RU2005105344A - METHODS FOR TREATING OR PREVENTING AUTOIMMUNE DISEASES USING 2,4-PYRIMIDINEDIAMINE COMPOUNDS - Google Patents

Claims (48)

1. A method of treating or preventing an autoimmune disease and / or one or more symptoms associated with the disease, characterized in that it comprises the step of administering to a subject who is suffering from an autoimmune disease or at risk of developing an autoimmune disease, an effective amount of compound 2.4 -pyrimidinediamines corresponding to the structural formula (I)

and its salts, hydrates, solvates, N-oxides, where L ¹ and L ² individually and independently from each other selected from the group consisting of a direct link and a linker; R ^{2 is} selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more identical or different R ⁸ groups, (C3-C8) cycloalkyl optionally substituted with one or more identical or different R ⁸ groups, cyclohexyl, optionally substituted with one or more identical or different R ⁸ groups, a 3-8 membered cycloheteroalkyl, optionally substituted with one or more identical or different R ⁸ groups, (C5-C15) aryl, optionally substituted with one or more identical or different R ⁸ - Rupp, phenyl optionally substituted with one or more identical or different R ⁸ -groups, and 5-15 membered heteroaryl optionally substituted with one or more identical or different R ⁸ -groups; R ^{4 is} selected from the group consisting of hydrogen, (C1-C6) alkyl optionally substituted with one or more identical or different R ⁸ groups, (C3-C8) cycloalkyl optionally substituted with one or more identical or different R ⁸ groups, cyclohexyl optionally substituted with one or more identical or different R ⁸ groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more identical or different R ⁸ groups, (C5-C15) aryl optionally substituted with one or more identical or different known R ⁸ groups, phenyl optionally substituted with one or more identical or different R ⁸ groups, and a 5-15 membered heteroaryl optionally substituted with one or more identical or different R ⁸ groups; R ^{5 is} selected from the group consisting of R ⁶ , (C1-C6) alkyl optionally substituted with one or more identical or different R ⁸ groups, (C1-C4) alkanyl optionally substituted with one or more identical or different R ⁸ groups , (C2-C4) alkenyl optionally substituted with one or more identical or different R ⁸ groups and (C2-C4) alkynyl optionally substituted with one or more identical or different R ⁸ groups; each R ^{6 is} independently selected from the group consisting of hydrogen, an electronegative group, -OR ^d , -SR ^d , (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, -NR ^c R ^c , halogen, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CF ₃ , —CH ₂ CF ₃ , —CF ₂ CF ₃ , —CN, —NC, —OCN, —SCN, —NO, —NO ₂ , —N ₃ , —S (O) R ^d , -S (O) ₂ R ^d , -S (O) ₂ OR ^d , -S (O) NR ^c R ^c ; -S (O) ₂ NR ^c R ^c , -OS (O) R ^d , -OS (O) ₂ R ^d , -OS (O) ₂ OR ^d , -OS (O) NR ^c R ^c , -OS ( O) ₂ NR ^c R ^c , -C (O) R ^d , -C (O) OR ^d , -C (O) NR ^c R ^c , -C (NH) NR ^c R ^c , -OC (O) R ^d , -SC (O) R ^d , -OC (O) OR ^d , -SC (O) OR ^d , -OC (O) NR ^c R ^c , -SC (O) NR ^c R ^c , -OC (NH ) NR ^c R ^c , -SC (NH) NR ^c R ^c , - [NHC (O)] _n R ^d , - [NHC (O)] _n OR ^d , - [NHC (O)] _n NR ^c R ^c and - [NHC (NH)] _n NR ^c R ^c , (C5-C10) aryl optionally substituted with one or more identical or different R ⁸ groups, phenyl optionally substituted with one or more identical or different R ⁸ groups, ( C6-C16) arylalkyl optionally substituted with one or more identical or different R ⁸ -groups, 5-10 membered heteroaryl optionally zameschennog one or more identical or different R ⁸ -groups and 6-16 membered heteroarylalkyl optionally substituted with one or more identical or different R ⁸ -groups; R ^{8 is} selected from the group consisting of R ^a , R ^b , R ^a substituted with one or more identical or different R ^a or R ^b , -OR ^a , substituted with one or more identical or different R ^a or R ^b , -B ( OR ^a ) ₂ , -B (NR ^c R ^c ) ₂ , - (CH ₂ ) _m -R ^b , - (CHR ^a ) _m -R ^b , -O- (CH ₂ ) _m , -R ^b , -S - (CH ₂ ) _m -R ^b , -O-CHR ^a R ^b , -O-CR ^a (R ^b ) ₂ , -O- (CHR ^a ) _m -R ^b , -O- (CH ₂ ) _m - CH [(CH ₂ ) _m R ^b ] R ^b , -S- (CHR ^a ) _m -R ^b , -C (O) NH- (CH ₂ ) _m -R ^b , -C (O) NH- (CHR ^a ) _m -R ^b , -O- (CH ₂ ) _m -C (O) NH- (CH ₂ ) _m -R ^b , -S- (CH ₂ ) _m -C (O) NH- (CH ₂ ) _m -R ^b , -O- (CHR ^a ) _m -C (O) NH- (CHR ^a ) _m -R ^b , -S- (CHR ^a ) _m -C (O) NH- (CHR ^a ) _m - R ^b , -NH- (CH ₂ ) _m -R ^b , -NH- (CHR ^a ) _m -R ^b , -NH [(CH ₂ ) _m R ^b ], -N [(CH ₂ ) _m R ^b ] ₂ , -NH-C (O) -NH- (CH ₂ ) _m -R ^b , -NH-C (O) - (CH ₂ ) _m -CHR ^b R ^b ) and -NH- (CH ₂ ) _m - C (O) —NH— (CH ₂ ) _m —R ^b , each R ^{a is} independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; each R ^b represents an appropriate group independently selected from the group consisting of = O, -OR ^d , (C1-C3) haloalkyloxy, -OCF ₃ , = S, -SR ^d , = NR ^d , = NOR ^d , - NR ^c R ^c , halogen, —CF ₃ , —CN, —NC, —OCN, —SCN, —NO, —NO ₂ , = N ₂ , —N ₃ , —S (O) R ^d , —S (O ) ₂ R ^d , -S (O) ₂ OR ^d , -S (O) NR ^c R ^c , -S (O) ₂ NR ^c R ^c , -OS (O) R ^d , -OS (O) ₂ R ^d , -OS (O) ₂ OR ^d , -OS (O) ₂ NR ^c R ^c , -C (O) OR ^d , -C (O) OR ^d , -C (O) NR ^c R ^c , -C (NH) NR ^c R ^c , -C (NR ^a ) NR ^c R ^c , -C (NOH) R ^a , -C (NOH) NR ^c R ^c , -OC (O) R ^d , -OC (O) OR ^d , —OC (O) NR ^c R ^c , —OC (NH) NR ^c R ^c , —OC (NR ³ ) NR ^c R ^c , - [NHC (O)] _n R ^d , - [NR ^a C (O)] _n R ^d , - [NHC (O)] _n OR ^d , - [NR ^a C (O)] _n OR ^d , - [NHC (O)] _n NR ^c R ^c , - [NR ^a C (O)] _n NR ^c R ^c , - [NHC (NH)] _n NR ^c R ^c and - [NR ^a C (NR ^a )] _n NR ^c R ^c ; each R ^c independently represents a protecting group or R ^a , or alternatively, each R ^c is taken together with the nitrogen atom to which it is attached to form a 5-8 membered cycloheteroalkyl or heteroaryl, which optionally may include one or more identical or different additional heteroatoms, and may optionally be substituted with one or more identical or different R ^a or suitable R ^b groups; each R ^d independently represents an R ^a group; each character m independently represents an integer from 1 to 3; and each character n independently represents an integer from 0 to 3, provided that (1) if L ¹ is a direct bond, and R ⁶ is hydrogen, then R ² is not 3,4,5-tri- (C1-C6) alkoxyphenyl, (2) if each of L ¹ and L ² is a direct bond, R ² is substituted phenyl, and R ⁶ is hydrogen, then R ^{5 is} not a cyano or —C (O) NHR group, where R is hydrogen or ( C1-C6) alkyl, (3) if each of L ¹ and L ² is a direct bond, and each of the radicals R ² and R ^{4 is} independently substituted or unsubstituted pyrrole or indole, then R ² and R ^{4 are} attached to the rest of the molecule via a carbon atom of the ring, and (4) the compound is not one of the following formula

where R ^e is (C1-C6) alkyl; each of R ^f and R ^g each, independently of one another, is straight or branched (C1-C6) alkyl, which is optionally substituted with one or more identical or different R ⁸ groups; wherein R ⁸ corresponds to the above definition. 2. The method according to claim 1, characterized in that each of L ¹ and L ² , independently from each other, is selected from the group consisting of a direct bond, (C1-C3) alkyl diyl, optionally substituted with one or more identical or different R ⁹ -groups, and a 1-3-membered heteroalkyl diyl optionally substituted with one or more identical or different R ⁹ -groups, where R ^{9 is} selected from the group consisting of (C1-C3) alkyl, —OR ^a , —C (O) OR ^a , (C5-C10) aryl optionally substituted with one or more identical or different halogens, phenyl optionally substituted with one or more identical or different halogens, a 5-10 membered heteroaryl optionally substituted with one or more identical or different halogens, and a 6 membered heteroaryl optionally substituted with one or more identical or different halogens; and R ³ in accordance with claim 1, 3. The method according to claim 2, characterized in that each of L ¹ and L ^{2 are} independently selected from the group consisting of methano, ethano and propano groups, each of which may optionally be monosubstituted by a group R ⁹ . 4. The method according to claim 3, characterized in that the group R ^{9 is} selected from the group consisting of —OR ^a , —C (O) OR ^a , halogen phenyl and 4-halogen phenyl, while R ^a corresponds to the definition of claim 1, 5. The method according to claim 1, characterized in that the group R ⁶ represents hydrogen. 6. The method according to claim 1, characterized in that the R ⁵ group is selected from the group consisting of an electronegative group, halogen, —F, —CN, —NO ₂ , —C (O) R ^a , —C (O) OR ^a , -C (O) CF ₃ , -C (O) OCF ₃ , (C1-C3) haloalkyl, (C1-C3) perhaloalkyl (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, -OCF ₃ and - CF ₃ . 7. The method according to claim 1, characterized in that at least one of the elements L1 or L2 is a direct link. 8. The method according to claim 1, characterized in that the compound of 2,4-ririmidinediamines is a compound corresponding to structural formula (Ia)

and its salts, hydrates and solvates, where R ² , R ⁴ , R ⁵ and R ⁶ correspond to the definitions given in paragraph 1. 9. The method of claim 8, wherein R ^{2 is} selected from the group consisting of phenyl, naphthyl, 5-10 membered heteroaryl, benzodioxanil, 1,4-benzodioxan- (5 or 6) -yl, benzodioxolyl, 1,3-benzodioxol- (4 or 5) -yl, benzoxazinyl, 1,4-benzoxazine- (5,6,7 or 8) -yl, benzoxazolyl, 1,3-benzoxazole- (4,5,6 or 7) -yl, benzopyranyl, benzopyran- (5,6,7 or 8) -yl, benzotriazolyl, benzotrazol- (4,5,6 or 7) -yl, 1,4-benzoxazinyl-2-one, 1,4-benzoxazin- (5,6,7 or 8) -yl-2-one, 2H-1,4-benzoxazinyl-3 (4H) -one, 2H-1,4-benzoxazine- (5,6,7 or 8) -yl-3 (4H) -one, 2H-1,3-benzoxazinyl- 2.4 (3H) dione 2H-1,3-benzoxazine- (5,6,7 or 8) -yl-2,4 (3H) -dione, benzoxazolyl-2-one, benzoxazol- (4,5,6 or 7) -yl-2-one, dihydrocoumarinyl, dihydrocoumarin- (5,6,7 or 8) -yl, 1,2-benzopyronyl, 1,2-benzopyron- (5,6,7 or 8) -yl, benzofuranyl, benzofuran- (4,5,6 or 7) -yl, benzo [b] furanyl, benzo [b] furan- (4,5,6 or 7) -yl, indolyl, indole- (4,5,6 or 7) -yl, pyrrolyl and pyrrole- (1 or 2) -yl, each of which can optionally substituted with one or more identical or different R ⁸ groups, where R ⁸ corresponds to the definition given in claim 1. 10. The method according to claim 8, characterized in that each of R ² and / or R ⁴ individually and independently from each other are optionally substituted heteroaryl selected from the group consisting of

where p is an integer from one to three; every character

independently represents a single or double bond; R ³⁵ represents hydrogen or a group R ⁸ where R ⁸ corresponds to the definition given in claim 1; X is selected from the group consisting of CH, N and N-O; each Y is independently selected from the group consisting of O, S, and NH; each Y ^{1 is} independently selected from the group consisting of O, S, SO, SO ₂ , SONR ³⁶ , NH, and NR ³⁷ ; each Y ^{2 is} independently selected from the group consisting of CH, CH ₂ , O, S, N, NH, and NR ³⁷ ; R ³⁶ represents hydrogen or alkyl; R ^{37 is} selected from the group consisting of hydrogen and a progroup, preferably hydrogen, or a progroup selected from the group consisting of aryl, arylalkyl, heteroaryl, R ^a , R ^b —CR ^a R ^b —OC (O) R ⁸ , —CR ^a R ^b —O — PO (OR ⁸ ) ₂ , —CH ₂ —O — PO (OR ⁸ ) ₂ , —CH ₂ —PO (OR ⁸ ) ₂ , —C (O) —CR ^a R ^b —N ( CH ₃ ) ₂ , —CR ^a R ^b —OC (O) —CR ^a R ^b —N (CH ₃ ) ₂ , —C (O) R ⁸ , —C (O) CF _3, and —C (O) - NR ⁸ -C (O) R ⁸ ; R ^{38 is} selected from the group consisting of alkyl and aryl; And selected from the group consisting of O, NH and NR ³⁸ ; R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R ⁹ and R ¹⁰ and / or R ¹¹ and R ¹² taken together form a ketal; each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester, carbamate and sulfonyl; Q is selected from the group consisting of —OH, OR ⁸ , —NR ^c R ^c , —NHR ³⁹ —C (O) —C (O) R ⁸ , —NHR ³⁹ —C (O) OR ⁸ , —NR ³⁹ - CHR ⁴⁰ —R ^b , —NR ³⁹ - (CH ₂ ) _m —R ^b and —NR ³⁹ —C (O) —CHR ⁴⁰ —NR ^c R ^c ; R ³⁹ and R ^{40 are} independently selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl; arylalkyl and NHR ⁸ ; and R ^a , R ^b and R ^c correspond to the definition given in paragraph 1 above. 11. The method according to claim 10, characterized in that R ² and R ⁴ are identical groups. 12. The method according to claim 10, characterized in that each group R ^{35 is} independently selected from the group consisting of hydrogen, R ^d , —NR ^c R ^c , - (CH ₂ ) _m —NR ^c R ^c , —C (O ) NR ^c R ^c , - (CH ₂ ) _m -C (O) NR ^c R ^c , -C (O) OR ^d , - (CH ₂ ) _m -C (O) OR ^d and - (CH ₂ ) _m -OR ^d , where m, R ^c and R ^d correspond to the definitions given in claim 1. 13. The method according to p. 12, characterized in that each value of m is equal to one. 14. The method of claim 8, wherein R ² is an optionally substituted heteroaryl attached to the rest of the molecule via a ring carbon atom. 15. The method of claim 8, wherein R ⁴ is an optionally substituted heteroaryl attached to the rest of the molecule via a ring carbon atom. 16. The method according to claim 8, characterized in that each of R ² and / or R ⁴ independently of one another is phenyl, which is optionally substituted with one, two or three R ⁸ groups, where R ⁸ corresponds to the definition given in p .one, 17. The method according to clause 16, wherein R ² and R ⁴ are the same or different, optionally substituted phenyls. 18. The method according to clause 16, wherein the optionally substituted phenyl is monosubstituted. 19. The method according to p. 18, characterized in that the substituent R ⁸ is in the ortho, meta or para position. 20. The method according to claim 19, wherein R ^{8 is} selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, -OR ^d , -O- (CH ₂ ) _m -NR ^c R, —O — C (O) NR ^c R ^c , —O— (CH ₂ ) _m —C (O) NR ^c R ^c , —OC (O) OR ^a , —O— (CH ₂ ) _m —C (O) OR ^a , -OC (NH) NR ^c R ^c , -O-C (CH ₂ ) _m -C (NH) NR ^c R ^c , -NH- (CH ₂ ) _m -NR ^c R ^c , - NH-C (O) NR ^c R ^c and -NH- (CH ₂ ) _m -C (O) NR ^c R ^c , where m, R ^a , R ^c and R ^d are as defined in claim 1. 21. The method according to clause 16, wherein the optionally substituted phenyl is disubstituted phenyl. 22. The method according to item 21, wherein the substituents R ⁸ occupy the position 2,3-; 2,4-; 2,5-; 2.6-; 3,4-; or 3,5. 23. The method according to item 21, wherein each R ^{8 is} independently selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, -OR ³ optionally substituted with one or more identical or different R ^a - or R ^b groups, —O— (CH ₂ ) _m —NR ^c R ^c , —O — C (O) NR ^c R ^c , —O— (CH ₂ ) _m —C (O) NR ^c R ^c , —O — C (O) OR ⁸ , —O— (CH ₂ ) _m —C (O) OR ^a , —O— (CH ₂ ) _m —C (NH) NR ^c R ^c , —O— ( CH ₂ ) _m -C (NH) NR ^c R ^c , -NH- (CH ₂ ) _m -NR ^c R ^c , -NH-C (O) NR ^c R ^c and -NH- (CH ₂ ) _m -C (O) NR ^c R ^c , where m, R ^a , R ^b and R ^c correspond to the definition given in claim 1. 24. The method according to clause 16, wherein the optionally substituted phenyl is trisubstituted. 25. The method according to paragraph 24, wherein the substituents R ⁸ occupy the position 2,3,4; 2,3,5; 2,3,6; 2,4,5; 2,4,6; 2.5.6 or 3.4.5. 26. The method according A.25, characterized in that each R ⁸ radical is independently selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, -OR ^a optionally substituted with one or more identical or different R ^a or R ^b groups, —O— (CH ₂ ) _m —NR ^c R ^c , —O — C (O) NR ^c R ^c , —O— (CH ₂ ) _m —C (O) NR ^c R ^c , —O — C (O) OR ^a , —O — C (NH) NR ^c R ^c , —O— (CH ₂ ) _m —C (O) OR ^a , —O— (CH ₂ ) _m - C (NH) NR ^c R ^c , -NH- (CH ₂ ) _m -NR ^c R ^c , -NH-C (O) NR ^c R ^c and -NH- (CH ₂ ) _m -C (O) NR ^c R ^c , where m, R ^a , R ^b and R ^c correspond to the definition given in paragraph 1. 27. The method according to paragraph 24, wherein the trisubstituted phenyl corresponds to the formula

where R ³¹ is methyl or (C1-C6) alkyl; R ³² is hydrogen, methyl or (C1-C6) alkyl; and R ³³ is a halogen group. 28. The method according to 17, characterized in that R ² and R ⁴ are identical groups. 29. The method according to claim 8, in accordance with the compound with structural formula (Ib)

and its salts, hydrates, solvates and N-oxides, characterized in that each of R ¹¹ , R ¹² , R ¹³ and R ¹⁴ , independently from each other, is selected from the group consisting of hydrogen, hydroxy, (C1-C6) alkoxy, and -NR ^c R ^c ; a R ⁵ , R ⁶ and R ^c correspond to the definition given in paragraph 1. 30. The method according to clause 29, wherein each of R ¹¹ , R ¹² , R ¹³ and R ¹⁴ is hydrogen. 31. The method according to clause 29, wherein each of R ¹² and R ¹³ is hydrogen. 32. The method of claim 8, wherein the 2,4-pyrimidinediamine compound is a compound of structural formula (Ic)

as well as its salts, hydrates, solvates and N-oxides, characterized in that R ⁴ is phenyl optionally substituted with 1-3 identical or different R ⁸ groups or a 5-14 membered heteroaryl optionally substituted with 1-4 identical or different R ⁸ groups; R ⁵ is an electronegative group, F or CF ₃ ; and R ¹⁸ - —O (CH ₂ ) _m —R ^b , where m R ^b correspond to the definition given in claim 1. 33. The method according to p, characterized in that R ⁴ is optionally substituted heteroaryl. 34. The method according to p, characterized in that R ⁸ is an —O — CH ₂ —C (O) —NHCH ₃ group. 35. The method according to claim 1, whereby the compound of 2,4-pyrimidinamines is a compound with the structural formula (Id)

as well as its salts, hydrates, solvates and N-oxides, characterized in that R ² and R ⁴ correspond to the definition given in claim 1; and R ¹⁵ is an electronegative group, provided that (1) if R ² is 3,4,5-tri (C1-C6) alkoxyphenyl and R ¹⁵ is halogen, then R ^{4 is} not 3,4,5-tri (C1-C6) alkoxyphenyl and (2) if R ² is a substituted phenyl group, then R ¹⁵ is a group other than cyano or —C (O) NHR, where R is hydrogen or (C1-C6) alkyl. 36. The method according to clause 37, wherein if R ¹⁵ is a halogen or nitro group, then R ^{2 is} not 3,4,5-tri (C1-C6) alkoxyphenyl. 37. The method according to § 38, wherein R ^{15 is} selected from the group consisting of —CN, —NC, —NO ₂ , halogen, —F, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, ( C1-C3) fluoroalkyl, (C1-C3) perfluoroalkyl, -CF ₃ , (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, (C1-C3) fluoroalkoxy, (C1-C3) perfluoroalkoxy and -OCF ₃ . 38. The method according to § 39, wherein R ^{15 is} selected from the group consisting of halogen, Br, F, —CF ₃ and —NO ₂ . 39. The method according to claim 1, characterized in that the compound of 2,4-pyrimidinediamines is selected from the group consisting of compounds R921302, R926891, R940323, R940347 and R921303. 40. The method according to any one of claims 1 to 39, characterized in that the compound is administered in the form of a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier, diluent or excipient. 41. The method according to any one of claims 1 to 39, characterized in that it is used in therapy. 42. The method according to any one of claims 1 to 39, characterized in that the subject is a person. 43. The method according to any one of claims 1 to 39, characterized in that the autoimmune disease is selected from the group consisting of autoimmune diseases, often qualifying as an autoimmune disorder of a particular organ or type of cell, as well as autoimmune diseases, often qualifying as including systemic autoimmune disorder. 44. The method according to any one of claims 1 to 39, characterized in that the autoimmune disease is selected from the group consisting of Hashimoto thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune immune syndrome and ophthalmia, bulbospinal paralysis, bazedovoy disease, biliary primary cirrhosis of the liver, chronic aggressive hepatitis, ulcerative colitis and membrane glomerulopathy. 45. The method according to item 43, wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, Reiter’s syndrome, polymyositis-dermatomyositis, systemic sclerosis, nodous panarteritis, multiple sclerosis and bullous. 46. The method according to item 45, wherein the autoimmune disease is systemic lupus erythematosus. 47. The method according to item 45, wherein the autoimmune disease is rheumatoid arthritis. 48. The method according to item 45, wherein the autoimmune disease is multiple sclerosis.