CN101618036A - Novel medicinal application of carboxyl aminotriazole and acceptable salts of the carboxyl aminotriazole - Google Patents
Novel medicinal application of carboxyl aminotriazole and acceptable salts of the carboxyl aminotriazole Download PDFInfo
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Abstract
The invention discloses application of carboxyl aminotriazole or pharmaceutically acceptable salts of the carboxyl aminotriazole in the preparation of medicaments for preventing and/or treating neurodegenerative diseases, amyotrophic lateral sclerosis and inflammatory bowel diseases and also relates to the medicament packages or kits comprising the medicaments.
Description
Technical field
The present invention relates to carboxylic amine triazole (carboxyamidotriazole, CAI) or the new medical use of its pharmaceutically acceptable salt, analog or derivant, particularly its application in preparation prevention or treatment neurodegenerative disease and/or inflammatory bowel disease medicine.More specifically, the present invention relates to comprise the compositions of carboxylic amine triazole or its pharmaceutically acceptable salt, derivant, analog and use the purposes of this compositions prevention or treatment amyotrophic lateral sclerosis and/or inflammatory bowel disease.
Technical background
Amyotrophic lateral sclerosis (amyotrophic lateral sclerosis, ALS) be a kind of progressive fatefulue motor neuron disease (motor neuron disease, MND), have another name called Lou GehrigShi disease, with the chronic progressive external degeneration of ventricornu and brain stem motor neuron and tractus pyramidalis, the neuron that moves up and down is simultaneously impaired to be feature.Mostly be person in middle and old age's onset, the man: woman=1.0～1.6: 1, the childhood period that being arranged in recent years, report plays the patient, and average age of onset is about 8 years old, and reckling only is 9 months.The annual morbidity of majority state ALS is 5～7/10
5, high reaches 40/10
5, area, Guam, the Pacific Ocean is this sick district occurred frequently.This disease progression is rapid, and is dead in 2～5 years that most patient sends out in disease.The patient mainly shows as muscle weakness, atrophy, the fasciculation that spinal cord and brain stem are arranged, bulbar paralysis and pyramidal sign; Sensory system generally is inviolable.The ALS morbidity is early stage, and along with motor neuron death, abnormal fatigue, clumsiness, muscle reduction, inarticulateness, amyotrophy and spasm appear in the patient.Along with progression of disease, the patient loses the effect of hands, arm, lower limb and musculi colli gradually, develops into paralysis at last, and forfeiture is spoken and swallow, and the general reason that causes death at last is the barrier film flesh forfeiture effect of control breathing.ALS can be divided into familial amyotrophic lateral sclerosis (FALS) and sporadic amyotrophy lateral sclerosis of spinal cord, and (sporadic amyotrophic lateral sclerosis, SALS), the former accounts for 5-10%.Its pathogenesis is unclear fully as yet, do not have yet specific treatment (T Caroscio, MN Mulvihill, RSterling, and B Abrams, Amyotrophic lateral sclerosis.Its natural history.J NeurolClin, Feb 1987; 5 (1): 1-8.).
Based on finding abnormal high glutamic acid salt level in some ALS patient's cerebrospinal fluid, one of Therapeutic Method that proposes at this disease is the level of regulating glutamate, Glu in the brain.Glutamate, Glu is transported sub-EAAT2 and is reduced in the cortex of ALS patient and mouse model and spinal cord, causes the glutamate, Glu excessive concentration, causes activation toxicity, i.e. the activation of glutamate receptor, and calcium ion overload in the neuron, and the downstream signal transduction is impaired.The research prompting can be used the glutamate, Glu antagonist, stops the release of glutamate, Glu in the brain.It is at present unique that widely used ALS curative material resources Shandong azoles (Riluzole) promptly belong to this type of by the U.S. FDA authentication and in the whole world, but it is not a kind of healing medicine, can not improve the trend of carrying out property of symptom or reverse deterioration, in addition, treatment easily causes the liver enzyme index to raise and granulocytopenia during the shortcoming of riluzole, must the monitoring liver enzyme levels and hemoglobin, packed cell volume, cytometry.Other glutamate, Glu antagonist comprises dromethan and lamotrigine (Lamictal), and the degraded situation of above-mentioned several drugs before by blood brain barrier still needs great concern.Parts of fine intracellular cytokine (Brain Derived Neurotrophic Factor etc.) obtains to prolong comparatively certainly the curative effect of motor neuron and model mouse life span in external and zoopery, but the result of clinical trial is pessimistic, may to be subjected to the interference of complicated factor in vivo relevant with cytokine.Gene therapy comprises and cytokine, gene strategy that apoptosis is relevant, as utilize carriers such as virus to carry related gene to enter pathological tissues and express neurotrophic factor, this kind mode makes cytokine more stably retain in target tissue, but the potential danger of viral vector, and the stability of expressing related gene is not good, all is the unfavorable factor that limits its application.
Inflammatory bowel disease (Inflammatory Bowel Disease, IBD) comprise ulcerative colitis (Ulcerative Colitis, UC) and clone disease (Crohn ' s disease, CD), be a class cause of disease complete clear and definite non-specific chronic inflammatory disease of intestinal as yet.Normally mucous membrane of colon inflammation of ulcerative colitis can expand tela submucosa to when serious.Rectum also can be encroached in addition, can involve ileum but have only under kind of a few cases.Clone disease is also referred to as regional enteritis or granulomatous colitis, is the common small intestinal that is positioned at, and especially is positioned at the disease of ileum, but also can influence any part of jejunum and colon, comprises rectum.Usually, this inflammation is different from ulcerative colitis, and is dark than mucosa to the influence of layer, less to the influence of epithelium simultaneously.The morbidity of UC and CD relates to a plurality of factors such as environment, heredity, microorganism, immunity, is characterized in pathological changes complexity, various, the misdiagnosis rate height, and complication is many, relapse rate is high.Clinical manifestation is diarrhoea, stomachache, and heating is become thin, and mucopurulent bloody stool, digestive tract block, performances such as peritoneal abscess and oral ulcer, state of an illness weight does not wait, and is outbreak repeatedly more.These two kinds of diseases are especially multiple in developed country, in the U.S., the sickness rate of ulcerative colitis is per 100,000 philtrum has 5-15 name patient, and the sickness rate of clone disease is about per 100,000 philtrum has 5 people ill, and this numeral is also raising at present, and also is the situation that rises appreciably at the sickness rate of China.Clinical treatment seldom has the specific treatment medicine except that hormone, immunosuppressant, aminosallcylic acid preparation.At present use more medicine to be sulfasalazine (SASP), seldom absorb after this medicine is oral, be decomposed into sulfapyridine and 5-aminosalicylic acid at enteral.The sulfapyridine major part absorbs at colon, is to cause the toxic main cause of SASP, and side reactions such as nauseating, vomiting, erythra, anemia, arthritis, headache are often arranged after patient's medication.Studies confirm that in recent years, IBD be body stimulate to external world produce the immune inflammation reaction after, the intestinal injury that a series of media cause in the active cell, this immunoreation shows as the abnormal activation of T cell, pro-inflammatory cytokine and anti-inflammatory factors unbalance.
In the prior art, carboxyamido-triazoles compound, for example carboxylic amine triazole soft gelatin capsule is used for the treatment of cancer.
The inventor finds the new purposes of medicine carboxylic amine triazole and analog thereof through long-term and deep research, and promptly it can obviously improve the disease symptoms of amyotrophy lateral spinal sclerosis mice, ulcerative colitis rat, prolongs the animal life-span.
Summary of the invention
The object of the present invention is to provide the new medical use of carboxyamido-triazoles compound.
One of specific purposes of the present invention provide carboxylic amine triazole in preparation prevention and/or postpone, or the application of the medicine of the mitigation symptom relevant with various neurodegenerative diseases.
Two of specific purposes provide the pharmaceutically useful salt of carboxylic amine triazole, analog or derivant in preparation prevention and/or postpone, or the application of the medicine of the mitigation symptom relevant with various neurodegenerative diseases.
Three of specific purposes provide carboxylic amine triazole prevents and/or treats the medicine of amyotrophic lateral sclerosis (ALS) in preparation application.
Four of specific purposes provide the pharmaceutically useful salt of carboxylic amine triazole, analog or derivant prevent and/or treat the medicine of amyotrophic lateral sclerosis (ALS) in preparation application.
Five of specific purposes provide the application of carboxylic amine triazole at inflammatory bowel disease medicines such as preparation treatment ulcerative colitis and clone diseases.
Six of specific purposes provide the application at inflammatory bowel disease medicines such as preparation treatment ulcerative colitis and clone diseases of the pharmaceutically useful salt of carboxylic amine triazole or its analog, derivant.
Seven of specific purposes provide a kind of medicated bag or test kit that is used to prevent and/or treat neurodegenerative diseases, prevents and/or treats amyotrophic lateral sclerosis and/or inflammatory bowel disease.
In order to finish purpose of the present invention, the invention provides following technical scheme:
The present invention relates to carboxylic amine triazole or the pharmaceutically useful salt of carboxylic amine triazole and prevent and/or treat neurodegenerative diseases in preparation, prevent and/or treat the purposes in the medicine of amyotrophic lateral sclerosis and/or inflammatory bowel disease, wherein said carboxylic amine triazole has the chemical compound of formula (I) structure:
Formula (I)
Wherein, R1 has formula (II) structure:
Formula (II)
In the formula (II), p is 0 to 2 integer; M is 0 to 4 integer; N is 0 to 5 integer; X can be O, S, SO, SO
2, CO, CHCN, CH
2Or C=NR
6, R wherein
6Be selected from hydrogen, the alkyl group of C1-C6, hydroxyl, the chain alkoxy of C1-C6, amino, the chain alkylamino of C1-C6, dialkylamino or cyano group;
R
4And R
5Be selected from halogen respectively, cyano group, trifluoromethyl, the C1-C6 alkanoyl, nitro, C1-C6 alkyl group, the C1-C6 chain alkoxy, carbonyl, carbalkoxy, trifluoromethoxy, acetylamino, C1-C6 chain alkylthio group, C1-C6 alkyl group sulfonyl, trichloro-vinyl, trifluoromethylthio, trifluoromethyl sulphinyl base, perhaps trifluoromethyl sulfonyl;
R
2Be selected from amino, C1-C6 chain alkylamino, dialkylamino, acetylamino, acetimide, urea groups acyl group, formamido group, formyl imines or guanidine radicals;
R
3Be selected from amine formyl, cyano group, carbamoyl, imido grpup or N-hydroxyl carbamyl.
In-individual concrete technical scheme, described carboxylic amine triazole is that n and m are respectively 0,1 or 2 in the formula (II); P equals 1; X is O, S, CO or CH
2R
4Be selected from fluorine, chlorine, bromine, methyl, trifluoromethyl, cyano group, methoxycarbonyl group, trifluoromethoxy, trifluoromethylthio, nitro or trichloro-vinyl; R
5Be chlorine, bromine, fluorine, methyl, trifluoromethyl, cyano group, carbalkoxy, trifluoro vinyl or nitro.
In another embodiment, described carboxylic amine triazole has as shown in the formula (III):
Wherein, X is CH
2, S, O or CO; R
4Be Cl, CF
3, Br or CH
3R
5Be Cl, Br or NO
2
Say that more specifically carboxylic amine triazole of the present invention can be 5-amido-1-[3,5-two chloro-4 (4-chlorobenzoyl chloride) benzyl]-1H-1,2,3-triazole-4-Benzoylamide.
Carboxylic amine triazole of the present invention comprises the pharmaceutically useful salt of carboxylic amine triazole, its analog or derivant.
The pharmaceutically useful salt of carboxylic amine triazole of the present invention includes, but are not limited to hydrochlorate, sulfate, the acetate of carboxylic amine triazole.
Medicine described in the present invention is a kind of pharmaceutical composition, and it comprises the carboxylic amine triazole and the pharmaceutically acceptable carrier of medicine effective dose.
Inflammatory bowel disease described in the present invention comprises ulcerative colitis and clone disease.
In other words, among the present invention, carboxyamido-triazoles compound comprises:
Chemical compound with formula (I) structure:
Formula (I)
Wherein, R1 has formula (II) structure:
Formula (II)
Wherein, p is 0 to 2 integer; M is 0 to 4 integer; N is 0 to 5 integer; X can be O, S, SO, SO
2, CO, CHCN, CH
2Or C=NR
6
R wherein
6Can be hydrogen, (C1-C6) alkyl group, hydroxyl, (C1-C6) chain alkoxy, amino, (C1-C6) chain alkylamino, dialkylamino or cyano group;
R
4And R
5Can be respectively halogen, cyano group, trifluoromethyl, (C1-C6) alkanoyl, nitro, (C1-C6) alkyl group, (C1-C6) chain alkoxy, carbonyl, carbalkoxy, trifluoromethoxy, acetylamino, (C1-C6) chain alkylthio group, (C1-C6) alkyl group sulfonyl, trichloro-vinyl, trifluoromethylthio, the trifluoromethyl sulphinyl base, trifluoromethyl sulfonyl;
R
2Be amino, (C1-C6) chain alkylamino, dialkylamino, acetylamino, acetimide, urea groups acyl group, formamido group, formyl imines or guanidine radicals;
R
3Be amine formyl, cyano group, carbamoyl, imido grpup or N-hydroxyl carbamyl.
According to technical scheme of the present invention, the preferred concrete chemical compound of the present invention is: n and m are respectively 0,1 or 2 in the formula (II); P equals 1; X is O, S, CO or CH
2
R
4Be fluorine, chlorine, bromine, methyl, trifluoromethyl, cyano group, methoxycarbonyl group, trifluoromethoxy, trifluoromethylthio, nitro or trichloro-vinyl;
R
5Be chlorine, bromine, fluorine, methyl, trifluoromethyl, cyano group, carbalkoxy, trifluoro vinyl or nitro.
According to technical scheme of the present invention, the present invention is concrete, and formula (I) structural formula of compound is as follows:
X is CH
2, S, O or CO; R
4Be Cl, CF
3, Br or CH
3R
5Be Cl, Br or NO
2
Preferred formula of the present invention (I) chemical compound is 5-amido-1-[3,5-two chloro-4 (4-chlorobenzoyl chloride) benzyl]-1H-1,2,3-triazole-4-Benzoylamide, i.e. carboxylic amine triazole (carboxyamidotriazole is called for short CAI).
Chemical compound of the present invention also comprises the pharmaceutically useful salt of these chemical compounds, example hydrochloric acid salt, sulfate, acetate etc.
The present invention at first proposes above-claimed cpd and prevents and/or treats application in neurodegenerative diseases, the inflammatory bowel disease medicine in preparation.Wherein said neurodegenerative diseases is including but not limited to the constitutional neurodegenerative disease; Hungtington's chorea; Apoplexy and other anoxia or ischemic disease; Secondary cases neurodegenerative disease (metabolic or viral disease); Parkinson's disease; Alzheimer; Alzheimer type alzheimer disease (SDAT); Relevant with cognitive dysfunction is aging; Vascular dementia, multi-infarct dementia, thunder dimension corpusculum dementia, neural degeneration dementia.Described inflammatory bowel disease is including but not limited to ulcerative colitis, and clone disease, Behcet disease (Behcet ' s disease, BD).
Second group of purpose of the present invention is to provide a kind of treatment to suffer from the patient's of neurodegenerative disease or inflammatory bowel disease method.The method comprising the steps of: give a kind of compositions that comprises a kind of carboxylic amine triazole activating agent and a kind of pharmaceutically acceptable carrier, wherein carboxylic amine triazole activating agent is basically by 5-amido-1-[3,5-two chloro-4 (4-chlorobenzoyl chloride) benzyl]-1H-1,2,3-triazole-4-Benzoylamide, promptly carboxylic amine triazole and its pharmaceutically acceptable salt, analog, derivant are formed.In one embodiment, the neurodegenerative disease of being treated is selected from amyotrophic lateral sclerosis, be selected from ulcerative colitis by the inflammatory bowel disease of being treated, the dosage of the compositions that is given is carboxylic amine triazole or its pharmaceutically acceptable salt, analog, derivant of about 10mg～about 300mg every day.
Employed dosage is certainly with being decided by the disease specific and the other factors of being treated, other factors comprise age, body weight, health status, symptom the order of severity, route of administration, treatment frequency and during treating, whether follow other medicine.Can easily determine the using dosage of each reactive compound by the known conventional method of those of ordinary skills.Coming-of-Age Day, dosage was usually in about 10mg～300mg scope, preferably in about 50mg～200mg scope.For example, people's TDD of can orally give suffering from ALS is the carboxyamido-triazoles compound of the present invention between 50mg～200mg.Perhaps, the of the present invention carboxyamido-triazoles compound of people's TDD between 50mg～200mg of can rectum suffering from UC.
The 3rd group of purpose of the present invention is to provide the pharmaceutical composition that comprises carboxyamido-triazoles compound of the present invention.More particularly, can use well-known to those skilled in the art pharmaceutically acceptable carrier, filler, solubilizing agent and the stabilizing agent of standard that carboxyamido-triazoles compound is mixed with pharmaceutical composition.
The pharmaceutical composition that comprises carboxyamido-triazoles compound needs the individuality of this medicine by in many approach any, include but not limited to, in local, oral, intravenous, intramuscular, intra-arterial, the marrow, in the sheath, in the ventricle, percutaneous, subcutaneous, intraperitoneal, intranasal, intestinal, part, Sublingual or rectal.Oral formulations can be solid preparation such as tablet, capsule, powder, granule or liquid preparation such as solution, suspension etc.The preparation that is fit to oral administration can contain pharmaceutically acceptable carrier or excipient.Pharmaceutically acceptable carrier or the excipient that is suitable for solid preparation (as tablet or capsule) can be: for example binding agent is (as arabic gum, gelatin, dextrin, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone), diluent is (as lactose, sucrose, mannitol, corn starch, potato starch, calcium phosphate, calcium citrate, crystalline cellulose), lubricant is (as magnesium stearate, calcium stearate, stearic acid, Pulvis Talci, anhydrous silica gel), disintegrating agent is (as corn starch, potato starch, carboxymethyl cellulose, carboxymethylcellulose calcium, alginic acid) and wetting agent (as sodium lauryl sulphate).The pharmaceutically acceptable carrier or the excipient that are suitable for liquid preparation (as solution or suspension) can be: for example aqueous lyase (as water), suspending agent (as arabic gum, gelatin, methylcellulose, sodium carboxymethyl cellulose, hydroxy methocel, aluminium stearate gel), surfactant (as lecithin, sorbitan monooleate, glyceryl monostearate) and non-aqueous lyase (as PEG400, glycerol, propylene glycol, vegetable oil).In addition, liquid preparation can contain antiseptic (as nipagin, propyl parabene), flavoring agent and/or coloring agent.
Enteral perfusion preparation (enema) can be to use the aqueous solution or the suspension dosage form of above-mentioned water-soluble enzyme or suspending agent preparation.In case of necessity, enema can be to use thickening agent such as polyacrylic acid, gelatin etc. and the colloidal sol or the gel preparation of preparation.
Suppository can make by mixing carboxylic amine triazole or its pharmaceutically acceptable salt, analog, derivant and commercially available oleaginous base such as Witepsole etc. or water-soluble base such as Polyethylene Glycol, glycerol, gelatin etc. with the method for routine.Suppository can be capsule formulation suppository, tablet form suppository or ointment dosage form suppository.
External preparation can comprise external pulvis, ointment, ointment etc.
The present invention also provides a kind of medicated bag or test kit that comprises one or more containers, wherein is full of the composition of one or more pharmaceutical compositions of the present invention in the container.
In other words, the invention still further relates to a kind of medicated bag or test kit that is used to prevent and/or treat neurodegenerative diseases, prevents and/or treats amyotrophic lateral sclerosis and/or inflammatory bowel disease, wherein comprise one or more carboxylic amine triazoles or the pharmaceutically useful salt of carboxylic amine triazole, comprise the container and the operation instructions of described carboxylic amine triazole or the pharmaceutically useful salt of carboxylic amine triazole.
According to a kind of embodiment, the invention provides a kind of test kit that is used for the treatment of amyotrophic lateral sclerosis (ALS) patient.In this embodiment, test kit comprises one or more carboxyamido-triazoles compounds of the present invention.These medicines can be packaged in the various containers, for example liquid medicine bottle, test tube, micro-orifice plate, bottle or the like.Preferably, test kit can also comprise operation instructions.
Description of drawings
Fig. 1: show that carboxylic amine triazole and analog thereof prolong the effect in ALS animal pattern life-span.
Fig. 2: carboxylic amine triazole and analog thereof are to the improvement of ALS animal movement function in the experiment of demonstration transfer rod.
Fig. 3: show the inhibitory action of carboxylic amine triazole to the inductive brain response to oxidative stress of MPTP.
Fig. 4: show that carboxyamido-triazoles is like the inhibitory action of thing to the inductive brain response to oxidative stress of MPTP.
Fig. 5: show the protective effect of carboxylic amine triazole and analog thereof to the ulcerative colitis rat colon.
Fig. 6: body condition score situation after the medication of demonstration ulcerative colitis rat.
Fig. 7: weight increase situation after the medication of demonstration ulcerative colitis rat.
The specific embodiment
Can understand some embodiments of present disclosure in conjunction with the following examples.Yet those skilled in the art can easily understand concrete material, compositions, and described result only illustrates present disclosure, and does not wish, also shall not be applied to the scope and the various embodiment thereof of restriction present disclosure.
Embodiment 1: medicine is to the protective effect of ALS transgenic models animal
B6SJL-Tg (SOD1*G93A) 1Gur/J transgenic mice, it can be crossed and express the people SOD1 gene that contains the sudden change of determining among the ALS patient, forms adult age is fallen ill, carrying out property animal deterioration.These transgenic mices are considered to the model of described disease, and have been used to test the many strategies that postpone progression of disease and mortality rate.
In order to estimate the potential benefit of the present invention to ALS, matched group and administration group SOD1G93A transgenic mice every day Orally administered PEG400 solvent, CAI or the multiple analog of CAI (structural formula is the chemical compound of A, wherein R
1Be Cl or H, R
2Be Cl, H, Br, CH
3, or CF
3, R
3Be Cl, Br, CF
3, NO
2Or CN, X is O, S or C=O).Four kinds of carboxyamido-triazoles that use in the present embodiment are respectively A1～A4 in the table 1 like thing, and dosage all adopts 20mg/kg.Mice begins administration during 70 day age, and lasts till death.
Several carboxyamido-triazoles of table 1 are like the chemical constitution of thing
Predicted life and result thereof: Fig. 1 shows the average predicted life of the mice (n=6) of control mice and oral carboxylic amine triazole and A1, A2, A3, four kinds of chemical compounds of A4.The mean survival time of control mice is 128.4 days, after carboxylic amine triazole and A1, A2, four kinds of compound treatment of A3, A4, each organizes the mean survival time of mice for being respectively 138.6 days, 133.5 days, 139 days, 138.2 days and 135.4 days, and life span has prolonged 5～10 days and do not waited.
Rotating rod experiment: mice is placed on the transfer rod, opposite with the direction of rotation of rod, force their to keep advance the puck to prevent landing from the transfer rod.Learn after several days, mice can remain on the transfer rod of the 15rpm speed of rotation and not fall.Test mice weekly 1 time, in each transfer rod experiment, every mice carries out 3 experiments, the retention time (incubation period) before the record landing on rod.From 3 experiments, select the measured value of the long residence time of animal on rod as motor behavior.Fig. 2 shows passing in time, the variation of control mice and the motor capacity of different pharmaceutical processed group mice transfer rod.Since 16 weeks, the time of staying of drug treating group mice on transfer rod such as carboxylic amine triazole and analog thereof obviously prolong than the control group mice time of staying.
Embodiment 2: carboxylic amine triazole suppresses the inductive oxidative stress of MPTP
Male C57BL/6 mice, body weight 18g～22g, is divided into 4 groups by 12/group.Animal gives carboxylic amine triazole by irritating stomach every day, and in continuous 8 weeks, dosage is respectively 0,10,20, or 40mg/kg/ days.On the same day of studying, give neurotoxin N-methyl-4-phenyl-1,2,3 of mouse subcutaneous injection 30mg/kg, 6-tetrahydropyridine (MPTP) is to increase the response to oxidative stress in the animal brain.After 1 hour, the sodium salicylate of injection 100mg/kg in the mouse peritoneal.Injected back 1 hour, and put to death animal, separate its forebrain, measure wherein 2, and the 3-resorcylic acid (2,3-DHBA) content.
As shown in Figure 3, the result shows: with dosage be respectively 20 and 40mg/kg/ days carboxylic amine triazole treat, can reduce the forebrain oxidative stress that produces by MPTP significantly, thereby suppress neurotoxin neuronic damage.Carry out toxicologic study in addition, do not detected the evidence of drug side effect.
Embodiment 3: carboxyamido-triazoles suppresses the inductive oxidative stress of MPTP like thing
Male C57BL/6 mice, body weight 18g～22g, is divided into 11 groups by 10/group.Animal every day gives in the table 1 chemical compounds such as A1～A10 by irritating stomach, and in continuous 8 weeks, dosage is 20mg/kg/ days.On the same day of studying, give neurotoxin N-methyl-4-phenyl-1,2,3 of mouse subcutaneous injection 30mg/kg, 6-tetrahydropyridine (MPTP) is to increase the response to oxidative stress in the animal brain.After 1 hour, the sodium salicylate of injection 100mg/kg in the mouse peritoneal.Injected back 1 hour, and put to death animal, separate its forebrain, measure wherein 2, and the 3-resorcylic acid (2,3-DHBA) content.
As shown in Figure 4, the result shows: carboxyamido-triazoles such as A1～A10 all can reduce the forebrain oxidative stress that is produced by MPTP to some extent like thing, thereby suppress neurotoxin to neuronic damage.
Embodiment 4: medicine is to the therapeutical effect of Animal Model of Ulcerative Colitis
Male Wistar rat, body weight 180g～220g, 12/group.Be divided into 9 groups: normal group (normal saline enema), ulcer model group (TNBS coloclysis), solvent control group (TNBS coloclysis+PEG 400), carboxylic amine triazole treatment group (TNBS coloclysis+CAI 20mg/kg), compound A-13 treatment group (the TNBS coloclysis+A320mg/kg), compd A 4 treatment groups (the TNBS coloclysis+A420mg/kg), compd A 7 treatment groups (the TNBS coloclysis+A720mg/kg), compound A-28 treatment group (the TNBS coloclysis+A820mg/kg), positive controls (TNBS coloclysis+SASP 30mg/kg).Every single cage of animal is raised.Wherein, compound A-13, A4, A7, A8 are carboxyamido-triazoles like thing, and structure is referring to table 1.
Experimental technique: 1% pentobarbital anesthetized rat (1mL/200g), with TNBS (2,4, the 6-trinitro-benzene-sulfonic acid) stock solution is dissolved in 50% (v/v) ethanol with 1: 1 ratio, pour into rat apart from colon place, the anus 8cm left and right sides by flexible pipe, every animal pours into 0.3ml, induces experimental colitis.Upwards carry after the coloclysis tail 30s then abdominal part upwards lie low and place (laying bedding and padding) in the little mouse cage.Treat the clear-headed back observation of animal animal situation, perform the operation successfully (bloody fluid appears in no death/anus place) with definite.Postoperative recovered food and drinking water supply in 12 hours.Respectively at preceding 1 hour of operation, and postoperative 1-5 days administration, 1 time/day.From postoperative 24 hours the following index of animal is monitored:
Daily observation:
● food ration
● body weight/body weight increment
● overall condition/mental status/autonomic activities
● the feces character
The result shows that PEG 400 processed group animal ingestion amounts reduce, and body weight obviously alleviates, loose stool, and body constitution is poor, the movable minimizing.Colon disease Neo-Confucianism shows as the body of gland decreased number, the organizational structure disorder, and mucosal bleeding has the ulcer speckle.And carboxylic amine triazole and analog processed group thereof and positive drug processed group animal ingestion quantitative changeization are little, and weight ratio normal group animal is slightly light, and feces is shaped substantially, and the pathological examination colon does not have adhesion, mucosa mild hyperaemia, no ulcer.Appraisal result is referring to Fig. 5～Fig. 7 in detail.
Attached: colon's morphology standards of grading
Attached: animal body condition score standard
Annotate: the scoring of health overall state be adding of two of sign mark and the scorings of feces form and.
Embodiment 5: the prevention or the therapeutic effect of carboxylic amine triazole and the infringement of analog Dichlorodiphenyl Acetate intestinal thereof:
Male Wistar rat, body weight 180g～220g, 10/group.Be divided into 8 groups: normal group (normal saline enema), ulcer model group (acetic acid coloclysis), solvent control group (acetic acid coloclysis+PEG 400), carboxylic amine triazole treatment group (acetic acid coloclysis+CAI 20mg/kg), compound A-13 treatment group (the acetic acid coloclysis+A320mg/kg), compd A 7 treatment groups (the acetic acid coloclysis+A720mg/kg), compd A 10 treatment groups (the acetic acid coloclysis+A1020mg/kg), positive controls (acetic acid coloclysis+SASP 30mg/kg).Every single cage of animal is raised.Wherein, compound A-13, A7, A10 are carboxyamido-triazoles like thing, and structure is referring to table 1.
Experimental technique: chemical compounds such as carboxylic amine triazole and A3, A7, A10 are dissolved in PEG 400 respectively, and the internal rectum injection gives Wistar rat, and dosage is 20mg/kg.After 1 hour, 25% acetum internal rectum injection gives described rat.Acetic acid stimulated after 2 hours, got the rat intestine sample, with the naked eye and microscopic examination field inner wall surface histopathology change, intestinal mucosal injury is carried out naked eyes and Histological evaluation.
Found that, observe the extensive intestinal mucosal injury that acetic acid causes, and, almost do not observe the intestinal infringement through the rat of carboxylic amine triazole and analogue treatment thereof in ulcer model group and solvent control group rat.The intestinal mucosal injury evaluation criterion is with reference to Classification and Evaluation of Macpherson, B.R.et al, and Digestion, 17,135-15 (1978), it is as shown in table 2 to mark.And table 2 has shown the protective effect of carboxylic amine triazole and the infringement of analog Dichlorodiphenyl Acetate intestinal thereof.
Table 2: the treatment scoring of acetic acid intestinal infringement
Annotate: the calculating of gained scoring is according to the meansigma methods ± standard error of following standards of grading to every item rating (0-3 branch) summation of animal intestine sample in the table 2.
The standards of grading of naked eyes visible damage degree:
The standards of grading of histology's extent of damage:
Claims (11)
1. carboxylic amine triazole or the pharmaceutically useful salt of carboxylic amine triazole prevent and/or treat neurodegenerative diseases in preparation, prevent and/or treat the purposes in the medicine of amyotrophic lateral sclerosis and/or inflammatory bowel disease, and wherein said carboxylic amine triazole has the chemical compound of formula (I) structure:
Formula (I)
Wherein, R1 has formula (II) structure:
Formula (II)
In the formula (II), p is 0 to 2 integer; M is 0 to 4 integer; N is 0 to 5 integer; X can be O, S, SO, SO
2, CO, CHCN, CH
2Or C=NR
6, R wherein
6Be selected from hydrogen, the alkyl group of C1-C6, hydroxyl, the chain alkoxy of C1-C6, amino, the chain alkylamino of C1-C6, dialkylamino or cyano group;
R
4And R
5Be selected from halogen respectively, cyano group, trifluoromethyl, the C1-C6 alkanoyl, nitro, C1-C6 alkyl group, the C1-C6 chain alkoxy, carbonyl, carbalkoxy, trifluoromethoxy, acetylamino, C1-C6 chain alkylthio group, C1-C6 alkyl group sulfonyl, trichloro-vinyl, trifluoromethylthio, trifluoromethyl sulphinyl base, perhaps trifluoromethyl sulfonyl;
R
2Be selected from amino, C1-C6 chain alkylamino, dialkylamino, acetylamino, acetimide, urea groups acyl group, formamido group, formyl imines or guanidine radicals;
R
3Be selected from amine formyl, cyano group, carbamoyl, imido grpup or N-hydroxyl carbamyl.
2. purposes according to claim 1 is characterized in that described carboxylic amine triazole is that middle n of formula (II) and m are respectively 0,1 or 2; P equals 1; X is O, S, CO or CH
2R
4Be selected from fluorine, chlorine, bromine, methyl, trifluoromethyl, cyano group, methoxycarbonyl group, trifluoromethoxy, trifluoromethylthio, nitro or trichloro-vinyl; R
5Be chlorine, bromine, fluorine, methyl, trifluoromethyl, cyano group, carbalkoxy, trifluoro vinyl or nitro.
3. purposes according to claim 1 is characterized in that described carboxylic amine triazole has as shown in the formula (III):
Wherein, X is CH
2, S, O or CO; R
4Be Cl, CF
3, Br or CH
3R
5Be Cl, Br or NO
2
4. purposes according to claim 1 is characterized in that described carboxylic amine triazole is 5-amido-1-[3,5-two chloro-4 (4-chlorobenzoyl chloride) benzyl]-1H-1,2,3-triazole-4-Benzoylamide.
5. according to any one described purposes of claim 1 to 4, it is characterized in that described carboxylic amine triazole comprises its analog or derivant.
6. purposes according to claim 1 is characterized in that the pharmaceutically useful salt of described carboxylic amine triazole comprises hydrochlorate, sulfate, the acetate of carboxylic amine triazole.
7. purposes according to claim 1 is characterized in that described medicine is a pharmaceutical composition, and it comprises the carboxylic amine triazole and the pharmaceutically acceptable carrier of medicine effective dose.
8. according to any one described purposes of claim 1 to 4, it is characterized in that described inflammatory bowel disease comprises ulcerative colitis, Behcet disease and clone disease.
9. according to any one described purposes of claim 5, it is characterized in that described inflammatory bowel disease comprises ulcerative colitis and clone disease.
10. according to any one described purposes of claim 1 to 4, it is characterized in that described neurodegenerative diseases comprises the constitutional neurodegenerative disease; Hungtington's chorea; Apoplexy and other anoxia or ischemic disease; Secondary cases neurodegenerative disease (metabolic or viral disease); Parkinson's disease; The alzheimer ' dementia, multi-infarct dementia, thunder dimension corpusculum dementia, neural degeneration dementia.
A 11. medicated bag or test kit that is used to prevent and/or treat neurodegenerative diseases, prevents and/or treats amyotrophic lateral sclerosis and/or inflammatory bowel disease, wherein comprise carboxylic amine triazole or the pharmaceutically useful salt of carboxylic amine triazole in one or more purposes as claimed in claim 1, comprise the container and the operation instructions of described carboxylic amine triazole or the pharmaceutically useful salt of carboxylic amine triazole.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010142167A1 (en) * | 2009-06-10 | 2010-12-16 | 中国医学科学院基础医学研究所 | New use of carboxyamidotriazole compounds or salts thereof in the preparation of the medicaments for preventing and treating interstitial pneumonia or pulmonary fibrosis |
| CN111253327A (en) * | 2018-12-03 | 2020-06-09 | 中国医学科学院基础医学研究所 | Application of carboxyamidotriazole compound or salt thereof in preparation of medicines for treating NLRP3 inflammatory-body-activation-related diseases |
| CN111249277A (en) * | 2018-12-03 | 2020-06-09 | 中国医学科学院基础医学研究所 | Application of carboxyamidotriazole compound in preparing medicine for treating or preventing autoinflammatory diseases |
| CN113582935A (en) * | 2021-08-27 | 2021-11-02 | 中国医学科学院放射医学研究所 | Inflammatory corpuscle nucleotide-binding oligomerization domain-like receptor protein 3 inhibitor and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101164538B (en) * | 2006-10-16 | 2011-12-14 | 中国医学科学院基础医学研究所 | Application of carboxyamido-triazoles compound and its salt in preparing medicine for treating painful diseases and/or inflammatory diseases |
-
2008
- 2008-06-30 CN CN 200810115851 patent/CN101618036B/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010142167A1 (en) * | 2009-06-10 | 2010-12-16 | 中国医学科学院基础医学研究所 | New use of carboxyamidotriazole compounds or salts thereof in the preparation of the medicaments for preventing and treating interstitial pneumonia or pulmonary fibrosis |
| CN111253327A (en) * | 2018-12-03 | 2020-06-09 | 中国医学科学院基础医学研究所 | Application of carboxyamidotriazole compound or salt thereof in preparation of medicines for treating NLRP3 inflammatory-body-activation-related diseases |
| CN111249277A (en) * | 2018-12-03 | 2020-06-09 | 中国医学科学院基础医学研究所 | Application of carboxyamidotriazole compound in preparing medicine for treating or preventing autoinflammatory diseases |
| CN113582935A (en) * | 2021-08-27 | 2021-11-02 | 中国医学科学院放射医学研究所 | Inflammatory corpuscle nucleotide-binding oligomerization domain-like receptor protein 3 inhibitor and preparation method and application thereof |
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| CN101618036B (en) | 2012-12-05 |
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