Consider thisAbstract
The present invention is related to a composition comprising a JNK inhibitor and a cyclosporin, in particular for the treatment of neuronal disorders, autoimmune diseases, cancer and cardiovascular diseases.
--------------------------------------------------------------------------------
Inventors: Rommel; Christian; (Geneva, CH) ; Vitte; Pierre-Alain; (Cranves-Sales, FR)
Correspondence Name and Address: OBLON, SPIVAK, MCCLELLAND MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
Assignee Name and Adress: Applied Research Systems ARS Holding N.V.
Pietermaai 15
Curacao
AN
Serial No.: 547967
Series Code: 11
Filed: April 8, 2005
PCT Filed: April 8, 2005
PCT NO: PCT/EP05/51572
371 Date: September 28, 2007
U.S. Current Class: 514/11
U.S. Class at Publication: 514/011
Intern'l Class: A61K 38/13 20060101 A61K038/13; A61P 37/00 20060101 A61P037/00; A61P 9/00 20060101 A61P009/00
--------------------------------------------------------------------------------
Foreign Application Data
--------------------------------------------------------------------------------
Date Code Application Number
Apr 8, 2004 EP 04101468.9
--------------------------------------------------------------------------------
Claims
--------------------------------------------------------------------------------
1: A pharmaceutical composition comprising a JNK inhibitor and a cyclosporin.
2: Pharmaceutical composition according to claim 1, wherein the JNK inhibitor is a JNK3 inhibitor.
3: Pharmaceutical composition according to claim 2, wherein the JNK inhibitor is a benzothiazole derivative according to formula I as well as its tautomers, its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein G is a pyrimidinyl group. L is an C.sub.1-C.sub.6-alkoxy, or an amino group, or an 3-8 membered heterocycloalkyl, containing at least one heteroatom selected from N, O, S; R.sup.1 is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl or C.sub.1-C.sub.6-alkoxy, aryl, halogen, cyano or hydroxy.
4: Pharmaceutical composition according to claim 3, wherein R.sup.1 is H or C.sub.1-C.sub.3 alkyl.
5: Pharmaceutical composition according to claim 3, wherein the JNK inhibitor has any of formulae (Ia), (Ia') or (Ia''): wherein R.sup.1 is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl or C.sub.1-C.sub.6-alkoxy, aryl, halogen, cyano or hydroxy; L is an amino group of the formula --NR.sup.3R.sup.4 wherein R.sup.3 and R.sup.4 are each independently from each other H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, (wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group), C.sub.1-C.sub.6-alkyl aryl, C.sub.1-C.sub.6-alkyl heteroaryl, C.sub.2-C.sub.6-alkenyl aryl, C.sub.2-C.sub.6-alkenyl heteroaryl, C.sub.2-C.sub.6-alkynyl aryl, C.sub.2-C.sub.6-alkynyl heteroaryl, C.sub.1-C.sub.6-alkyl cycloalkyl, C.sub.1-C.sub.6-alkyl heterocycloalkyl, C.sub.2-C.sub.6-alkenyl cycloalkyl, C.sub.2-C.sub.6-alkenyl heterocycloalkyl, C.sub.2-C.sub.6-alkynyl cycloalkyl, C.sub.2-C.sub.6-alkynyl heterocycloalkyl, or R.sup.3 and R.sup.4 may form a ring together with the nitrogen to which they are bound.
6: Pharmaceutical composition according to claim 5, wherein R.sup.3 is hydrogen or a methyl or ethyl or propyl group and R.sup.4 is selected from the group consisting of (C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 alkyl-aryl, C.sub.1-C.sub.6-alkyl-heteroaryl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl and 4-8 membered saturated or unsaturated cycloalkyl.
7: Pharmaceutical composition according to claim 5, wherein R.sup.3 and R.sup.4 form an optionally substituted piperazine or a piperidine or a morpholine or a pyrrolidine ring together with the nitrogen to which they are bound, whereby said optional substituent is selected from the group consisting of C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, (wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group), C.sub.1-C.sub.6-alkyl aryl, C.sub.1-C.sub.6-alkyl heteroaryl, C.sub.2-C.sub.6-alkenyl aryl, C.sub.2-C.sub.6-alkenyl heteroaryl, C.sub.2-C.sub.6-alkynyl aryl, C.sub.2-C.sub.6-alkynyl heteroaryl, C.sub.1-C.sub.6-alkyl cycloalkyl, C.sub.1-C.sub.6-alkyl heterocycloalkyl, C.sub.2-C.sub.6-alkenyl cycloalkyl, C.sub.2-C.sub.6-alkenyl heterocycloalkyl, C.sub.2-C.sub.6-alkynyl cycloalkyl, C.sub.2-C.sub.6-alkynyl heterocycloalkyl.
8: Pharmaceutical composition according to claim 5 wherein L is selected from: wherein n is 1 to 10, preferably 1 to 6, R.sup.5 and R.sup.5' are independently selected from each other from the group consisting of H, C.sub.1-C.sub.10 alkyl, aryl or hetero-aryl, C.sub.1-C.sub.6 alkyl-aryl and C.sub.1-C.sub.6-alkyl-heteroaryl.
9: Pharmaceutical composition according to claim 5 wherein L is selected from: wherein n is 1 to 10, preferably 1 to 6, R.sup.5 and R.sup.5' are independently selected from each other from the group consisting of H, C.sub.1-C.sub.10 alkyl, aryl or hetero-aryl, C.sub.1-C.sub.6 alkyl-aryl and C.sub.1-C.sub.6-alkyl-heteroaryl
Description
--------------------------------------------------------------------------------
FIELD OF THE INVENTION
[0001] The present invention is related to a composition containing a JNK inhibitor and a cyclosporin, in particular for the treatment of neuronal disorders, autoimmune diseases, cancer and cardiovascular diseases.
BACKGROUND OF THE INVENTION
c-Jun N-Terminal Kinases (JNKs)
[0002] Mammalian cells respond to some extracellular stimuli by activating signaling cascades which are mediated by various mitogen-activated protein kinases (MAPKs). Despite the differences in their response to upstream stimuli, the MAP kinase cascades are organized in a similar fashion, consisting of MAP kinase kinase kinases (MAPKKK or MEKK), MAP kinase kinases (MAPKK or MKK) and MAP kinases (MAPK). MAP kinases are a broad family of kinases, which includes c-Jun N-Terminal kinases (JNKs), also known as "stress-activated protein kinases" (SAPKs), as well as extracellular signal regulated kinases (ERKs) and p38 MAP kinases. Each of these three MAP kinases sub-families is involved in at least three different but parallel pathways conveying the information triggered by external stimuli. The JNK signaling pathway is activated by exposure of cells to environmental stress--such as chemical toxins, radiation, hypoxia and osmotic shock--as well as by treatment of cells with growth factors or pro-inflammatory cytokines--such as tumour necrosis factor alpha (TNF-.alpha.) or interleukin-1 beta (IL-1.beta.).
[0003] Two MAP kinase kinases (known as MKKs or MAPKKs), i.e. MKK4 (known also as JNKK1) and MKK7, activate JNK by a dual phosphorylation of specific threonine and tyrosine residues located within a Thr-Pro-Tyr motif on the activation loop on the enzyme, in response to cytokines and stress signals. Even further upstream in the signaling cascade, MKK4 is known to be activated itself also by a MAP kinase kinase kinase, MEKK1 through phosphorylation at serine and threonine residues.
[0004] Once activated, JNK binds to the N-terminal region of transcription factor targets and phosphorylates the transcriptional activation domains resulting in the up-regulation of expression of various gene products, which can lead to apoptosis, inflammatory responses or oncogenic processes (1).
[0005] Some transcription factors known to be JNK substrates are the Jun proteins (c-jun, JunB and Jun D), the related transcription factors ATF2 and ATFa, Ets transcription factors such as Elk-1 and Sap-1, the tumor suppressor p53 and a cell death domain protein (DENN).
[0006] Three distinct JNK enzymes have been identified as products of the genes JNK1, JNK2 and JNK3 and ten different isoforms of JNK have been identified (2). JNK1 and -2 are ubiquitously expressed in human tissues, whereas JNK3 is selectively expressed in the brain, heart and testes (2). Each isoform binds to the substrates with different affinities, suggesting, in vivo, a substrate specific regulation of the signaling pathways by the different JNK isoforms.
[0007] Activation of the JNK pathway has been documented in a number of disease processes, thus providing a rationale for targeting this pathway for drug discovery. In addition, molecular genetic approaches have validated the pathogenic role of this pathway in several diseases.
[0008] For example, auto-immune and inflammatory diseases derive from the inappropriate activation of the immune system. Activated immune cells express many genes encoding inflammatory molecules, including cytokines, growth factors, cell surface receptors, cell adhesion molecules and degradative enzymes. Many of these genes are known to be regulated by the JNK pathway, through the activation of the transcription factors c-Jun and ATF-2.
[0009] The inhibition of JNK activation in bacterial lipopolysaccharide-stimulated macrophages, effectively modulates the production of the key pro-inflammatory cytokine, TNF.alpha. (3).
[0010] The inhibition of JNK activation decreases the transcription factor activation responsible of the inducible expression of matrix metalloproteinases (MMPs) (4), which are known to be responsible of the promotion of cartilage and bone erosion in rheumatoid arthritis and of generalized tissue destruction in other auto-immune diseases.
[0011] The JNK cascade is also activated in T cells by antigen stimulation and CD28 receptor co-stimulation (5) and regulates the production of the IL-2 promoter (6). Inappropriate activation of T lymphocytes initiates and perpetuates many auto-immune diseases, including asthma, inflammatory bowel syndrome and multiple sclerosis.
[0012] In neurons vulnerable to damage from Alzheimer's disease and in CA1 neurons of patients with acute hypoxia (7), JNK3 protein is highly expressed. The JNK3 gene was also found to be expressed in the damaged regions of the brains of Alzheimer's patients (8). In addition, neurons from JNK3 KO mice were found to become resistant to kainic acid induced neuronal apoptosis compared to neurons from wild-type mice.
[0013] Based on these findings, the JNK signaling pathway and especially that of JNK2 and JNK3, is thought to be implicated in apoptosis-driven neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, epilepsy and seizures, Huntington's disease, CNS disorders, traumatic brain injuries as well as ischemic disorders and hemorrhaging strokes.
[0014] Several small molecules have been proposed as modulators of JNK pathway.
[0015] Aryl-oxindole derivatives of respectively the generic formula (A) (WO 00/35909; WO 00/35906; WO 00/3592) and formula (B) (WO 00/64872) have been developed for the treatment of neurodegenerative diseases, inflammation and solid tumors for formula (A) and for the treatment of a broad range of disorders including, neurodegenerative diseases, inflammatory and autoimmune diseases, cardiovascular and bone disorders for formula (B).
[0016] Pyrazoloanthrones derivatives of formula (C) have been reported to inhibit JNK for the treatment of neurological degenerative diseases, inflammatory and auto-immune disorders as well as cardiovascular pathologies (WO 01/12609).
[0017] Tetrahydro-pyrimidine derivatives of formula (D) were reported to be JNK inhibitors useful in the treatment of a wide range of diseases including neurodegenerative diseases, inflammatory and auto-immune disorders, cardiac and destructive bone pathologies (WO 00/75118).
[0018] Other heterocyclic compounds of formula (E) have been proposed to inhibit protein kinases and especially c-un-N-Terminal kinases (WO 01/12621) for treating "JNK-mediated conditions" including neurodegenerative diseases, inflammatory and auto-immune disorders, destructive bone disorders, cardiovascular and infectious diseases.
[0019] Benzazoles derivatives such as represented by formula (F) (WO 01/47920) have been described as modulators of the JNK pathway for the treatment of neuronal disorders, auto-immune diseases, cancers and cardiovascular diseases.
[0020] Several sulphonamide derivatives of formula (G) (WO 01/23378), sulfonyl amino acid derivatives of formula (H) (WO 01/23379) and sulfonyl hydrazide derivatives of formula (J) (WO 01/23382), were also developed to inhibit JNKs especially JNK2 and JNK3 for treating neurodegenerative diseases, auto-immune disorders, cancers and cardiovascular diseases. Cyclosporine
[0021] Cyclosporin derivatives compose a class of cyclic polypeptides, consisting of eleven amino acids, that are produced as secondary metabolites by the fungus species Tolypocladium inflatum Gams. They have been observed to reversibly inhibit immuno-competent lymphocytes, particularly T-lymphocytes, in the G0 or G1 phase of the cell cycle. Cyclosporin derivatives have also been observed to reversibly inhibit the production and release of lymphokines (16). Although a number of cyclosporin derivatives are known, cyclosporin A is the most widely used. The suppressive effects of cyclosporin A are related to the inhibition of T-cell mediated activation events. This suppression is accomplished by the binding of cyclosporin to the ubiquitous intracellular protein, cyclophilin. This complex, in turn, inhibits the calcium- and calmodulin-dependent serine-threonine phosphatase activity of the enzyme calcineurin. Inhibition of calcineurin prevents the activation of transcription factors such as NFATp/c and NF-[kappa]B, which are necessary for the induction of the cytokine genes (IL-2, IFN-[gamma], IL-4, and GM-CSF) during T-cell activation. Cyclosporin also inhibits lymphokine production by T-helper cells in vitro and arrests the development of mature CD8 and CD4 cells in the thymus (16). Other in vitro properties of cyclosporin include the inhibition of IL-2 producing T-lymphocytes and cytotoxic T-lymphocytes, inhibition of IL-2 released by activated T-cells, inhibition of resting T-lymphocytes in response to alloantigen and exogenous lymphokine, inhibition of IL-1 production, and inhibition of mitogen activation of IL-2 producing T-lymphocytes (16).
[0022] Cyclosporin is a potent immunosuppressive agent that has been demonstrated to suppress humoral immunity and cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis and graft vs. host disease. It is used for the prophylaxis of organ rejection subsequent to organ transplantation; for treatment of rheumatoid arthritis; for the treatment of psoriasis; and for the treatment of other autoimmune diseases, including type I diabetes, Crohn's disease, lupus, and the like.
[0023] Since the original discovery of cyclosporin, a wide variety of naturally occurring cyclosporins have been isolated and identified and many further non-natural cyclosporins have been prepared by total- or semi-synthetic means or by the application of modified culture techniques. The class comprised by the cyclosporins is thus now substantial and includes, for example, the naturally occurring cyclosporins A through Z (17, 18, 19, 20), as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins including the dihydro- and iso-cyclosporins; derivatized cyclosporins (e.g., in which the 3'-O-atom of the -MeBmt-residue is acylated or a farther substituent is introduced at the [alpha]-carbon atom of the sarcosyl residue at the 3-position); cyclosporins in which the -MeBmt-residue is present in isomeric form (e.g., in which the configuration across positions 6' and 7' of the -MeBmt-residue is cis rather than trans); and cyclosporins wherein variant amino acids are incorporated at specific positions within the peptide sequence employing, e.g., the total synthetic method for the production of cyclosporins developed by (21, 17, 18, 19, 21, 22, 23 cf also U.S. Pat. No. 4,108,985, U.S. Pat. No. 4,210,581, U.S. Pat. No. 4,220,641, U.S. Pat. No. 4,288,431, U.S. Pat. No. 4,554,351 and U.S. Pat. No. 4,396,542, EP-0 034 567 and EP-0 056 782, WO 86/02080).
[0024] Cyclosporin A analogues containing modified amino acids in the 1-position are reported by Rich et al. (24). Immunosuppressive, anti-inflammatory, and anti-parasitic cyclosporin A analogues are described in U.S. Pat. No. 4,384,996; U.S. Pat. No. 4,771,122; U.S. Pat. No. 5,284,826; and U.S. Pat. No. 5,525,590, all assigned to Sandoz. Additional cyclosporin analogues are disclosed in WO 99/18120, assigned to Isotechnika. The terms Ciclosporin, ciclosporin, cyclosporine, and Cyclosporin are interchangeable and refer to cyclosporin.
[0025] There are numerous adverse effects associated with cyclosporin A therapy, including nephrotoxicity, hepatotoxicity, cataractogenesis, hirsutism, parathesis, and gingival hyperplasia to name a few. Of these, nephrotoxicity is one of the more serious, dose-related adverse effects resulting from cyclosporin A administration.
[0026] Immediate-release cyclosporin A drug products (e.g., Neoral.RTM. and Sandimmune.RTM. of Novartis) can cause nephrotoxicities and other toxic side effects due to their rapid release and the absorption of high blood concentrations of the drug. It is postulated that the peak concentrations of the drug are associated with the side effects.
SUMMARY OF THE INVENTION
[0027] The present invention relates to a composition containing a JNK inhibitor and a cyclosporin, in particular for the treatment of neuronal disorders, autoimmune diseases, cancer and cardiovascular diseases.
[0028] In one embodiment the JNK inhibitor is a benzazole of formula (I).