blockor, glutamate receptor antagonists, nmda antagonist etc..With ischemia
The high incidence of property apoplexy, high fatality rate and high disability rate are compared, currently used for the medicine of prophylactic treatment cerebral infarction
Of less types, far can not meet clinical needs.
Research shows, the great majority tissue of human body has regeneration and repair ability after injury, but in Adult Mammals
But it is difficult with reparation, in cerebral ischemic injury relevant disease, spinal cord injury and many to there is regeneration after damaging in pivot nervous system
In the case of neuropathy, central nervous system function recovers very limited, and is susceptible to limb motion and sensory disturbance
Etc. the disease having a strong impact on personal lifestyle quality.Therefore, central nervous system regrowth problem is always medical circle and neuroscience
Boundary's great difficult problem urgently to be resolved hurrily in theoretical research and clinical practice.The existing breakthrough of research that recent two decades come, mesh
Before think that the neuranagenesis after central nervous system injury is closely related with later stage rehabilitation efficacy, but be subject to intrinsic factor and external rings
The restriction in border.Intrinsic factor include growth related gene, albumen, and external environment condition includes neurotrophic factor, nerve growth suppression
The factor, glial scar etc..Trk-B is the high-affinity receptor of Brain Derived Neurotrophic Factor, focuses primarily upon central nervous system
Expression in system, be intracerebral distribution the most extensively, be also indispensable neurotrophic factor acceptor.Nogo-A has now been found that
Nerve fiber regeneration inhibiting substances the strongest, the distance life of suppression injured nerve regeneration, especially regenerated nervous fibers
Long, it all shows the effect of suppression neural axon growth in vivo and in vitro.And the nerve being obtained after antagonism nogo-A
Regeneration is functional property, and can form tool functional synaptic contact.Trk-B and nogo-A represents nerve more respectively
The nerve growth trophic factors of raw microenvironment and two aspects of inhibitive factor.Therefore, finding affects the medicine of this expressions of both, than
The power of relatively its activity is it may be appreciated that Chinese medicine Central nervous regenerate the effect of microenvironment, non-to clinical treatment central nervous system injury
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
Reveal such compound and there is to HCV virus obvious inhibitory action, preparation method has comprised the steps：Comprise the following steps：
(1) heteroauxing and C1-C5 alcohol occur esterification to obtain ethychlozate ester；(2) ethychlozate ester shown in Formula II and hydrazine hydrate
Reaction obtains indole acethydrazide；(3) aromatic carboxylic acids shown in formula IV are reacted with chlorination reagent and prepare aryl-acyl chlorides；(4) by
Indole acethydrazide shown in formula III and aryl-acyl chlorides shown in Formula V react and obtain N '-(2- (1H- indol-3-yl) acetyl group) virtue hydrazides
Class compound.However, prior art does not disclose such compound can be used for treating the medium Cranial nerve injury as birth trauma of ischemic cerebral apoplexy
Property disease.
Content of the invention
It is an object of the invention to provide a kind of drug regimen promoting ischemic ischemic cerebral stroke patients neuranagenesis
Thing and its application.In order to realize the purpose of the present invention, inventor by lot of experiments research and unremitting effort, be finally obtained as
Lower technical scheme：
A kind of pharmaceutical composition for neuranagenesis after cerebral infarction, this pharmaceutical composition is oral formulations, by
Active component and pharmaceutic adjuvant are prepared from, and described active component includes the N ' shown in formula (I)-(2- (1H- indol-3-yl)
Acetyl group) aromatic hydrazide kind compound (N '-(2- (1H- indol-3-yl) acetyl group) -2- iodobenzene formylhydrazine)：
Preferably, the pharmaceutical composition for neuranagenesis after cerebral infarction as described above, active component therein
N ' shown in described formula (I)-(2- (1H- indol-3-yl) acetyl group) aromatic hydrazide kind compound forms.
It is further preferred that being used for the pharmaceutical composition of neuranagenesis after cerebral infarction as mentioned above, wherein said
Pharmaceutical composition be oral formulations, described oral formulations include tablet, capsule, granule.
The present invention by with coagulation method prepare middle cerebral artery occlusion rat model experimental study N '-(2- (1H- indole-
3- yl) acetyl group) aromatic hydrazide kind compound is to cerebral infarction rat model motor function and cerebral tissue tyrosine kinase receptors
Kinase b (trk-B) and the impact that filamentous actin A (Nogo-A) does not express, it is found that this compound can significantly increase trk-B and press down
The expression of Nogo-A processed, thus improving neuranagenesis microenvironment, promotes cerebral infarction rat motor functional rehabilitation.Therefore,
The present invention also provides a kind of pharmaceutical applications, that is,：N '-(2- (1H- indol-3-yl) acetyl group) -2- iodobenzene formylhydrazine is used in preparation
Application in the medicine of neuranagenesis after the cerebral infarction；Or：N '-(2- (1H- indol-3-yl) acetyl group) -2- iodine
Application in the medicine of preparation prevention or treatment cerebral infarction for the benzoyl hydrazine.
Compared with prior art, the pharmaceutical composition of the present invention can be by increasing the table of nerve growth positivity regulatory factor
Reach, the expression of suppression nerve growth negative regulators, give full play to the various repair mechanisms to nervous system injury for the Post stroke,
Promote the nerve regeneration after cerebral infarction, and then promote motion function rehabilitation.
Specific embodiment
The following is the specific embodiment of the present invention, technical scheme is done and is described further, but the present invention
Protection domain be not limited to these embodiments.Every change without departing substantially from present inventive concept or equivalent substitute are included in this
Within bright protection domain.
Embodiment 1：The preparation of N '-(2- (1H- indol-3-yl) acetyl group) -2- iodobenzene formylhydrazine
(1) heteroauxing 8.8g (50mmol), methanol (60mL), concentrated sulphuric acid are added in 500 milliliters of round-bottomed flasks
(3mL), 70 DEG C of reaction 1-3 hours, TLC detects after completion of the reaction, steams methanol, adds water (50mL), separates organic faciess, aqueous phase
With ethyl acetate (3 × 20mL) extraction, merge organic faciess, use saturated sodium bicarbonate solution and water washing, anhydrous sodium sulfate successively
It is dried, after concentrating under reduced pressure, obtain heteroauxing methyl ester crude product.
(2) addition heteroauxing methyl ester 9.46g (48mmol) in 500 milliliters of round-bottomed flasks, ethylene glycol monomethyl ether (40mL),
Hydrazine hydrate 5mL, 115 DEG C of heating reflux reactions about 20 hours, thin layer chromatography (TLC) detection raw material point disappears, stopped reaction, cooling
To room temperature, add water (50mL), standing separates out white solid, and sucking filtration obtains crude product, obtains indole acethydrazide with ethyl alcohol recrystallization
9.2 grams of white solid.
(3) aromatic carboxylic acids 1.6mmol, anhydrous tetrahydro furan 10mL, Deca one are added in 100 milliliters of round-bottomed flasks
DMF, adds 0.5mL thionyl chloride, oil bath, 70 DEG C of reacting by heating about 10 hours, TLC detects after completion of the reaction, steams solvent, obtains
2- iodobenzoyl chloride crude product is directly used in next step reaction.
(4) 3- indole acethydrazide (300mg, 1.59mmol), anhydrous tetrahydro furan 10 are added in 100 milliliters of round-bottomed flasks
Milliliter, Et3N (3mL, 1.59mmol), the tetrahydrofuran solution of Deca 2- iodobenzoyl chloride (1.59mmol), produce precipitation, continue
Continuous (25 DEG C) stirrings of room temperature 12 hours, TLC detects that removal of solvent under reduced pressure obtains orange/yellow solid, uses acetic acid respectively after completion of the reaction
Ethyl ester, water washing, sucking filtration obtains faint yellow crude product, and recrystallization obtains 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, indole-
NH)；m/z418.0[M+-1].
Embodiment 2：The impact test to middle cerebral artery occlusion model for the compound
Adult SD rats 55, male, healthy cleaning grade, weight 280～320g, takes out 15 rat conducts at random
Sham operated rats, remaining rat makes middle cerebral artery occlusion model as follows：With 0.4% pentobarbital sodium 10mL/kg abdomen
Chamber injecting anesthetic rat, lateral position is fixed on operating-table, along right external auditory canal and right eye outer canthus line midpoint, cuts perpendicular to line
Open skin about 2cm, then in operating microscope lower edge temporalis center line, cut-out temporalis and masseter successively, and to both sides separately, expose
Go out zygomatic arch.Remove zygomatic arch with rongeur and cut off fascia along skull, expose temporo precoila, with little Distraction Apparatus by zygomatic arch and mandibular bone
Distance support big, expose the major part of squamosal bone, then boring at united front lower place about 2mm before cheekbone and squamosal bone, open
One diameter about 2mm microcephalia window, punctures cerebral dura mater, the pia mater encephali around separating blood vessel and spider web membrane tissue, is allowed to free.Then exist
Tractus olfactorius and middle cerebral artery intersection gently provoke middle cerebral artery, and electric knife is put bipolar coagulation position, select 3-4 shelves coagulation to open
Close, coagulation burns one section of middle cerebral artery to inferior cerebral vein for the 2mm in tractus olfactorius, blood vessel blocking after distally cut-out in case
Only re perfusion, layer-by-layer suture wound, postoperative recovery is sent former cage back to and is raised.Above procedure is all in room temperature constant (24-25 DEG C) situation
Under carry out, be beneficial to evaluation cerebral ischemia degree.Left limb pain in 24h after anesthesia is awake stimulates shrinkage phenomenon to disappear, to the left
Roll or turn-take, carry left upper extremity during tail and can not extend straight forward for model copy successfully, the successful rat of modeling is divided into model pair
According to group (18), compounds for treating group (18).Rats in sham-operated group row equally opens cranium art, but does not coagulate and close middle cerebral artery, its
The same model control group of remaining operation.
On the basis of rat weight, compounds for treating group gavage gives N '-(2- (1H- indol-3-yl) acetyl group) -2- iodine
Gavage gives normal saline respectively for benzoyl hydrazine 60mg/kg/ time, model control group and sham operated rats, daily early 9 points of points
Each with late 6 points 1 time, totally 2 weeks.6h administration after modeling success, solid feed and water freely absorb.Model pair in experimentation
There is 1 death according to group rat.After off-test, using forelimb place detection method (HuaY, SchallertT, KeepRF,
Elal.Behavioral tests after intracerebral hemorrhage in therat [J] .Stroke,
2002,33：2478.) measure rat motor function.The hand-held rat dorsum skin of examiner makes extremity hanging, by side beard brush
Tactile desktop corner edge, the movable Sui condition of test homonymy forelimb, forelimb can be put into rapidly desktop by intact person, and during brain injury, this moves
Make there is different degrees of infringement.Tested 10 times of the every side of rat, the percentage rate that forelimb touches desktop corner edge number of times is this side and obtains
Point.Note：Grasp that rat is soft, forelimb freely dangles, gently moving rats before test, allow it loosen, as rat is earned as far as possible
Prick, muscular tone or limbs are placed on including experimenter disregards on hand.After modeling success, scored in 24h, 3d, 1,2 week.
In addition, detect the expression of trk-B, nogo-A using immunohistochemical method, hybridization in situ.Test statistics result referring to
Table 1, table 2.
Table 1 each group rat motor function score compares
Note：Compare with model control group,#P ＜ 0.05；##P ＜ 0.01.
Table 2 each group rat trk-B, nogo-A average gray compares
Note：Compare with model control group,#P ＜ 0.05；##P ＜ 0.01.
Postoperative 24h model control group be can be seen that by the result of the test of table 1 all notable with the scoring of compounds for treating group
Less than sham operated rats；Each time point model control group and the scoring of compounds for treating group are improved later, and compounds for treating group
Become apparent from, compare with model control group and have significant difference (P ＜ 0.05 or P ＜ 0.01).Result of the test by table 2 is permissible
Find out, after 2 weeks, the trk-B dyeing average gray of model control group and compounds for treating group all significantly reduces compared with sham operated rats, but
The reduction of compounds for treating group becomes apparent from, and has pole significant difference (P ＜ 0.01) compared with model control group；Model control group
Nogo-A dyeing average gray significantly reduces compared with sham operated rats, compounds for treating group then close to sham operated rats, with model control group
Relatively there is pole significant difference (P ＜ 0.01).
Claims (5)
1. a kind of pharmaceutical composition for neuranagenesis after cerebral infarction, this pharmaceutical composition is oral formulations, by living
Property composition and pharmaceutic adjuvant be prepared from it is characterised in that：Described active component includes the N ' shown in following formula-(2- (1H- Yin
Diindyl -3- base) acetyl group) aromatic hydrazide kind compound：
2. according to claim 1 be used for cerebral infarction after neuranagenesis pharmaceutical composition it is characterised in that：Described
Active component be made up of as sole component described N '-(2- (1H- indol-3-yl) acetyl group) aromatic hydrazide kind compound.
3. the pharmaceutical composition for neuranagenesis after cerebral infarction according to claim 1 or claim 2 it is characterised in that：
Described oral formulations include tablet, capsule, granule.
4.N '-(2- (1H- indol-3-yl) acetyl group) -2- iodobenzene formylhydrazine is in preparation for nerve after cerebral infarction again
Application in raw medicine.
5.N '-(2- (1H- indol-3-yl) acetyl group) -2- iodobenzene formylhydrazine in preparation prevention or treats cerebral infarction
Application in medicine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610782033.5A CN106474113B (en) | 2016-08-30 | 2016-08-30 | A kind of pharmaceutical composition and its application for nerve regneration after cerebral arterial thrombosis |
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| CN201610782033.5A CN106474113B (en) | 2016-08-30 | 2016-08-30 | A kind of pharmaceutical composition and its application for nerve regneration after cerebral arterial thrombosis |
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| CN106474113A true CN106474113A (en) | 2017-03-08 |
| CN106474113B CN106474113B (en) | 2019-02-26 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2016
- 2016-08-30 CN CN201610782033.5A patent/CN106474113B/en not_active Expired - Fee Related
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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| CN106474113B (en) | 2019-02-26 |
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| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
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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