U.S. patent application number 12/541961 was filed with the patent office on 2009-12-10 for use of lck inhibitors for treatment of immunologic diseases.
This patent application is currently assigned to BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG. Invention is credited to Florian Colbatzky, Steffan Ernest, Rudolf Hauptmann, Armin Heckel, Frank Hilberg, Gerald Juergen Roth, Martin Fredrich Stefanic, Rainer Walter.
Application Number | 20090306104 12/541961 |
Document ID | / |
Family ID | 33135440 |
Filed Date | 2009-12-10 |
United States Patent
Application |
20090306104 |
Kind Code |
A1 |
Roth; Gerald Juergen ; et
al. |
December 10, 2009 |
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.
Inventors: |
Roth; Gerald Juergen;
(Biberach, DE) ; Heckel; Armin; (Biberach, DE)
; Walter; Rainer; (Biberach, DE) ; Hilberg;
Frank; (Wein, AT) ; Hauptmann; Rudolf;
(Ebreichsdorf, AT) ; Stefanic; Martin Fredrich;
(Warthausen-Birkenhard, DE) ; Colbatzky; Florian;
(Stafflangen, DE) ; Ernest; Steffan; (Moelnlycke,
SE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY RD, P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
BOEHRINGER INGELHEIM PHARMA GMBH
& CO. KG
Ingelheim
DE
|
Family ID: |
33135440 |
Appl. No.: |
12/541961 |
Filed: |
August 16, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10640926 |
Aug 14, 2003 |
|
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12541961 |
|
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60409204 |
Sep 9, 2002 |
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Current U.S.
Class: |
514/266.22 ;
514/323; 514/418 |
Current CPC
Class: |
A61K 31/404 20130101;
A61P 29/00 20180101; A61K 31/454 20130101; A61K 31/517 20130101;
A61P 37/00 20180101; A61K 45/06 20130101; A61K 31/404 20130101;
A61K 2300/00 20130101; A61K 31/454 20130101; A61K 2300/00 20130101;
A61K 31/517 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/266.22 ;
514/323; 514/418 |
International
Class: |
A61K 31/404 20060101
A61K031/404; A61K 31/454 20060101 A61K031/454; A61K 31/517 20060101
A61K031/517; A61P 37/00 20060101 A61P037/00; A61P 29/00 20060101
A61P029/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 16, 2002 |
DE |
102 37 423 |
Claims
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-(m-
ethylsulfonylamino)-2-indolinone; (B)
(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(e-
thylsulfonylamino)-2-indolinone; (C)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(eth-
ylsulfonylamino)-2-indolinone; (D)
(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(p-
henylsulfonylamino)-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-pheny-
l-methylene)-5-(ethylsulfonylamino)-2-indolinone; (H)
(Z)-3-(1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino)-phenylamin-
o)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone; (I)
(Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenyl-ami-
no)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinone;
(J)
(Z)-3-(1-(4-(N-methyl-N-(piperidin-1-yl-methylcarbonyl)-amino)-phenyl-
amino)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinon-
e; (K)
(Z)-3-(1-(2-benzimidazolyl-amino)-1-phenyl-methylene)-5-amido-2-ind-
olinone; (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-ami-
no)-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-(but-
ylcarbamoyl)-2-indolinone; (P)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(naph-
th-1-yl-methyl-carbamoyl)-2-indolinone; (O)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(N-b-
utyl-N-phenyl-carbamoyl)-2-indolinone; (R)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(hexy-
lcarbamoyl)-2-indolinone; (S)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cycl-
ohexylmethyl-carbamoyl)-2-indolinone; (T)
(Z)-3-(1-(4-(N-methylsulfonyl-N-(2-dimethylamino-ethyl)-amino)-phenylamin-
o)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;
(U)
(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclo-h-
exylmethyl-carbamoyl)-2-indolinone; (V)
(Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylen)-5-(c-
yclohexylmethyl-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-(but-
ylcarbamoyl)-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-phe-
nyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; (AB)
(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-ch-
lorobenzyl)-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-meth-
oxycarbonyl-2-indolinone; (AF)
(Z)-3-(1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-phenylamino)-1-ph-
enyl-methylene)-6-methoxycarbonyl-2-indolinone; (AG)
(Z)-3-(1-(4-(ethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxy-
carbonyl-2-indolinone; (AH)
(Z)-3-(1-(4-(1-methyl-imidazol-2-yl)-phenylamino)-1-phenyl-methylene)-6-m-
ethoxycarbonyl-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-methoxycar-
bonyl-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)-q-
uinazoline 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.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/640,926, filed Aug. 14, 2003.
TECHNICAL FIELD OF THE INVENTION
[0002] This invention relates to a method for treating immunologic
diseases or pathological conditions, which conditions have an
immunologic component, using a compound selected from compounds (A)
to (AL) listed below. Such compounds are already known as kinase
inhibitors for therapy in oncology.
BACKGROUND OF THE INVENTION
[0003] Compounds (A) to (AL) listed below, their preparation as
well as the pharmacological activity of these compounds based on
inhibition of kinases, e.g., VEGFR-2, suitable for therapy in
oncology, are disclosed in WO 02/36564, WO 99/52869, WO 00/18734,
WO 00/73297, WO 01/27080, WO 01/27081 and WO 01/32651. The cited
documents are herewith incorporated by reference.
[0004] Lck, a further tyrosine kinase belonging to the src family
of tyrosine kinases not mentioned in the references cited above, is
functionally required for T-cell activation through the T-cell
antigen receptor (TCR) (see A. E. Nel: T-cell activation through
antigen receptor. Part 1: Signaling components, signaling pathways,
and signal integration at the T-cell antigen receptor synapse. J.
Allergy Clin Immunol, 109, 5, 758-770, 2002) and possibly T-cell
survival (Seddon, B.; Legname, G.; Tomlinson, P.; Zamoyska, R.:
Long-term survival but impaired homeostatic proliferation of naive
T cells in the absence of p56(lck). Science 290: 127-131, 2000).
Therefore, any Lck inhibitor has a high possible therapeutic
potential in the treatment of T-cell mediated diseases, e.g., in
the treatment of immunologic diseases. Certain autoimmune diseases
such as inflammatory diseases (for example, inflammatory bowel
disease, rheumatoid arthritis, glomerulonephritis and lung
fibrosis, psoriasis, hypersensitivity reactions of the skin,
atherosclerosis, restenosis, allergic asthma, multiple sclerosis
and type 1 diabetes) are believed to be associated with
inappropriate T cell activation (J. H. Hanke et al., Inflamm. Res.,
1995, 357). In addition, the acute rejection of transplanted organs
as well as Graft versus Host Disease (GvHD) after allogeneic bone
marrow and stem cell transplantation can also be interpreted as a
consequence of inappropriate T cell activation. Lck inhibitors
offer an approach for treatment of the indications mentioned
hereinbefore. Agents of this kind would offer therapy for
transplant rejection and autoimmune diseases whilst avoiding
toxicities associated with the commonly used, less selective
immunosuppressants. The leading agent for prevention or treatment
of transplant rejection is cyclosporin A which, although effective,
is often associated with side-effects such as renal damage and
hypertension, which results in kidney failure in a substantial
number of patients. It is contemporary practice to treat rheumatoid
arthritis initially with symptom relief agents such as NSAIDs,
which have no effect on disease progression and are often
associated with unwanted side-effects. A rationally based, disease
modifying agent, without such deleterious side-effects, would
therefore offer significant benefits in the prevention or treatment
of transplant rejection or autoimmune conditions such as rheumatoid
arthritis.
[0005] There is considerable evidence that VEGF plays a key role in
the pathogegenesis in rheumatoid arthritis, especially in the
formation of the pannus (Paleolog E M, Arthritis Res 2002; 4 Suppl
3:S81-90, Pavonen et al, J Rheumatol 2002 January; 29(1):39-45,
Afuwape A O et al, Histol Histopathol 2002; 17(3):961-72). Thus,
combined inhibition of VEGFR-tyrosine kinases and Lck is considered
of potentially high benefit for patients with this disease. The
same considerations can be applied to psoriasis and inflammatory
bowel disease (Folkman J, Nat. Med. 1995 January; 1(1):27-31.
Review; Griga T et al, Hepatogastroenterology 2002
January-February; 49(43):116-23, Creamer D et al, Arch Dermatol
2002 June; 138(6):791-6).
BRIEF SUMMARY OF THE INVENTION
[0006] In view of the work cited above, there is a clear need for
compounds which are Lck inhibitors for the treatment of T-cell
mediated diseases, e.g., in the treatment of immunologic diseases
or pathological conditions involving an immunologic component.
[0007] It is therefore an object of the invention to provide 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 compounds (A) to (AL), which compounds are already
known as agents usefully in oncology.
[0008] A second object of the invention is a pharmaceutical
composition comprising a compound selected from compounds (A) to
(AL) together with one or more other drugs selected from
nonsteroidal anti-inflammatory drugs (NSAIDs), steroids,
disease-modifying antirheumatic drugs (DMARDs), immunsuppressives,
biologic response modifiers and antinfectives for use in treatment
of immunologic diseases or pathological conditions involving an
immunologic component.
[0009] A third object of the invention is the use of a compound
selected from compounds (A) to (AL) for the manufacture of a
pharmaceutical composition for the treatment of immunologic
diseases or pathological conditions involving an immunologic
component.
DETAILED DESCRIPTION OF THE INVENTION
[0010] It has now surprisingly been found that compounds [0011] (A)
(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(m-
ethylsulfonylamino)-2-indolinone; [0012] (B)
(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(e-
thylsulfonylamino)-2-indolinone; [0013] (C)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(eth-
ylsulfonylamino)-2-indolinone; [0014] (D)
(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(p-
henylsulfonylamino)-2-indolinone; [0015] (E)
(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(4-
-amino-phenylsulfonylamino)-2-indolinone; [0016] (F)
(Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(-
ethylsulfonylamino)-2-indolinone; [0017] (G)
(Z)-3-(1-(4-(4-(3-aminopropyl-piperidin-1-yl-methyl)-phenylamino)-1-pheny-
l-methylene)-5-(ethylsulfonylamino)-2-indolinone; [0018] (H)
(Z)-3-(1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino)-phenylamin-
o)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone; [0019]
(I)
(Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenyl-ami-
no)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinone;
[0020] (J)
(Z)-3-(1-(4-(N-methyl-N-(piperidin-1-yl-methylcarbonyl)-amino)-phenylamin-
o)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonyl-amino)-2-indolinone;
[0021] (K)
(Z)-3-(1-(2-benzimidazolyl-amino)-1-phenyl-methylene)-5-amido-2-indolinon-
e; [0022] (L)
(Z)-3-(1-(4-(N-methyl-propionylamino)-phenylamino)-1-phenyl-methylene)-5--
amido-2-indolinone; [0023] (M)
(Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenyl-ami-
no)-1-phenyl-methylene)-2-indolinone; [0024] (N)
(Z)-3-(1-(4-(N-(3-dimethylaminopropyl)-N-propionyl-amino)-phenylamino)-1--
phenyl-methylene)-2-indolinone; [0025] (O)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(but-
ylcarbamoyl)-2-indolinone; [0026] (P)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(naph-
th-1-yl-methyl-carbamoyl)-2-indolinone; [0027] (Q)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(N-b-
utyl-N-phenyl-carbamoyl)-2-indolinone; [0028] (R)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(hexy-
lcarbamoyl)-2-indolinone; [0029] (S)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cycl-
ohexylmethyl-carbamoyl)-2-indolinone; [0030] (T)
(Z)-3-(1-(4-(N-methylsulfonyl-N-(2-dimethylamino-ethyl)-amino)-phenylamin-
o)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;
[0031] (U)
(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyc-
lo-hexylmethyl-carbamoyl)-2-indolinone; [0032] (V)
(Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylen)-5-(c-
yclohexylmethyl-carbamoyl)-2-indolinone; [0033] (W)
(Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclo-
-hexylmethyl-carbamoyl)-2-indolinone; [0034] (X)
(Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3--
chlorobenzyl)-carbamoyl)-2-indolinone; [0035] (Y)
(Z)-3-(1-(4-(diethanolaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(but-
ylcarbamoyl)-2-indolinone; [0036] (Z)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-
-chlorobenzyl)-carbamoyl)-2-indolinone; [0037] (AA)
(Z)-3-(1-(4-(N-acetyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phe-
nyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; [0038]
(AB)
(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-ch-
lorobenzyl)-carbamoyl)-2-indolinone; [0039] (AC)
(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(N-
-methyl-N-phenyl-aminosulfonyl)-2-indolinone; [0040] (AD)
(Z)-3-(1-(4-(piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(N-
-butyl-N-methyl-aminosulfonyl)-2-indolinone [0041] (AE)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-meth-
oxycarbonyl-2-indolinone; [0042] (AF)
(Z)-3-(1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-phenylamino)-1-ph-
enyl-methylene)-6-methoxycarbonyl-2-indolinone; [0043] (AG)
(Z)-3-(1-(4-(ethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxy-
carbonyl-2-indolinone; [0044] (AH)
(Z)-3-(1-(4-(1-methyl-imidazol-2-yl)-phenylamino)-1-phenyl-methylene)-6-m-
ethoxycarbonyl-2-indolinone; [0045] (AI)
(Z)-3-(1-(4-(N-(dimethylaminomethylcarbonyl)-N-methyl-amino)-phenylamino)-
-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone; [0046] (AJ)
(Z)-3-(1-(4-(methylaminomethyl)-anilino)-1-phenyl-methylene)-6-methoxycar-
bonyl-2-indolinone; [0047] (AK)
(Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-
-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone;
and [0048] (AL)
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-q-
uinazoline, the tautomers, the stereoisomers and the
physiologically acceptable salts thereof, are effective inhibitors
of Lck and therefore are especially suitable and effective in the
treatment of immunologic diseases or pathological conditions
involving an immunologic component.
[0049] Compounds (A) to (J) are described in WO 02/36564, compounds
(K) to (L) are described in WO 99/52869, compounds (M) to (N) are
described in WO 00/18734, compounds (O) to (AB) are described in WO
00/73297, compounds (AC) to (AD) are described in WO 01/27080,
compounds (AE) to (AK) are described in WO 01/27081, and compound
(AL) is described in WO 01/32651.
[0050] Viewed from a first aspect, the present invention provides 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
compounds (A) to (AL), the tautomers, the stereoisomers and the
physiologically acceptable salts thereof, optionally in combination
with one or more other drugs selected from NSAIDs, steroids,
DMARDs, immunsuppressives, biologic response modifiers and
antinfectives.
[0051] The expression "patient" is meant to comprise the human and
the non-human mammal patient.
[0052] The indication "immunologic diseases or pathological
conditions involving an immunologic component" should be understood
in a non-limiting manner to comprise:
autoimmune diseases, for instance inflammatory diseases having an
autoimmune component such as inflammatory diseases selected
from
[0053] inflammatory bowel disease (e.g., colitis ulcerosa and
Morbus Crohn), rheumatoid arthritis, glomerulonephritis and 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, e.g., acute or chronic
graft-versus-host disease, allograft or xenograft rejection etc.
(the transplanted organ being kidney, heart, liver, lung, bone
marrow, peripheral blood stem cells, pancreas or islet cells
thereof, cornea, small bowel, skin, or heart valve).
[0054] Preferred indications which may be treated by the method
according to the invention are [0055] rheumatoid arthritis, [0056]
inflammatory bowel disease such as colitis ulcerosa and Morbus
Crohn, [0057] psoriasis, psoriasis arthritis, [0058] prevention or
therapy of tissue or organ transplant rejection, acute or chronic
graft-versus-host disease, allograft or xenograft rejection, and
[0059] allergic asthma, multiple sclerosis and type 1 diabetes.
[0060] A further subgroup of indications which may be treated by
the method according to the invention, and deserves special
mention, comprises 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.
[0061] A preferred embodiment of the method according to the
invention comprises administration of a compound selected from
compounds
(A), (B), (C), (D), (F), (G), (P), (T), (V), (X), (Z), (AA), (AE),
(Al), (AK) and (AL),
[0062] the tautomers, the stereoisomers and the physiologically
acceptable salts thereof, optionally in combination with one or
more other drugs selected from NSAIDs, steroids, DMARDs,
immunsuppressives, biologic response modifiers and
antinfectives.
[0063] Another preferred embodiment of the method according to the
invention comprises administration of a compound selected from the
following combined inhibitors of VEGFR-2 and Lck:
(M), (N), (O), (S), (T), (U), (V), (W), (X), (Y), (Z), (AA), (AB),
(AE), (AF), (AG), (AH), (AI), (AJ), (AK) and (AL),
[0064] the tautomers, the stereoisomers and the physiologically
acceptable salts thereof, optionally in combination with one or
more other drugs selected from NSAIDs, steroids, DMARDs,
immunsuppressives, biologic response modifiers and antinfectives.
Since VEGF also plays an important pathogenetical role in chronic
inflammatory bowel diseases such as colitis ulcerosa and morbus
crohn as well as in rheumatoid arthritis, psoriasis and psoriasis
arthritis, these combined inhibitors of VEGFR-2 and Lck are of
special advantage in these most preferred indications.
[0065] A further preferred embodiment of the method according to
the invention comprises administration of a compound selected from
compounds
(AK), (Al) and (AL),
[0066] the tautomers, the stereoisomers and the physiologically
acceptable salts thereof,
[0067] Especially preferred is administration of compound (AK).
[0068] In the method of treatment according to the invention
compounds (A) to (AL) can be 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 in topical formulations. Oral
administration is preferred.
[0069] In oral, rectal or topical administration, the compounds may
be given, if required, in divided doses, in a daily dosage of 0.1
to 20 mg/kg body weight, preferably 0.5 to 20 mg/kg body weight,
most preferred 1 to 10 mg/kg body weight.
[0070] Parenterally, the compounds may be administered in lower
doses, for instance in a total daily dosage of 0.01 to 5 mg/kg body
weight, preferably 0.05 to 2 mg/kg body weight, most preferred 0.1
to 1 mg/kg body weight.
[0071] For administration, the compounds may be formulated with one
or more conventional inert carriers and/or diluents as known in the
art, e.g., with corn starch, lactose, glucose, microcrystalline
cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid,
tartaric acid, water, water/ethanol, water/glycerol,
water/sorbitol, water/polyethylene glycol, propylene glycol,
stearyl alcohol, carboxymethylcellulose or fatty substances such as
hard fat or suitable mixtures thereof, in conventional galenic
preparations such as plain or coated tablets, lozenges, hard or
soft capsules, dispersible powders or granules, syrups or elixirs,
injectable solutions, ampoules, aqueous or oily suspensions,
emulsions, solutions, sprays, creams, ointments, gels, or
suppositories. Suitable galenic formulations are disclosed in the
documents cited hereinbefore.
[0072] Furthermore, in the method according to the invention a
compound selected from compounds (A) to (AL) may be administered in
combination, simultaneously or sequentially, with one or more other
drugs selected from NSAIDs, steroids, DMARDs, immunsuppressives,
biologic response modifiers, antinfectives and, in case of lung
indications, also with bronchodilators.
[0073] In particular, a compound selected from compounds (A) to
(AL) could be used in combination with immunosuppressives in the
prevention or treatment of the acute rejection of transplanted
organs,
in combination with NSAIDs, steroids, immuno-suppressives, DMARDs,
biologic response modifiers (e.g., anti-TNF), and anti-infectives
for the treatment of inflammatory bowel disease (e.g., colitis
ulcerosa and morbus crohn), rheumatoid arthritis and psoriasis,
whereby the NSAID-dose can be significantly reduced compared to
what otherwise would be required or needed to produce a therapeutic
effect. Thus, there would be a reduction in the risk of adverse
side-effects from the NSAID, such as gastrointestinal effects.
[0074] Such compound selected from (A) to (AL) can also be used in
combination with biologic response modifiers (e.g., leukotriene
antagonists), and bronchodilators for the treatment of asthma.
[0075] Suitable NSAIDs for combination treatment are meant to
include all COX (cyclooxygenase) inhibitors, e.g.,
non-selective COX-inhibitors such as 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 and nimesulide and the
pharmaceutically acceptable salts thereof, as well as selective COX
2-inhibitors such as meloxicam, celecoxib and rofecoxib and the
pharmaceutically acceptable salts thereof.
[0076] Suitable steroids for combination treatment are meant to
include in a non-limiting manner prednisone, prednisolone,
methylprednisolone, dexamethasone, budenoside, fluocortolone and
triamcinolone.
[0077] Suitable DMARDs for combination treatment are meant to
include in a non-limiting manner sulfasalazine, olsalazine,
chloroquin, gold derivatives (Auranofin), D-penicillamine and
cytostatics such as methotrexate and cyclophosphamide.
[0078] Suitable immunsuppressives for combination treatment are
meant to include in a non-limiting manner cyclosporin A and
derivatives thereof, mycophenolatemofetil, FK 506, OKT-3, ATG,
15-desoxyspergualin, mizoribine, misoprostol, rapamycin,
reflunomide, azathioprine and NF-Kappa B-inhibitors.
[0079] Suitable biologic response modifiers for combination
treatment are meant to include in a non-limiting manner interferon
beta, anti-TNF-alpha (Etanercept), IL-10, oral and parenteral
tolerance induction strategies (orally e.g., with genetically
modified enteric bacteria), leukotrien-antagonists, anti-CD3 or
anti-CD25.
[0080] Suitable antinfectives for combination treatment are meant
to include in a non-limiting manner metronidazol and chinolone for
treatment of chronic inflammatory bowel diseases.
[0081] Suitable bronchodilators for combination treatment are meant
to include in a non-limiting manner those disclosed under
"broncholytics/antiasthmatics" in Rote Liste.RTM. 2002, Editio
Cantor Verlag Aulendorf, Germany, being herewith incorporated by
reference, for instance ipratropium bromide, oxitropium bromide,
tiotropium bromide, epinephrine hydrochloride, salbutamole,
terbutaline sulfate, fenoterol hydrobromide, salmeterol,
formoterol, cromiclinic acid, theophylline derivatives etc.
[0082] In such combinations each active ingredient can be
administered either in accordance with its usual dosage range or a
dose below its usual dosage range. The dosage for the combined
NSAIDs, steroids, DMARDs, immunsuppressives, biologic response
modifiers and antinfectives is appropriately 1/50 of the lowest
dose normally recommended up to 1/1 of the normally recommended
dosage, preferably 1/20 to 1/2 and more preferably 1/10 to 1/5. The
normally recommended dose for the combined drug should be
understood to be the dose disclosed for example in Rote Liste.RTM.
2002, Editio Cantor Verlag Aulendorf, Germany, or in Physician's
Desk Reference.
[0083] It can be expected that combination treatment comprising
administration of Lck inhibitors together with a second drug
selected from those mentioned hereinbefore may provide synergistic
efficacy, thus providing significant dose reduction compared to
what would normally be required or necessary to produce a
therapeutic effect. This would be especially beneficial with regard
to medications having a high risk of adverse side-effects, as is
the case with non-selective COX inhibitors, cyclosporin A or
DMARDs.
[0084] Viewed from a second aspect, the present invention also
relates to pharmaceutical compositions comprising [0085] (a) a
compound selected from compounds (A) to (AL), the tautomers, the
stereoisomers and the physiologically acceptable salts thereof,
[0086] (b) and one or more other drugs selected from NSAIDs,
steroids, DMARDs, immunsuppressives, biologic response modifiers
and antinfectives, optionally together with pharmaceutically
acceptable diluents and/or carriers, as a combined preparation or a
kit of parts containing components (a) and (b) in separate
containments for simultaneous, separate or sequential use in
treatment of immunologic diseases or pathological conditions
involving an immunologic component.
[0087] Viewed from a third aspect, the present invention provides
the use of a compound selected from compounds (A) to (AL), the
tautomers, the stereoisomers and the physiologically acceptable
salts thereof, optionally in combination with one or more other
drugs selected from NSAIDs, steroids, DMARDs, immunsuppressives,
biologic response modifiers and antinfectives, for the manufacture
of a pharmaceutical composition for the treatment of a patient
suffering from immunologic diseases or pathological conditions
involving an immunologic component.
[0088] Preferred embodiments of either the composition aspect or
the use aspect of the invention with respect to the combined
VEGFR-2/Lck component correspond to those mentioned hereinbefore
for the method of treatment aspect.
Example 1
Non-Radioactive Kinase Assay (Ick)
Methodology
[0089] The Ick enzyme comprises the entire Ick molecule except the
first nine amino acids which are replaced by an His-tag for
purification purposes. The enzyme is affinity purified.
[0090] The assay mix is assembled in a well of a 96-well round
bottom microtiter plate and contains 10 .mu.l PBS (either as such
or with an inhibitor dissolved at an appropriate concentration), 20
.mu.l substrate solution (200 mM Hepes, pH=7.4; 50 mM MgAc.sub.2; 1
mM Na.sub.3VO.sub.4; 250 pg/ml poly-Glu-Tyr (Sigma PO.sub.275); 200
ng/ml biotinylated peptide
(biot-Ala-Glu-Glu-Glu-11e-Tyr-Gly-Glu-Phe-Glu-Ala-Lys-Lys-Lys-Lys)
and 20 .mu.l of 2.5 ng/.mu.l enzyme (diluted from affinity purified
stock with enzyme dilution buffer, EDB: 20 mM Hepes, pH=7.4, 130 mM
NaCl, 0.05% Triton X-100).
[0091] The reaction is started by the addition of 50 .mu.l 500
.mu.M ATP (in 10 mM MgAc.sub.2) and is performed at room
temperature. After 30 minutes 50 .mu.l stop solution (20 mM Hepes,
pH=7.4; 250 mM EDTA) are added and 100 .mu.l of this solution
transferred to the well of a streptavidin coated microtiter plate
(SA-MTP, Boehringer Mannheim, #1664-760).
[0092] The solution is incubated for one hour at room temperature
and the supernatant discarded. The well is washed twice with 300
.mu.l PBS.
[0093] The streptavidin bound biotinylated peptide is incubated for
1 hour at room temperature with 100 .mu.l Eu.sup.3+-labelled
anti-phosphotyrosine antibody solution (0.3 mg/ml
DELFIA-Eu-labelled PT66 (Wallac, AD0041); 50 mM Tris, pH=7.8; 0.05%
Tween 20; 0.5% (w7v) BSA (Serva, diagnostic grade) under gentle
agitation. The well is washed three times with 1.times. Delfia wash
buffer (Wallac, 1244-114, 25.times. concentrate, diluted with
water) and finally 100 .mu.l Delfia enhancement solution (Wallac,
1244-105) are added.
[0094] Time resolved fluorescense is measured in a Wallac Victor2
1420 Multilabel Counter, excitation is at 340 nm, emission is
measured at 615 nm (delay time 400 .mu.sec, window time 1000
.mu.sec).
Results
[0095] In two independent experiments the IC.sub.50s of compounds
(A) to (AL) on the kinase have been determined. The data (mean
values) obtained with three representative compounds are summarised
in the following table:
TABLE-US-00001 compound Lck; IC.sub.50 [nM] (AK) 16 (AI) 36 (AL)
58
Compounds (A) to (AH) and (AJ) inhibit the Ick kinase function with
an IC.sub.50<1 .mu.M.
* * * * *