CN107721949A - A kind of compound and its pharmaceutical composition for being used to treat demyelinating disease - Google Patents

A kind of compound and its pharmaceutical composition for being used to treat demyelinating disease Download PDF

Info

Publication number
CN107721949A
CN107721949A CN201710703453.4A CN201710703453A CN107721949A CN 107721949 A CN107721949 A CN 107721949A CN 201710703453 A CN201710703453 A CN 201710703453A CN 107721949 A CN107721949 A CN 107721949A
Authority
CN
China
Prior art keywords
compound
benzthiazide
disease
pharmaceutical composition
demyelinating disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201710703453.4A
Other languages
Chinese (zh)
Inventor
乔志平
汤凯婷
单磊
周宝珠
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong Xtem Biotechnology Co Ltd
Original Assignee
Guangdong Xtem Biotechnology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangdong Xtem Biotechnology Co Ltd filed Critical Guangdong Xtem Biotechnology Co Ltd
Priority to CN201710703453.4A priority Critical patent/CN107721949A/en
Publication of CN107721949A publication Critical patent/CN107721949A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
    • C07D285/30—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with hydrocarbon radicals, substituted by hetero atoms, attached in position 3
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the technical field that a kind of application of compound in treatment demyelinating disease medicine is prepared belongs to biological medicine, the compound is benzthiazide (Benzthiazide), and its structural formula is as follows：And provide the pharmaceutical composition of the compound for containing described benzthiazide or its other pharmaceutically acceptable existence form as active component and pharmaceutically acceptable carrier composition, the application in demyelinating disease medicine preparation is treated.The present inventor is found through experiments that benzthiazide can improve, maintain or delay the deterioration of myelin disease, can reduce the effect of myelinoclasis.Therefore benzthiazide has critically important clinical meaning and application prospect as treatment demyelinating disease medicine.

Description

A kind of compound and its pharmaceutical composition for being used to treat demyelinating disease
Technical field
The present invention relates to biomedicine technical field, and in particular to a kind of compound for being used to treat demyelinating disease, it is special It is not related to a kind of pharmaceutical composition for being used to treat demyelinating disease.
Background technology
Demyelinating disease (demyelinating disease) is the disease of nervous system, wherein the myelin of neuron by Damage.The signal transduction that the damage is damaged in impacted neuron.Then, according to it is impacted be which nerve, the reduction of transduction Cause to feel, move, recognizing or the defects of other functions.
Demyelinating disease can include the disease for influenceing central nervous system and peripheral nervous system.Central nervous system takes off Myelin disease includes multiple sclerosis, devic's disease (Devic ' s disease), inflammatory demyelinating disease, central nervous system Neuropathy is as caused by vitamin B12 deficiency；Myelopathy such as tabetic crisis (Tabes dorsalis), leukoencephalopathy (leukoencephalopathies) such as progressive multifocal leukoencephalopathy (progressive multifocal Leukoencephalopathy), leukodystrophy (leukodystrophies) or its combination.Peripheral nervous system Demyelinating disease includes Guillain Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (chronic Inflammatory demyelinating polyradiculoneuropathy) (CIDP), the multifocal motion god of block Marrow is taken off through sick (multifocal motor neuropathy with conduction block) (MMN) and paraproteinemia Sheath peripheral nerve disease (paraproteinaemic demyelinating peripheral neuropathy) (PDN).
Nuclear factor-kappa B (Nuclear factor-kappa B, NF- κ B) are a kind of with multidirectional transcription tune The protein of section effect, NF- κ B are found as B cell nuclear factor.Because NF- κ B have to a variety of nerve cells Bioactivity, the activation for there are NF- κ B is found in a variety of the nervous system diseases, and NF- κ B persistent activation can cause nerve The tardive death of member, block NF- kB activations to be likely to become the important means for treating the nervous system disease from now on, be nerveous system New approach is opened up in the treatment of system disease.
Benzthiazide (Benzthiazide), also known as benzyl sulfide chlorothiazide；Benzothiazide；Molecular formula C15H14ClN3O4S3, Molecular weight 431.94, white crystalline powder, 221-223 DEG C of fusing point.By 3- methyl fluoride aniline -4,6- disulfonic acid chlorides and hydroxide After ammonium carries out amination, then it is made with phenylacetaldehyde cyclization.For diuretic, suitable for various oedema, such as congestive heart failure, kidney Caused oedema when popular name for, hepatic sclerosis, eclampsia, premenstruum (premenstrua) disease, time group and cortisone class drug therapy, it can also be used to Treat vascular hypertension.But the application in demyelinate peripheral nerve disease medicine preparation is treated has no that document discloses report through retrieval. The present inventor is found through experiments that benzthiazide can improve, maintain or delay the deterioration of myelin disease, can reduce myelinoclasis Effect.Therefore benzthiazide has critically important clinical meaning and application prospect as treatment demyelinating disease medicine.
The content of the invention
It is used to treat the compound in demyelinating disease medicine the technical problem to be solved in the present invention is to provide a kind of.
The structural formula of the compound is as follows：
The Chinese of the compound is benzthiazide；Benzyl sulfide chlorothiazide；Benzothiazide, English name Benzthiazide。
The compounds of this invention can exist in different forms, such as free acid, free alkali, ester and other prodrugs, salt and change Isomers, for example, the application includes all variant forms of the compound.
It is an object of the invention to provide a kind of application of benzthiazide in demyelinating disease medicine preparation.
It is a further object of the present invention to provide using benzthiazide compound as active component, treated or prevented respectively for preparing The pharmaceutical composition of kind demyelinating disease.
Above-mentioned pharmaceutical composition, it forms the benzthiazide compound containing therapeutically effective amount, described benzthiazide chemical combination Thing can be single use among pharmaceutical composition, can also be used cooperatively with other drugs.Wherein described pharmaceutical composition Effective content of single dose benzthiazide containing the active component compound in pharmaceutical composition be 1-95%.Medicinal group of the present invention The actual dose level of active component in compound can be changed so as to obtain can for specific patient, composition and Effectively reach a certain amount of reactive compound of the treatment response of needs for mode of administration.Selected dosage level depends on tool The activity of body compound, method of administration, situation and the preceding medical history of the order of severity of disease to be treated and patient to be treated.So And those skilled in the art can be administered since relatively low dosage, the dosage is less than required for reaching ideal treatment Dosage, be then gradually increased dosage until obtain Preferred effects.
Except shape be present containing the benzthiazide of therapeutically effective amount or its pharmaceutically acceptable other in above-mentioned pharmaceutical composition Outside the compound of formula, also contain pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier refers to that pharmaceutical field is normal The pharmaceutical carrier of rule, such as：Diluent, excipient and water etc.；Filler such as starch, sucrose, lactose, microcrystalline cellulose etc.；It is viscous Mixture such as cellulose derivative, alginates, gelatin, polyvinylpyrrolidone etc.；Wetting agent such as glycerine；Disintegrant such as agar, carbon Sour calcium, sodium acid carbonate etc.；Sorbefacient such as quaternary ammonium compound；Surfactant such as hexadecanol etc.；Absorption carrier such as kaolinite Soil and soap clay；Lubricant such as talcum powder, calcium stearate, polyethylene glycol etc., it is other auxiliary it can in addition contain add in the composition Agent such as flavouring agent, sweetener etc..
Aforementioned pharmaceutical compositions are any formulations described in pharmacy, including tablet, capsule, soft capsule, solidifying Jelly, oral agents, supensoid agent, electuary, patch, ointment, pill, powder, injection, infusion solution, freeze dried injection, vein breast Agent, lipidosome injection, suppository, sustained release preparation or controlled release preparation.Preferable form is tablet, coated tablet, capsule, particle Agent, oral liquid and injection.
The compounds of this invention generally can by oral, intravenous, subcutaneous, cheek, rectum, skin, intranasal, tracheae, branch Intratracheal administration, by oral or nasal spray or it can for example can also be passed through by any other Parenteral Inhalation.
The various formulations of pharmaceutical composition of the present invention can be prepared according to the conventional production process of pharmaceutical field, then by it Required formulation is made.
The compounds of this invention can be used for treating various demyelinating diseases, including influence central nervous system and peripheral nerve The disease of system.Such as：Demyelinating disease includes：Multiple sclerosis, optic neuritis, idiopathic inflammatory demyelinating disease, lattice Woods-Barre syndrome, chronic inflammatory Demyelinating Polyneuropathy disease, transverse myelitis, Balo concentric sclerosis, pernicious anaemia, brain Myelinolysis, tabetic crisis, neuromyelitis optica, progressive multifocal leukoencephalopathy, anti-MAG neuropathy, heredity fortune in the middle part of bridge Dynamic and esthesioneurosis, cerebrotendinous xanthomatosis and leukodystrophy, including adrenoleukodystrophy, adrenal gland Spinal cord neuropathy, canavan's disease, deorienting white matter disease, Alexander disease, Refsum disease and pendant profit arrange Yi Si-Mei Ci Bach Disease, metachromatic leukodystrophy, globoid leukodystrophy.
Preferably described demyelinating disease is acute or chronic demyelinating neuropathies or actue infectious polyradiculoneuritis.
Term " treatment " includes improving the treatment of one or more symptoms of demyelinating disease, or delays such disease process Treatment, such as prevent or delay demyelinate；It also includes the treatment for curing such disease so that patient enters normal function shape State and/or by patient maintain normal functional state or extend recurrence time, reduce myelinoclasis.
The therapeutical uses of compound can include preventive use, prevention, control or mitigation patient demyelinating disease breaking-out The order of severity, in addition to control or mitigate existing disease seriousness treatment.Compound can give before paresthesia epilepsy Medicine, it can also be administered after paresthesia epilepsy.Can deliver medicine to may have the patient of demyelinating disease breaking-out risk.
In research of the present inventor by the NF- κ B inhibitory action of benzthiazide compound, it is found that it is extremely strong benzthiazide has NF- κ B inhibitory activity, animal effect experiment has been carried out to benzthiazide, as a result finds that it shows suppression inflammation, can be effective Protect the effect of myelinoclasis.The benzthiazide of therapeutically effective amount can reduce inflammation, reduce demyelinate, reduce aixs cylinder lose and/ Or reduce neuron loss.
Therefore benzthiazide compound can be developed into the medicine of prevention or treatment demyelinating disease, before having application well Scape.
Brief description of the drawings
Fig. 1 is inhibitory action of the benzthiazide based on reporter gene targeting NF- κ B signal paths.
1 is blank control group in Fig. 1, and 2 be model group, and 3 be positive drug control group, 4,5,6, be benzthiazide group (concentration Respectively 0.1,1,10 μm/L), * P<0.05, * * P<0.01, * * * P<0.001.
Fig. 2 is influence of the benzthiazide to rat lymph nodes MNC proliferation experiment.
1 is Normal group in Fig. 2, and 2 be EAN groups, and 3 be benzthiazide group, * P<0.05, * * P<0.01***.
Fig. 3 is benzthiazide to cytokine TNF-α, IFN-γ and IL-17 in experimental autoimmune neuritis model Horizontal influence figure.
■ is Normal group in Fig. 3,For EAN groups,For benzthiazide group, * P<0.05, * * P<0.01.
Fig. 4 is the influence that benzthiazide is cut into slices to sciatic nerve pathology in experimental autoimmune neuritis model.
A is Normal group in Fig. 4, and B is EAN groups, and C is benzthiazide group.
Fig. 5 is that the acute myelinoclasis animal model group MBP myelin marker protein contents of CPZ mediations change with time.* P<0.05, * * P<0.01.
Fig. 6 is acute two kinds of myelin mark eggs of myelinoclasis animal model group PLP and CNPase that benzthiazide mediates to CPZ Bai Hanliang changes with time.*P<0.05, * * P<0.01.
Fig. 7 is the GST-pi marks for the acute myelinoclasis animal model that benzthiazide mediates to CPZ and the shadow of BDNF expression Ring.
1 is normal group in Fig. 7, and 2 be CPZ model groups, and 3 be 25mg/kg benzthiazide groups, and 4 be 50mg/kg benzthiazide groups, * P< 0.05, * * P<0.01.
Fig. 8 is the influence of the MBP ELISA (MBP) for the acute myelinoclasis animal model that benzthiazide mediates to CPZ.
1 is Normal group in Fig. 8, and 2 be CPZ model groups, and 3 be 25mg/kg benzthiazide groups, and 4 be 50mg/kg benzthiazides Group, * P<0.05, * * P<0.01.
Embodiment
, hereafter will be with specific the invention discloses a kind of application of compound in the medicine for preparing treatment demyelinating disease The form of embodiment illustrates the present invention.It should be understood that these specific embodiments are only illustrative, and it is nonrestrictive. In the case of without departing from spirit and scope of the invention, appropriate modification and variation can be made to the present invention.These modifications and variation It is within the scope of the present invention.The various reagents used in experiment are all commercially available, and its dosage is unless otherwise indicated Otherwise used according to the amount of routine.
Embodiment 1：Inhibitory action of the benzthiazide compound based on reporter gene targeting NF- κ B signal paths
The cell lines of NF- κ B-RE-Luci 293 (the luxuriant industry biotech firm of Beijing English) for being grown on logarithmic phase are blown and beaten, one The cell of individual bottle adjusts cell suspension with 1:3 ratio is inoculated with 96 porocyte culture plates, per the μ L of hole 200.37 DEG C are put, 5%CO2 After incubator culture 24h, 100 μ L culture mediums are abandoned per hole.Blank group is not added with TNF-α (Jin Sirui companies), adds 100 μ L and experimental group With the PBS of DMSO ratios；Inflammatory model group adds 50 μ L and the PBS and 50 μ L1000ng/mL of the identical DMSO ratios of experimental group per hole TNF-α stimulate；Positive controls add the μ L 200ng/mL of 50 μ LPDTC solution (green skies company) 50 TNF-α to stimulate per hole； TNF-α solution (the note of drug solution and 50 μ L200ng/mLs of the experimental group per hole plus various concentrations：TNF-α solution is adding Added after medicine after 1h).Continue after cultivating 24h, suction out each hole nutrient solution, gently add 25 μ L PBS, put -80 DEG C of cracking extremely Few 30min.Take out culture plate room temperature to melt, substrate Steady- is added per holeThe μ L of Reagent (Promega companies) 25, keep away Photodestruciton at least 20min.40 μ L to 384 hole white ELISA Plates are extracted reaction solution, values of chemiluminescence (RLU) is detected with ELIASA, this Value represents the expression of luciferase in each detection sample, so as to reflect NF- κ B activation levels indirectly.
Result is shown after drug-treated, and benzthiazide (upper sea blue wooden chemical industry) has obvious when concentration is 0.1,1,10 μm/L NF- κ B inhibitory activity, and into dose-effect relationship.
Embodiment 2：Influence of the benzthiazide to experimental autoimmune neuritis (EAN) rat model model
Male, the body weight 220g-280g by healthy Male Lewis rats (Nanfang Medical Univ's Experimental Animal Center), at random It is divided into 3 groups, Normal group, EAN groups and benzthiazide group every group 10, it is more that 200 μ L P257-81 are subcutaneously injected in rat root of the tail portion The mixed emulsion of peptide and Freund's complete adjuvant (MPbio companies), weighs every other day, observes incidence.Benzthiazide group was from immune 0 day Start be injected intraperitoneally 200 μ L benzthiazides, 5mg/kg, the next day once, Normal group gives the PBS of same volume.By morbidity journey Degree is divided into 0~10 grade, 0 grade：It is without exception；1 grade：Afterbody tension force reduces, and tail point upwarps；2 grades：Tail paralysis, righting reflex excalation； 3 grades：Righting reflex lacks；4 grades：Ataxic gait, posture are abnormal；5 grades：Hind leg paresis；6 grades：Moderate is paralysed；7 grades：Hind leg is serious Paralysis；8 grades：Quadriplegia；9 grades：It is dying；10 grades：It is dead.
CCK8 methods determine vitro lymphocyte proliferation:Sensitization the 16th day, every group of experimental group selects 5 rats at random, is drenched Mononuclearcell (MNC) separation is fawned on, by rat lymphocyte suspension (2xl06/ ml), it is inoculated into 96 well culture plates, per hole 200 μ L, each every 3 hole of sample, 10 μ LRPMI1640 nutrient solutions, 5 μ g/mLConA culture 72h are separately added into, is added into every hole 10 μ LCCK8 (are purchased from Sigma), culture plate are placed in into 37 DEG C, 5%CO2After continuing culture in incubator 4 hours, ELIASA (purchase From match Mo Feishier companies) survey 450nm OD values.
The 16th day lymph node MNC (2 × 10 of sensitization6/ mL) after culture 56h, nutrient solution supernatant is taken, using ELISA method, is carried out TNF-α, IFN-γ and IL-17 assays.
Sensitization puts to death rat on the 16th day, takes bilateral sciatic nerve, carries out sciatic nerve pathology section, Hematoxylin-eosin (HE) dye, the area and inflammatory cell number of section epineural tissue are determined with image analysis system.
Experimental result:
Normal group is fallen ill without rat；EAN groups rat starts to fall ill on the 8th day, paralyses within the 16th day or so and reaches peak, and the 18th Gradually alleviate after it；Start to fall ill within the 9th day after benzthiazide group sensitization, paralysis in the 19th day or so reaches peak, after the 21st day gradually delays Solution.
The 16th day rat lymph nodes MNC of sensitization is to the proliferation experiment results of different antigenic stimulus, compared with EAN groups, benzyl thiophene Piperazine group can substantially suppress the mononuclearcell propagation of ConA inductions.
After the 16th day lymph node MNC cultures 56h of sensitization, TNF-α, IFN-γ, IL-17 are horizontal in nutrient solution supernatant, benzyl thiophene Piperazine group is substantially less than EAN groups.
Sciatic nerve pathology inspection result：The 16th day Normal group of sensitization is normal, and benzthiazide group rat sciatic nerve is scorching Property cellular infiltration number is substantially less than EAN groups (P ＜ 0.01).
Test result indicates that benzthiazide can mitigate the damage of sciatic nerve, inflammatory cell infiltration and myelinoclasis feelings are reduced Condition, EAN peripheral nerve inflammations can be mitigated, so as to play neuroprotection.
The experiment for the acute myelinoclasis animal model that the benzthiazide of embodiment 3 is induced CPZ
Experimental method：
6-8 week old C57Bl/6 male mices (Nanfang Medical Univ's Experimental Animal Center), body weight about 18-20g, SPF levels, Factually testing needs to be divided into following 4 groups very much：1. Normal group：Feed 6 weeks conventional feeds and normal water；2. model group (is designated as CPZ groups)：Feeding 6 weeks feeds and normal water containing 0.2% chelating copper ions agent CPZ (Sigma companies)；3. 25mg/kg benzyl thiophenes Piperazine group：6 weeks feeds containing 0.2%CPZ are fed, normal water simultaneously gives (25mg/kg/ pcs/day of benzthiazide at the 3rd weekend；④ 50mg/kg benzthiazide groups：6 weeks feeds containing 0.2%CPZ are fed, normal water simultaneously gives benzthiazide 50mg/kg/ at the 3rd weekend Pcs/day；Until experiment terminates, Normal group and model group animal give isometric solvent to test medicine successive administration within 3 weeks.
Experimental result：
1st, CPZ mediation acute myelinoclasis model group, weekly using content sxemiquantitative statistical method detect MBP, Tri- kinds of myelin marker protein contents of PLP, CNPase change with time.As shown in Figure 5 and Figure 6, feed of the detoxification containing CPZ Tri- kinds of myelin marker protein contents of MBP, PLP and CNPase change with time and are remarkably decreased in mouse brain afterwards, illustrate that CPZ is mediated Acute myelinoclasis animal model in the gradual depigmentation of myelin myelin.
2nd, after feeding 6 weeks, the brain-derived neurotrophy of acute myelinoclasis animal model that detection each group mediates to CPZ because Sub (BDNF) expression, ripe oligodendroglia (GST-pi marks), the influence of MBP ELISA (MBP).Such as Fig. 7 and Fig. 8 It is shown.
MBP is MBP ELISA, is the main constituents of myelin, MBP ELISA (MBP) average area semidefinite Measure statistical result showed, feeding feed containing CPZ after 6 weeks model group animal myelinic phospholipid depigmentation it is serious, benzthiazide group have protect The effect of myelinoclasis.
Ripe oligodendroglia (OLs) (GST-pi marks) is the myelin producing cells of central nervous system, can be dropped The quantity of low myelinoclasis position oligodendrocyte precursors, increases ripe oligodendrocyte numbers, model group with just Normal control group is compared, and GST-pi positive cell numbers significantly reduce, and GST-pi sun can all be increased by giving the benzthiazide group of various dose Property cell number, * * P<0.01.Benzthiazide group to the positive cell number of GST-pi in increase unit area with having dose dependent. Illustrate that benzthiazide has and promote potential of the oligodendrocyte precursors to ripe oligodendrocyte differentiation.
BDNF is a kind of important neurotrophic factor of intracerebral, and nutritional support is provided for the formation of myelin.Increase BDNF's Expression can provide nutrition support so as to resist or reverse the myelinoclasis as caused by CPZ for the myelin of depigmentation, as a result show Benzthiazide group can significantly raise the expression of BDNF in brain during acute, * * P<0.01.
Experiment conclusion：
Benzthiazide can promote myelinoclasis position OLs (GST- in the acute myelinoclasis animal model that CPZ is induced Pi mark) expression and raise neurotrophic factor BDNF expression, illustrate that benzthiazide takes off to the acute myelin that CPZ is mediated Losing has significant confrontation and mitigation.
From the foregoing, it will be observed that by above example test result indicates that, benzthiazide has stronger NF- κ B inhibitory action, Can lighter neuroinflamation and myelinoclasis situation, so as to play neuroprotection.Therefore it can be confirmed that benzthiazide can be used for Prepare the medicine of prevention or treatment demyelinating disease.

Claims (10)

  1. A kind of 1. compound and its pharmaceutical composition for being used to treat demyelinating disease, it is characterised in that the knot of the compound Structure formula is as follows：
  2. 2. compound according to claim 1, it is characterised in that the compound is benzthiazide.
  3. 3. compound according to claim 1, it is characterised in that the compound can be deposited with benzthiazide multi-form , including free acid or free alkali or ester or other prodrugs, salt or dynamic isomer.
  4. 4. compound according to claim 1, it is characterised in that the compound is formed for treatment by demyelinate, myelin The compound of demyelinating disease caused by deficiency or myelin sheath hypoplasia.
  5. 5. compound according to claim 1, it is characterised in that wherein described demyelinating disease includes：Multiple sclerosis Disease, optic neuritis, idiopathic inflammatory demyelinating disease, actue infectious polyradiculoneuritis, chronic inflammatory Demyelinating Polyneuropathy disease, traverse Property myelitis, Balo concentric sclerosis, pernicious anaemia, central pontine myelinolysis, tabetic crisis, neuromyelitis optica, progressive Multifocal leukoencephalopathy, anti-MAG neuropathy, Hereditary motor and sensory neuropathy, cerebrotendinous xanthomatosis and white matter of brain nutrition are not It is good, including adrenoleukodystrophy, adrenomyeloneuropathy, canavan's disease, deorienting white matter disease, Alexandria Disease, Refsum disease and Pelizaeus Merzbacher disease, metachromatic leukodystrophy, ball like cell white matter of brain battalion Support bad.
  6. 6. compound according to claim 1, it is characterised in that wherein described demyelinating disease is preferably acute and chronic inflammatory Demyelinating Polyneuropathy or actue infectious polyradiculoneuritis.
  7. 7. a kind of pharmaceutical composition for being used to treat demyelinating disease, it is characterised in that described pharmaceutical composition is by benzthiazide Or the compound of its other pharmaceutically acceptable existence form is as active component, and with pharmaceutically acceptable carrier Manufactured pharmaceutical composition.
  8. 8. pharmaceutical composition according to claim 7, it is characterised in that described pharmaceutical composition includes one or more medicines Acceptable diluent, wetting agent, adhesive, disintegrant, lubricant, conditioning agent and other auxiliary materials on or in bromatology.
  9. 9. pharmaceutical composition according to claim 7, it is characterised in that described pharmaceutical composition formulation is tablet, coating Tablet, capsule, granule, oral liquid and injection.
  10. 10. pharmaceutical composition according to claim 7, it is characterised in that the single dose of described pharmaceutical composition is containing activity Effective content of the compound of composition benzthiazide or its other pharmaceutically acceptable existence form in pharmaceutical composition is 1- 95%.
CN201710703453.4A 2017-08-16 2017-08-16 A kind of compound and its pharmaceutical composition for being used to treat demyelinating disease Pending CN107721949A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710703453.4A CN107721949A (en) 2017-08-16 2017-08-16 A kind of compound and its pharmaceutical composition for being used to treat demyelinating disease

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710703453.4A CN107721949A (en) 2017-08-16 2017-08-16 A kind of compound and its pharmaceutical composition for being used to treat demyelinating disease

Publications (1)

Publication Number Publication Date
CN107721949A true CN107721949A (en) 2018-02-23

Family

ID=61205105

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710703453.4A Pending CN107721949A (en) 2017-08-16 2017-08-16 A kind of compound and its pharmaceutical composition for being used to treat demyelinating disease

Country Status (1)

Country Link
CN (1) CN107721949A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115844917A (en) * 2023-02-24 2023-03-28 广东创药联和医药科技有限公司 Medicinal use of jujuboside A

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB909689A (en) * 1958-02-17 1962-10-31 Pfizer & Co C 3,6-disubstituted-7-sulfamyl-2,4-benzothiadiazine-1,1-dioxides
CN101048164A (en) * 2004-11-01 2007-10-03 柳署弘 Methods and compositions for reducing neurodegeneration in amyotrophic lateral sclerosis
CN102283852A (en) * 2011-09-22 2011-12-21 中国人民解放军第二军医大学 Application of diosgenin to preparation of medicament for treating demyelinating disease
WO2013061161A2 (en) * 2011-10-28 2013-05-02 Green Bcn Consulting Services Sl New combination therapies for treating neurological disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB909689A (en) * 1958-02-17 1962-10-31 Pfizer & Co C 3,6-disubstituted-7-sulfamyl-2,4-benzothiadiazine-1,1-dioxides
CN101048164A (en) * 2004-11-01 2007-10-03 柳署弘 Methods and compositions for reducing neurodegeneration in amyotrophic lateral sclerosis
CN102283852A (en) * 2011-09-22 2011-12-21 中国人民解放军第二军医大学 Application of diosgenin to preparation of medicament for treating demyelinating disease
WO2013061161A2 (en) * 2011-10-28 2013-05-02 Green Bcn Consulting Services Sl New combination therapies for treating neurological disorders

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115844917A (en) * 2023-02-24 2023-03-28 广东创药联和医药科技有限公司 Medicinal use of jujuboside A

Similar Documents

Publication Publication Date Title
AU725249B2 (en) Use of a thienotriazolodiazepine to increase apolipoprotein A-I levels
US20220265559A1 (en) Delayed release deferiprone tablets and methods of using the same
Wang et al. Glutamatergic receptor and neuroplasticity in depression: Implications for ketamine and rapastinel as the rapid-acting antidepressants
CN107721949A (en) A kind of compound and its pharmaceutical composition for being used to treat demyelinating disease
CN109966277B (en) Pharmaceutical composition for treating intractable epilepsy and application thereof
US6489356B2 (en) Method for treating pain in humans
US6248774B1 (en) Method for treating hyper-excited sensory nerve functions in humans
EP1032402B1 (en) Use of citicoline for the treatment of multiple sclerosis (MS)
TW201507725A (en) The uses of hydroxyl polymethoxylflavones and/or derivative thereof
CN114209708A (en) Application of alendronic acid in preparation of medicine for treating hepatic fibrosis
CA3104916C (en) Pharmaceutical composition for preventing diabetes and use thereof
CN114569601B (en) Application of neogambogic acid in preparation of medicines for preventing and/or treating kidney diseases
CN113244405B (en) Pharmaceutical composition of forskolin/isoforskolin and pentacyclic triterpenoid and application thereof
US20230226018A1 (en) Application of compound using intra-cyclic peroxo-bridged sesquiterpenes as parent nucleus in metabolism-related fatty liver diseases
CN117298095B (en) Application of eupatorium sesquiterpene lactone compounds in preparation of medicines for treating/preventing NLRP3 inflammatory small body mediated diseases
CN107929281B (en) Medical application of ginkgolide composition
US8765188B2 (en) Composition for treating and/or preventing osteoporosis
WO2022221988A1 (en) Pharmaceutical hydronidone formulations for diseases
WO2022135462A1 (en) Medicinal use of magl inhibitor
WO2022061962A1 (en) Method for effectively intervening diabetes by using l-type amino acid transporter inhibitor or antagonist
CN106581151B (en) Application of traditional Chinese medicine composition for promoting blood circulation and removing stasis
US20020198172A1 (en) Method of treating motor neuron diseases and demyelinating diseases with citicoline
CN115844917A (en) Medicinal use of jujuboside A
CN116585334A (en) Application of paeoniflorin in preparation of medicines for treating inflammatory bowel disease
CN110638851A (en) Application of pien Tze Huang in preparation of medicine for treating rheumatoid arthritis

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20180223

RJ01 Rejection of invention patent application after publication