CN101137366A - Compounds for treating autoimmune and demyelinating diseases - Google Patents

Abstract

A method of treating a patient suffering from an inflammatory and/or demyelinating disorders, comprising administering to said patient a therapeutically effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof. R1 :N R (A). Definitions for the variables are provided therein.

Description

The chemical compound of treatment inflammatory and demyelination

Related application

The application requires the priority of U.S. Provisional Patent Application of submitting on January 28th, 2,005 60/647,980 and the U.S. Provisional Patent Application of submitting on January 9th, 2,006 60/757,736.Incorporate whole instructions of above-mentioned application into this paper by reference.

Background of invention

Autoimmune disease, for example, multiple sclerosis (MS), systemic lupus erythematosus (sle) (SLE), rheumatoid arthritis (RA), inflammatory bowel (IBD) and psoriasis have showed the immune attack of health, it can be a general in nature, also can be the indivedual organs at health.In the disease that they showed, immune system makes a mistake, and is not the mediate protection function, but becomes the assailant.

Multiple sclerosis (MS) is a kind of inflammatory, nervous system disease of the people's of making weakness, is characterised in that central nervous system's demyelination.In West Europe and North America, MS be in the Young Adults modal day after tomorrow sacred disease, the sickness rate in the women is higher.Aspect revenue losses and medical treatment and nursing, it has caused more anergy and economic loss than other any sacred disease of this age group.In the U.S.'s nearly 250,000 routine MS cases.The symptom of this disease comprises fatigue, numbness, trembles, tingling, insensitive, visual disorder, dizziness, cognitive impairment, urinary system obstacle, mobility reduces and depressed.The clinical module of this disease is divided into four types: recurrence-remission form, secondary progress type, former progress type and progress-recurrence type (S.L.Hauser and D.E.Goodkin, Multiple sclerosis and Other DemyelinatingDiseases in Harrison ' s Principals of Internal Medicine 14 ^ThEdition, vol.2, Mc Graw-Hill, 1998, pp.2409-2419).

MS influences the central nervous system, comprises the demyelination process, i.e. myelin forfeiture, and aixs cylinder keeps.In the later stage of disease, aixs cylinder also suffers damage.Myelin provides the separate substance that can conduct neural impulse fast.Obviously, this character forfeiture in demyelination.The cause of disease that MS is definite or the unknown; Although also do not understand the mechanism of causing a disease of MS, there are several evidences to show, demyelination has the immunopathology basis, and the demyelination feature of disease may be for example result from immunne response of viral infection initiation of environmental damage.Pathologic lesion, i.e. speckle is characterized in that for example infiltration of macrophage and activating T cell of immunologically activated cell.Especially, infer that MS is by cell-mediated the causing from the immune inflammation reaction of T.The autoimmunity basis obtains the strong support of the following fact: found the specific antibody of myelin basic protein (MBP) in MS patient's serum and cerebrospinal fluid, these antibody and MBP and other myelin protein fat are had active T-cell increase along with the activity of disease.In addition, on cellular level, infer T cell proliferation and other cell incident, for example activation of B cell and macrophage, and the cytokine secretion that is accompanied by blood-brain barrier disruption can cause the damage of myelin and oligodendrocyte.(R.A.Adams, M.V.Victor and A.H.Roppereds, Principals of Neurology, Mc Graw-Hill, New York, 1997, pp.903-921).Carrying out property MS (former and secondary) can be based on the neurodegenerative process that demyelination takes place.

Current, can't cure MS.The target of present therapy is to alleviate the symptom of disease as much as possible and stop its development.According to its type, Drug therapy generally includes uses the amelioration of disease agent, for example for example methylprednisolone and prednisone of interferon (interferon beta 1-a, β 1-b and α), acetic acid glatiramer or corticosteroid.Simultaneously, also can use chemotherapeutant for example mitoxantrone, methotrexate, azathioprine, cladribine, cyclophosphamide, ciclosporin and tysabri.Side effect all takes place in above-mentioned all treatments easily, and to tired and depression does not have or almost not effect, limited to the effect of relapse rate, the limited in one's ability of deterioration wards off disease.Also can induce the generation neutralizing antibody with interferon therapy, it finally can reduce the effectiveness of this treatment.Therefore, still need new medicine consumingly, it can be separately or is co-administered with other drug, with development and the symptom of treatment MS.Although immunotherapy has greatly improved, particularly introduced the anti-alpha 2 integrin blocking antibody that is called as natalizumab (natalizumab) in 2005, not can be used as and generally can accept or extensively effectively treatment but the treatment of new micromolecule also occurs, particularly be used for the Secondary cases PD for a long time.

The progress of disability is multiple sclerosis (MS) patient's a main focus, and the trial of its progress is all disappointing but present great majority slow down.The treatment of the immunomodulator of current approval have only less benefit for carrying out property of Secondary cases MS or be no advantage (Lancet 1998,54,2352; Neurology 2000,54, and 2352; Neurology2001,56,1496; Neurology2002,59,679).Recently find that specific immunity suppresses therapy (monoclonal antibody) and can eradicate deterioration, but make progress without any significant benefits (Neurology 1999,53,751) for it.

General immunity has suppressed to be used to carrying out property MS decades, but its effectiveness is still disputable.Yet, " clinical remarkable benefit " (the treatment group leads reduction by 50% with respect to placebo group TF) of using treatment failure (TF) to define as people such as clinical parameter (confirming that EDSS point increases by 1 point 3 months the time) and Goodkin, find Ciclosporin A (Ann Neurol 1990,27,591), methotrexate (Ann Neurol 1995,37,30) and azathioprine (Neurology1989,39,1018) do not realize clinical remarkable benefit.More effective immunosuppressive therapy provides and has been no more than the of short duration benefit in 1 year.This is in the total lymph radiation (Lancet 1986,8495,1405) of short-term (2 months) and used cyclophosphamide (CY) in every month and continue to observe after (Arch Neurol 1987,44,823) in 2 years.

Therefore, need the acceptable immunomodulating therapy of a kind of like this pharmacy, it can stop neurodegenerative process, comprise by inflammatory cell and attacking and those processes of initiation, have higher clinical efficacy, secular clinical benefit is provided, and do not have pronounced side effects.

The invention summary

The present invention is a kind of treatment inflammation and demyelination, comprises the method for multiple sclerosis.More specifically, the present invention be a kind of by using the imidazoles acridine some inflammation of derivatives for treatment and the method for demyelination.

In one embodiment, the present invention is a kind of method for the treatment of the patient who suffers from inflammation disease, comprises chemical compound or the acceptable salt of its pharmacy to the general formula (A) of described patient's administering therapeutic effective dose.

In another embodiment, the present invention is a kind of method for the treatment of the patient who suffers from the demyelination disease, comprises chemical compound or the acceptable salt of its pharmacy to the general formula (A) of described patient's administering therapeutic effective dose.

In another embodiment, the present invention is a kind of method that promotes the neurocyte Remyelination in the patient of needs, comprises chemical compound or the acceptable salt of its pharmacy to the general formula (A) of described patient's administering therapeutic effective dose.

In another embodiment, the present invention is a kind of compositions, and it comprises the chemical compound or the acceptable salt of its pharmacy of the following general formula (A) for the treatment of effective dose, and antiinflammatory.

In another embodiment, the present invention is a kind of method that reverses the paralysis that is caused by demyelination in the patient, comprise to the patient and use a kind of chemical compound, the amount of application of this chemical compound is enough to suppress the immunocyte in the lymphocytic infiltration spinal cord, to promote the Remyelination of neurocyte in the spinal cord, and the paralysis for the treatment of described patient thus, wherein this chemical compound is the chemical compound or the acceptable salt of its pharmacy of general formula (A).

The imidazoles acridine of Shi Yonging is represented by general formula (A) in the present invention:

Wherein:

R is-H, the optional alkyl that replaces, hydroxyl, alkoxyl, halogen, the group represented by following structural formula:

Or, R and R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them;

Or, R and R ⁴With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them; With

R ²Be-H, choose the C1-C10 alkyl that replaces wantonly or choose aryl or the heteroaryl that replaces wantonly;

R ³Be-(CH ₂) n-NR ^aR ^b, n=1-5 wherein, R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently, or-NR ^aR ^bBe on one or more commutable carbon atom by optional N-morpholinyl or the N-pyrazinyl that replaces of methyl, hydroxyl or methoxyl group, and wherein the N-pyrazinyl be by the C1-C4 alkyl or-NR ^cR ^dThe C1-C4 alkyl that replaces is chosen N '-replacement, wherein R wantonly ^cAnd R ^dBe respectively-H, methyl or ethyl; With

R ⁴, R ⁵And R ⁶Be independently respectively-H ,-OH, halogen or C1-C6 alkoxyl; Or

R ⁵And R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them.

The accompanying drawing summary

Figure 1A is bar figure, and being illustrated in lipopolysaccharide (LPS) stimulates back Symadex ^TMInhibition to the B-cell proliferation.

Figure 1B is bar figure, and being illustrated in concanavalin A (Con A) stimulates back Symadex ^TMInhibition to the T-cell proliferation.

Fig. 2 A is bar figure, and being illustrated in concanavalin A (Con A) stimulates back Symadex ^TMInhibition to IL-4 release.

Fig. 2 B is bar figure, and being illustrated in concanavalin A (Con A) stimulates back Symadex ^TMInhibition to IL-10 release.

Fig. 3 compares with vehicle Control, with 20 and the Symadex of 40mg/kg ^TMAppointed date after the treatment, the bar figure of the average clinical score of the animal of trouble chronic phase experimental autoimmune encephalomyelitis (EAE).

Fig. 4 compares with vehicle Control, is using Symadex ^TMAppointed date after the treatment, the time-dependent figure of the average clinical score of the animal of trouble chronic phase experimental autoimmune encephalomyelitis (EAE) (performance scoring).

Fig. 5 compares with vehicle Control, at the Symadex with 20mg/kg dosage ^TMTreat the appointed date after 4 weeks, suffer from the time-dependent figure of the average clinical score (performance scoring) of the animal of chronic phase experimental autoimmune encephalomyelitis (EAE).

Fig. 6 compares with vehicle Control, at the Symadex with 20mg/kg dosage ^TMTreat the appointed date after 6 weeks, suffer from the time-dependent figure of the average clinical score (performance scoring) of the animal of chronic phase experimental autoimmune encephalomyelitis (EAE).

Fig. 7 compares with vehicle Control, at the Symadex with 20mg/kg dosage ^TMTreat the appointed date after 8 weeks, suffer from the time-dependent figure of the average clinical score (performance scoring) of the animal of chronic phase experimental autoimmune encephalomyelitis (EAE).

Fig. 8 A compares with vehicle Control, at the Symadex with 20mg/kg dosage ^TMAppointed date after 4,6 and 8 weeks of treatment, the bar figure of the Cytometric time-histories of T of the animal of trouble chronic phase experimental autoimmune encephalomyelitis (EAE).

Fig. 8 B compares with vehicle Control, at the Symadex with 20mg/kg dosage ^TMAppointed date after 4,6 and 8 weeks of treatment, the bar figure of the Cytometric time-histories of CD-4 of the animal of trouble chronic phase experimental autoimmune encephalomyelitis (EAE).

Fig. 8 C compares with vehicle Control, at the Symadex with 20mg/kg dosage ^TMAppointed date after 4,6 and 8 weeks of treatment, the bar figure of the Cytometric time-histories of CD-8 of the animal of trouble chronic phase experimental autoimmune encephalomyelitis (EAE).

Fig. 8 D compares with vehicle Control, at the Symadex with 20mg/kg dosage ^TMAppointed date after 4,6 and 8 weeks of treatment, the bar figure of the Cytometric time-histories of B of the animal of trouble chronic phase experimental autoimmune encephalomyelitis (EAE).

Fig. 9 compares with vehicle Control, at the 72 hours double 20mg/kgSymadex that give in interval ^TMAppointed date after the treatment, the time-dependent figure of the average clinical score of the animal of trouble chronic phase experimental autoimmune encephalomyelitis (EAE) (performance scoring).

Figure 10 is the Symadex that gave 6mg/kg continuous 15 day every day ^TMAfter appointed date, suffer from the time-dependent figure of average clinical score of the animal of acute stage experimental autoimmune encephalomyelitis (EAE).

Figure 11 is the Symadex that gave 6mg/kg continuous 15 day every day ^TMAfter appointed date, the average weight of suffering from the animal of acute stage experimental autoimmune encephalomyelitis (EAE) increases the time-dependent figure of record.

Figure 12 is the Symadex that gave 6mg/kg continuous 15 day every day ^TMAfter appointed date, suffer from the bar figure of average pathological score of the animal postmortem of acute stage experimental autoimmune encephalomyelitis (EAE).

Figure 13 is the Symadex at orally give 30mg/kg every day for three days on end ^TMAfter appointed date, suffer from the time-dependent figure of the average performance of the inductive arthritic animal of acute stage collagen monoclonal antibody (mAB).

Figure 14 be can with the tabulation of the chemical constitution of the co-administered medicine of chemical compound disclosed by the invention.

Detailed Description Of The Invention

Have been found that now the derivative of using some imidazoles acridine can treat and/or alleviate the symptom of various inflammatory diseases and the disease relevant with demyelinate.

Especially, the compound or the acceptable salt of its pharmacy that have been found that the general formula (A) by giving ill patient's administering therapeutic effective dose can be treated various inflammatory diseases and the disease relevant with demyelinate:

In general formula (A), the substituting group difference is following the definition independently.

R representative-H, optional alkyl, hydroxyl, alkoxyl, the halogen that replaces, perhaps R and R⁵Or R and R⁴With form 5,6 or 7 yuan of nonaromatic heterocycles of choosing the cycloalkyl that replace wantonly or comprising one or more oxygen, sulphur or the optional nitrogen that replaces between the carbon atom between them.

Preferably, R is-H; The C1-C4 alkyl, its optional quilt-OH ,-SH, halogen, cyano group, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, C1-C3 halogenated alkoxy or C1-C3 alkyl thiol (sulfanyl), amine replacement; The C1-C2 alkylamine; Or C1-C2 dialkylamine; Perhaps R and R⁵Or R and R⁴Also optional by the 5-6 unit nonaromatic heterocycles of methyl or hydroxyl replacement with forming 5-6 unit's cycloalkyl between the carbon atom between them or comprising one or two oxygen atom.

In one embodiment, R represents with lower array structure:

More preferably, R be-H ,-OH, C1-C6 alkyl, C1-C6 alkoxyl ,-F or and R⁴Or alternately with R⁵Form together methylene dioxy base. More preferably, R is-H or C1-C6 alkoxyl. Alternately, R be-OH or-OCH₃。

R ²Expression hydrogen, the optional C1-C10 alkyl that replaces or optional aryl or the heteroaryl that replaces. Preferably, R²Be-H, the C1-C8 alkyl or phenyl, optional replaced by one or more C1-C4 alkyl, C1-C4 alkoxyl, C1-C4 halogenated alkoxy or cyano group. More preferably, R²Be-H or C1-C4 alkyl.

R ³Expression-(CH₂) _n-NR ^aR ^b, wherein n is 1 to 5 integer, R^aAnd R^bCan be identical or different, expression hydrogen or the optional alkyl that replaces. Substituent example comprises hydroxyl, C1-C4 hydroxyalkyl, amino, N-alkyl-amino or N, N-dialkyl amido on this alkyl.

In addition ,-NR^aR ^bBe N-morpholinyl or N-pyrazinyl, it is replaced by methyl, hydroxyl or methoxyl group are optional on one or more commutable carbon respectively, and wherein the N-pyrazinyl be by the C1-C4 alkyl or-NR^cR ^dThe C1-C4 alkyl that replaces is chosen N '-replacement, wherein R wantonly^cAnd R^dBe respectively-H, methyl or ethyl.

Preferably, n is 2 to 3 integer, R^aAnd R^bBe independently respectively-H or C1-C4 alkyl.

R ⁴And R⁶Be independently respectively-H ,-OH, halogen or a C1-C6 alkoxyl. In some embodiments, R and R⁴With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them. As R and R⁴And when the carbon atom between them linked together, they had been preferably formed 5-6 unit's cycloalkyl or have comprised one or two oxygen atom also optional by the 5-6 unit nonaromatic heterocycles of methyl or hydroxyl replacement; More preferably, R⁴Be-H ,-OH, C1-C3 alkoxyl or be joined together to form methylene dioxy base with R; And R⁶Be-H ,-OH or C1-C3 alkoxyl.

More preferably, R⁴And R⁶Be independently respectively-H ,-OH or-OCH₃。

R ⁵Be-H ,-OH, halogen, C1-C6 alkoxyl. In some embodiments, R and R⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them. Work as R⁵And R, or R alternately⁵And R⁶And when the carbon atom between them linked together, they had been preferably formed 5-6 unit's cycloalkyl or have comprised one or two oxygen atom also optional by the 5-6 unit nonaromatic heterocycles of methyl or hydroxyl replacement; More preferably, R⁵Be-H ,-OH, C1-C3 alkoxyl or and R, or alternately with R⁶Be joined together to form methylene dioxy base.

In some embodiments, the following definition of substituting group in the general formula (A):

R is-H; The C1-C4 alkyl, its optional quilt-OH ,-SH, halogen, cyano group, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, C1-C3 halogenated alkoxy or the replacement of C1-C3 alkyl thiol, amine; C1-C2 alkylamine or C1-C2 dialkylamine; Perhaps R and R ⁵Also optional with forming 5-6 unit's cycloalkyl between the carbon atom between them or comprising one or two oxygen atom by the 5-6 unit nonaromatic heterocycles of methyl or hydroxyl replacement;

R ²Be-H, the C1-C8 alkyl or phenyl, optional replaced by one or more C1-C4 alkyl, C1-C4 alkoxyl, C1-C4 halogenated alkoxy or cyano group;

R ³Be-(CH ₂) n-NR ^aR ^b, wherein n is 2 to 3 integer, R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently, perhaps-NR ^aR ^bBe N-morpholinyl or N-pyrazinyl, it is replaced by methyl, hydroxyl or methoxyl group are optional on one or more commutable carbon respectively, and wherein the N-pyrazinyl be by the C1-C4 alkyl or-NR ^cR ^dThe C1-C4 alkyl that replaces is chosen N '-replacement, wherein R wantonly ^cAnd R ^dBe respectively-H, methyl or ethyl;

R ⁴, R ⁵And R ⁶Be independently respectively-H ,-OH or C1-C3 alkoxyl, perhaps R ⁴Or R alternately ⁵Form methylene dioxy base with R.

Preferably, the chemical compound of general formula (A) is represented by general formula (I):

In general formula (I), variable R, R ², n, R ^aAnd R ^bCan get above-mentioned value or preferred value for general formula (A) definition.The preferred value of these variablees provides in the following passage in general formula (I):

R represents hydroxyl or alkoxyl, for example, and the C1-C6 alkoxyl.Alternately, R be-OH or-OCH ₃

R ^aAnd R ^bCan be identical or different, can be hydrogen or the optional alkyl that replaces.Preferably, R ^aAnd R ^bIt is the C1-C3 alkyl.More preferably, R ^aAnd R ^bBe respectively ethyl independently.Alternately, R ^aAnd R ^bIt is respectively methyl.In other embodiments, R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently.

Work as R ^aAnd R ^bWhen being the alkyl that replaces, suitable substituent group comprises hydroxyl, C1-C4 hydroxyalkyl, amino, N-alkyl-amino or N on this alkyl, and the N-dialkyl amido preferably comprises 1-4 carbon atom.These substituent examples are ethoxy, amino-ethyl, N-alkyl amino ethyl and N, N-dialkyl amido ethyl.

In other embodiments of general formula (I) ,-NR ^aR ^bBe N-morpholinyl or N-pyrazinyl, it is replaced by methyl, hydroxyl or methoxyl group are optional on one or more commutable carbon respectively, and wherein the N-pyrazinyl be by the C1-C4 alkyl or-NR ^cR ^dThe C1-C4 alkyl that replaces is chosen N '-replacement, wherein R wantonly ^cAnd R ^dBe respectively-H, methyl or ethyl.

Preferably, n is 2 or 3 in general formula (I).

In general formula (I), R ²Be hydrogen or C1-C6 alkyl.Preferably, R ²Be hydrogen or C1-C4 alkyl.More preferably, R ²Be-H.

In some embodiment preferred of the chemical compound of general formula (I), R is-OH or-OCH ₃, R ^aAnd R ^bIdentical and expression C1-C6 alkyl, preferable methyl or ethyl; N is 2 or 3; R ²Expression hydrogen or straight chain C 1-C4 alkyl.Preferably, R ²Be-H.

The example of the chemical compound of general formula (I) comprises that chemical compound (IIA) arrives (IIH):

In a most preferred embodiment, the chemical compound of general formula (I) is the 5-[[(diethylamino) ethyl] amino]-8-hydroxyl imidazo [4,5,1-de]-acridine-6-ketone, its structure is shown in general formula (III):

In another embodiment, the chemical compound of general formula (A) is represented by structural formula (IV):

Except as otherwise noted, term used herein " alkyl " comprises the saturated unit price hydrocarbyl group of straight or branched, typically C1-C10, preferably C1-C6.The example of alkyl includes but not limited to methyl, ethyl, propyl group, isopropyl and the tert-butyl group.The suitable substituent group of substituted alkyl comprises-OH ,-SH, halogen, cyano group, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl, C1-C3 halogenated alkoxy or C1-C3 alkyl thiol.

Term used herein " cycloalkyl " is meant the saturated carbon ring part of non-fragrance.The example of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.The suitable substituent group of cycloalkyl such as above-mentioned defined for alkyl.

Term used herein " haloalkyl " comprises the alkyl that is replaced by one or more F, Cl, Br or I, wherein alkyl such as above-mentioned definition.

Term used herein " alkoxyl " is meant " alkyl-O-" base, wherein alkyl such as above-mentioned definition.

Term used herein " halogenated alkoxy " is meant " haloalkyl-O-", wherein haloalkyl such as above-mentioned definition.

Amino used herein can be the primary (NH ₂), secondary (NHR _x) or uncle (NR _xR _y) amino, wherein R _xAnd R _yIt is the alkyl of arbitrarily above-mentioned optional replacement.

Term used herein " aryl " is meant the carbocyclic ring aromatic group.The example of aryl includes but not limited to phenyl and naphthyl.

Term used herein " heteroaryl " is meant the aromatic radical that comprises one or more hetero atoms (O, S or N).Heteroaryl can be a monocycle or multi-ring, for example with one or more carbocyclic ring aromatic radicals or the condensed bicyclic heteroaryl ring of other bicyclic heteroaryls.Heteroaryl of the present invention also can comprise the loop systems that is partly replaced by one or more oxygen.The example of heteroaryl includes but not limited to, pyridine radicals, pyridazinyl, imidazole radicals, pyrimidine radicals, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazole radical, furyl, thienyl isoxazolyl, thiazolyl oxazolyl, isothiazolyl, pyrrole radicals, the quinoline subbase, the isoquinolin subbase, indyl, benzimidazolyl, benzofuranyl, cinnolines base (cinnolinyl), indazolyl, the indolizine base, phthalazinyl, pyridazinyl, triazine radical, isoindolyl, purine radicals oxadiazole base, thiazolyl, thiadiazolyl group, furan a word used for translation base (furazanyl), benzo furan a word used for translation base, the benzimidazole thiophanate phenyl, the benzotriazole base, benzothiazolyl benzoxazolyl, quinazolyl quinoxalinyl, naphthyridinyl (naphthyridinyl), the dihydroquinoline base, tetrahydric quinoline group, the dihydro-isoquinoline base, tetrahydro isoquinolyl, benzofuranyl, the fluorinated pyridine base, pyrroles's pyrimidine radicals and azaindolyl.

Term used herein " nonaromatic heterocycles " is meant common 4-8 unit, the non-fragrant carbon-loop system of preferred 5-6 unit, wherein one or more, for example N, O or S replace preferred 1 to 4 ring carbon by hetero atom respectively.The example of nonaromatic heterocycles comprises the 3-tetrahydrofuran base, the 2-tetrahydrofuran base, the 3-THP trtrahydropyranyl, the 4-THP trtrahydropyranyl, [1,3]-dioxolanyl, [1,3]-the dithiolane base, [1,3]-alkyl dioxins, 2-tetrahydrochysene sulfur phenenyl, 3-tetrahydrochysene sulfur phenenyl, the 2-morpholinyl, morpholinyl, the 4-morpholinyl, 2-tetrahydro-1,4-thiazine base, 3-tetrahydro-1,4-thiazine base, 4-tetrahydro-1,4-thiazine base, the 1-pyrrolidinyl, the 2-pyrrolidinyl, the 3-pyrrolidinyl, the 1-piperazinyl, the 2-piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 4-thiazolidinyl, diazolonyl, N-replaces diazolonyl and 1-phthalimide-based (pthalimidyl).

Heteroaryl or nonaromatic heterocycles base can be that C-connects or N-connects (if possible).For example, the group of pyrrole derivatives can be pyrroles-1-base (N-connection) or pyrroles-3-base (C-connection).

The suitable substituent group of aryl, heteroaryl or nonaromatic heterocycles base can be those groups that do not influence the pharmacologically active of disclosed chemical compound basically.Can there be one or more identical or different substituent groups.Suitable substituent example in the nonaromatic heterocycles base on the substitutable carbon atom comprises-OH, halogen (F ,-Cl ,-Br and-I) ,-R ' ,-OR ' ,-CH ₂R ' ,-CH ₂OR ' ,-CH ₂CH ₂OR ' ,-CH ₂OC (O) R ' ,-O-COR ' ,-COR ' ,-SR ' ,-SCH ₂R ' ,-CH ₂SR ' ,-SOR ' ,-SO ₂R ' ,-CN ,-NO ₂,-COOH ,-SO ₃H ,-NH ₂,-NHR ' ,-N (R ') ₂,-COOR ' ,-CH ₂COOR ' ,-CH ₂CH ₂COOR ' ,-CHO ,-CONH ₂,-CONHR ' ,-CON (R ') ₂,-NHCOR ' ,-NR ' COR ' ,-NHCONH ₂,-NHCONR ' H ,-NHCON (R ') ₂,-NR ' CONH ₂,-NR ' CONR ' H ,-NR ' CON (R ') ₂,-C (=NH)-NH ₂,-C (=NH)-NHR ' ,-C (=NH)-N (R ') ₂,-C (=NR ')-NH ₂,-C (=NR ')-NHR ' ,-C (=NR ')-N (R ') ₂,-NH-C (=NH)-NH ₂,-NH-C (=NH)-NHR ' ,-NH-C (=NH)-N (R ') ₂,-NH-C (=NR ')-NH ₂,-NH-C (=NR ')-NHR ' ,-NH-C (=NR ')-N (R ') ₂,-NR ' H-C (=NH)-NH ₂,-NR '-C (=NH)-NHR ' ,-NR '-C (=NH)-N (R ') ₂,-NR '-C (=NR ')-NH ₂,-NR '-C (=NR ')-NHR ' ,-NR '-C (=NR ')-N (R ') ₂,-SO ₂NH ₂,-SO ₂NHR ' ,-SO ₂NR ' ₂,-SH ,-SO _kR ' (k is 0,1 or 2) and-NH-C (=NH)-NH ₂R ' is respectively alkyl independently.

Suitable substituent group on the nitrogen of nonaromatic heterocycles base or heteroaryl comprises-R " ,-N (R ") ₂,-C (O) R " ,-CO ₂R " ,-C (O) C (O) R " ,-C (O) CH ₂C (O) R " ,-SO ₂R " ,-SO ₂N (R ") ₂,-C (=S) N (R ") ₂,-C (=NH)-N (R ") ₂With-NR " SO ₂R ".R " is hydrogen, alkyl or alkoxyl.

Chemical compound (IIA) is to (IIH) and (III) can be according to U.S.5, and 231,100 and 6,229, the 015 different synthetic schemes that disclose synthesize, and by reference their integral body are incorporated herein.An example of these schemes is as follows:

(scheme I)

Commodity are called Symadex ^TMChemical compound (III) be known.Have been found that Symadex now ^TMSuppressing LPS stimulates the propagation of back B cell and the propagation that Con A stimulates back T cell, and Symadex ^TMSuppress for example release (embodiment 1) of IL-4 and IL-10 of cytokine.Find Symadex in this external microarray test ^TMTreatment causes several expression of gene to change, and these several genes relate to the key that influences inflammation and vegetative state and regulate approach, particularly invade cell assembling and accumulative ability, the downward modulation of on cell proliferation and cell-cell signal (embodiment 3).These molecular pharmacologies studies show that, Symadex ^TMBring into play the effect of reducing for gene that relates to cell aggregation and mechanism of proliferation and the process relevant with the cell growth of invading, wherein said process is the inflammation etiologic etiological sign relevant with autoimmune disease.In a word, these results show, Symadex ^TMCan be used for the treatment of disease, comprise autoimmune disease with inflammatory component.

Find Symadex in addition ^TMHave activity in female Hartley Cavia porcellus experimental autoimmune encephalomyelitis (EAE) model, wherein said model is the classical animal model (embodiment 2) of chronic-carrying out property MS.Result with embodiment 3 is summarised in, and the result shows Symadex ^TMCan be used for the treatment of disease with demyelination and inflammatory component.

Therefore, in one embodiment, the present invention is a kind of method for the treatment of the patient who suffers from inflammatory diseases.This disease can be systemic lupus erythematosus (sle), inflammatory bowel, psoriasis, Ke Laoen disease, rheumatoid arthritis, sarcoid, Alzheimer, chronic inflammatory demyelinating neuropathy, insulin dependent diabetes mellitus (IDDM), atherosclerosis, asthma, spinal cord injury or apoplexy.

The example of chronic inflammatory demyelinating neuropathy comprises: chronic immunity demyelinating polyneuropathy (CIDP); Many focuses CIDP; Many focuses motor neuron (MMN); Anti--MAG syndrome (having neuropathy) with the bonded I gM of myelin associated glycoprotein; GALOP syndrome (gait disorder, autoantibody late onset polyneuropathy); Anti--sulfatide antibody syndrome; Anti--GM2 ganglioside antibody syndrome; POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy or edema M-albumen skin change); Perineuritis; Resist-GD1b ganglioside antibody syndrome with IgM.

This method comprises to the chemical compound of the general formula of patient's administering therapeutic effective dose (A) or the acceptable salt of its pharmacy.For example can use the chemical compound of general formula (IIA) to (IIH).Preferably, can use the chemical compound of general formula (III).Alternately, use the chemical compound of general formula (IV).

In another embodiment, the present invention is a kind of method for the treatment of the patient who suffers from demyelination." demyelination " used herein is meant destruction, breaks the disease of the integrity or the destruction myelin of myelin.Term used herein " myelin " is meant the sealing coat around the vertebra peripheral neurons, and it increases conduction velocity, is formed by the Schwann cell of peripheral nervous system or the oligodendrocyte among the central nervous system.These diseases can be multiple sclerosis, congenital metabolic disease, have the neuropathy that unusual myelin forms, drug-induced demyelination, radiation-induced demyelination, heritability demyelination, the inductive demyelination of Protein virus, the inductive demyelination of encephalitis, spinal cord injury, Alzheimer or chronic inflammatory demyelinating neuropathy, its example such as above-mentioned given.In one embodiment, this disease is a multiple sclerosis.This method comprises to the chemical compound of the general formula of patient's administering therapeutic effective dose (A) or the acceptable salt of its pharmacy.For example can use the chemical compound of general formula (IIA) to (IIH).Preferably, can use the chemical compound of general formula (III).Alternately, use the chemical compound of general formula (IV).

Term used herein " patient " is meant homoiothermic animal, for example rat, mice, Canis familiaris L., cat, Cavia porcellus and primate, for example people.Term " treatment " comprises any treatment, includes but not limited to mitigation symptoms, the temporary transient or permanently symptomatolytic cause of disease, or prevention or the generation of the symptom that slows down and the progress of described disease or disease.Term " treatment effective dose " is meant the amount that can treat the chemical compound of described disease or disease effectively.In some embodiments, the treatment effective dose is meant the amount that is enough to realize effectively the neurocyte Remyelination in the patient.

In another embodiment, the present invention is a kind of method that promotes the neurocyte Remyelination in the patient, comprises chemical compound or the acceptable salt of its pharmacy to general formula I, general formula (HA)-(IIH), general formula (III) or the general formula (IV) of patient's administering therapeutic effective dose of needs.The patient can suffer from above-mentioned listed demyelination arbitrarily.

In another embodiment, the present invention be a kind of in the patient of needs prevention demyelination and promote the method for Remyelination, comprise the combination of the chemical compound of general formula I, general formula (HA)-(IIH), general formula (III) or general formula (IV) of administering therapeutic effective dose or the acceptable salt of its pharmacy and following antiinflammatory.

In another embodiment, the present invention is a kind of method that reverses paralysis in the patient of the needs of suffering from demyelination, comprise to the patient and use a kind of chemical compound, the amount of application of this chemical compound is enough to suppress the immunocyte in the lymphocytic infiltration spinal cord, to promote the Remyelination of neurocyte in the spinal cord, and the paralysis for the treatment of described patient thus, wherein this chemical compound is the chemical compound or the acceptable salt of its pharmacy of general formula I, general formula (HA)-(IIH), general formula (III) or general formula (IV).

The chemical compound of general formula disclosed herein (A), comprise general formula (HA)-(IIH), (III) and chemical compound (IV), show the state of other potential diseases that the dosage range of therapeutic ability to function can suffer from according to severity, patient, preparation, the patient of disease, be applied to patient's other drug and difference simultaneously.Usually, chemical compound of the present invention at dosage for about 0.001mg/kg weight in patients/day demonstration therapeutic activity during to about 100mg/kg weight in patients/day.For example, dosage can be every day, every other day or weekly 0.1-100mg/kg, 1-100mg/kg, 10-100mg/kg, 1-50mg/kg, 10-50mg/k g or 10-30mg/kg.

In other embodiment, can use this chemical compound by following any approach, preferred intravenous is used, and preferred amounts arrives the 20mg/kg body weight for the 1mg/kg body weight.Can be once a day, once or once in a week used this chemical compound in per 72 hours.

Be used for the treatment of in the embodiment of rheumatoid arthritis at this chemical compound, can every day, every other day or this chemical compound of the amount of oral weekly 1-50mg/kg, 10-40mg/kg, 20-30mg/kg or 30mg/kg body weight.

In another embodiment, chemical compound of the present invention can chronic administration in the patient of needs.For example, the chronic administration of this chemical compound be every day, weekly, per two weeks or used in every month at least 1 year, at least 2 years, at least 3 years or more for many years.

In one embodiment, the chemical compound of general formula (A) comprises that general formula (IIA)-(IIH), (III) and chemical compound (IV) use with the amount intravenous of 1.5-30mg/kg, every 1-3 month interval 1 time.In another embodiment, with this chemical compound of the amount of the oral 5-100mg/kg of above-mentioned same approach.Alternately, the chemical compound of general formula (A) administered several times in time up to 3 months, accumulated dose is up to 1.5 to 30mg/kg.In another embodiment, accumulated dose is 5 to 100mg/kg.

In another embodiment, the chemical compound of general formula (A) is with amount intravenous administration 8-24 week of 2.5-10mg/kg weekly, repetitive administration more then if desired after drug withdrawal 6-18 week.Alternately, the chemical compound of general formula (A) in the time in 14 to 42 weeks administered several times to reach the accumulated dose of 20mg/kg to 240mg/kg.Can be in the time period in one or more 14-42 week repetitive administration.

In another embodiment, the chemical compound of general formula (A) is used 2 times with 72 hours intravenouss in amount interval of 2.5-10mg/kg, and in totally 1 to 2 week, every month repeats once.Alternately, the chemical compound of general formula (A) administered several times in, accumulated dose up to the time in 2 weeks up to 11mg/kg to 47mg/kg.Can every month repetitive administration.

In another embodiment, the chemical compound of general formula (A) can be in 10-15 days with every day 1-3mg/kg amount oral, every 30-45 days repeat.Alternately, the chemical compound of general formula (A) administered several times in, accumulated dose up to 40-60 days time up to 10mg/kg to 45mg/kg.Can one or more up to 40-60 days time period in repetitive administration.

In another embodiment, chemical compound of the present invention can be in weekly 3 days with every day 2-6mg/kg amount oral, every 15-30 days repeat.Alternately, the chemical compound of general formula (A) administered several times in up to 40-60 days time, accumulated dose is up to 6-18mg/kg.Can one or more up to 30 days time period in repetitive administration.

Preferably, using chemical compound as herein described or combination of compounds causes the valid density of this chemical compound in the blood samples of patients more than or equal to 10ng/ml.For example, this chemical compound can be used to the amount intravenous of about 500 μ g/kg weight in patients with 20 μ g/kg.

The preferred dose of treatment chronic (alleviation-recurrence type) multiple sclerosis of people (MS) is that 0.1mg/kg is to 10mg/kg, 1-10mg/kg, 1-5mg/kg, 2-7mg/kg, 2-5mg/kg.Dosage regimen can be every month 1 time, every month 2 times, every month 3 times or 1 or 2 time weekly, altogether March, June, December or longer.

The preferred dose of treatment people acute MS be 0.1mg/kg to 10mg/kg, 0.1-5mg/kg, 0.1-2mg/kg, 0.5-2mg/kg or 0.5-1mg/kg, every day 3 times, every day 2 times or every day 1 time, based on weekly, per two weeks or 1 time every month.

Treatment human rheumatoid arthritic preferred dose be 0.1mg/kg to 10mg/kg, 1-10mg/kg, 1-5mg/kg, 2-7mg/k g, 2-5mg/kg, every day 3 times, every day 2 times or every day 1 time, based on weekly, per two weeks or 1 time every month.

When the patient who states disease is suffered from treatment, can be so that disclosed all chemical compounds of biological effective any form of chemical compound or pattern administering therapeutic effective dose.For example, the chemical compound of general formula (A) can be used with the form of the acceptable salt of pharmacy.Term " the acceptable salt of pharmacy " is meant acid-addition salts or base addition salts, and these two kinds of salt all can prepare with chemical compound of the present invention." the acceptable acid-addition salts of pharmacy " is any avirulence organic or inorganic acid-addition salts of the alkali compounds of general formula (A) expression.The exemplary inorganic acid that forms suitable salt comprises hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and acid metal salt for example disodium-hydrogen and potassium acid sulfate.The exemplary organic acid that forms suitable salt comprises list, two and tricarboxylic acids.These sour examples are, for example for example methanesulfonic acid and 2-ethylenehydrinsulfonic acid of acetic acid, glycolic, lactic acid, acetone acid, malonic acid, succinic acid, 1,3-propanedicarboxylic acid, Fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxy benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxy benzoic acid, p-methyl benzenesulfonic acid and sulfonic acid class.Can form single hydrochlorate or diacid salt, these salt can exist with hydration or substantially anhydrous form.Usually, the easier dissolving in water and various hydrophilic organic solvent of the acid-addition salts of these chemical compounds is compared with their free alkali form, the higher fusing point of general demonstration." the acceptable base addition salts of pharmacy " is meant the chemical compound of general formula (A), comprises the avirulence organic or inorganic base addition salts of general formula (IIA)-(IIH), (III) and chemical compound (IV).Example is hydroxide for example sodium hydroxide, potassium, calcium, magnesium or the barium of alkali metal or alkaline-earth metal; Ammonia and aliphatic, alicyclic or aromatic series organic amine be methylamine, trimethylamine and picoline for example.It is important selecting suitable salt, so that this ester can hydrolysis.It is well known by persons skilled in the art selecting the standard of suitable salt.

Chemical compound of the present invention can be used by a lot of approach, comprises oral, Sublingual, containing, subcutaneous, intramuscular, intravenous, percutaneous, intranasal, rectum, local or the like.The technical staff in formulation preparation field can determine suitable administration form and pattern according to the concrete property of the chemical compound of selecting for the disease that will treat or disease, the stage of disease, patient's situation and other correlation circumstances.For example referring to Remington ' s PharmaceuticalSciences, 18th Edition, Mack Publishing Co. (1990), with it by with reference to being incorporated herein.

The chemical compound of general formula of the present invention (A) also can local application, and when using like this, carrier can suitably comprise solution, ointment or gel-type vehicle.For example, the vaseline, lanoline, Polyethylene Glycol, Cera Flava, mineral oil, diluent that substrate can comprise one or more be water and alcohol for example, and emulsifying agent and stabilizing agent.

Solution or suspension also can comprise one or more following adjuvants: sterile diluent is water for injection, saline solution, nonvolatile oil, Polyethylene Glycol, glycerol, propylene glycol or other synthetic for example; Antibacterial is benzyl alcohol or methyl butex for example; Antioxidant is ascorbic acid or sodium sulfite for example; Chelating agen is ethylenediaminetetraacetic acid for example; Buffer agent is the reagent for example sodium chloride or the glucose of acetate, citrate or phosphate and opening property of adjusting for example.Parenteral formulation can be encapsulated in ampoule, disposable syringe or the multi-dose vials.

The chemical compound that uses among the present invention can be used separately, or co-administered to inflammatory diseases and/or effective other forms of pharmacologically active agents of demyelination that will treat with one or more.

Relate to the term used herein " combination " of forms of pharmacologically active agents and " co-administered " and " coupling " and be meant in a treatment cycle and use more than one forms of pharmacologically active agents to the patient, but not necessarily use simultaneously or in a kind of mixture, use.

In another embodiment, chemical compound of the present invention and antiinflammatory are co-administered.Antiinflammatory can be thyroliberin, corticosteroid, interferon, acetic acid glatiramer or NSAID (non-steroidal anti-inflammatory drug) (NSAID).

The example of suitable antiinflammatory comprises corticosteroid, for example prednisone, meprednisone, dexamethasone, hydrocortisone, cortisone, fludrocortisone, prednisolone, 6 α-methylprednisolone, triamcinolone or betamethasone.

Other examples of suitable antiinflammatory comprise NSAID; For example the aminoaryl carboxylic acid derivates (for example; Enfenamic acid; Etofenamate; Flufenamic acid; Isonixin; Meclofenamic acid; Niflumic Acid; Talniflumate; Terofenamate and Tolfenamic Acid); The Arylacetic acids derivative (for example; Acemetacin (Acematicin); Alclofenac; The fragrant acid of ammonia; Bufexamac; Carprofen; Cinmetacin; Clopirac; Diclofenac; C14H10Cl2NNaO2; Etodolac; Felbinac; Fenclofenac; Fenclorac; Fenclozic acid; Fenoprofen; Fentiazac; Flurbiprofen; Glucametacin; Ibufenac; Brufen; Indomethacin; Isofezolac; Isoxepac; Ketoprofen; Lonazolac; Metiazinic acid; Naproxen; Oxametacin; Proglumetacin; Sulindac; Tenidap; Tiaramide (Tiramide); Tolectin; Tolmetin; Zomepirac sodium and Zuo Mei acid); Arylbutyric acid derivatives (for example; Bumadizon; Butibufen; Fenbufen and xenbucine); Aryl carboxylic acid (for example; Clidanac; Ketorolac and Tinoridine); Aryl propionic acid derivatives (for example; Alminoprofen; Benoxaprofen; The bucloxic acid; Carprofen; Fenoprofen; Flunoxaprofen; Flurbiprofen; Brufen; Ibuproxam; Indoprofen; Ketoprofen; The loxoprofen; Miroprofen; Naproxen; Oxaprozin; Piketoprofen; Pirprofen (Piroprofen); Pranoprofen; Protizinic acid (Protinizinic Acid); Suprofen and Tiaprofenic Acid); Pyrazoles (for example; Diphenylimidazolidin-4-one and epirizole); Pyrazolone (for example; Apazone; Benzpiperylone; Feprazone; Mofebutazone; Morazone; Oxyphenbutazone; Phenylbutazone; Pipebuzone; Propyphenazone; Ramifenazone; Suxibuzone and thiazolinobutazone (thiazolinobutazone)); Salicyclic acid derivatives (for example; Acetaminosalol; 5-aminosalicylic acid; Aspirin; Benorylate; The biphenyl aspirin; Bromosaligenin; Tylcalsin; Diflunisal; The Yi Teliu ester; Fendosal; Flufenisal; Gentianic acid; Glycol salicylate; Imidazole salicylate; Lysine acetylsalicylate; Mesalazine; Morophine salicylate; 1-naphthyl salicylic acid; Olsalazine; Parsalmide; Acetylphenyl salicylate; Phenyl salicytate; 2-phosphorus oxybenzoic acid; Salacetamide; Salicylamide O-acetic Acid; Salicylic acid; Disalicylic acid; Salicylsulfuric Acid; Salsalate and SASP); Thiazine carbamyl class (for example; Zhuo Xikang; Isoxicam; Piroxicam and tenoxicam); ε-acetylamino caproic acid; SAM; 3-amino-4-hydroxybutyric acid; Amixetrine; Bendazac; Benzydamine; Bucolome; Difenpiramide; Ditazole; Emorfazone; Guaiazulene; Ketorolac; Meclofenamic Acid; Mefenamic acid; Nabumetone; Aulin; Orgotein; Oxaceprol; Paranyline; Perisoxal; Pifoxime; Piroxicam; Proquazone; Tenidap and cox 2 inhibitor (for example, rofecoxib; Valdecoxib and celecoxib).

Other example of antiinflammatory comprise aspirin, sodium salicylate, Choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine, Olsalazine, p-aminophenyl amphyl, the furanone that replaces of indole, indeneacetic acid, heteroaryl acetic acid, ortho-aminobenzoic acid, bmap acid, alkane ketone, diaryl, pyrazoles, heteroauxing or the sulfonanilide that diaryl replaces.

In some embodiments, chemical compound of the present invention can with immunotherapeutic agent for example interferon and anti-alpha 2 integrin blocking antibody for example natalizumab is co-administered.

The example that is fit to the reagent of treatment demyelination comprises pirfenidone, epalrestat, hydrochloric acid nefazodone, memantine hydrochloride, mitoxantrone hydrochloride, mitoxantrone hydrochloride, Thalidomide, Roquinimex, VENLAFAXINE HCL, Intaxel, paclitaxel, recombinant human nerve growth factor; Nerve growth factor, ibudilast, cladribine, Beraprost Sodium, hydrochloric acid Levacecarnine; The hydrochloric acid acetyl-L-camitine; The hydrochloric acid acetyl levocarnitine, droxidopa, interferon-ALPHA, natural interferon alpha, human lymphocyte sample interferon, interferon beta-1b, interferon beta-Ser, alemtuzumab, mycophenolate mofetil, one hydration zoledronic acid, adapalene, eliprodil, donepezil hydrochloride, dexabinol, the ground plug compares ketone, the hydrochloric acid xaliproden, Alferon N, thioctic acid, dithio-octanoic acid, teriflunomide, atorvastatin, piminodine (Pymadin), 4-aminopyridine, Fampridine, fidarestat, priliximab, maleic acid Pixantrone, dacliximab, daclizumab, the acetic acid glatiramer, Rituximab, hydrochloric acid Fingolimod, interferon beta-1a, natalizumab, Abatacept, Temsirolimu s, Lenercept, hydration methanesulfonic acid Ruboxistaurin, sulphuric acid dextromethorphan/chinidine, capsaicin, dimethyl fumarate salt or dronabinol/cannabidiol.

In some embodiments, chemical compound of the present invention can be co-administered with one or more other forms of pharmacologically active agents that effectively resist multiple sclerosis.The example of these reagent comprises interferon (interferon beta 1-a, β 1-b and α), acetic acid glatiramer or corticosteroid for example methylprednisolone and prednisone, and chemotherapeutant for example mitoxantrone, methotrexate, azathioprine, cladribine, cyclophosphamide, ciclosporin and tysabri.

Effectively antagonism multiple sclerosis and other examples suitable and forms of pharmacologically active agents that chemical compound of the present invention is co-administered comprise the chemical compound with following structural:

Can comprise with other examples of the medicament of the chemical compound coupling of general formula (A):

T-cell receptors (TCR) V β 6CDR2 peptide vaccine is made up of TCR V β 6, aminoacid sequence 39-58, Leu-Gly-Gln-Gly-Pro-Glu-Phe-Leu-Thr-Tyr-Phe-Gln-Asn-Glu-Ala-Gln-Leu-Glu-Lys-Ser (SEQ ID NO:1);

Myelin basic protein immunogen peptide, aminoacid sequence 75-95, Lys-Ser-His-Gly-Arg-Thr-Gln-Asp-Glu-Asn-Pro-Val-Val-His-Phe-Phe-Lys-Asn-Ile-Val-Thr (SEQI D NO:2);

Tiplimotide, myelin basic protein immunogen vaccine peptide, aminoacid sequence 83-99, D-Ala-lys-pro-val-val-his-leu-phe-ala-asp-ile-val-thr-pr o-arg-thr-pro, (SEQID NO:3);

Myelin basic protein immunogen peptide, aminoacid sequence 82-98, Asp-glu-asp-pro-val-val-his-phe-phe-lys-asp-ile-val-thr-pro-arg-thr, (SEQID NO:4);

Thyroliberin (ACTH), Ser-Tyr-Ser-met-glu-his-phe-arg-try-gly-lys-pro-val-gly-lys-lys-arg-arg-pro-val-lys-val-tyr-pro-asp-gly-ala-glu-asp-glu-leu-ala-glu-ala-phe-pro-leu-glut-phe, (SEQ ID NO:5).

Effectively antagonism multiple sclerosis and other examples suitable and forms of pharmacologically active agents that chemical compound of the present invention is co-administered comprise:

The 3-4 diamino-pyridine; ABT-874; Actos  (pyrroles's row ketone); ALCAR (acetyl-L-camitine); Alpha lipoic acid; AndroGel  (testosterone gel); Trimethoprim and ascorbic combination; The combination of azithromycin and rifampicin; Minocycline; Donezepil HCl; Avandia  (rosiglitazone maleate; The combination of IFN β-1a) and acetaminophen, ibuprofen or prednisone; The combination of Avonex  (interferon beta-1a)+CellCept  (mycophenolate mofetil); The combination of Avonex  (interferon beta-1a) and Copaxone  (acetic acid glatiramer); The combination of Avonex  (interferon beta-1a) and doxycycline; The combination of Avonex  (interferon beta-1a) and EMLA (lignocaine and prilocaine) anesthetic cream; Avonex  (interferon beta-1a) and estrogen and progesterone; The combination of Avonex  (interferon beta-1a)+Fludara  (fludarabine phosphate); Avonex  (interferon beta-1a) and methotrexate and folinic acid rescue the combination of agent; The combination of Avonex  (interferon beta-1a) and methotrexate and methylprednisolone; The combination of Avonex  (interferon beta-1a) and Novantrone  (mitoxantrone); The combination of Avonex  (interferon beta-1a) and Prozac  (fluoxetine); The combination of Avonex  (interferon beta-1a) and Topamax  (topiramate); The combination of Avonex  (interferon beta-1a) and Zocor  (simvastatin); AVP-923 (dextromethorphan/chinidine); The combination of Betaseron  (interferon beta-1b) and Imuran  (azathioprine); The combination of Betaseron  (interferon beta-1b) and Copaxone  (acetic acid glatiramer); The combination of BHT-3009-01 and Lipitor  (atorvastatin); Bone marrow/peripheral stem cell graft; CellCept  (mycophenolate mofetil); The combination of CellCept  (mycophenolate mofetil) and Avonex  (interferon beta-1a); Oral cladribine; CNTO1275 (monoclonal antibody); The combination of Copaxone  (acetic acid glatiramer) and antibacterial therapy agent (minocycline); The combination of Copaxone  (acetic acid glatiramer) and Novantrone  (mitoxantrone); The combination of Copaxone  (acetic acid glatiramer) and prednisone; The combination of Copaxone  (acetic acid glatiramer) and Proventil  (albuterol); Cyclophosphamide; Daclizumab; Deskar  (pirfenidone); Estriol; Fumarate; Gabitril  (Tiagabine HCL); Semen Ginkgo; IDEC-131 (anti-CD 40 L or anti-cd 154); The combination of immunoglobulin and methylprednisolone; Inosine; Interferon-tau; Lamictal  (lamotrigine); Lexapro  (escitalopram); Lipitor  (atorvastatin); The combination of Lipitor  (atorvastatin) and Rebif  (interferon beta-1a); The combination of lymphocyte extract (removing immunocyte), Imuran  (azathioprine) and prednisone; MBP8298; Methylprednisolone; The combination of methylprednisolone and Avonex (interferon beta-1a); Modiodal (modafinil); NBI-5788 (the peptide part of change); The combination of Novantrone  (injection mitoxantrone concentrated solution) and Avonex  (interferon beta-1a) or Copaxone  (acetic acid glatiramer); The omega-fatty acid tonic; Pixantrone (BBR2778); The combination of Provigil  (modafinil) and Avonex  (interferon beta-1a); Rapamune  (sirolimus); RG2077; Rituxan  (sharp holder former times monoclonal antibody); Rolipram (inhibitors of phosphodiesterase-4); SAIK-MS (laquinimod, ABR-215062); T cell inoculation thing; Teriflunomide; Tetrahydrocannabinol; Tetrahydrocannabinol (dronabinol); Thalamus analeptic; The combination of Tysabri  (natalizumab) and Avonex  (interferon beta-1a); The combination of Tysabri  (natalizumab) and Copaxone  (acetic acid glatiramer); With Viagra  (citric acid sldenafil).

Effectively antagonism multiple sclerosis and other examples suitable and forms of pharmacologically active agents that chemical compound of the present invention is co-administered comprise those chemical compounds that Figure 14 is listed.In addition, Copaxone (glatiramer) can with the oral coupling of chemical compound of the present invention.

In other embodiment, effectively antagonism multiple sclerosis and forms of pharmacologically active agents suitable and that chemical compound of the present invention is co-administered comprise following chemical compound: Mylinax, a kind of cladribine oral formulations that uses in leukemia treating is developed by Serono/Ivex; Teriflunomide, the metabolite of Arava, a kind of oral immunity inhibitor is developed by Sanofl-Aventis; FTY720, a kind of oral immunity regulator (sphingosine-1-phosphate receptor agonist) is developed by Novartis; MBP8298, a kind of being used to reduces the synthetic myelin basic protein that produces anti-myelin antibody, developed by Bio MS Medical; Seldom used medicine 4-aminopyridine (4-AP), a kind of potassium channel antagonists is developed by Acorda; Gamunex, a kind of vein immunoglobulin preparation is developed by Bayer; Fumaric acid BG-12, a kind of oral futnarate of the second filial generation is developed by Biogen Idec/Fumapharm; Temsirolimus, a kind of T-lymphopoiesis blocker is developed by Wyeth; E-2007, a kind of ampa receptor agonist is developed by Eisal; Campath, a kind of humanized anti-CD 52 antibody is developed by Genzyme; NeuroVax, a kind of vaccine is developed by Immune Response; Simvastatin (Zocor), a kind of statins is developed by Merck; NBI 5788, and a kind of plan myelin peptide part is developed by Neurocrine; Tauferon, interferon-tau is developed by Pepgen; Zenapax (Zenapax), a kind of humanization resists-the CD25 immunosuppressive antibody, is developed by Protein Design; The combination of MS-IET and EMZ701, a kind of methyl donor is developed by Transition Therapeutics; Laquinlmod, a kind of oral formulations of derivant of linomide is developed by Active Biotech/Teva; The deskar pirfenidone, a kind of TNF-alpha inhibitor is developed by Mama c; ATL-1102, the second filial generation antisense inhibitor of a kind of targeting VLA4 is developed by Antisense Therapeutics.

In some embodiments, the chemical compound of general formula (A) can with anti-angiogenic dose, the reagent that particularly suppresses growth factor receptors, EGF-R ELISA (EGFR), angiogenesis factor receptor (VEGFR) and fibroblast growth factor acceptor (FGFR) is co-administered.The example of these reagent comprises, Iressa, Tarceva, Erbitux, Pelitinib, AEE-788, CP-547632, CP-547623, Tykerb (GW-2016), INCB-7839, ARRY-334543, BMS-599626, BIBW-2992, falnidamol, AG1517, E-7080, KRN-951, GFKI-258, BAY-579352, CP-7055, CEP-5214, Sutent, Macugen, Nexavar, Neovastat, succinic acid Vatalanib, GW-78603413, Lucentis, Teavigo, AG-13958, AMG-706, Axitinib, ABT-869, Evizon, Aplidin, NM-3, PI-88, Coprexa, AZD-2171, XL-189, XL-880, XL-820, XL-647, ZK-CDK, VEGFTrap, OSI-930, Avastin, Revlimid, Endostar, linomide, Xinlay, SU-668, BIBF-1120, BMS-5826624, BMS-540215.

In some embodiments, the chemical compound of general formula (A) comprises the chemical compound of general formula (I)-(IV), can with influence the T-cell and go back to the nest, blend that to become the reagent that moves co-administered outward.The example of these reagent comprises FTY-720PK I-166, PTK-787, SU-11248.

In some embodiments, the chemical compound of general formula (A) comprises the chemical compound of general formula (I)-(IV), can be co-administered with the reagent that suppresses VLA-4.The example of these reagent comprises Tysabri, Bio-1211.HMR-1031, SB-683698, RBx-4638, RO-0272441, RBx-7796, SB-683699, DW-908e, AJM-300 and PS-460644.

In one embodiment, application dosage every day of chemical compound of the present invention can repeat a week.In other embodiments, every day, dosage can repeat 1 month to 6 months; 6 months to 1 year; 1 year to 5 years; With 5 years to 10 years.In other embodiment, the length of repetitive administration treatment is determined by the doctor.

Explain the present invention by the following examples, rather than be intended to limit by any way.

Embodiment

Embodiment 1 Symadex in vitro tests ^TM Suppressing LPS stimulates the propagation of back B cell Propagation with Con A stimulation back T-cell

In several in vitro testses, compare Symadex ^TMWith the activity of mitoxantrone, to determine Symadex ^TMEffect for the crucial regulating system of neural inflammation of several participation multiple sclerosis and antigen presentation.

IL-4 is the growth and the differentiation factor of B cell, mastocyte and macrophage, is the switch factor of synthetic IgE in mice.It also promotes the CD4 that clones ⁺The growth of T cell strengthens the expression of II class MHC molecule and the increase of static bone-marrow-derived lymphocyte.In human body, CD4 ⁺The T lymphocyte also produces IL-4, but does not show at people IL-4 and can be used as B cell or mast cell growth factor.Mus and people IL-4 induce bone-marrow-derived lymphocyte to be converted to synthetic IgE.People IL-4 also induces the CD23 of human B lymphocyte and macrophage to express.IL-4 may have certain effect by tool for cell-mediated immunity.

IL-10 suppresses T _HThe cytokine of 1 cell is synthetic, blocking-up antigen presentation, and the generation of inhibition interferon gamma.IL-10 suppresses the macrophage antigen-presenting and forms the ability of IL-1, IL-6 and TNF-α.IL-10 also participates in IgE and regulates.Although IL-10 suppresses cell-mediated immunity, it is at the lymphocytic responsiveness of stimulated in vitro bone-marrow-derived lymphocyte, IL-2 and IL-4T, and the Mus mastocyte is exposed among IL-3 and the IL-4.By suppressing T lymphocyte autoimmune, IL-10 can be applied in multiple sclerosis and the type i diabetes to therapeutic, and is used to promote allograft's survival.

This experiment in, in RPMI pH of buffer 7.4 with test-compound and/or carrier and human peripheral Monocyte (PBML, 1x10 ⁶/ m l) precincubation is 2 hours.Then at 37 ℃ and 5%CO ₂Under add concanavalin A (Con A, 20 μ g/ml) and stimulate this cell to spend the night.With the sandwich ELISA test kit level of IL-4 in the conditioned medium and IL-10 cytokine is carried out quantitatively then.Screen this chemical compound with 10,1,0.1,0.01 and 0.001 μ M.

Use is an isolating B-lymphocyte the spleen of balb/c mice of 17 ± 1g from weight.Under 37 ℃, in AIM-V medium pH 7.4, in the presence of 10 μ g/m l lipopolysaccharide (LPS), this cell (1.5x10 ⁶/ ml) with test-compound and/or carrier incubation 24 hours.Add then [ ³H] thymidine (120nM) enters another incubation period of spending the night.Estimating thymidine by liquid scintillation counting mixes.

Use is an isolating T-lymphocyte the thymus of balb/c mice of 17 ± 1g from weight.Under 37 ℃, in AIM-V medium pH 7.4, in the presence of 3 μ g/mL concanavalin As (Con A), this cell (4x10 ⁶/ ml) with test-compound and/or carrier incubation 24 hours.Add then [ ³H] thymidine (120nM) enters another incubation period of spending the night.Estimating thymidine by liquid scintillation counting mixes.

Screen this chemical compound with 10,1,0.1,0.01 and 0.001 μ M.

Mitoxantrone and Symadex ^TMThe results are shown in the table 1.Than vehicle Control reply high 50% or the inhibition of the inductive on cell proliferation of test-compound of more (〉=50%) shown that it suppresses active significantly.

Table 1		Symadex TM		Mitoxantrone
							Concentration	The % growth inhibited	IC50	The % growth inhibited	IC50
Medium discharges, IL-4
							10μM	105	3.33μM	108	2.96μM
	1μM	-9		-4
							0.1μM	2		18
	10nM	7		13
							1nM	8		11
Medium discharges, IL-10
							10μM	99	1.2μM	102	0.759μM
	1μM	39		60
							0.1μM	16		5
	10nM	16		1
							1nM	1		2
Cell proliferation, B-cell+LPS
							10μM	103	0.038μM	102	7.31nM
	1μM	101		102
							0.1μM	80		93
	10nM	38		54

	1nM	0		18
						Cell proliferation, T-cell+Con A
	10μM	104	0.014μM	103	0.032μM
							1μM	103		103
	0.1μM	82		80
							10nM	44		19
	1nM	10		-1

The result of table 1, Figure 1A and 1B and Fig. 2 A and 2B shows, Symadex ^TMSuppressed in for example release of very important inflammatory mediator IL-4 and IL-10 in the multiple sclerosis of neural inflammatory diseases.In addition, Symadex in relating to B-and T-cells in vitro proliferation test ^TMShown high-caliber growth inhibited.Symadex ^TMActivity suitable with the control compound mitoxantrone.

Embodiment 2 is continuing in the treatment cycle in 4 weeks Symadex once in a week ^TM Alleviate slow The disease of property multiple sclerosis animal model-experimental autoimmune encephalomyelitis (EAE) Shape

The method that a kind of demonstration medical compounds is used for the treatment of the application of the various diseases relevant with multiple sclerosis (MS) is its ability that suppresses the experimental autoimmune encephalomyelitis effect in laboratory animal.

Experimental autoimmune encephalomyelitis (EAE) is the animal model of MS, and it need induce the cell-mediated autoimmune disease at the T-of myelin basic protein in some responsive mammal kind.The EAE model be a kind of suitable research brain relevant and spinal cord inflammation with MS method (referring to Bolton, C.Mult, Scler, 1995; 1 (3); 143-9).

In rodent, injection of whole spinal cord or spinal cord components for example myelin basic protein can induce autoimmune response based on the T-lymphocyte activation.8-10 days left and right sides clinical diseases become obviously usually after inoculation, observe multiple dystropy, and scope comprises that slight gait disorder and tail are unable until complete paralysis and death.Typically taken place to lose weight.In the animal that survives, spontaneous recovery has taken place, be attended by the recovery in various degree of most of motor functions.Different with employed method according to species, allergen, the animal by the EAE model measurement may be subjected to once (acute EAE) or (chronic recurrent EAE) invasion and attack several times.

The treatment of EAE has many versions: treatment can be preventative, wherein administering therapeutic compositions before immunity; Treatment can be in inductive first week beginning; And treatment can be intervention property, begins after clinical symptoms development (acute or chronic).Preventative in the literature scheme right and wrong usually see that the treatment after the morbidity is more rare, and the treatment after the several weeks of falling ill is the most rare.The experiment that this paper reported belongs to last a kind of classification, and wherein treatment is to have the animal of demyelination speckle widely in chronic-progress (CP) phase.In complete Freund's adjuvant, be a kind of vigorous disease that extensive inflammatory and demyelination change that has by the inductive CP-EAE of full CNS.As general principle, we believe that the intervention of success can be predicted the effectiveness in the human disease better later the time.This is relevant especially with the situation of Prevention Research, and what wherein this Prevention Research was paid close attention to is the periphery immune system, rather than at the problem as the CNS inflammation of the existence of MS character.

Method

The deactivation tubercule bacillus that the complete Freund's adjuvant of the full CNS (in saline) of usefulness homogenate and equivalent and 10mg add in this experiment is with female Hartley Cavia porcellus childhood (225g) immunity.The acute events of the different orders of severity taking place between the 7th to 20 day, successive clinical abnormal conditions take place then, comprises back acroparalysis, fecal impaction and incontinence.Table 2 has shown the clinical score standard.The spinal column marrow demyelination of these Clinical symptoms indication inflammation-induced.Recently to studies show that of previous experiment, check that after 40 days clinical score be that " 2 " continue the animal above 1 week, has 97% the demyelination speckle to occur in spinal cord.

In these experiments, the animal of immunity is nursed, until the 40th or the 52nd day, then weekly 1 time with 8mg/kg and 16mg/kgSymadex ^TM(intracardiac) or 20mg/kg and 40mg/kg Symadex ^TM(intraperitoneal) 4 weeks of treatment.Matched group gives carrier.Note down clinical indication every day, and the record body weight.After the treatment phase finishes, cut brain and spinal cord, with formalin fixed and sealing, with hematoxylin-eosin with scratch Lip river chromium-R-anthocyanin stained is carried out meningitis, perivascular infiltration (forming cover (cuffing)), essence myelitis and demyelination by the double blinding observer routine pathology inspection.

Put to death untreated chronic EAE animal (n=5) and non-EAE control animal (n=5) at the 40th day.According to per 10 days treatment at interval, put to death 5 animals (0.25ml pentobarbital sodium) of every group, collect blood sample and carry out facs analysis (seeing below), cut brain and spinal cord and make section.Use three spinal cord slices, corresponding to lumbar region, regio pectoris and the neck region of spinal cord.Brain is cut into 5 transverse sections: preceding 3 nearsides section is combined into one, and latter two distally section is disconnected from each other.To be organized in 10% formalin and fix, and be embedded in the paraffin.With hematoxylin-eosin (H-E) or scratch Lip river chromium-R-anthocyanin (SCR), be evaluated as a kind of of following 4 apoplexy due to endogenous wind by the double blinding observer: meningitis, perivascular infiltration, encephalitis or myelitis and demyelination (table 2) with 5 microns section statining.The histological scores that merges is represented the overall score (may be 20 fens) of all 5 CNS sections of every animal.

Table 2

The histological scores standard

____________________________________________________________________________

M: the inflammatory reaction in the meninges

0: do not change

1: around the monocytic blood vessel and/or meninges soak into, relate to 1-3 root blood vessel

2: relate to 4-6 root blood vessel

3: relate to 6 more than the blood vessel

4: the intensive infiltration of meninges relates to all or nearly all blood vessel

P: essence perivascular infiltration

0: do not change

1:1-3 root essence blood vessel soaks in virchow-Robin spaces

2: relate to 4-6 root blood vessel

3: relate to 6 more than the blood vessel

4: in fact relate to all blood vessels

E: encephalitis or myelitis

0: do not invade neural essence; Microgliacyte or inflammatory cell are invaded neural essence

1: the dispersive cell of minority

2: the cell from several perivascular cuffs is invaded

3: relate to large-area neural essence

4: in fact whole section is soaked into

D: demyelination, Remyelination and myelin fragment

0: do not have demyelination

Demyelination kitchen range or myelin fragment under 1: one mantle

2: several little demyelination kitchen ranges

3: one big demyelination merge areas

4: the demyelination merge area that several are big

_________________________________________________________________________________

Abnormal conditions in order quantitatively to observe in spinal cord will be divided into 12 representational pie-shaped sections with the painted section of H-E.In each district, count at 0.12-mm with Sigma Scan Pro image analysis software (SPSS) ²The number of cell in the big visual field, the summation of calculating cell average in all 12 districts is to be used for whole spinal cord (36 visuals field of every animal).It should be noted that when counting all nucleus, the number of cell may comprise neuron and neurogliocyte except soaking into.Therefore, with the cell counting of non--EAE animal as baseline.

The result

When with 20 and Symadex during 40mg/kg (intraperitoneal) administration ^TMIn clinical progress and pathology discovery, all produced very big and change in essence.The average clinical score of animal when Fig. 3 has shown the appointed date after this.The animal of treatment all demonstrates clinical recovery to a certain degree, and wherein the 40mg/kg group has realized recovery at begin treatment in 2 weeks.

Fig. 4 further illustrates the time-histories of recovering from disease.In this experiment, vehicle Control has shown the stable course of disease.20 and the treatment animal of 40mg/kg group enter this research at the severity of disease during greater than matched group, the phenomenon of random packet has caused the situation of this unanimity before the TA group.As the arrow indication,, carry out 4 dosage altogether at the 40th day begin treatment.When treatment finished, two treatment groups had shown that all disease significantly is improved to the level that significantly is lower than matched group, although disease levels is on matched group when entering research.Even for the groups of 3 to 4 animals, the p value also shows significance,statistical, thereby has supported treatment can produce the result's who significantly is different from matched group hypothesis.This relatively comes to determine by with Mann-Whitney or Wilcoxon rank test median difference being carried out nonparametric.For 40 and 20mg/kg group, the significance value is respectively 0.001 and 0.004.

It is very uncommon that pathology are found.The scoring of meningitis and perivascular infiltration is ratio even more serious in the vehicle Control group (data are unlisted) in the treatment group.But we observe two very important discoveries: existing damage has great loss cell (data are unlisted), and we to observe previous myelin pale (myelin pallor) be because demyelination regeneration (data are unlisted).Discovery in back and CNS are owing to the forfeiture inflammatory cell allows Remyelination to match.

Demyelination is the crucial pathological characteristics of MS infringement.This has not only changed the electroresponse of aixs cylinder, and present viewpoint thinks that long demyelination can cause the permanent damage and the death of aixs cylinder.Neural degeneration also is a key factor of MS pathological conditions.In this, verified Symadex ^TMIn chronic progressivity model even at the progression of disease after date that reaches 97% spinal cord demyelination, also can allow endogenic Remyelination effectively.As if it can recover CNS by the inflammation that reduces in the existing damage.The Symadex that is prolonging ^TMIn the treatment, may observe chronic demyelination speckle, in fact not have the inflammatory cell of reservation, some such damages have shown the myelin pale (being called the YIN macules among the MS) of indication Remyelination.By removing these cells or downward modulation or suppressing cell and transport and prevent new T-cellular infiltration can prevent of the gathering of other macrophage to inflammation damnification.As a result, the death of the immunocyte of injury region owing to apoptosis, damage can not soaked into relatively.Thereby the tissue toxicity of removing the macrophage of cytokine and ROS-mediation will allow CNS to carry out repair mechanism to come to life, and observes Remyelination.Therefore, Symadex probably ^TMAlso has effect for the periphery immune system, although can not get rid of direct effect to the CNS inflammation.

The lasting existence of big inflammation cover (inflammatory cuffs) and the meninges inflammation scoring that is higher than matched group are consistent with immunocompetent leukocytic continuous generation, and these leukocyte are accumulated in the CNS blood vessel, but can not be transported in the essence.

Embodiment 3 in the weekly treatment cycle that continued for 4,6,8 weeks and administration 4 week- Stop to treat in the cycle in 4 weeks Symadex ^TM Alleviate chronic multiple sclerosis animal mould The symptom of type---experimental autoimmune encephalomyelitis (EAE)

According to several targets of hope, embodiment 2 described experiments are expanded to bigger group and long treatment cycle.Except the discovery of confirming the initial stage, concerted effort is intended to prove the degree and the persistency of response, comprises that effect after the drug withdrawal and proof Drug therapy for Immune Effects, to disclose infringement or toxic any signal may take place.

After inducing disease as mentioned above, animal is divided into 5 groups at random, 1 vehicle Control group and 4 treatment groups.The animal of treatment group is used the medicine (Symadex that is studied with the 20mg/kg intraperitoneal ^TMTwo hydrochloric acid trihydrates), 1 time weekly, totally 4,6 and 8 weeks, another group is treated totally 4 weeks and treated for 4 weeks again and observe with carrier solution (saline) rather than medicine weekly 1 time.

This group immune animal that obviously is not both of comparing with the method for embodiment 2 on only scheme gets rid of the disease severity and selects greater than 2 animal, and random packet is so that every group average disease severity and severity scoring scope 1 is complementary to 1.5.Adopting this standard is for fear of at 2 kinds of cas fortuits that observe of embodiment, and the animal of promptly selecting to be used for the treatment of should be with the severity begin treatment greater than the respective carrier matched group.

The animal of all treatments has shown that aspect disease statistics improves significantly.That is to say, they since the paralysis symptom that the demyelination progress of inflammatory cell invasion and attack nerve cord essence is produced be reduced near baseline, premorbid level.Only promptly can prove these results, also can prove the significance of its height by the statistical analysis of nonparametric, rank order by observing course of disease figure.

As shown in Figure 5, the result of 4 all treatment cycle (n=14) show the scoring of clinical severity have from begin to occur disease average 1.3 to average level 0.7 downward trend.This change and matched group (n=13) have significant difference, and the median of the p value of difference is 0.0001.In Fig. 6, prove similar dose response, this Figure illustrates the therapeutic process in 6 weeks.Simultaneously disease improves, and drops to 0.3 (n=3) of treatment group from the average severity scoring 1.3 of matched group (n=4), and significance,statistical p value is 0.009.What Fig. 7 showed is the treatment group in 8 weeks.It should be noted that the vehicle Control group, its disease shows to more serious degree progress, therefore owing to demyelination shows more serious paralysis, rises to 1.7 from 1.3 gradually after 4 weeks.On the contrary, in two treatment groups, shown the improvement of PD, shown and reversed demyelination.In the animal groups with the treatment of 8 successive doses, the trend that clinical score changes before normal, disease is indefinite during in beginning, but has all reached baseline when finish the course of treatment.Although recovery curve has interindividual variation, total rank order the analysis showed that the difference between treatment group (n=3) and the matched group (n=5) is significant, and the p value is 0.0006.The treatment group stops treatment after 4 weeks, disease keeps stable between withdrawal time, and its level also has significant difference with matched group, and the p value is 0.002.

The result of this research as shown in Figure 7.At first, the treatment answer list understands it is the time response step by step that is different from matched group.Infected animal is more healthy gradually along with replying the persistent period weekly, and control animals irreversibly develops into dysneuria completely, and its basic reason is irreversible demyelination.Secondly, the drug action of accumulating of Drug therapy is persistent, because animal of being treated and treatment degree correspondingly remain on steady statue, and untreated matched group keeps expediting the progress of disease.According to present most promising carrying out property MS therapeutic agent is that alpha 4 integrin antagonists such as Tysabri and the resulting effect of micromolecule part equivalent thereof are (as people (J.Neuroimmunology such as Piraino P.S., 131:147-159,2002) described), this is noticeable especially observed result.When stopping to treat in the Cavia porcellus EAE of identical MS model, the animal of treatment group returned to the disease levels of untreated matched group in 7 days, did not have evidence to show that useful effect of drugs prolongs.

Between Symadex and the alpha 4 integrin antagonists, and Symadex and other stop the adverse consequences that occurs between the therapeutic agent of the cell-mediated inflammatory response of T-, are because Symadex is not the activation by inflammatory cell and raises its effect of bringing into play.Shown in embodiment 2, the histopathology of the animal spinal cord of putting to death with regular intervals of time in whole disease recovery time-histories has shown accumulating of inflammatory cell in blood vessel and the perivascular cuff, rather than reduces.But these cells have obviously been blocked the change of passing through the essence basement membrane and moved, and prompting is blocked by the mechanism that relates to following aspect: cell adhesion, mobility and extracellular matrix are rebuild.

Compare with the corticosteroid, interferon and the integrin antagonist for treating that do not change T cell mass or T-cell subsets ratio, can prove having any different property of Symadex binding mode and beyond thought feature.In this embodiment, shown in the A figure among Fig. 8, between treatment group arbitrarily and vehicle Control group, do not observe the Cytometric difference of total T-.As scheme shown in B and the C Symadex ^TMTreatment can not regulated CD4 or CD8 T-cell mass.Even the B-cell is also less than showing that there were significant differences with matched group, although along with the time of disease or treatment has a declining tendency.Treat with the cytotoxicity of MS that for example mitoxantrone and cyclophosphamide are similar, according to the evidence of embodiment 1, Symadex ^TMCan in post-stimulatory cell culture, temporarily reduce the B-cell number, but this effect and not obvious when the long period is exposed in the body.Viewpoint below this observation has further been supported: Symadex ^TMPlay a role by new mechanism, this mechanism is not got rid of immune system, can not reduce the defence of host to the pathogen of antigen presentation yet.This character is that people are in demand, and all is favourable in any treatment of MS and healthy receptor for example being intended to treatment of chronic diseases or acute illness.

Embodiment 4 after at interval using 2 dosage with 72 hours, Symadex ^TM Alleviate slow Property multiple sclerosis animal model---experimental autoimmune encephalomyelitis (EAE) Symptom

To using Symadex once in a week ^TMThe disease recovery time-histories the analysis showed that the improvement of disease has 2 to 3 days periodicity during treatment.This phenomenon is obvious especially in 8 all treatment groups shown in Figure 7.In this group, can see different the replying of animal individual, thereby average drug effect is replied at successive administration and is presented " sawtooth " pattern between interval.When this organized the record of concrete animal in tracking, the demonstration some of them were temporarily recovered, and showed amelioration of disease in 2-3 days after giving a dosage, were returned to the disease with high scoring then.This total trend caused amelioration of disease 8 weeks, and still " sawtooth " type is replied the treatment time of steadily the reversing problem at interval that phenomenon has proposed to realize about the best disease symptoms.

In order to test the probability that more frequent dosage regimen solves disease symptoms more quickly, to test administration cycle and the property of being observed acknowledge cycle are complementary.Therefore, test 2 method is applied to a treated animal and matched group, makes it in the immunity back chronic phase that reached disease in 30 days.The selection disease score is 6 animals of 1, and half uses 20mg/kgSymadex by intraperitoneal ^TMTreatment.Gave these 3 animals 2 dosage at interval with 72 hours.3 animals are as vehicle Control in addition.

As shown in Figure 9, the Symadex of 72 hours programs ^TMTreatment has reversed the progress of disease, has only just returned to the baseline clinical score with 2 dosage, and disease continues progress in matched group.This difference is that statistics is significant, and by rank test, the p value is 0.002.

This experiment shows, can regulate more frequent Symadex ^TMUse, so that between medicine holdup time, inflammatory cell intrinsic procedure, reach specific balance the time character of myelinic invasion and attack and the Remyelination that allowed.Therefore, expect that reasonably the combination of dosage regimen can at first be used for quickening by more frequent or intensive medicine delivery program the recovery of disease, then with lower frequency but regular booster dose is kept the beneficial effect of blocking inflammatory cell." sawtooth " pattern formula prompting Symadex that the treatment of proof and disease reverse in Fig. 7 and embodiment 3 ^TMEffect can be between administration decay in 2-3 days interval.This experimental results show that Symadex ^TMEffectiveness can strengthen by more frequent administration.

Embodiment 5 induces administration every day at initial stage, Symadex in disease ^TM Alleviate acute multiple The symptom of sclerosis animal model---experimental autoimmune encephalomyelitis (EAE)

As described in embodiment 2, the EAE model in the Cavia porcellus is biphasic.In initial immunity myelin basic protein impaired after, the typical clinical pattern of nerve injury is that the acute sign with the 9th day disease after the immunity begins.Clinical episodes causes losing weight, back myasthenia of limbs and righting reflex are unusual.The severity of these symptoms was reaching the peak after 6-7 days, be that transient continuous and part disappear then, until the 20th day, when the course of disease is changed into stable carrying out property and disappeared, did not just have clinical recovery.

As an important expansion of the application of Symadex, check that it in disease early stage therapeutical effect takes place.This experiment is further set up on the result's of embodiment 4 basis, and the results suggest of embodiment 4 administration more continually can quicker and uniaxially mitigation symptoms.Because the acute stage of EAE is the still not necessarily progressive disease of simulation game also, as desired in alleviation-recurrence type multiple sclerosis human patients, this experiment further is designed for the effectiveness that check is compared with mitoxantrone.As described in the early time, mitoxantrone is the therapeutic agent of approved, has been the Symadex of cardiac toxicity causative agent as becoming known ^TMThe starting point of the chemical evolution of molecule minus toxicophore.

Therefore, use the Symadex of 6mg/kg respectively ^TMThe mitoxantrone treatment of (total salt hydrate) and 0.35mg/kg suffers from the Cavia porcellus by three random group of the inductive EAE of method of embodiment 2.Once a day by peritoneal injection treatment animal, the 7th day began 15 days totally after the immunity.The matched group vehicle treatment.Our inference, 15 successive dosage are the Symadex of 6mg/kg ^TMRepresented drug exposure level is identical with " per 72 hours 20mg/kg " scheme of embodiment 4, and with embodiment 2 in to give the moderate exposure level of 20mg/kg and 40mg/kg scheme weekly consistent.The dosage of mitoxantrone is chosen as and reflects that give the typical high dose of rat or mice every day in the prior art, but Cavia porcellus is amplified in proportion.

From result shown in Figure 10 as can be seen, use Symadex ^TMOr the group of rice holder anthracene treatment has shown and the diverse trend of vehicle Control group.Clinical score stably increases after the seizure of disease in matched group, until the 15th day, is distinctive of short duration recovery then, and begins the soaring for the second time higher disease severity that reached by the 20th day.In the situation of mitoxantrone and Symadex, stoped the rising of nerve injury when beginning, all animals continuation recover to foundation level in the whole administration phase.But, show Symadex by the statistical analysis of Mann-Whitney rank test ^TMTherapeutic effect all have significance,statistical with respect to the effect of matched group and mitoxantrone, the p value is less than 0.05.The difference of the effect of mitoxantrone and the scoring of the median between the matched group does not have significance,statistical.Figure 11 has shown the weight increase curve, and weight increase is the sensitive indicator of Cavia porcellus overall health.Acute EAE seizure of disease has caused the quick reduction of body weight, develops into after the 15th day and stably recovers.Control animals and Symadex ^TMThe animal of treatment has recovered the ability of weight increase every day, and this is when Cavia porcellus is healthy or at the preictal sign of serious chronic disease.But in the environment of this experiment, the mitoxantrone of low relative dosage can alleviate the acute clinical symptoms of EAE, but it has also damaged the increase of body weight, and this is the sign that the general of effective and wide spectrum cytotoxic drug is independently replied.By the Mann-Whitney rank test, vehicle Control group and Symadex ^TMThe weight increase curve ratio of group does not more show significance,statistical, and Symadex ^TMAnd the difference between the mitoxantrone reached significance,statistical, and the p value is 0.034.

These results show, in the whole process of active disease, no matter be early stage acute stage or chronic phase, and Symadex ^TMAll change the performance of EAE, and do not brought deleterious cytotoxicity load.Observation before pathological analysis shown in Figure 12 has confirmed by embodiment 2 described Histological methods, i.e. Symadex ^TMStoped inflammatory cell invasion and attack essence.This is because between the model of action of the inhibitive ability of immunity medicine in mitoxantrone and the mitoxantrone classification significant difference is arranged.Although two kinds of medicines have identical result for reduction perivascular cuff (P), myelitis (E) with the effect of demyelination (D), judge Symadex according to the statistical significant difference of comparing with matched group (p value＜0.05) ^TMWith mitoxantrone meninges inflammation (M) is not shown identical effect.Mitoxantrone is a kind of immunosuppressant, the blocking-up inflammatory cell activation and raise, cause meninges inflammation (M) statistics to reduce significantly.And Symadex ^TMThen not like this, although similar substantially according to all the other 3 its therapeutic outcomes of histopathological evaluation.

These discoveries are relevant with people's morbid state because think it does not damage for effective treatment MS disease the host create antagonism sporadic infection immunity be that the ability of replying of inflammatory is particularly advantageous.It is replied for damaging the cytotoxic agent that gastrointestinal function and nutrition keeps, and the negative effect of normal growth and weight increase has not been shown the advantage of another safety in these Cavia porcelluss tests, and this has the Symadex of helping ^TMTreatment.Symadex ^TMThe 15 days dosage of accumulation for the treatment of acute active disease is 90mg/kg.

Proportionally amplifying to people's dosage level has obtained corresponding people's dosage is 540mg/m ²Body surface area (as free alkali), this has proved safe and well-tolerated single dose, and it is lower than the 640mg/m as per three all repeat administrations ²Dosage.On the other hand, mitoxantrone dosage amplify in proportion obtain total physiognomy when dosage be 45mg/m ²Owing to use 12mg/m in the administration cycle at 3 months when treatment MS ²Mitoxantrone, this represented 1 year the treatment accumulated dose.Therefore, in the comparative example about Symadex ^TMFind to show with the experiment of the relative effectivenes of mitoxantrone, in human body, single dose Symadex ^TMShown and be similar to (if not being higher than) mitoxantrone treatment benefit of 1 year course of treatment.

Embodiment 6Symadex ^TM Alleviate the inductive arthritis (rheumatoid of collagen antibodies in the mice The animal model of property arthritis and autoimmune disease) symptom

Rheumatoid arthritis (RA) is a kind of autoimmune disease, is characterised in that the chronic erosive inflammation in the joint, causes the infringement of cartilage and bone.Some diseases change property rheumatism (DMARDS) can be used for the treatment of RA.Current, two kinds of inhibitor and methotrexates (MTX) that most important DMARDS is a tumor necrosis factor (TNF-α).A kind of method of the application of proof pharmaceutical compound in the various RA relevant diseases of treatment is to suppress collagen monoclonal antibody (mABs) to induce arthritic in mice.

Collagen-induced arthritis (CIA) is the experimental autoimmune disease, can induce in rodent (rat and mice) and non-human primate's sensitive strain by II Collagen Type VI (the main constitutive protein of articular cartilage) immunity.CIA shows as mice limb edema and erythema.This autoimmune model has several identical clinical and pathological characteristicses with rheumatoid arthritis (RA), and has become research RA model the most widely.People such as Courtenay were at (Courtnay in 1980, J.S., Dallman, M.J., Dayman, A.D., Martin A., and Mosedale, B. (1980) Immunisation againstheterologou stype II collagen induces arthritis in mice.Nature283 666-668) has at first described the CIA in the mouse model.Similar with RA, the II quasi-molecule of major histocompatibility complex (MHC) has been regulated the sensitivity to CIA, has shown that the T cell brought into play conclusive effect.

Method

Induce arthritis with all big BALB/c strain mices of every group of 3 6-7 by anti-II Collagen Type VI monoclonal antibody (mABs) and lipopolysaccharide (LPS).The combination intravenous of 4 kinds of different mA Bs of 4mg/ mice (D8, F10, DI-2G and A2) was applied to animal altogether at the 0th day, and (the 3rd day) uses the LPS intravenous of 25mg/ mice to stimulate after 72 hours then.Since the 3rd day, respectively oral test material and carrier, every day 1 time for three days on end.For every animal, the 0th, 5,7,10,14 and 17 days volumes with two rear solid ends of plethysmometer mensuration with moisture unit (12mm diameter).Calculate the inhibition percentage ratio that the inductive volume of mABs+LPS increases by following formula:

Suppress (%): [1-(Tn-T0)/(Cn-CO)] x100%

Wherein:

C0 (Cn): the volume of the 0th day (n days) in the vehicle Control group

T0 (Tn): the volume of the 0th day (n days) in the test-compound treatment group

The edema of rear solid end reduces 30% or be considered to significant more.

The result

Be the outbreak of monitoring CIA, measure the volume of two rear solid ends of mice of mAB treatment.In the animal of matched group (carrier) treatment, the very fast inflammation of claw increases by 42% at the 5th day volume, observes maximum volume at the 10th day, and swelling begins to disappear then.As shown in figure 13, at Symadex ^TMIn the treatment group, the 5th day initial stage swelling is a shade below matched group (32% to 42%), and at the 10th day (29% to 75%), the 14th day (18% to 70%) and the 17th day (19% to 47%) observed the remarkable reduction (measuring by corpus unguis is long-pending) of inflammation.Show all that according to the average difference of paired t-test with according to the median difference of nonparametric Mann-Whitney rank test the p value is less than 0.01.

Conclusion

In mice CIA model, Symadex ^TMProof has significant arthritis activity, shows significant anti-inflammatory activity in the 10th day (61% suppresses), the 14th day (74% suppresses) and the 17th day (59% suppresses).These find that usually the content about EAE and autoimmune disease conforms among the embodiment with the front, because they have proved Symadex ^TMRender a service by beyond thought mechanism performance.The collagen antibodies model of rheumatoid arthritis has meaning, because it has walked around the main inflammation damnification of antigen presentation.Classical antiinflammatory for example corticosteroid and antifol for example methotrexate can alleviate consequence by the main incident of inflammation-inhibiting cell-stimulating and reconstruction from the immune inflammation disease.The model of antibody induction has produced the symptom of disease, and this symptom comes across the later stage that autoimmunity is replied, after activated cell invasion is in the cartilage, have outer blend to become move, just as the situation of the long-term invasion and attack essence of MS.

Methotrexate, a kind of standard care agent has shown to produce the benefit that disappears in the model of antibody induction, than transportation and transport property, its less in essence T-cell-stimulating that depends on.People's such as Lange work can refer to herein { Annals ofRheumatoid Disease64:599-605,2005}.On the contrary, Symadex ^TMThen in full force and effect in this model.The result of this embodiment is relevant especially with the treatment human patients, because this therapeutic effect is by oral acquisition.In injectable biological preparation epoch of blocking antibody for example, it is special needs that by oral route adds effective non-inhibitive ability of immunity treatment.

Embodiment 7 Symadex ^TM The downward modulation inflammatory cell adheres to, cell surface signal conduction and thin The target drone system of other overexpressions of born of the same parents' propagation

In order to study Symadex ^TMTreatment is carried out the microarray test for the effect of gene expression.

Select two kinds of colorectal cancer cell strains (HT29 and HCT116) to study, its behavior as the invasive cell of fast breeding goes for many other such cell types of different tissue sources.These two kinds of colon cancer cells that cell strain is an infinite multiplication.Known their gene expression ways is the behavior of analog neuron-enterocyte, has therefore suitably simulated the adjusting pattern of the type of finding in the cell in similar epithelium or endothelium source.Cell with these body roots (ontological root) also is to be adapted at the autoimmune common in the tissue in neural intestinal source and the model of inflammation sensitivity, for example itself has the situation of inflammatory bowel.

Here note to use differential gene expression array (people such as Zhang J., " Neuralsystem-enriched expression:relationship to biologicalpathways and neurological diseases ", Physiol.Genomics 18:167-183,2004) study it is verified in axoneure and the incoherent tissue of anatomy gene expression pattern redundant and concomitant completely.For example, Zhang and he's colleagues have studied 8734 kinds of expression of gene products in 10 districts of nervous system and 30 peripheral organs, with its instruction by with reference to being incorporated herein.They the analysis showed that, about 70% gene relevant with nervous system disease also comprises in the tissue of epithelial origin and the peripheral blood at a plurality of tissues expresses.These researcheres are further pointed out, but the preface type analysis of gene that derive from the different peripheral tissues of easier sampling relevant with nervous system disease will help to obtain the understanding to the better machine-processed aspect of these diseases.Therefore, in gene expression research, use colon cell as exemplary model understand medicine to the common approach of these cells and neural system tissue to act on that experiment learns be incontrovertible.

Therefore, (hereinafter be called Symadex with preferred imidazoles acridine compositions ^TM) as described belowly specifically study, to prove the mechanism of action of chemical compound of the present invention.

Cell is at the Symadex of GI50 concentration (being respectively 0.68 and 0.21 μ M for HT29 and HCT116 cell strain) ^TMThere is growth down, after exposing 1,8 and 48 hour, above-mentioned cell collected with untreated contrast part.With the refrigerated cell precipitation thing of in triplicate form cracking, the total RNA of purifies and separates (all reagent are all from Ambion) on the spin post.After reaching purity and obtaining QC approval, change total RNA into cRNA by linear amplification, 10 μ g samples are added on the CodeLink Human Whole GenomeBioarrays (GE Healthcare and GenUs Biosystems).

This array is handled with in triplicate form, and is carrying out comparing behind the strong statistical analysis to repeating diversity.Use CodeLink Expression Analysis (GEHealthcare) and GeneSpring (Silicon Genetics) software, if the change of comparing with baseline by the t testing identity is significant (p＜0.05, α=0.025), then thinks gene (comprising ESTs) differential expression.Change by software kit EASE and GoMiner that uses open acquisition and " multiple " that uses Pathways Analysis (Ingenuity Systems) to filter in expressing then, determine wrong discovery rate and performance in standardized gene ontology (gene ontology)/approach.Further seeking function then in MedMiner literature search environment explains.

In the sampling interval that test in 24 hours is cultivated, the gene of 271 kinds of downward modulations is performance significantly in from two kinds of cell types in the array of 55000 login genetic fragments.Table 3 is listed it, and wherein the data representation on first hurdle is with respect to the multiple of matched group change, and gene symbol is represented on second hurdle, and third column has been quoted the Genbank accession number, and the 4th hurdle provides the concise and to the point description of gene function.

Table 3: because Symadex ^TMThe gene that acts on and significantly reduce

Average multiple with respect to the contrast change	Gene symbol	The GENBANK accession number	Describe
				-17.00-9.43-2.07-21.74-12.02-22.71-2.71-1.92-13.15-2.29-2.21-8.24-9.43	ACTA2ACVRL1ACYP1ADCYAP1ADH1CAGTALG5ANAPC4APOA1ARL6IPASAH2ATP1B4ATP2B3	AL713608NM_000020AA664719NM_001117NM_000669NM_000029NM_013338NM_013367NM_000039NM_015161AF250847AI659245NM_021949	Actin; α 2; smooth muscle; large artery trunks I I type activin A receptor-sample 1 acylphosphatase 1; erythrocyte (common) type adenyl cyclase activated polypeptides 1 (hypophysis cerebri) alcoholdehydrogenase 1C (I class); γ polypeptide proangiotensin (serine (or cysteine) protease inhibitor; evolution A (α-1 protease inhibitor; antitrypsin); the member 8) the glycosylation 5 homologue (yeast that connect of agedoite; dol i chyl-phosphoric acid β-glucosyltransferase) promotes complex subunit 4 apolipoprotein A-1 ADP-ribosylation-samples 6 interaction protein N-acyl sphingosine asparaginase (non-lysosome ceramidase) 2ATP enzymes the anaphase of cell division; (Na+)/the K+ transportation; β 4 polypeptide A TP enzymes, Ca++ transportation, plasma membrane 3

-2.08-2.22-23.65-2.17-12.57-1.91-2.58-2.11-15.52-1.92-11.45-12.99-2.51-2.14-2.40-13.25-2.09-2.99-8.14-19.89-2.14-2.38-54.48-2.54-23.19-2.13-2.53-26.26-20.65-1.88-1.94-3.14-2.09-2.36-2.95-3.39-2.15-2.24-89.97-9.75-3.07-2.18-2.08-28.71-15.24-2.13-15.36-6.35-3.39-3.32-2.11

BADBAG2BBS2BCAP29BGNBIRC5BLMC10ORF7C3AR1CAMK1CASRCCL23CCNB2CD164CD58CD5LCDC2CDC25CCDKL1CENTA1CHRNA5CKS1BCOL1A2COPS3COX6A2CREMCSE1LCSRP3CYP19A1D8S2298EDCKDCLRE1ADDX1DEKDHFRDLEU2DNAJB11DNAJD1DSC3DSCR1L1DTYMKDUSP12DUTEGFL6EIF2AK4EIF2S1EIF4EL3ENGERHFAIMFARS1

NMJD04322NM_004282T26496NM_018844NM001711NM_001168NM_000057NM_006023NM_004054NM_003656BX106711NMJD05064NM_004701NM_006016NM_001779NM_005894NM_001786NM_001790NM_004196NM_006869NM_000745NM_001826NM_000089NM_003653NM_005205NM_001881NM_001316NM_003476NM_000103NM_005671NM_000788NM_014881NM_004939NM_003472AU127142NM_006021NM_016306NM_013238NM_001941NM_005822NM_012145NM_007240NM_001948NM_015507AI630242NM_004094BX111619BM665467NM_004450NM_018147NM_006567

Athanogene2 bardet-Biedl syndrome B-cell receptor related protein 29 biglycans that the BCL2-antagonist BCL2 of cell death is relevant comprise protein kinase I calcium conduction receptor (the low urine calcium hypercalcemia 1 that baculovirus IAP multiple 5 (survivin) Bloom syndrome chromosome 10 opening code-reading frames 7 complement component 3a receptors 1 depend on calcium/calmodulin, CaM, severe neonate hyperparathyroidism) chemotactic factor (C-C motif) part 23 mitotic cycle protein B 2 CD164 antigens, sialomucin CD58 antigen, (antigen 3 that lymphocyte function is relevant) CD5 antigen-sample (being rich in the family that removes the receptor cysteine) cell division cycle 2, G1 to S and G2 to M cell division cycle 25C cell cycle dependant kinase sample-1 (CDC2-relevant enzyme) centaurin, α 1 cholinoceptor, nicotine, α polypeptide 5CDC28 protein kinase is regulated subunit 1B collagen, the I type, α 2COP9 composing type photomorphogenesis homologue subunit 3 (arabidopsis) cytochrome C oxidase subunit unit VI a polypeptide 2cAMP response element regulator CSE1 chromosome separation 1-sample (yeast) is rich in protein 3 (the heart LIM albumen) Cytochrome P450 of cysteine and glycine, family 19, subtribe A, polypeptide 1 duplicates the crosslinked reparation of 8 deoxycytidine kinase enzyme dnas 1A (PSO2 homologue, saccharomyces cerevisiae) DEAD (Asp-Glu-Al a-As p) box polypeptide 1DEK oncogene (DNA combination) dihydrofolate reductase lacks in Lymphocytic leukemia, 2DnaJ (H s p40) homologue, subtribe B, member 11DnaJ (H sp40) homologue, subtribe D, member's Bridge 1 grain glycoprotein 3 mongolism key area gene 1-samples 1 deoxyribosylthymine acid kinase (thymidylate kinase) dual specificity phosphotase 12 dUTP pyrophosphatase EGF-sample-territory, multi ple6 eukaryotic translation initiation factor 2 alpha kinases 4 eukaryotic translation initiation factors 2, the enhancer Fa s apoptosis that subunit 1 α, 35kDa eukaryotic translation initiation factor 4E-sample 3endoglin (O s ler-Rendu-Weber syndrome 1) do not grow homologue (fruit bat) suppresses molecule phenylalanine-tRNA synthetase 1 (mitochondrion)

-17.42-13.00-11.62-2.87-9.02-9.60-10.14-2.44-1.96-19.73-62.09-2.51-2.81-18.16-11.49-80.43-13.80-2.56-2.31-2.35-2.63-1.97-2.94-7.42-1.93-2.08-13.76-58.56-9.79-11.23-28.60-25.20-10.64-27.91-2.12-2.73-15.06-15.93-6.83-24.13-7.23-2.52-11.04-24.24-3.34-11.85-57.61-87.48-11.94

FBLN1FBN1FCARFEN1FNTAFOXN1GABRA3GDAP1GGHGIPRGJB5GLAGMNNGNALGPR1GPR15GPR24GPR54H2AFXH2AFZHAT1HMGB1HMMRHNF4AHNRPA2B1HSGT1HSPB2IBSPIL13RA2IL1RAPIL1RL1IL7RITGA2BITGA9ITGAETGB3BPITSN1KCNJ12KCNJ15KCNQ2KIAA0089KIF2CKIF5AKLRG1KRT13LCP2LIMS2LNXLPAAT-E

NM_001996NM_000138NM002000NM_004111BI715309NM_003593NM_000808NM_018972NM_003878NM_000164NM_005268NM_000169NM_015895BX116836CB992712NM_005290NMJD05297NMJ332551NM_002105NM_002106NMJD03642NM_002128NM_012484NM_000457NM_002137NM_007265NM_001541NM_004967NM_000640AK095107NM_003856NM_002185NM_000419BF959890NM_002208NM_014288NM_003024NM_021012NM_002243NM_004518NM_015141NM_006845AL118561NM_005810NM_002274NMJ305565NM017980AL565198NM_018361

The Fc fragment of fi bulin1 fibrillin 1 (Marfan syndrome) I gA, receptor valve structure specificity endonuclease 1 method Buddhist nun acyltransferase, the CAAX box, α jaw box N1 γ-An Jidingsuan (GABA) A receptor, α 3 gangliosides-inductive differentiation associated protein 1 gamma-glutamyl base hydrolase (conjugase, the leaf acyl gathers gamma-Glutamyl hydrolase) CIP receptor gap junction protein, β 5 (connecting protein 31 .1) Lac Bovis seu Bubali glycosidase, α geminin, dna replication dna inhibitor guanine nucleotide binding protein (G albumen), α activates active polypeptide, olfactory sensation type G albumen-coupled receptor 1G albumen-coupled receptor 15G albumen-coupled receptor 24G albumen-coupled receptor 54H2A histone family, member XH2A histone family, movable receptor (RHAMM) the stem cell nuclear factor 4 of member Z histone acetyltransferase 1 high migration group box 1 hyaluronan mediation, inhibitor heat shock 27kDa albumen 2 integrins-bonded sialoprotein (bone sialoprotein of α heterogeneity nucleic acid ribonucleoprotein A2/B1 saccharomyces cerevisiae gcr2, bone sialoprotein III) interleukin-13 receptor, α 2 interleukin 1 receptor auxilin interleukin 1 receptor-samples 1 interleukin-17 receptor beta 2 integrin alpha 2b (platelet glycoprotein of Nb11b/111a complex, antigens c D41B) integrin, α 9 beta 2 integrin alpha E (antigens c D103, people's mucosa lymphocyte antigen 1; The α polypeptide) the inner passage of revising of integrin β 3 conjugated protein (β 3-endonexin) inter sect in1 (SH3 territory albumen) potassium; subtribe J; the inner passage of revising of member's 12 potassium; subtribe J; member's 15 potassium voltage-gated channels; KQT-sample subtribe member 2KIAA0089 albumen kinesin family member 2C kinesin family member 5A killer cell agglutinin-sample receptor subtribe G, the part acid acyltransferase ε of member's 1 keratin 13 lymphocyte solute albumen 2 (the 76kDa leukocyte albumen that comprises the SH2 territory) LIM and senile cell antigen-sample territory 2 numb albumin Xs

-2.40-15.01-12.57-3.14-12.89-2.14-26.53-1.89-1.97-2.69-2.39-10.83-2.20-2.04-2.02-2.97-2.16-2.29-2.20-17.46-16.21-2.09-59.05-2.66-21.22-50.59-33.67-21.83-2.51-15.58-10.52-6.89-16.69-2.01-2.41-2.12-15.94-54.82-14.89-17.54-2.08-17.10-2.34-2.02-1.89-2.68-16.33

LPAAT-ELRP1BLTBMAD2L1MAP6MAPK13MAPTMAZMCM6MCM7MEAMGAT4AMIS12MPZL1MRPL1MRPL11MRPL13MRPL23MRPL39MSLNMT1AMT2AMTIF2MXD3MYBPC2MYO15ANCF1NCF2NDUFA6NDUFB3NDUFV3NEBNFATC1NFKBIBNMINMUNR0B1NR2E1NR2E3NRG1NT5C3NT5ENTHL1NUCKSNUDT1NUP107OLR1

NM_018361NM_018557NM_002341NM_002358AB058781NM_002754BM714794NM_002383NM_005915NM_005916NM_014623AI364966NM_024039NM_003953NM_020236NM_016050NM_014078NM_021134NM_017446NM_005823BM684446BG505162AI064964BQ053282NM_004533NM_016239BI021745NM_000433NM_002490NM_002491AW139027AI079911NM_006162NM_002503NM_004688NM_006681NM_000475NM_003269NM_016346NM013956AA188573BM994339NM_002528NM_022731NM_002452NM_020401CD678960

Acid acyltransferase ε low density lipoprotein, LDL associated protein 1 B (in tumor, lacking) lymphotoxin-beta (TNF superfamily; the member 3) the MAD2 mitosis stops relevant zinc finger protein (the bonded transcription factor of purine) the MCM6 minichromosomes of defective-sample 1 (yeast) microtubule-associated protein 6 mitogen activated protein kinases 13 microtubule-associated protein tauMYC-and keeps defective 6 (MI S5 homologue; the Semen setariae yeast) (saccharomyces cerevisiae) MCM7 minichromosomes is kept and is lacked 7 (saccharomyces cerevisiae) male enhanced antigen manno syl (α-1; 3-)-glycoprotein β-1; the 4-N-acetylglucosaminyl transferase; mitochondrial ribosomal protein L 13 mitochondrial ribosomal protein L 23 mitochondrial ribosomal protein L 39me sothel in metallothionein 1A (functional) the metallothionein 2AI factor (component) MAX protein dimerizations 3 cardiac myosin binding protein-C of the homologue myelin protein 0-sample 1 mitochondrial ribosomal protein L 1 mitochondrial ribosomal protein L 11 of isozyme A yeast Mi s12; the quick type myosin XVA neutrophilic granulocyte solute factor 1 (47kDa; chronic granulo matosis; autosome 1) the neutrophilic granulocyte solute factor 2 (65kDa; chronic granulo matosis; autosome 2) the inferior complex of nadh dehydrogenase (ubiquinone) 1 α; 6; the inferior complex of 14kDaNADH dehydrogenase (ubiquinone) 1 β; 3; 12kDaNADH dehydrogenase (ubiquinone) fiavoprotein3; the nuclear factor of the activated T-cell of 10kDa nebulin; Cytoplasm; the nuclear factor of the kappa light polypeptide genetic enhancer of neurocalcin dependency 1 in the B-cytostatics; β N-myc (and STAT) interaction agent neuromedin U nuclear receptor subtribe 0; the B group; member's 1 nuclear receptor subtribe 2; the E group; member's 1 nuclear receptor subtribe 2; the E group; member's 3 neuregulins 15 '-nucleotidase; cytosol III5 '-nucleotidase, outer (CD73) n Cobra venom endonuclease I I I-sample 1 (escherichia coli) nuclear ubiquitous casein kinase and cell cycle protein dependent kinase substrate nudi x (the part X that nucleoside diphosphate is connected)-type motif nucleoporin 107kDa lysyl oxidase

-2.68-12.85-2.25-2.03-19.65-16.89-2.21-16.85-17.53-10.55-2.17-2.95-3.73-2.39-8.04-15.36-1.88-2.62-2.04-2.24-2.49-26.54-36.93-3.78-3.47-25.92-22.21-18.91-2.43-6.00-2.31-2.28-2.21-2.04-84.42-8.81-7.09-2.02-2.31-2.29-11.95-2.54-2.22-39.17-68.37-2.38-2.43-2.14-2.00-14.52-16.54

OXCTPAFAH1B1PAFAH1B2PAICSPCDH7PCSK2PDCD5PDE11APECAM1PFKLPHAXPHF5APIR51PLK4PLXNA3PMPCBPOIAPOLE2POLE4POLR3KPPIHPPP1R9APPP2R5APRDM1PRIM1PRLRPRSS21PTPRGPTTG1PXNRACGAP1RAD18RAD51RAD54BRB1RBBP9RCOR1RFC4RNASEH2ARNF141ROBO4RPA3RPC62RPL4RPS3RQCD1RYR3SARA1SCAMP3SCNN1GSEMA7A

NM_000436AI674778NM_002572NM_006452NM_032457NM_002594NM_004708NM_016953BG739826AK098228NM_032177NM_032758NM_006479NM_014264BF926082AK090763NM_016937NM_002692NM_019896NM_016310NM_006347AB033048AA496141NM_001198NM_000946AA708864NM_006799C047734NM_004219AW969600NM_013277NM_020165NM_002875NM_012415BI769614NM_006606NM015156NM_002916NM_006397NM_016422NM_019055NM_002947NM_006468BF308998BM693455NMJ305444BU533957NM_020150NM_005698NM_001039NM_003612

3-keto acid CoA transferring enzyme 1 platelet activating factor PAF-AH, special-shaped Ib, α subunit 45kDa platelet activating factor PAF-AH, special-shaped Ib, β subunit 30kDa ribose phosphate aminooimidazole carboxylase, the preceding convertase of ribose phosphate aminooimidazole succinum carbamyl synthetase BH-protocadher in (brain-heart), subtilisin/kexin2 type programmed cell death 5 phosphodiesterase 11A platelet/endothelial cell adhesion molecule (CD31 antigen) phosphofructokinases, the mice phosphorylation convergence body of liver RNA output possible directly to congener PHD finger protein 5ARAD51-interaction protein polo-sample kinases 4 (fruit bat) plexin A3 peptidase (mitochondrion processing) β polymerase (DNA guiding), α polymerase (DNA guiding), ε 2 (p59 subunit) polymerase (DNA guiding), ε 4 (p12 subunit) polymerase (RNA guiding) I I I (DNA guiding) polypeptide K, 12.3kD peptidyl prolyl isomerase H (cyclophilin H) protein phosphatase 1, regulate (inhibitor) subunit 9A phosphoprotein phosphatase 2, regulate subunit B (B56), αYi Gouti comprises 1 of PR territory, has ZNF territory primase, polypeptide 1,49kDa prolactin antagonist receptor protein enzyme, serine, 21 (te sti sin) Protein-tyrosine-phosphatase, receptor type, G hypophysis cerebri tumor-conversion 1 post albumen Rac gtpase activating protein 1RAD18 homologue (saccharomyces cerevisiae) RAD51 homologue (RecA homologue, escherichia coli) (saccharomyces cerevisiae) RAD54 homologue B (saccharomyces cerevisiae) retinoblastoma retinoblastoma bindin 9 REST 1 (comprising osteosarcoma) corpresor 1 replication factor C (activator 1) 4,37kDa ribonuclease H 2, big subunit ring finger protein 141roundabout homologue 4, magi c roundabout (fruit bat) replication protein A 3,14kDa polymerase (RNA) II I (DNA guiding) peptide C (62kD) nucleoglucoprotein L4 nucleoglucoprotein S3 needs RCD1 Sri Lanka Cortex Cinnamomi alkali receptor 3SAR1a gene homologue 1 (saccharomyces cerevisiae) secretion vector memebrane protein 3 sodium channels of cell differentiation 1 homologue (Semen setariae yeast), non-valtage-gated 1, γ sema territory, immunoglobulin territory (Ig), with the GPI membrane anchor, (letter

-2.84-7.34-11.76-2.93-2.78-11.21-11.51-18.72-2.23-19.44-27.75-15.57-8.20-17.45-2.31-14.75-6.57-16.71-13.79-2.20-1.92-2.41-10.91-293.18-2.33-2.23-1481.77-12.26-2.04-9.82-11.00-20.30-3.41-2.23-2.02-2.34-2.21-2.64-36.20-13.71-2.55-8.14-2.11-2.24-2.13-12.47

SFRS3SHOXSIAT7ASIN3BSIVASLC1A2SLC22A13SLC27A6SLC35B1SLC6A4SLC7A13SLC9A3SLC9A7SNAI2SNRPD3SPO11SPOCKSPTBSRYSSSCA1STK6STMN1SULT1E1SULT4A1SUV39H2SYNCRIPSYNE1TAC3TADA2LTCP11TFAP2ATFECTHOC4T1MM10TIMM23TK1TMEM4TMPOTNP1TPSD1TRA2ATRHTSFMTTKTXNDCTYRP1

NMJ303017NM_000451NM_018414AW051366NM_006427NM_004171NM_004256NM_014031NM_005827NM_001045NMJ38817NM_004174AA279477NM_003068NM_004175NM_012444NM_004598NM_000347NM_003140NM_006396NM_003600NM_005563NM_005420NM_014351NM_024670NM_006372NM033071NM_013251NM_001488NM_018679NM_003220NM_012252NM_005782NM_012456NM_006327NM_003258NM_014255H57815NM_003284NM_012217BF093914NM_007117AW603708NM_003318NM_030755NM_000550

Number element) 7A splicing factor; be rich in arginine/serine 3 short stature homology frame sialyltransferases 7 ((neural aminoacyl-2 of α-N-acetyl; 3-beta galactose base-1; 3)-N-acetamino galactosidase α-2; the 6-sialyltransferase) ASIN3 homologue B; transcriptional regulatory (yeast) CD27-is in conjunction with (Siva) albumen solute carrier family 1 (neuroglia high-affinity glutamic acid carrier); member 2 solute carrier families 22 (organic cation carrier); member 13 solute carrier families 27 (fatty acid carrier); member 6 solute carrier families 35; member B1 solute carrier family 6 (neurotransmitter carriers; 5-hydroxy tryptamine); member 4 solute carrier families 7; (cation amino acid vectors; the y+ system); member 13 solute carrier families 9 (sodium/hydrogen exchange dose); isomer 3 solute carrier families 9 (sodium/hydrogen exchange dose); isomer 7 Limax homologue 2 (fruit bat) small nuclear ribonucleoprotein D3 polypeptide 18kDa and the covalently bound SPO11 meiosis of DSB-sample albumen (saccharomyces cerevisiae) spa rc/ osteonectin; cwcv and kazal-sample territory Dan Baijutang (te stican) spectrin; β; erythrocyte (comprises spherocytosis; clinical I type) sex-determining region Y's Sjogren syndrome/scleroderma autoantigen 1 serine/threonine kinase 6stathmin1/ cancer protein 18 1E of sulfotransferase family; estrogen is preferred; member 1 4A of sulfotransferase family; the inhibitor synaptotagmin combination of member's 1 piebaldism 3-9 homologue 2 (fruit bat); the cytoplasm rna interaction protein comprises spectrin to be repeated; nuclear envelope 1 tachykinin 3 (neuromedin K; neurokinin β) transcribes adapter 2 (ADA2 homologue; yeast)-sample t-compound 11 (mice) transcription factor AP-1-2 α (activating enhancer binding protein 2 α) transcription factor ECTHO complex 4 mitochondrial inner membranes 10 translocase homologue (yeast) mitochondrial inner membranes 23 translocase homologue (yeast) thymidine kinases 1; solvable transmembrane protein 4 thymopoietin transitional proteins 1 (at histone in protamine transforms) plasmin δ 1 changes son-2 α throtropin releasing hormone T s translation elongation factors, and mitochondrion TTK protein kinase comprises thioredoxin territory tyrosinase-related protein 1

-1.99-10.12-1.92-66.26-12.46-2.22-2.79-2.07-30.18-2.66-2.03-31.24-2.17-2.31

U2AF1UBL4UMPKUSP16VAPAVDAC3VRK1WWOXZNF145ZNF258ZNF265ZNF282ZNRD1ZW10

NM_006758A873769NMJD12474NM_006447AI671488NM_005662NM_003384NM_016373BU607554NM_007167NM_005455NM_003575NM014596NM004724

U2 (RNU2) small nuclear rna cofactor 1 general peptide-sample 4 uridnine monophosphate kinases general peptide specific protease 16VAMP (vesicle related membrane protein)-associated protein A, 33kDa voltage dependent form anion channel cowpox associated kinase 1 comprises oxidoreductase zinc finger protein 14 5 (the Kruppel-sample in WW territory, reaching at the promyelocytic leukemia invading the exterior) zinc-finger protein 25 8 zinc finger protein 26s 5 zinc finger protein 28s 2 comprise the banded territory of zinc, 1ZW10 homologue, centromere/kinetochore protein (fruit bat)

Analyze

Look back the tabulation of gene ontology in this article, shown Syma dex ^TMFor cell aggregation and mechanism of proliferation with the process relevant with the growth of invasive cell had great pleiotropic effects, these processes are signs of the inflammation cause of disease relevant with the described autoimmune disease of beginning.

For example, the more labor of evidence shows in the his-and-hers watches 3, the conduction of the gene of quite a few downward modulation and cell surface signal, movable, migration is relevant with adherent mechanism, it allows inflammatory cell to pass the blood vessel barrier, is penetrated in the essential layer.It will be understood to those of skill in the art that these bodies close in the document that ties up in the data base of public sphere more detailed description is arranged, and can take passages following information therefrom.These data bases comprise DAVID (Database forAnnotation, Visualization and Integrated Discovery, from National Institute of Allergy and Infectious Disease, http://appsl.niaid.nih.gov/david/; At sister's program EASE of same site (Expression Analysis Systematic Explorer); With GeneCardsbioinformatics project (http//genome- Www.stanford.edu/genecards/index.shtml).

For example, in the differential gene expression experiment that is discussed below, gene A CTA2, ACVRL1, BGN, DSC3, ENG, FBAN1, FBLN1, HMMR, IGTA2B, ITGA2B, ITGA9, ITGAE, LIMS2, LTB, MAPT, MSLN, NMI, PCDH7, PECAM1, PRDM1, SEMA7A, the VAPA of downward modulation pass through directly to regulate adhesion factor for example integrin and cadherins, or participate in the adjusting of these processes by destroying the auxilin assembling that promotes the growth factor signal of expressing and further promote adhesion process.Particularly importantly significant 1500 times of downward modulations of SYNE1 spectrin repeating part in this article.Keep the structural intergrity of the tissue and the cytoskeleton of nuclear by the auxilin of the nesprin family of this gene code, the downward modulation of estimating SYNE1 will weaken inflammatory cell in shape and the geometric ability of keeping them between the invasion and attack active stages.Therefore, Symadex ^TMThis effect for the differential gene expression of the mechanism of keeping the cell conformation will make these cells during transportation collapse, and this result also is consistent with the histopathology of the therapeutical effect pattern of Syma dex.

The necessary process that calcium ion and energy-rich phosphate produce is affected in succession, and this can be confirmed by the downward modulation of ATP1B4, ATP2B3, CAMK1, EGFL6, GPR24, IBSP, NUDT1, RAD54B, RYR3 and SLC9A7.Cell proliferation is again by B I RC5, CCL23, CCNB2, CDC2, CDC25C, CKS1B, CREM, EGFL6, FCAR, IL13RA2, IL1RAP, IL1RL1, and the cell cycle of MAPK13, NRG1, PTPRG, STK6 and the mediation of other related genes is blocked process and is prevented from.The neuroregulation of controlling by paracrine and autocrine also is significantly in the downward modulation of system, and this system further produces neural inflammation infringement and replys, and comprises that the neurotransmitter carrier relevant with infringement, glutamic acid signal out of control conduct.Example at the gene of back one apoplexy due to endogenous wind downward modulation comprises ADCYAP1, GABRA3, GGH, KCNQ3, SLC1A2 (and the solute carrier homologue of SLC family) and SULT4A1.A kind of gene in back has shown nearly 300 times downward modulation.It is the gene relevant with the heparan sulphation.Sulfated heparan has constituted " strand ", allows integrin to be attached on the laminin, therefore provides to allow the invasive inflammatory cell to move to connection in the CNS essence by basement membrane.The downward modulation of estimating this process can remain on inflammatory cell in the scope of vascular cuffing, as shown in the embodiment 2-8 to Symadex ^TMIt is viewed such during the histopathology of therapeutical effect is estimated.

Be subjected to Symadex ^TMThe integration function of these genes of influence is consistent with the differential expression spectrum that observes in the microarray test, people such as ArnettHA for example, " Functional genomicanalysis of remyelination reveals importance of inflammationin oligodendrocyte regeneration ", J.Neuroscience23 (30): 9824-9832,2003; People such as Lindberg RLP, " Multiplesclerosis as ageneralized CNS disease-comparative microarray analysis ofnormal appearing white matter and lesions in secondaryprogressive MS ", J.Neuroimmunology152:154-167,2004; With people such as Tajouri L., " Quantitative and qualitative changes in geneexpression patterns characterize the activity of plaques inMultiplesclerosis ", Mol.Brain Res.119:170-183,2003 work.These researchs have been listed the characteristic of representative autoimmune inflammation damage and recovery subsequently in the mode that is similar to gene description as herein described, particularly in the content of multiple sclerosis as the autoimmunity demyelination model of main conditions.Therefore, Symadex ^TMAnd congener is used for the treatment of the multiple sclerosis with similar cause of disease and the viewpoint of autoimmune disease, can prove aspect the molecular pharmacology of chemical compound.

Although the present invention has been carried out concrete expression and statement with reference to embodiment preferred, but it will be understood to those of skill in the art that, can under not breaking away from the condition that is included in the scope of the present invention in the appended claims, make various changes in form and details.

Sequence table

＜110〉Xanthus Pharmaceuticals Inc.

A.M. A Jiami

M.A. win this

J. Pei Tesen

＜120〉be used for the treatment of the chemical compound of autoimmune disease and demyelination

<130>3287.1006-004

<140>PCT/US2006/002952

<141>2006-01-27

<150>60/647,980

<151>2005-01-28

<150>60/757,736

<151>2006-01-09

<160>5

<170>FastSEQ for Windows Version4.0

<210>1

<211>20

<212>PRT

＜213〉artificial sequence

<220>

＜223〉corresponding to the polypeptide of the position 39-58 of human T cell receptor Vbeta6CDR2

<400>1

Leu Gly Gln Gly Pro Glu Phe Leu Thr Tyr Phe Gln Asn Glu Ala Gln

1 5 10 15

Leu Glu Lys Ser

20

<210>2

<211>21

<212>PRT

＜213〉artificial sequence

<220>

＜223〉corresponding to the immunogenic polypeptide of the position 75-95 of human myelin basic protein

<400>2

Lys Ser His Gly Arg Thr Gln Asp Glu Asn Pro Val Val His Phe Phe

1 5 10 15

Lys Asn Ile Val Thr

20

<210>3

<211>17

<212>PRT

＜213〉artificial sequence

<220>

＜223〉tiplimotide is corresponding to the immunogenic polypeptide of the position 83-99 of human myelin basic protein

<400>3

Ala Lys Pro Val Val His Leu Phe Ala Asp Ile Val Thr Pro Arg Thr

1 5 10 15

Pro

<210>4

<211>17

<212>PRT

＜213〉artificial sequence

<220>

＜223〉derive from the immunogenic peptide of human myelin basic protein

<400>4

Asp Glu Asp Pro Val Val His Phe Phe Lys Asp Ile Val Thr Pro Arg

1 5 10 15

Thr

<210>5

<211>39

<212>PRT

＜213〉people

<220>

＜221〉peptide

<222>(0)...(0)

＜223〉people ACTH

<400>5

Ser Tyr Ser Met Glu His Phe Arg Trp Gly Lys Pro Val Gly Lys Lys

1 5 10 15

Arg Arg Pro Val Lys Val Tyr Pro Asp Gly Ala Glu Asp Glu Leu Ala

20 25 30

Glu Ala Phe Pro Leu Glu Phe

35

Claims (96)

1. method for the treatment of the patient who suffers from inflammatory diseases comprises chemical compound or the acceptable salt of its pharmacy to the general formula (A) of described patient's administering therapeutic effective dose:

Wherein:

R is-H, the optional alkyl that replaces, hydroxyl, alkoxyl, halogen, the group represented by following structural formula:

Or, R and R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them;

Or, R and R ⁴With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them; With

R ²Be-H, choose the C1-C10 alkyl that replaces wantonly or choose aryl or the heteroaryl that replaces wantonly;

R ³Be-(CH ₂) n-NR ^aR ^b, n=1-5 wherein, R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently, or-NR ^aR ^bBe on one or more commutable carbon atom by optional N-morpholinyl or the N-pyrazinyl that replaces of methyl, hydroxyl or methoxyl group, and wherein the N-pyrazinyl be by the C1-C4 alkyl or-NR ^cR ^dThe C1-C4 alkyl that replaces is chosen N '-replacement, wherein R wantonly ^cAnd R ^dBe respectively-H, methyl or ethyl; With

R ⁴, R ⁵And R ⁶Be independently respectively-H ,-OH, halogen or C1-C6 alkoxyl; Or

R ⁵And R ⁶With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them.

2. the process of claim 1 wherein that the chemical compound of general formula (A) represented by general formula (I):

Wherein

R is-OH or C1-C6 alkoxyl;

R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently;

R ²Be-H or C1-C6 alkyl; With

N is the integer between 2 and 5.

3. the method for claim 2, wherein inflammatory diseases is systemic lupus erythematosus (sle), inflammatory bowel, psoriasis, Ke Laoen disease, rheumatoid arthritis, sarcoid, Alzheimer, chronic inflammatory demyelinating neuropathy, insulin dependent diabetes mellitus (IDDM), atherosclerosis, asthma, spinal cord injury or apoplexy.

4. the method for claim 2, wherein R be-OH or-OCH ₃

5. the method for claim 2, wherein n is 2 or 3.

6. the method for claim 2, wherein R ²Be-H or C1-C4 alkyl.

7. the method for claim 2, wherein R ^aAnd R ^bBe respectively the C1-C3 alkyl independently.

8. the method for claim 7, wherein R ^aAnd R ^bBe respectively ethyl or methyl independently.

9. the method for claim 2, wherein R ^aAnd R ^bBe respectively alkyl and optional by C1-C4 hydroxyalkyl, amino, C1-C4 N-alkyl-amino or C1-C4 N independently, the N-dialkyl amido replaces.

10. the method for claim 2, wherein R ^aAnd R ^bBe independently respectively-H or alkyl and optional by C1-C4 hydroxyalkyl, amino, C1-C4 N-alkyl-amino or C1-C4 N, the N-dialkyl amido replaces.

11. the method for claim 9, wherein R ^aAnd R ^bOn substituent group be ethoxy, amino-ethyl, N-alkyl amino ethyl and N independently, N-dialkyl amido ethyl.

12. the method for claim 2, wherein R be-OH or-OCH ₃, R ^aAnd R ^bIdentical and be methyl or ethyl; N is 2 or 3; R ²Be hydrogen or C1-C4 alkyl.

13. the method for claim 2, the chemical compound of its formula of (I) is selected from

14. the method for claim 2, the chemical compound of its formula of (I) is the chemical compound of general formula (III):

15. a method for the treatment of the patient who suffers from demyelination comprises chemical compound or the acceptable salt of its pharmacy to the general formula (A) of described patient's administering therapeutic effective dose:

Wherein:

R is-H, the optional alkyl that replaces, hydroxyl, alkoxyl, halogen, the group represented by following structural formula:

Or, R and R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them;

Or, R and R ⁴With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them;

R ²Be-H, choose the C1-C10 alkyl that replaces wantonly or choose aryl or the heteroaryl that replaces wantonly;

R ³Be-(CH ₂) n-NR ^aR ^b, n=1-5 wherein, R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently, or-NR ^aR ^bBe on one or more commutable carbon atom by optional N-morpholinyl or the N-pyrazinyl that replaces of methyl, hydroxyl or methoxyl group, and wherein the N-pyrazinyl be by the C1-C4 alkyl or-NR ^cR ^dThe C1-C4 alkyl that replaces is chosen N '-replacement, wherein R wantonly ^cAnd R ^dBe respectively-H, methyl or ethyl;

R ⁴, R ⁵And R ⁶Be independently respectively-H ,-OH, halogen or C1-C6 alkoxyl; Or

R ⁵And R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them.

16. the method for claim 15, the chemical compound of its formula of (A) is represented by general formula (I):

Wherein

R is-OH or C1-C6 alkoxyl;

R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently;

R ²Be-H or C1-C6 alkyl; With

N is the integer between 2 and 5.

17. the method for claim 16, wherein said disease be multiple sclerosis, congenital metabolic disease, have the neuropathy that unusual myelin forms, drug-induced demyelination, radiation-induced demyelination, heritability demyelination, the inductive demyelination of Protein virus, the inductive demyelination of encephalitis, spinal cord injury, Alzheimer or chronic inflammatory demyelinating neuropathy.

18. the method for claim 16, wherein R be-OH or-OCH ₃

19. the method for claim 16, wherein n is 2 or 3.

20. the method for claim 16, wherein R ²Be-H or C1-C4 alkyl.

21. the method for claim 16, wherein R ^aAnd R ^bBe respectively the C1-C3 alkyl independently.

22. the method for claim 21, wherein R ^aAnd R ^bBe respectively ethyl or methyl independently.

23. the method for claim 16, wherein R ^aAnd R ^bBe respectively alkyl and optional by C1-C4 hydroxyalkyl, amino, C1-C4 N-alkyl-amino or C1-C4 N independently, the N-dialkyl amido replaces.

24. the method for claim 16, wherein R ^aAnd R ^bBe independently respectively-H or alkyl and optional by C1-C4 hydroxyalkyl, amino, C1-C4 N-alkyl-amino or C1-C4 N, the N-dialkyl amido replaces.

25. the method for claim 23, wherein R ^aAnd R ^bOn substituent group be ethoxy, amino-ethyl, N-alkyl amino ethyl and N independently, N-dialkyl amido ethyl.

26. the method for claim 16, wherein R be-OH or-OCH ₃, R ^aAnd R ^bIdentical and be methyl or ethyl; N is 2 or 3; R ²Be hydrogen or C1-C4 alkyl.

27. the method for claim 16, the chemical compound of its formula of (I) is selected from

28. the method for claim 16, the chemical compound of its formula of (I) is the chemical compound of general formula (III):

29. a method for the treatment of the patient who suffers from multiple sclerosis comprises chemical compound or the acceptable salt of its pharmacy to the general formula (A) of described patient's administering therapeutic effective dose:

Wherein:

R is-H, the optional alkyl that replaces, hydroxyl, alkoxyl, halogen, the group represented by following structural formula:

Or, R and R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them;

Or, R and R ⁴With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them; With

R ²Be-H, choose the C1-C10 alkyl that replaces wantonly or choose aryl or the heteroaryl that replaces wantonly;

R ³Be-(CH ₂) n-NR ^aR ^b, n=1-5 wherein, R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently, or-NR ^aR ^bBe on one or more commutable carbon atom by optional N-morpholinyl or the N-pyrazinyl that replaces of methyl, hydroxyl or methoxyl group, and wherein the N-pyrazinyl be by the C1-C4 alkyl or-NR ^cR ^dThe C1-C4 alkyl that replaces is chosen N '-replacement, wherein R wantonly ^cAnd R ^dBe respectively-H, methyl or ethyl;

R ⁴, R ⁵And R ⁶Be independently respectively-H ,-OH, halogen or C1-C6 alkoxyl; Or

R ⁵And R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them.

30. the method for claim 29, the chemical compound of its formula of (A) is represented by general formula (III):

31. a method that promotes the neurocyte Remyelination in the patient of needs comprises chemical compound or the acceptable salt of its pharmacy to the general formula (A) of described patient's administering therapeutic effective dose:

Wherein:

R is-H, the optional alkyl that replaces, hydroxyl, alkoxyl, halogen, the group represented by following structural formula:

Or, R and R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them;

Or, R and R ⁴With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them;

R ²Be-H, choose the C1-C10 alkyl that replaces wantonly or choose aryl or the heteroaryl that replaces wantonly;

R ³Be-(CH ₂) n-NR ^aR ^b, n=1-5 wherein, R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently, or-NR ^aR ^bBe on one or more commutable carbon atom by optional N-morpholinyl or the N-pyrazinyl that replaces of methyl, hydroxyl or methoxyl group, and wherein the N-pyrazinyl be by the C1-C4 alkyl or-NR ^cR ^dThe C1-C4 alkyl that replaces is chosen N '-replacement, wherein R wantonly ^cAnd R ^dBe respectively-H, methyl or ethyl;

R ⁴, R ⁵And R ⁶Be independently respectively-H ,-OH, halogen or C1-C6 alkoxyl; Or

R ⁵And R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them.

32. the method for claim 31, the chemical compound of its formula of (A) is represented by general formula (I):

Wherein

R is-OH or C1-C6 alkoxyl;

R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently;

R ²Be-H or C1-C6 alkyl; With

N is the integer between 2 and 5.

33. the method for claim 32, wherein R be-OH or-OCH ₃

34. the method for claim 32, wherein n is 2 or 3.

35. the method for claim 32, wherein R ²Be-H or C1-C4 alkyl.

36. the method for claim 32, wherein R ^aAnd R ^bBe respectively the C1-C3 alkyl independently.

37. the method for claim 36, wherein R ^aAnd R ^bBe respectively ethyl or methyl independently.

38. the method for claim 32, wherein R ^aAnd R ^bBe respectively alkyl and optional by C1-C4 hydroxyalkyl, amino, C1-C4 N-alkyl-amino or C1-C4 N independently, the N-dialkyl amido replaces.

39. the method for claim 32, wherein R ^aAnd R ^bBe independently respectively-H or alkyl and optional by C1-C4 hydroxyalkyl, amino, C1-C4 N-alkyl-amino or C1-C4 N, the N-dialkyl amido replaces.

40. the method for claim 32, wherein R ^aAnd R ^bOn substituent group be ethoxy, amino-ethyl, N-alkyl amino ethyl and N independently, N-dialkyl amido ethyl.

41. the method for claim 32, wherein R be-OH or-OCH ₃, R ^aAnd R ^bIdentical and be methyl or ethyl; N is 2 or 3; R ²Be hydrogen or C1-C4 alkyl.

42. the method for claim 32, the chemical compound of its formula of (I) is selected from

43. the method for claim 32, the chemical compound of its formula of (I) is the chemical compound of general formula (III):

44. the method for claim 32, wherein said patient is the people.

45. the method for claim 44, wherein this people suffers from the disease that makes the cell demyelination, and wherein this disease is multiple sclerosis, congenital metabolic disease, has the neuropathy that unusual myelin forms, drug-induced demyelination, radiation-induced demyelination, heritability demyelination, the inductive demyelination of Protein virus, the inductive demyelination of encephalitis, spinal cord injury, Alzheimer or a chronic inflammatory demyelinating neuropathy.

46. the method for claim 44, wherein this people suffers from multiple sclerosis.

47. the method for claim 32, wherein this chemical compound is that parenteral is used.

48. the method for claim 32, wherein this chemical compound is the patient of chronic administration in needs.

49. the method for claim 48, wherein the chronic administration of this chemical compound be at least one year weekly or used in every month.

50. the method for claim 32, wherein antiinflammatory and described chemical compound are co-administered in the patient.

51. the method for claim 32, wherein EGFR inhibitor and described chemical compound are co-administered in the patient.

52. the method for claim 32, wherein VEGFR inhibitor and described chemical compound are co-administered in the patient.

53. the method for claim 32, wherein FGFR inhibitor and described chemical compound are co-administered in the patient.

54. the method for claim 32, wherein the T cell is gone back to the nest, is exosmosed or to become the inhibitor and the described chemical compound that move co-administered in the patient.

55. the method for claim 32, wherein VLA4 inhibitor and described chemical compound are co-administered in the patient.

56. the method for claim 32, wherein interferon and described chemical compound are co-administered in the patient.

57. the method for claim 32, wherein chemotherapeutant and described chemical compound are co-administered in the patient.

58. the method for claim 32, wherein immunotherapeutic agent and described chemical compound are co-administered in the patient.

59. the method for claim 50, wherein said antiinflammatory are thyroliberin, corticosteroid, interferon, acetic acid glatiramer or NSAID (non-steroidal anti-inflammatory drug).

60. the method for claim 59, wherein said interferon are interferon beta-1b or interferon beta-1a.

61. the method for claim 59, wherein said corticosteroid are prednisone, meprednisone, dexamethasone, hydrocortisone, cortisone, fludrocortisone, prednisolone, 6 α-methylprednisolone, triamcinolone or betamethasone.

62. the method for claim 59, wherein said corticosteroid is a prednisone.

63. the method for claim 59, wherein said NSAID (non-steroidal anti-inflammatory drug) be aspirin, sodium salicylate, Choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine, Olsalazine, p-aminophenyl amphyl, the furanone that replaces of indole, indeneacetic acid, heteroaryl acetic acid, ortho-aminobenzoic acid, bmap acid, alkane ketone, diaryl, pyrazoles, heteroauxing or the sulfonanilide that diaryl replaces.

64. the method for claim 32, wherein said chemical compound are oral, vein or subcutaneous administration.

65. the method for claim 64, wherein said chemical compound be intravenous administration in the patient, this use cause this chemical compound in the blood samples of patients valid density more than or equal to 10ng/ml.

66. the method for claim 64, wherein said chemical compound are to the amount intravenous administration of about 500 μ g with the every kg body weight 20 μ g of patient.

67. a compositions, it comprises chemical compound or the acceptable salt of its pharmacy and the antiinflammatory of the general formula (A) for the treatment of effective dose:

Wherein:

R is-H, the optional alkyl that replaces, hydroxyl, alkoxyl, halogen, the group represented by following structural formula:

Or, R and R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them;

Or, R and R ⁴With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them; With

R ²Be-H, choose the C1-C10 alkyl that replaces wantonly or choose aryl or the heteroaryl that replaces wantonly;

R ³Be-(CH ₂) n-NR ^aR ^b, n=1-5 wherein, R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently, or-NR ^aR ^bBe on one or more commutable carbon atom by optional N-morpholinyl or the N-pyrazinyl that replaces of methyl, hydroxyl or methoxyl group, and wherein the N-pyrazinyl be by the C1-C4 alkyl or-NR ^cR ^dThe C1-C4 alkyl that replaces is chosen N '-replacement, wherein R wantonly ^cAnd R ^dBe respectively-H, methyl or ethyl;

R ⁴, R ⁵And R ⁶Be independently respectively-H ,-OH, halogen or C1-C6 alkoxyl; Or

R ⁵And R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them.

68. the compositions of claim 67, the chemical compound of its formula of (A) is represented by general formula (I):

Wherein

R is-OH or C1-C6 alkoxyl;

R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently;

R ²Be-H or C1-C6 alkyl; With

N is the integer between 2 and 5.

69. the compositions of claim 68, wherein R be-OH or-OCH ₃

70. the compositions of claim 68, wherein n is 2 or 3.

71. the compositions of claim 68, wherein R ²Be-H or C1-C4 alkyl.

72. the compositions of claim 68, wherein R ^aAnd R ^bBe respectively the C1-C3 alkyl independently.

73. the compositions of claim 68, wherein R ^aAnd R ^bBe respectively ethyl or methyl independently.

74. the method for claim 68, wherein R ^aAnd R ^bBe respectively alkyl and optional by C1-C4 hydroxyalkyl, amino, C1-C4 N-alkyl-amino or C1-C4 N independently, the N-dialkyl amido replaces.

75. the method for claim 68, wherein R ^aAnd R ^bBe independently respectively-H or alkyl and optional by C1-C4 hydroxyalkyl, amino, C1-C4 N-alkyl-amino or C1-C4 N, the N-dialkyl amido replaces.

76. the compositions of claim 75, wherein R ^aAnd R ^bOn substituent group be ethoxy, amino-ethyl, N-alkyl amino ethyl and N independently, N-dialkyl amido ethyl.

77. the compositions of claim 68, wherein R be-OH or-OCH ₃, R ^aAnd R ^bIdentical and be methyl or ethyl; N is 2 or 3; R ²Be hydrogen or C1-C4 alkyl.

78. the compositions of claim 68, the chemical compound of its formula of (I) is selected from

79. the compositions of claim 68, the chemical compound of its formula of (I) is the chemical compound of general formula (III):

80. method that in the patient, reverses the paralysis that causes by demyelination, comprise administered compound to the patient, the amount of application of this chemical compound is enough to suppress the immunocyte in the lymphocytic infiltration spinal cord, to promote the Remyelination of neurocyte in the spinal cord, and the paralysis for the treatment of described patient thus, wherein this chemical compound is the chemical compound or the acceptable salt of its pharmacy of general formula (A):

Wherein:

R is-H, the optional alkyl that replaces, hydroxyl, alkoxyl, halogen, the group represented by following structural formula:

Or, R and R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them;

Or, R and R ⁴With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them;

R ²Be-H, choose the C1-C10 alkyl that replaces wantonly or choose aryl or the heteroaryl that replaces wantonly;

R ³Be-(CH ₂) _n-NR ^aR ^b, n=1-5 wherein, R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently, or-NR ^aR ^bBe on one or more commutable carbon atom by optional N-morpholinyl or the N-pyrazinyl that replaces of methyl, hydroxyl or methoxyl group, and wherein the N-pyrazinyl be by the C1-C4 alkyl or-NR ^cR ^dThe C1-C4 alkyl that replaces is chosen N '-replacement, wherein R wantonly ^cAnd R ^dBe respectively-H, methyl or ethyl;

R ⁴, R ⁵And R ⁶Be independently respectively-H ,-OH, halogen or C1-C6 alkoxyl; Or

R ⁵And R ⁵With form 5,6 or 7 yuan of optional cycloalkyl or nonaromatic heterocycles that replace between the carbon atom between them.

81. the method for claim 80, the chemical compound of its formula of (A) is represented by general formula (I):

Wherein

R is-OH or C1-C6 alkoxyl;

R ^aAnd R ^bBe respectively hydrogen or the optional alkyl that replaces independently;

R ²Be-H or C1-C6 alkyl; With

N is the integer between 2 and 5.

82. the method for claim 81, wherein R be-OH or-OCH ₃

83. the method for claim 81, wherein n is 2 or 3.

84. the method for claim 81, wherein R ²Be-H or C1-C4 alkyl.

85. the method for claim 81, wherein R ^aAnd R ^bBe respectively the C1-C3 alkyl independently.

86. the method for claim 81, wherein R ^aAnd R ^bBe respectively ethyl or methyl independently.

87. the method for claim 81, wherein R ^aAnd R ^bBe respectively alkyl and optional by C1-C4 hydroxyalkyl, amino, C1-C4 N-alkyl-amino or C1-C4 N independently, the N-dialkyl amido replaces.

88. the method for claim 81, wherein R ^aAnd R ^bBe independently respectively-H or alkyl and optional by C1-C4 hydroxyalkyl, amino, C1-C4 N-alkyl-amino or C1-C4 N, the N-dialkyl amido replaces.

89. the method for claim 87, wherein R ^aAnd R ^bOn substituent group be ethoxy, amino-ethyl, N-alkyl amino ethyl and N independently, N-dialkyl amido ethyl.

90. the method for claim 81, wherein R be-OH or-OCH ₃, R ^aAnd R ^bIdentical and be methyl or ethyl; N is 2 or 3; R ²Be hydrogen or C1-C4 alkyl.

91. the method for claim 81, the chemical compound of its formula of (I) is selected from

92. the method for claim 81, the chemical compound of its formula of (I) is the chemical compound of general formula (III):

93. the method for claim 81 also comprises co-administered immunosuppressant.

94. the method for claim 93, wherein said immunosuppressant are thyroliberin, corticosteroid or interferon.

95. the method for claim 94, wherein said interferon are interferon beta-1b or IF1 a.

96. the method for claim 94, wherein said corticosteroid are prednisone, meprednisone, dexamethasone, hydrocortisone, cortisone, fludrocortisone, prednisolone, 6 α-methylprednisolone, triamcinolone or betamethasone.

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