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.

What is claimed is:  
     
         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;    (Q) (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.q., 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), (AI), (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.  
     
     
         11 . A pharmaceutical composition comprising 
 (i) 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)-l -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;  
 (Q) (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  
   (b) one or more other drugs selected from NSAIDs, steroids, DMARDs, immunsuppressives, biologic response modifiers and antinfectives.    
     
     
         12 . The pharmaceutical composition according to  claim 11  further comprising one or more pharmaceutically acceptable diluents and/or carriers.  
     
     
         13 . The composition of  claim 11 , wherein the NSAID is a non-selective COX-inhibitor or a COX-2 selective inhibitor.  
     
     
         14 . The composition of  claim 11 , wherein the NSAID is selected from 
 acetylsalicyclic acid, mesalazin,    ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen,    indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac,    mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, tenoxicam, lornoxicam, nimesulide,    meloxicam, celecoxib and rofecoxib,    and the pharmaceutically acceptable salts thereof.    
     
     
         15 . The composition of  claim 11 , wherein the steroid is selected from 
 prednisone, prednisolone, methylprednisolone, dexamethasone, budenoside, fluocortolone and triamcinolone.    
     
     
         16 . The composition of  claim 11 , wherein the DMARD is selected from sulfasalazine, olsalazine, chloroquin, gold derivatives (Auranofin), D-penicillamine and cytostatics such as methotrexate and cyclophosphamide.  
     
     
         17 . The composition of  claim 11 , wherein the immunsuppressive is selected from cyclosporin A and derivatives thereof, mycophenolatemofetil, FK 506, OKT-3, ATG, 15-desoxyspergualin, mizoribine, misoprostol, rapamycin, reflunomide, azathioprine and NF-Kappa B-inhibitors.  
     
     
         18 . The composition of  claim 11 , wherein the biologic response modifier is selected from interferon beta, anti-TNF-alpha (Etanercept), IL-10, oral and parenteral tolerance induction strategies, leukotrien-antagonists, anti-CD3 and anti-CD25.  
     
     
         19 . The composition of  claim 11 , wherein the biologic response modifier is a bronchodilator selected from ipratropium bromide, oxitropium bromide, tiotropium bromide, epinephrine hydrochloride, salbutamol, terbutaline sulphate, fenoterol hydrobromide, salmeterol, formoterol, cromiclinic acid, a theophylline derivative and a combination of any of the above.  
     
     
         20 . The composition of  claim 11 , wherein the antinfective is selected from metronidazol and chinolone.