CN1279612A - Modulation of immune responses - Google Patents
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- CN1279612A CN1279612A CN98810397A CN98810397A CN1279612A CN 1279612 A CN1279612 A CN 1279612A CN 98810397 A CN98810397 A CN 98810397A CN 98810397 A CN98810397 A CN 98810397A CN 1279612 A CN1279612 A CN 1279612A
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Abstract
A method of affecting or modulating for stimulation or suppression of the immune cell product pursuant to an immune response to an external or endogenous immune stimulant in an animal comprising the steps of administering to such animal a non-toxic immune modulating effective quantity of a compound selected from the group consisting of compounds of the general chemical formula (I) R1-CO-NR2R3 wherein R1 is selected from the group consisting of H and lower (i.e. C1 to C3) alkyl and C2 to C3 alkenyl groups; R2 and R3 are the same or different and each is selected from the group consisting of H, lower (i.e. C1 to C3) alkyl and C2 to C3 alkenyl groups which may optionally be halogenated or hydroxylated, or which may in combination with one another from a -(CH2)n- group wherein n is any number from 2 to 5, or the group -(CH2)2-O-(CH2)2 and metabolites and prodrugs thereof. The method is useful in the treatment of a variety of ailments associated with inappropriate immune responses and the invention provides for the use of compounds of Formula (I) in the manufacture of medicaments for use in the treatment of such ailments and for pharmaceutical preparations containing same.
Description
The present invention relates to treatment of diseases relevant in the human body with unsuitable immunne response.More particularly, the present invention relates to wherein unsuitable immunne response and the relevant treatment of diseases of unsuitable immunocyte metabolic activity, unsuitable immunocyte metabolic activity is mediated again, perhaps be considered at least with the tyrosine kinase cascade (wherein, protein tyrosine kinase (claiming that hereinafter it is " PTK ") plays an important role) relevant, perhaps with to depend on the kinases (claiming that hereinafter it is " CDK ") of cyclin relevant in the immunocyte.Therefore, the invention provides multiple treatment of diseases relevant and the medicament that is used for this treatment with unsuitable immunne response in the animal body (this term of this paper is intended to comprise human body).
People know, and immunocyte plays an important role in the immune system of animal body.Identified multiple such cell.In these cells, people generally acknowledge T lymphocyte (being also referred to as the T cell) and the important function of bone-marrow-derived lymphocyte (being also referred to as the B cell) in the immunne response that animal body infects external source.In addition, other cell that can produce amboceptor,immune also has immunologic function.This class cell to extraneous stimulus (for example viral infection of animal body or bacterial infection) or to endogenous immunologic stimulant (for example carcinogenecity conversion) normal or suitable reply the activation that can cause described cellular metabolism approach; cause producing amboceptor,immune (comprising cytokine, lymphokine, chemotactic factor, somatomedin and cytotoxic cell), and also cause the propagation of this para-immunity cell usually.Amboceptor,immune is fulfiled again or additional inhibit feature, the toxin that promptly suppresses infectious agent or discharged by it, a part that infects antagonistic process or rehabilitation course as body's natural.These approach relate to complicated biochemical system and signaling system (hereinafter will further relate to them).
Also know (not understanding fully its reason at present fully), immune replying is unusual sometimes and causes that the immunocyte that is considered to unsuitable product is expressed and secretion.Though this unusually may be relevant with the abnormality proliferation of this class cell, situation is not necessarily like this.This immunologic cellular activity unusually may be only by the secretion performance of the immunocyte product of undue amounts, not necessarily the increase with the proliferation activity of this class cell is relevant.
Unsuitable immunne response and the multiple disease association that influences human body and animal body.The present invention relates to this class treatment of diseases (hereinafter will illustrate).In described disease, the performance of unsuitable immunne response (comprise exist cytotoxic cell and/or undue amounts, specific infection or the required immunocyte product of disease of antagonism), cause anything may be considered to the attack of immune system to self health certain organs, perhaps even to the nonspecific immunity of whole health attack, rather than should attack by directed outwards suitably or endogenous antigen or medium or metabolite (for example consequent toxin).The target organ of this inappropriate attack has multiple and can find out from the disease of hereinafter enumerating and comprises skin, muscle, skeletal structure, joint, blood, brain and nervous system, the internal comprises intestinal, kidney, lung, liver, and even sensory organ (comprising eyes).
In some diseases that the present invention relates to or syndrome, identified the elementary or initial pathogen or the stimulus object of immunne response.But, this class disease or syndromic one are characterised in that, after even described pathogen or stimulus object (for example viral infection or infected by microbes or antigenic other form) have been eliminated by the self-defense mechanism of health (being immune system), after perhaps eliminating by means of medicine or by the two combination, immunne response may exist.In other cases, do not know or do not know at least as yet the pathogen that is identified.All these diseases all are considered to immune-mediated disease.
In order to be expressly understood character of the present invention and impact effect, be necessary to explain simply present understanding to the active character of immunne response in the body.Immunocyte (especially T lymphocyte) depends on signal transduction by TXi Baoshouti (it is that the T lymphocyte is exclusive and only be present in the T lymphocytic cell surface) with regard to their biological function.Described TXi Baoshouti is one group of complicated surface molecular, and it comprises CD
4Or CD
8Surface molecular.CD
4, CD
8Other surface molecular can send a signal to the interior environment (promptly being sent to the Cytoplasm of cell) of cell from the outer surface of this cell membrane with some.These signals are to send by the enzymatic pathway that is called as the tyrosine kinase cascade.Activatory tyrosine kinase makes some protein phosphorylation, causes the generation of new signal intermediate.In this cascade, the enzyme that is called as protein tyrosine kinase [PTK] plays an important role.This enzyme be a kind of be the protein of feature with the free sulfhydryl groups.The tyrosine kinase cascade ends at the expression of specific gene in the T cell at last.These genes encode respectively various amboceptor,immunes (comprising cytokine) and the required structural protein of cell proliferation.The disease of the immunne response mediation that the present invention relates to as previously mentioned, is relevant by the nothing control expression and the uncontrolled cytotoxic cell activity of immunocyte with amboceptor,immune.
Dimethyl formamide or DMF at room temperature are a kind of volatile nonionic liquid, and people know its application as industrial solvent.It especially is used to comprise the production process of pharmaceutical preparation in the production process for the various products of human consumption.Its toxicity was fully studied.Known it under high a lot of content doubly, be nontoxic than content involved in the present invention.This toxicity that DMF has under the high concentration value in human body is because it makes hepatocyte glutathion inside exhaustion in the liver, causes hepatic necrosis.
Cryopreservation Technologies CC claims that dimethyl formamide and allied compound can be used to the treatment of viral infection and/or infected by microbes in the PCT application PCT/US96/19697 that announced with WO97/22248 on June 26th, 1997.This announcement listed examples shows, can percutaneous use DMF to the patient and make DMF concentration in the blood reach the desired value of 100ppm, but according to reports, the actual value that reaches is different from this desired value in the HIV positive patient.It has further been reported, and after this treatment of using DMF was less than three weeks, the virus that the patient carries dropped to 500/ml from 120000/ml.It has also been reported, and makes DMF content in the blood reach the improvement of acne and rubella symptom among the patient of 50～100ppm with DMF treatment.The disclosure relates to the application of DMF as antiviral agent and antimicrobial, and, and keep silent in the application facet that production is used for the treatment of the medicament of this class disease at application or this compounds aspect the relevant disease of treatment immunocyte for this compounds for the immune response regulation property retention silence of the chemical compound that the present invention relates to.
An object of the present invention is to provide the method for a kind of modulation intravital immunne response of animal or human and the treatment disease relevant with unsuitable immunne response in animal (the comprising the people) body.
Now be surprised to find that, with about the prior art knowledge of the toxicity of DMF and antiviral and antibacterium performance different be, such product can be used for modulating immunologic responsiveness metabolic process in the cell with immunologic function with inferior toxicity dosage (sub-toxic dosage), promptly stimulates or suppresses and do not destroy this cell again by this class cellular expression or secretory immune amboceptor by health being used the such process of DMF influence.
So, the invention provides a kind of method that influences the immunne response of animal, this method comprises the steps: to use chemical compound nontoxic, immunity modulation effective dose to such animal, and this chemical compound is selected from the chemical compound of chemical general formula (I)
R
1-CO-NR
2R
3(I) wherein,
R
1Be selected from H and rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl;
R
2And R
3Identical or different, and be selected from separately H, rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl, they are chosen wantonly can be by halogenation or hydroxylating, and perhaps they can be interconnected to constitute-(CH
2)
n-Ji (wherein, n is any number of 2～5) or-(CH
2)
2-O-(CH
2)
2Base, and metabolite and prodrug.
Immunne response by the said method influence may be the immunne response that constitutes the immunocyte of the immune part of health.
Described immunocyte may be T lymphocyte and/or bone-marrow-derived lymphocyte.
Can carry out this method and reduce the expression or the secretion of immunocyte product in the body.
The present invention provides the method for the animal (this disease is relevant with unsuitable immunne response in this animal) that a kind of treatment suffers from disease on the other hand, this method comprises the steps: to use chemical compound nontoxic, the treatment effective dose to such animal, and this chemical compound is selected from the chemical compound of chemical general formula (I)
R
1-CO-NR
2R
3(I) wherein,
R
1Be selected from H and rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl;
R
2And R
3Identical or different, and be selected from separately H, rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl, they are chosen wantonly can be by halogenation or hydroxylating, and perhaps they can be interconnected to constitute-(CH
2)
n-Ji (wherein, n is any number of 2～5) or-(CH
2)
2-O-(CH
2)
2Base, and metabolite and prodrug.
Another aspect of the invention relates to the application of chemical compound aspect preparation is used for the treatment of medicament in the method for the animal (described disease is relevant with unsuitable immunne response in this animal) that suffers from disease, and described chemical compound is selected from the chemical compound of chemical general formula (I)
R
1-CO-NR
2R
3(I) wherein,
R
1Be selected from H and rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl;
R
2And R
3Identical or different, and be selected from separately H, rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl, they are chosen wantonly can be by halogenation or hydroxylating, and perhaps they can be interconnected to constitute-(CH
2)
n-Ji (wherein, n is any number of 2～5) or-(CH
2)
2-O-(CH
2)
2Base, and metabolite and prodrug.
The invention still further relates to a kind of pharmaceutical composition that is pharmaceutically acceptable dosage form, is used for the treatment of the animal (described disease is relevant with unsuitable immunne response in this animal) that suffers from disease, said composition comprises a kind of chemical compound, and this chemical compound is selected from the chemical compound of chemical general formula (I)
R
1-CO-NR
2R
3(I) wherein,
R
1Be selected from H and rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl;
R
2And R
3Identical or different, and be selected from separately H, rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl, they are chosen wantonly can be by halogenation or hydroxylating, and perhaps they can be interconnected to constitute-(CH
2)
n-Ji (wherein, n is any number of 2～5) or-(CH
2)
2-O-(CH
2)
2Base, and metabolite and prodrug.
In of the present invention and the relevant each side for the treatment of, disease to be treated may be following any: the acute Transversmielitis head of systemic loupus erythematosus [SLE] chorionitis [Sjogren's syndrome disease] vasculitic syndrome [comprising Wa Genashi thrombosis and various forms of giant cell arthritis] the systemic inflammatory reaction syndrome of dermatomyositis (dermatomiositis) asthma adult respiratory distress syndrome (ARDS) [ARDS] [SIRS] inflammatory bowel disease chronic hepatitis rheumatoid arthritis rheumatic fever myasthenia gravis multiple sclerosis psoriasis eczema Huppert's disease reiter syndrome glomerulonephritis polymyalgia rheumatism ankylosing spondylitis PAN allergic rhinitis diabetes ophthalmoneuritis damages the vasopasm after the spinal cord injury subarachnoid hemorrhage.
In aforementioned each side of the present invention, selected chemical compound is dimethyl formamide and metabolite thereof, be N-methylformamide, N-methyl-isocyanide (N-methyl-isocyanite) and carbamate thereof, and any prodrug of N-acetyl-S-(N-methyl carbamyl) cysteine and this metabolite.
In addition, by the present invention, be the described method of implementing like this: use a certain amount of DMF for patient to be treated, it is 0.001%～0.1% that this consumption is enough to keep plasma D MF content, most preferably is 0.01%～0.05%.Equally, thus medicament of the present invention is applicable to that using with speed like this that a certain amount of DMF reaches and keep plasma D MF content to the patient is 0.001%～0.1%, most preferably is 0.01%～0.05%.
Also have, in each side of the present invention, can use described chemical compound, for example per os, per nasal, per rectum, intravenous, intramuscular, subcutaneous or percutaneous by any drug delivery route.The optimization approach of administered compound is an applied dermally.But, preferably use by transdermal patch (transdermal patch).
Will find out that from embodiment hereinafter mixed lymphocytes is exposed in per 200 μ l1～lymphocytic nonspecific stimulation thing of 10 μ g (for example PHA).When these lymphocytes also are exposed to the DMF of low concentration very simultaneously, experiment confirm the minimizing of metabolic activity because in fact these cells not too can reduce [United States Patent (USP) NO.5,501, the 959] oxidation-reduction indicator that patents.The inhibition of this metabolic activity is not because direct Cytotoxic result produces the concentration that the treatment concentration that suppresses is lower than the activation (thereby causing propagation) that causes cellular metabolism because fact proved to metabolic activity (thereby to propagation).
Need synthetic immunologically competent cell to contact by making, might reduce the metabolic activity of cell with immunologic function with DMF or its any metabolite of treatment concentration.By reducing the lymphocytic metabolic activity of T, will these T lymphocytes of severe inhibition to some T lymphocyte specific antigen and antigen, the responsiveness of major histocompatibility complex molecular combination.The antigenic specificity that is exactly the T lymphocyte responses suppresses to have constituted the clinical practice basis that the DMF that is proposed by the present invention modulates the disease of immunocyte mediation.
As for giving the patient's applied dermally DMF that needs treatment by the present invention, suggestion is used to send and is passed the various medicines multi-functional transdermal delivery system of (comprising DMF and above-mentioned relevant treatment chemical compound).
Think that important patch design parameter comprises following: 1. this paster must have predetermined size, because the activity group that its decision absorbs at certain hour
The amount of dividing [medicine].2. administration must not rely on the time.3. drug level should become according to patient profile (patient profile).4. this paster must be stable, but and send the medicament [medicine that is applied to of passing repetitive therapy concentration
Thing].5. the rhythm and pace of moving things (tempo) of administration [medicament] determined by skin, thus medicine pass film desorbing should with
The absorption rhythm and pace of moving things of skin is identical or very approaching.6. this paster and medicine must have long storage period.
In order to reach above-mentioned requirements, designed a kind of paster: 1. high density nylon back lining materials with following properties.2. by PATFE[Teflon] the secure border that constitutes of nylon.3. low-density septa NYLON or PTFE.4. hydrophilic or hydrophobicity NYLON or PTFE film [depending on the medicine that is applied to].5. membrane aperture is 0.05～0.45 micron, and it depends on the medicine that is applied to.6. kieselguhr [SiO
2] adsorbing material.7. stabilizing agent [salt forming agent, the uniform distribution of weight that reduces evaporation and pass film].8. suitable skin binding agent (it not with drug responses).Counter-stimulus-vitamin E [this counter-stimulus can the application of protection skin and anti-side effect it
Before, use during or use after use].
More particularly, a kind of paster is made of following ingredients: 1. back lining materials and septa
2.Teflon film
3.Teflon Boundary Loop
| Explanation | Circular translucent nylon6 chips, 0.1～0.4mm is thick |
| Diameter | ?????????????20-100mm |
| Average quality | ????????????100mg-600mg |
| The Septa explanation | Circular soft polypropylene/polyethylene has nylon or PTFE backing |
| The Septa diameter | ??????????????5-25mm |
| Septa thickness | ?????????????0．2-1mm |
| Explanation | Circular white films |
| Diameter | ?????20-100mm |
| Average quality | ?????50-500mg |
| The aperture | 0.2-0.8 micron |
| Explanation | Circular translucent 0.1～0.4mm is thick |
| Internal diameter | ???????????10-90mm |
| External diameter | ???????????20-100mm |
| Average quality | ???????????20-200mg |
| Explanation | Silicon dioxide [kieselguhr] |
| Quality/sheet | ?????????1-10g |
| The stabilizing agent explanation | Sodium chloride and magnesium carbonate/calcium |
Indirectly drug administration (for example DMF) can carry out like this: after being attached to paster on the skin, with syringe the activating agent of known quantity is injected described silicon dioxide adsorbent.
Obtain following advantage by using this method: 1. the controlled dispenser on from ampoule/container to paster.2. can be by patient profile's predetermined treatment agent dose.3. by described medicament is become concentration dependent, treatment time and skin are sudden and violent in therapeutic process
The area that reveals just keeps constant.4. can use paster and medicament and can be to patient's overdose confidently.5. paster and medicament are all used easily, and the patient can leave hospital after dispenser.6. paster is very stable, has unlimited storage period, and, unless otherwise prescribed, execute from ampoule
With medicament have the expiration date at least two years.
Set forth the present invention now with reference to following embodiment, but be not whereby scope of the present invention to be defined in this illustrative embodiment.
By use described well in the immune Research document and known density gradient separation from healthy volunteer's separation of whole blood human peripheral lymphocyte.Briefly, by this method, with phosphate buffered saline (PBS) or cell culture medium (for example RPMI1640) dilution in 1: 2 periphery whole blood.Then, and density gradient (for example Histopaque 1077[Sigma Cat#1077]) just layering below the peripheral blood after the dilution, must carefully make it to form tangible interface.Centrifugal this density gradient 20～25 minutes under 600g then.See easily after centrifugal that one deck contains most of lymphocytic limpid dark yellow top layer.Again this layer is separated and further handles, be about to this dark yellow top layer and place another test tube, with PBS or cell culture medium with cell washing 3 times.Behind each washing step all under 400g with cell centrifugation 9 minutes.After the washing, collect lymphocyte for the third time from granular precipitation.Count this cell and be diluted to required cell concentration.
Use complete cell culture medium and prepare all DMF concentration as diluent.Prepared following concentration: 1%, 0.1%, 0.05%, 0.01% and 0.001%.
Use complete cell culture medium isolating lymphocyte is diluted to desired concentration.
The complete cell culture medium of using in above-mentioned steps contains RPMI1640 (containing HEPES) 20～25mM, L-glutaminate 1mM, 3-mercaptoethanol 2X10
-5MM and 10% heat-inactivated hyclone.
The lymphocyte of preparation is placed 96 porocyte culture plates with the concentration of 150,000 cells in every hole.Adding concentration toward each test hole is the PHA[phytohemagglutinin of 1～10 μ g/200 μ l].Simultaneously, toward the DMF of each test hole interpolation predetermined concentration, under 37 ℃, at 5%CO
2, 95%O
2In the atmosphere described culture hole is incubated 1～4 day.
With 10% volume: volume adds the oxidation-reduction indicator of selling with trade mark " AlamarBlue " toward each culture hole.Culture is incubated 18 hours with AlamarBlue, is the absorbance that reference is measured the 570nm place then with 630nm.
The result can be summarized as follows:
Culture (wherein, the periphery lymphocyte that derives from the healthy volunteer be exposed to PHA and concentration be that the DMF of % reaches 24 hours) reduced be in that AlamarBlue that culture reduces in the normal PHA growth hole measures 102%.But, added that culture that concentration has only 0.05% DMF only reduced that the AlamarBlue that lymphocytic culture reduces that contains PHA and stimulate measures 52%.This has shown the remarkable inhibition of metabolic activity in the culture hole, and the level of cell proliferation is closely related in it and this particular bore.
When the indicated metabolic activity of the lymphocyte that does not more stimulate and the lymphocyte that does not the stimulate reduction AlamarBlue that is exposed to low concentration DMF, observe the reductive AlamarBlue of the lymphocyte that is exposed to 0.05%DMF concentration and reduced 40%.[see Fig. 1 and 2, this two width of cloth figure has represented the representative result of some repeated experiments].
In order to illustrate DMF, carried out the experiment of another series at the mechanism of action that causes supposition aspect the inhibition of lymphocyte metabolic activity.In these experiments, the method for describing in the Application Example 1 has been separated healthy volunteer's lymphocyte.After having separated lymphocyte, the DMF that this lymphocyte is exposed to variable concentrations reaches the temperature retention time of different length.The DMF concentration of using is 0.1%, 0.01% and 0.001%, and temperature retention time is: 5,15,30,75,120 and 180 minutes.Use commercially available tyrosine kinase assay kit (can derive from Boehringer Mannheim[classification number is 1534505]) and measured tyrosine kinase activity.The result is as shown in Fig. 3 and 4.After being exposed to concentration and being 0.01% DMF3 hour, the lymphocytic tyrosine kinase activity that is put to the test has been suppressed 71%.Be to be noted that in the figure the absorbance reading is low more, the degree that tyrosine kinase activity suppresses is just high more.It is identical that the general shape of this figure keeps, and this developing time with chromogenic reaction has nothing to do.This result has supported the hypothesis as basis of the present invention, and promptly lymphocyte contacts with it and reaches certain hour, certain density DMF, plays the retardance tyrosine kinase activity.This probability is arranged, and the reduction of observed tyrosine kinase activity may be owing to stimulate the cause of some tyrosine phosphatase in the lymphocyte that is put to the test.The figure that provides is the representative instance of a lot of figure of acquisition.
Embodiment 3
Further with experiment confirm the PTK of DMF and two kinds of metabolite thereof suppress active, promptly by relatively it and commercially available ptk inhibitor Piceattanol (by Boehringer Mannheim with the #1534505 sale) effect to two kinds of cell lines [being HELA (a kind of cervical cancer cell system) and HEP3B (a kind of hepatoma cell line)].Obtained following result:
Described inhibitor is used with 10%DMSO solution.
Test is carried out under following condition, obtains result as follows: Slank:0,043Funct:Cntrl endogenous phosphatase: 20.3% endogenous phosphorylation: 0.14[0,208]
The active average HELA inhibitor that suppresses: 0,076[0,132] [Pilleattanol+10%DMSO] 66% 75% 29,5% cleaning cell 0,115[0,176] 100% 0%2% metabolite I 0,099[0,167] 86% 95% 9,5%0,2% thanks to thing II 0,074[0,140] 64% 80% 28,5%2% metabolite II 0,055[0,091] 48% 55% 48,5%0,2%DMF 0,073[0,146] 63% 83% 27%2%DMF 0,042[0,082] 37% 47% 58%HEP3B inhibitor: 0,055[0,111] 60% 60% 40%[Pilleattanol+10%DMSO] 66% 75% 29,5% cleaning cell 0,091[0,186] 100% 0%2% metabolite I 0,090[0,150] 99% 81% 10%0,2% metabolite II 0,036[0,060] 40% 32% 64%2% metabolite II 0,095[0,095] 60% 51% 44,5%0,2%DMF 0,080[0,123] 88% 66% 33,3%2%DMF 0,040[0,064] 44% 34% 6,1%I,C50 1,7-17 μ M is determined IC50 1, and 7-17 μ M is determined symbol metabolite I-N-methylformamide metabolite II-N-methyl-isocyanide DMF-dimethyl formamide
Claims (12)
1. method that influences immunne response in the animal, this method comprise the steps: to use chemical compound nontoxic, immunity modulation effective dose to this class animal, and this chemical compound is selected from the chemical compound of chemical general formula (I)
R
1-CO-NR
2R
3(I) wherein,
R
1Be selected from H and rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl;
R
2And R
3Identical or different, and be selected from separately H, rudimentary [be C
1～C
3] alkyl and C
2-C
3Alkenyl, they are chosen wantonly can be by halogenation or hydroxylating, and perhaps they can be interconnected to constitute-(CH
2)
n-Ji, wherein n is any number of 2～5, or-(CH
2)
2-O-(CH
2)
2Base, and metabolite and prodrug.
2. the process of claim 1 wherein that the immunne response that is subjected to this method affect is the immunne response that constitutes the immunocyte of the immune part of health.
3. the method for claim 2, wherein, described cell is selected from T lymphocyte and bone-marrow-derived lymphocyte.
4. the method for claim 1 is carried out this method and is expression and secretion in order to reduce immunocyte product in the body.
5. a treatment suffers from the method for the animal of disease, this disease is relevant with unsuitable immunne response in this animal, described method comprises the steps: to use the chemical compound of effective dose in nontoxic, the treatment to such animal, and this chemical compound is selected from the chemical compound of chemical general formula (I)
R
1-CO-NR
2R
3(I) wherein,
R
1Be selected from H and rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl;
R
2And R
3Identical or different, and be selected from separately H, rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl, they are chosen wantonly can be by halogenation or hydroxylating, and perhaps they can be interconnected to constitute-(CH
2)
n-Ji, wherein n is any number of 2～5, or-(CH
2)
2-O-(CH
2)
2Base, and metabolite and prodrug.
6. the application of a compounds aspect preparation is used for the treatment of medicament in the method for the animal that suffers from disease, this disease is relevant with unsuitable immunne response in this animal, and described chemical compound is selected from the chemical compound of chemical general formula (I)
R
1-CO-NR
2R
3(I) wherein,
R
1Be selected from H and rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl;
R
2And R
3Identical or different, and be selected from separately H, rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl, they are chosen wantonly can be by halogenation or hydroxylating, and perhaps they can be interconnected to constitute-(CH
2)
n-Ji, wherein n is any number of 2～5, or-(CH
2)
2-O-(CH
2)
2Base, and metabolite and prodrug.
7. pharmaceutical composition that is used for the treatment of the animal that suffers from disease, this disease is relevant with unsuitable immunne response in this animal, and described compositions comprises a kind of chemical compound, and this chemical compound is selected from the chemical compound of chemical general formula (I)
R
1-CO-NR
2R
3(I) wherein,
R
1Be selected from H and rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl;
R
2And R
3Identical or different, and be selected from separately H, rudimentary [be C
1～C
3] alkyl and C
2～C
3Alkenyl, they are chosen wantonly can be by halogenation or hydroxylating, and perhaps they can be interconnected to constitute-(CH
2)
n-Ji, wherein n is any number of 2～5, or-(CH
2)
2-O-(CH
2)
2Base, and metabolite and prodrug are pharmaceutically acceptable dosage form.
8. the compositions of the application of the method for claim 5, claim 6 or claim 7, wherein, described disease is selected from down group:
Systemic lupus erythematosus (sle) [SLE]
Scleroderma [Sjogren's syndrome disease]
Vasculitic syndrome [comprising Wa Genashi thrombosis and various forms of giant cell arthritis]
Dermatomyositis
Asthma
Adult respiratory distress syndrome [ARDS]
Systemic inflammatory responses syndrome [SIRS]
Inflammatory bowel
Chronic hepatitis
Rheumatoid arthritis
Rheumatic fever
Myasthenia gravis
Multiple sclerosis
Psoriasis
Eczema
Multiple myeloma
Reiter syndrome
Glomerulonephritis
The polymyalgia rheumatism
Ankylosing spondylitis
Polyarteritis nodosa
Allergic rhinitis
Diabetes
Ophthalmoneuritis
Acute Transversmielitis
The head damage
Spinal cord injury
Vasospasm behind the subarachnoid hemorrhage.
9. each method, application or compositions of claim 1～8, wherein, described chemical compound is a dimethyl formamide.
10. the method for claim 9 wherein, gives patient to be treated with certain speed and a certain amount of dimethyl formamide of using, and it is 0.001%～0.1% that described amount and speed are enough to keep plasma D MF content.
11. the method for the method of claim 9, application or compositions or claim 10, wherein, described medicament is by percutaneous dosing or suitable percutaneous dosing.
12. the method for claim 11, application or compositions, wherein, DMF uses by means of transdermal patch roughly as described herein or is fit to and uses like this.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA97/8319 | 1997-09-16 | ||
| ZA978319 | 1997-09-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1279612A true CN1279612A (en) | 2001-01-10 |
Family
ID=25586589
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98810397A Pending CN1279612A (en) | 1997-09-16 | 1998-09-16 | Modulation of immune responses |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1019063A4 (en) |
| JP (1) | JP2001516721A (en) |
| CN (1) | CN1279612A (en) |
| AU (1) | AU737867B2 (en) |
| BR (1) | BR9812321A (en) |
| CA (1) | CA2304119A1 (en) |
| IL (1) | IL135091A0 (en) |
| NO (1) | NO20001341L (en) |
| NZ (1) | NZ503418A (en) |
| WO (1) | WO1999013885A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2324631A1 (en) * | 2000-10-26 | 2002-04-26 | Virodene Pharmaceutical Holdings (Proprietary) Limited | A substance or composition for the treatment of cancer |
| WO2005053641A1 (en) * | 2003-12-05 | 2005-06-16 | Namibia Medical Investments (Pty) Limited | Patch |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5814659A (en) * | 1996-04-23 | 1998-09-29 | Dtr Dermal Therapy (Barbados) Inc. | Topical analgesic composition |
-
1998
- 1998-09-16 CA CA002304119A patent/CA2304119A1/en not_active Abandoned
- 1998-09-16 WO PCT/US1998/019126 patent/WO1999013885A1/en not_active Application Discontinuation
- 1998-09-16 AU AU93890/98A patent/AU737867B2/en not_active Ceased
- 1998-09-16 NZ NZ503418A patent/NZ503418A/en not_active IP Right Cessation
- 1998-09-16 JP JP2000511505A patent/JP2001516721A/en active Pending
- 1998-09-16 CN CN98810397A patent/CN1279612A/en active Pending
- 1998-09-16 BR BR9812321-1A patent/BR9812321A/en not_active IP Right Cessation
- 1998-09-16 EP EP98946998A patent/EP1019063A4/en not_active Withdrawn
- 1998-09-16 IL IL13509198A patent/IL135091A0/en unknown
-
2000
- 2000-03-15 NO NO20001341A patent/NO20001341L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999013885A1 (en) | 1999-03-25 |
| NZ503418A (en) | 2001-02-23 |
| JP2001516721A (en) | 2001-10-02 |
| EP1019063A1 (en) | 2000-07-19 |
| AU737867B2 (en) | 2001-09-06 |
| IL135091A0 (en) | 2001-05-20 |
| EP1019063A4 (en) | 2003-09-03 |
| NO20001341D0 (en) | 2000-03-15 |
| NO20001341L (en) | 2000-05-16 |
| CA2304119A1 (en) | 1999-03-25 |
| AU9389098A (en) | 1999-04-05 |
| BR9812321A (en) | 2000-09-05 |
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