Use of Lck inhibitors for treatment of immunologic diseases

Abstract

The invention relates to a method of treating immunologic diseases or pathological conditions involving an immunologic component using certain Lck inhibitors already known as kinase inhibitors for therapy in oncology, optionally in combination with one or more other drugs selected from NSAIDs, steroids, DMARDs, immunsuppressives, biologic response modifiers and antinfectives, pharmaceutical compositions comprising said Lck inhibitors together with said other drugs, and the use of the Lck inhibitors for the manufacture of a pharmaceutical composition for the treatment of immunologic diseases or pathological conditions involving an immunologic component.

1 . A method for treating immunologic diseases or pathological conditions involving an immunologic component comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical composition comprising a compound selected from 
     (A) (Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(methylsulfonylamino)-2-indolinone; 
     (B) (Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone; 
     (C) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone; 
     (D) (Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone; 
     (E) (Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(4-amino-phenylsulfonylamino)-2-indolinone; 
     (F) (Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone; 
     (G) (Z)-3-(1-(4-(4-(3-aminopropyl-piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone; 
     (H) (Z)-3-(1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone; 
     (I) (Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenyl-amino)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinone; 
     (J) (Z)-3-(1-(4-(N-methyl-N-(piperidin-1-yl-methylcarbonyl)-amino)-phenylamino)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinone; 
     (K) (Z)-3-(1-(2-benzimidazolyl-amino)-1-phenyl-methylene)-5-amido-2-indolinone; 
     (L) (Z)-3-(1-(4-(N-methyl-propionylamino)-phenylamino)-1-phenyl-methylene)-5-amido-2-indolinone; 
     (M) (Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenyl-amino)-1-phenyl-methylene)-2-indolinone; 
     (N) (Z)-3-(1-(4-(N-(3-dimethylaminopropyl)-N-propionyl-amino)-phenylamino)-1-phenyl-methylene)-2-indolinone; 
     (O) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(butylcarbamoyl)-2-indolinone; 
     (P) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(naphth-1-yl-methyl-carbamoyl)-2-indolinone; 
     (O) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(N-butyl-N-phenyl-carbamoyl)-2-indolinone; 
     (R) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(hexylcarbamoyl)-2-indolinone; 
     (S) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone; 
     (T) (Z)-3-(1-(4-(N-methylsulfonyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone; 
     (U) (Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclo-hexylmethyl-carbamoyl)-2-indolinone; 
     (V) (Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone; 
     (W) (Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclo-hexylmethyl-carbamoyl)-2-indolinone; 
     (X) (Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; 
     (Y) (Z)-3-(1-(4-(diethanolaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(butylcarbamoyl)-2-indolinone; 
     (Z) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; 
     (AA) (Z)-3-(1-(4-(N-acetyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; 
     (AB) (Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; 
     (AC) (Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(N-methyl-N-phenyl-aminosulfonyl)-2-indolinone; 
     (AD) (Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(N-butyl-N-methyl-aminosulfonyl)-2-indolinone; 
     (AE) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone; 
     (AF) (Z)-3-(1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone; 
     (AG) (Z)-3-(1-(4-(ethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone; 
     (AH) (Z)-3-(1-(4-(1-methyl-imidazol-2-yl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone; 
     (AI) (Z)-3-(1-(4-(N-(dimethylaminomethylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone; 
     (AJ) (Z)-3-(1-(4-(methylaminomethyl)-anilino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone; 
     (AK) (Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone; and 
     (AL) 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-quinazoline 
     the tautomers, the stereoisomers and the physiologically acceptable salts thereof, or a combination of any of the above. 
   
   
       2 . The method of  claim 1 , wherein the pharmaceutical composition further comprises one or more other drugs selected from nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, disease-modifying antirheumatic drugs (DMARDs), immunsuppressives, biologic response modifiers, antinfectives, and combinations of any of the above. 
   
   
       3 . The method of  claim 1 , wherein the immunologic disease or pathological condition involving an immunologic component is selected from
 autoimmune diseases, for instance inflammatory diseases having an autoimmune component such as inflammatory diseases selected from
 inflammatory bowel disease (e.g., colitis ulcerosa and Morbus Crohn), rheumatoid arthritis, glomerulonephritisand lung fibrosis, 
   furthermore, psoriasis, psoriasis arthritis, hypersensitivity reactions of the skin, atherosclerosis, restenosis, asthma, multiple sclerosis and type 1 diabetes,   and indications which need immunosuppressant therapy, for instance prevention or therapy of tissue or organ transplant rejection.   
   
   
       4 . The method of  claim 3 , wherein the immunologic disease or pathological condition involving an immunologic component is selected from
 rheumatoid arthritis,   inflammatory bowel disease such as colitis ulcerosa and Morbus Crohn,   psoriasis, psoriasis arthritis,   prevention or therapy of tissue or organ transplant rejection, acute or chronic graft-versus-host disease, allograft or xenograft rejection,   allergic asthma, multiple sclerosis and type 1 diabetes.   
   
   
       5 . The method of  claim 3 , wherein the immunologic disease or pathological condition involving an immunologic component is selected from morbus crohn, lung fibrosis, psoriasis arthritis, hypersensitivity reactions of the skin, graft-versus-host disease (acute and chronic), asthma, multiple sclerosis and type 1 diabetes. 
   
   
       6 . The method of  claim 3 , wherein the immunologic disease or pathological condition involving an immunologic component is selected from chronic inflammatory bowel diseases, such as colitis ulcerosa and morbus crohn, from rheumatoid arthritis, psoriasis and psoriasis arthritis. 
   
   
       7 . The method according to  claim 1 , which method comprises administration of a pharmaceutical composition comprising
 (A), (B), (C), (D), (F), (G), (P), (T), (V), (X), (Z), (AA), (AE), (Al), (AK), and (AL)   the tautomers, the stereoisomers and the physiologically acceptable salts thereof, or a combination of any of the above.   
   
   
       8 . The method of  claim 6 , which method comprises administration of a compound selected from
 (M), (N), (O), (S), (T), (U), (V), (W), (X), (Y), (Z), (AA), (AB), (AE), (AF), (AG), (AH), (AI), (AJ), (AK) and (AL),   the tautomers, the stereoisomers and the physiologically acceptable salts thereof, or a combination of any of the above.   
   
   
       9 . The method according to  claim 1 , which method comprises administration of a pharmaceutical composition comprising from (AK), (AI) and (AL)
 the tautomers, the stereoisomers and the physiologically acceptable salts thereof.   
   
   
       10 . The method according to  claim 1 , wherein the pharmaceutical composition is administered orally, parenterally, rectally or, with respect to indications involving treatment of the skin such as psoriasis, psoriasis arthritis or hypersensitivity reactions of the skin, also topically.