DE102005020882A1 - Use of gaboxadol and its derivatives as kinase inhibitor for the treatment of e.g. kinase induced disease, cancer, age-related macular degeneration, diabetic retinopathy and angiogenesis - Google Patents

Abstract

Use of gaboxadol and its derivatives (A) as a kinase inhibitor for the treatment of kinase induced diseases. ACTIVITY : Cytostatic; Ophthalmological; Antiangiogenic; Antiarthritic; Antiarteriosclerotic; Antipsoriatic; Dermatological; Endocrine-Gen.; Neuroprotective; Nootropic; Antiparkinsonian; CNS-Gen.; Muscular-Gen.; Vasotropic; Cerebroprotective; Anticonvulsant; Anti-HIV; Tranquilizer. MECHANISM OF ACTION : Kinase inhibitor; Rho-kinase inhibitor. The kinase inhibiting activity of (I) to treat kinase-induced disease was tested using biological assays. The results showed that (I) inhibits the kinase induced disease at 10 mu M.

Description

The The present invention relates to the use of 5-hydroxyisoxazoles as drugs for the treatment of kinase-induced diseases.

kinases catalyze the phosphorylation of the amino acid residues serine, threonine and Tyrosine in proteins. ATP or GTP reacts with the substrate to ADP or GDP and the phosphorylated hydroxy group of the amino acid. phosphatases however, catalyze the reverse reaction.

protein kinases play a crucial role in regulating the activity of acceptor proteins (signal transduction cascade). Signals from outside The cell are by cell surface receptors such. As tyrosine kinases (RTKs). By binding "signaling" molecules or so-called effectors or ligands, the RTKs are autophosphorylated. This autophosphorylation allows the RTKs to interact with other proteins, called adapter proteins, to enter into an interaction. These protein complexes are in turn capable of other intracellular Activating proteins, resulting in a whole chain of protein interactions leads by that originally extracellular Signal from the cell surface to transferred to the nucleus becomes. The transferred Signal is thus able to cycle the cell or other important To influence cell functions.

The effectors of the receptor tyrosine kinases include, for example, insulin and many growth factors, such as. Platelet growth factors (PDGF) or epidermal growth factors (EGF). Receptor tyrosine kinases play an important role in regulating the formation of blood vessels (angiogenesis) or lymphatic vessels (lymphangiogenesis). Here, endothelial cells from already existing vessels are stimulated to grow, sprout and expand to form new capillaries. In this context, the cell surface receptors VEGFR (vascular endothelial growth factor receptor) and FGFR (fibroblast growth factor receptor) as well as effectors corresponding growth factors of the VEGF family or FGF family should be mentioned in particular. Other known examples of natural angiogenic effectors (ligands) include the Turtior necrosis factor (TNF-α), Interleukin 8 or the so-called Tie ₂ ligand.

The Uncontrolled stimulation of protein kinases can be pathological Processes, such as B. cause cancer. For example, a genetically modified receptor, so a mutant receptor tyrosine kinase, even in the absence of a suitable effectors constitutively relay signals to other proteins, for Cause cancer. Such activation mutations of RTKs are with a variety of human Diseases linked. For example, constitutively active FGF receptors are responsible for a variety of hereditary diseases responsible. The incorrect regulation of angiogenesis plays an important role in the course of a large number of diseases. Thus, in the case of cancer, various studies have revealed that tumors critically dependent on adequate blood supply. If angiogenesis can be inhibited, tumor growth can also be stopped or even reverted. Also the induction is lymphangiogenesis plays an important role in cancers and.

The Regulation of protein kinase activity of receptor tyrosine kinases can in principle done in different ways. So, for example antibody used, which the interaction of the receptors with the Block ligands. Alternatively, the use is 1össlicher extracellular Receptor sections for binding the corresponding ligand in one inactive complex (sequestration) in Aiello et al. (1995, Proc. Natl. Acad. Vol. 92: 10457-10461) described. Both the aforementioned antibodies and the soluble ones Receptor shares, however, have significant disadvantages. Both will quickly removed from the circulatory system. Further, it is in this case, very large molecules their ability for tissue penetration is very limited. Their production, in particular the antibodies for the pharmaceutical application is very complicated and expensive. Furthermore represent They are compounds that can trigger an immune response, so that their biological effectiveness strongly decreases or completely except Force is set.

Another possibility to regulate the activity of protein kinases is the inhibition by similar compounds that compete, for example, with the natural substrate ATG or GTP for the substrate binding domain. In this context, a number of molecules (eg indolinones) are described which are capable of inhibiting receptor tyrosine kinases (RTKs). Crystallographic studies on the RTK Fibroblast Growth Factor Receptor (FGFR) have shown that the oxindole portion of the indolinones interact with the same binding site as the adenine ring of the natural substrate ATP (Mohammadi, M. et Science, 276: 955-960). Low molecular weight kinase inhibitors often have disadvantages such as side effects and Moreover, they are not potent enough to be used as monotherapy in the disease to be treated.

to Treatment of diseases in which the regulated by protein kinases Signal transduction except Control, it is therefore of enormous medical relevance, Connections available with which the activity of surface receptor protein kinases, advantageously receptor tyrosine kinases (RTKs), can be regulated or preferably blocked to thereby to reduce or even prevent the course of the diseases. Diseases in which the activity of protein kinases is pathologically out of control guessed, can e.g. Cancers in which a disturbed apoptosis for uncontrolled cell proliferation leads.

The Age-related macular blindness (AMD) is another example a disease caused by pathogenic angiogenesis. It grows new blood vessels in the eyeball and obstruct the light to the photoreceptors of the Retina to come. AMD is the most important cause of the occurrence from blindness in old age.

Farther it can be diseases such. B. Filariasis act or order Diseases that are disturbed by operations in angiogenesis or lymphangiogenesis. Desirable is in this context also the provision of connections, the natural ones activity or pathologically changed (constitutive) activity block protein kinase-directed angiogenesis / lymphangiogenesis, see above on the one hand worsens the blood supply of the tumor or is even inhibited, causing it to curb tumor growth or a death of the diseased tissue comes, or otherwise Metastasis of tumor cells is prevented.

Krankheitsrelvante Kinases can his Abl, ALK, Aurora-A, Axl, Blk, Bmx, BTK, CaMKII, CaMKIV, CDK1 / cyclinB, CDK2 / cyclinA, CDK2 / cyclinE, CDK3 / cyclinE, CDK5 / p35, CDK6 / cyclinD3, CDK7 / cyclinH / MAT1, CHK1, CHK2, CK1 (yeast), CK1δδ, CK2, CSK, EGFR, EphB2, EphB4, Fes, FGFR3, Flt3, Fms, Fyn, GSK3α, GSK3β, IGF-1R, IKKα, IKKβ, IR, JNK1α1, JNK2α2, JNK3, Lck, Lyn, MAPK1, MAPK2, MAPKAP-K2, MEK1, Met, MKK4, MKK6, MKK7β, MSK1, MST2, NEK2, p70S6K, PAR-1Bαα, PDGFRα, PDGFRβ, PDK1, PAK2, PKA, PKBα, PKBβ, PKBγ, PKCα, PKCβII, PKCγ, PKCδ, PKCε, PKCη, PKCι, PKCμ, PKCθ, PKCζζ, PKD2, PRAK, PRK2, c-RAF, ROCK-II, Ros, Rsk1, Rsk2, Rsk3, SAPK2a, SAPK2b, SAPK3, SAPK4, SGK, cSRC, Syk, Tie2, TrkB, Yes, ZAP-70, are not limited to this. Preferred are kinases from mammals. Further preferred are kinases of bacteria. Further preferred are kinases of yeasts.

Gaboxazol (Formula 1) is a GABA agonist and is currently in clinical use Development.

The over- or Underregulation of kinases is a feature in many different Diseases.

It It is the object of the present invention to provide novel kinase inhibitors to provide with improved properties.

According to the invention and surprisingly it was found that gaboxadol and its derivatives act as kinase inhibitors and thereby to Treatment of a variety of diseases can be used.

The Compounds of the invention are thus able, not only in general, because of their structure the activity of protein kinases, but also human diseases to treat caused by mutated (constitutively) active RTKs become. Here's the use of every single connection, though also their combinations conceivable.

Because they are small molecules with very good cell or tissue penetration they are very suitable for administration to patients, preferably orally. The preparation of the compounds is possible on an industrial scale and thus makes the pharmaceutical use simple and inexpensive. In addition, it is particularly advantageous that these compounds do not trigger an immune response.

object The present invention also includes agents containing at least a compound of the invention of the aforementioned kind for the treatment of diseases in whose Genesis, course, relief or cure of naturally occurring pathological changed Protein kinases are involved. This comprises means according to the invention to inhibit uncontrolled proliferation and / or induction apoptosis of cells or to inhibit angiogenesis / lymphangiogenesis containing at least one compound of the aforementioned kind are the agents of the invention containing at least one compound of the invention for treatment angiogenic and lymphangiogenesis-dependent diseases suitable.

The The aforementioned means are further distinguished by the fact that they are at least a compound of the type according to the invention in a concentration from about 1-20, preferably from about 2-15, more preferably from about 3-10 and in particular from about 4-8 body weight of the subject included. Also conceivable are combinations of the compounds according to the invention in freely combinable concentration proportions of said ranges. According to the invention are also agents containing at least one compound of the above mentioned above can out the agents according to the invention additionally Contain substances for better processing or administration necessary or suitable for the patient. These substances as well the manufacturing processes are common Laboratory practice and are therefore not explained here. Subject of the present Invention is the use of the compounds of the aforementioned Way of producing means of inhibiting the uncontrolled Propagation inducing apoptosis of cells to inhibit angiogenesis Lymphangiogenesis. Likewise, the use of the compounds to Treatment of angiogenesis, lymphangiogenesis-dependent.

The The present invention thus relates to the use of gaboxadol and its derivatives as kinase inhibitors, in particular of human Kinases (especially the compounds described in the examples) for fighting of kinase-induced diseases, especially of mammals, in particular of the human.

worin
R¹ unabhängig voneinander ein Wasserstoffatom, ein Alkyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Heterocycloalkyl-, Aralkyl-, ein Heteroaralkylrest oder zusammen Teil eines Heterocycloalkylrings sind;
worin
R² unabhängig voneinander ein Wasserstoffatom, ein Alkyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Heterocycloalkyl-, Aralkyl-, ein Heteroaralkylrest oder zusammen Teil eines Heterocycloalkylrings sind;
oder ein pharmakologisch akzeptables Salz, Solvat, Hydrat oder eine pharmakologisch akzeptable Formulierung derselben.Examples of known GABA agonists are e.g. For example, the compounds of the general formula (II) described in WO 2004112786, WO 9626929:

wherein
R ^{1 is} independently a hydrogen atom, an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl or together part of a heterocycloalkyl ring are;
wherein
R ^{2 are} independently a hydrogen atom, an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, or together are part of a heterocycloalkyl ring;
or a pharmacologically acceptable salt, solvate, hydrate or pharmacologically acceptable formulation thereof.

Other examples of known hydroxyisoxazoles GABA agonists are those in Knopfel, Thomas; Madge, David; Nicoletti, Ferdinando; Metabotropic glutamate receptors. Expert Opinion on Therapeutic Patents (1996), 6 (10), 1061-1067.
and
Ornstein, PL; Schoepp, DD; Monn, JA Agonists and antagonists for metabotropic glutamate receptors. Current Pharmaceutical Design (1995), 1 (3), 355-62.
described compounds.

Of the Expression alkyl refers to a saturated or at least partial unsaturated (eg alkenyl, alkynyl), straight-chain or branched hydrocarbon group, the 1 or 2 to 20 carbon atoms, preferably 1 or 2 to 12 carbon atoms, more preferably 1 or 2 to 6 carbon atoms has, e.g. the methyl, ethyl, isopropyl, isobutyl, tert-butyl, n-hexyl, 2,2-dimethylbutyl, n-octyl, allyl, isoprenyl or Hex-2-enyl group.

Of the Expression Heteroalkyl refers to an alkyl group in which one or more (preferred 1, 2 or 3) carbon atoms by an oxygen, nitrogen, Phosphorus or sulfur atom are replaced (preferably oxygen or Nitrogen), e.g. an alkyloxy group such as e.g. Methoxy or ethoxy, or a methoxymethyl, nitrile, methylcarboxyalkyl ester, carboxyalkylester or 2,3-dioxyethyl group. The term heteroalkyl further refers to a carboxylic acid or one from a carboxylic acid derived group such. Acyl, acyloxy, carboxyalkyl, carboxyalkylester e.g. Methylcarboxyalkylester, carboxyalkylamide, alkoxycarbonyl or Alkoxycarbonyloxy.

Of the Expression cycloalkyl or cyclo refers to a saturated or partially unsaturated cyclic group having one or more rings containing a framework which has 3 to 14 carbon atoms, preferably 3 to 10 Contains carbon atoms, e.g. the cyclopropyl, cyclohexyl, tetralin or cyclohex-2-enyl group.

Of the Expressing heterocycloalkyl or heterocyclo refers to a Cycloalkyl group as defined above, in which one or more (preferred 1, 2 or 3) carbon atoms by an oxygen, nitrogen, phosphorus or sulfur atom and can be substituted for example for the piperidine, Morpholine, N-methylpiperazine or N-phenylpiperazine group.

Of the Term aryl or Ar refers to an aromatic group, which has one or more rings, and formed by a framework is 5 to 14 carbon atoms, preferably 5 or 6 to 10 Contains carbon atoms e.g. a phenyl, naphthyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 4-carboxyphenylalkyl or 4-hydroxyphenyl group.

Of the Heteroaryl refers to an aryl group in which one or more (preferred 1, 2 or 3) carbon atoms by an oxygen, nitrogen, Phosphorus or sulfur atom, e.g. the 4-pyridyl, 2-imidazolyl, 3-pyrazolyl and isoquinolinyl group.

The expressions Aralkyl or heteroaralkyl refer to groups corresponding to the above Definitonen both aryl or heteroaryl as well as alkyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl ring systems include, e.g. the tetrahydroisoquinolinyl, benzyl, 2- or 3-ethyl-indolyl or 4-methylpyridino group.

The terms alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups in which one or more hydrogen atoms of such groups by fluorine, chlorine, bromine or iodine atoms or OH, SH, NH ₂ or NO ₂ - groups are replaced. These terms also refer to groups substituted with unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups.

gaboxadol can be prepared by known methods, e.g. Petersen, Hans; Bech Summer, Michael; Dancer, Robert. Method for the manufacture of THIP. PCT Int. Appl. (2005), 34 pp. WO 2005023820 and methods mentioned therein getting produced.

links of the general formula (II) are inhibitors with activities between 10 μM and 1 nM at various kinases e.g. from the following group: Abl, ALK, Aurora-A, Axl, Blk, Bmx, BTK, CaMKII, CaMKIV, CDK1 / cyclinB, CDK2 / cyclinA, CDK2 / cyclinE, CDK3 / cyclinE, CDK5 / p35, CDK6 / cyclinD3, CDK7 / cyclinH / MAT1, CHK1, CHK2, CK1 (yeast), CK1δδ, CK2, CSK, EGFR, EphB2, EphB4, Fes, FGFR3, Flt3, Fms, Fyn, GSK3α, GSK3β, IGF-1R, IKKα, IKKβ, IR, JNK1α1, JNK2α2, JNK3, Lck, Lyn, MAPK1, MAPK2, MAPKAP-K2, MEK1, Met, MKK4, MKK6, MKK7β, MSK1, MST2, NEK2, p70S6K, PAR1Bαα, PDGFRα, PDGFRβ, PDK1, PAK2, PCA, PKBα, PKBβ, PKBγ, PKCα, PKCβII, PKCγ, PKCδ, PKCε, PKCη, PKCι, PKCμ, PKCθ, PKCζζ, PKD2, PRAK, PRK2, c-RAF, ROCK-II, Ros, Rsk1, Rsk2, Rsk3, SAPK2a, SAPK2b, SAPK3, SAPK4, SGK, cSRC, Syk, Tie2, TrkB, Yes, ZAP-70, but are not on it limited.

The compounds of general formulas (II) described above may contain one or more chiral centers due to their substitution. The present invention therefore includes all pure ones Enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio.

worin
R unabhängig voneinander ein Wasserstoffatom, Fluor, ein Alkyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Heterocycloalkyl-, Aralkyl-, ein Heteroaralkylrest oder zusammen Teil eines Heterocycloalkylrings sind.Particularly preferred kinase inhibitors are compounds of the formulas (III), (IV), (V) and (VI):

wherein
R independently of one another are a hydrogen atom, fluorine, an alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, a heteroaralkyl radical or together form part of a heterocycloalkyl ring.

Claims (18)

Use of gaboxadol and derivatives as kinase inhibitors for the treatment of kinase-induced diseases. Use of gaboxadol and derivatives as kinase inhibitors for the treatment of cancer. Use of gaboxadol and derivatives as kinase inhibitors for the treatment of age-related macular degeneration. Use of gaboxadol and derivatives as inhibitors of Rho kinases for neutralization of regeneration inhibitors the scar tissue. Use of gaboxadol and derivatives as kinase inhibitors for the treatment of diabetes related retinopathy. Use of inhibitors of Rho kinases for neutralization of regeneration inhibitors on the surface of astrocytes, macrophages, Microglia. Use of gaboxadol and derivatives or a pharmaceutical composition as kinase inhibitors for treatment and / or prevention according to any one of claims 1 to 6 of diseases with pathogenic kinase activity and / or disturbed Angiogenesis, arterial restenosis, cancer, angiofibroma, arteriovenous malformation, Arthritis, atherosclerotic plaques, neovascularization in corneal transplantation, delayed wound healing, Diabetic retinopathy, granulation after combustion, Hemangioma, haemophilia Joints, Hypertrophic Scars, Neovascular Glaucoma, Bad Healing Fractures, Osler-Weber syndrome, psoriasis, Progenic granuloma, Retrolental fibroplasia, age-related macular blindness, scleroderma, Tumor Formation and Metastasis, Trachoma, Vascular Adhesion, Von Hippel-Lindau Syndrome, Craniosynostosis, Dwarfism Syndrome, Lethales Dwarfism syndrome, familial medullary Thyroid carcinoma, Multiple endocrine neoplasia type 2, hereditary papillary renal cell carcinoma, Gastrointestinal stromal tumors, mastocytosis, vascular dysfunction and other disorders mediated by kinase activity become. Use of gaboxadol and derivatives as kinase inhibitors for the treatment according to any one of claims 1-7 for the treatment of neuronal damage. Use of gaboxadol and derivatives as kinase inhibitors for the treatment according to any one of claims 1-8 for the treatment of acute Injuries to the brain and spinal cord. Use of gaboxadol and derivatives as kinase inhibitors according to one of the claims 1-9 for treatment of chronic damage of the brain and spinal cord. Use of gaboxadol and derivatives as kinase inhibitors according to any one of claims 1-10 Treatment of neurological and neurodegenerative diseases of the central nervous system. Use of gaboxadol and derivatives as kinase inhibitors according to one of the claims 1-11 for regenerative Treatment of Alzheimer's disease, Parkinson's disease, multiple sclerosis and similar Diseases associated with nerve fiber loss and demyelinization, as well as amyotrophic lateral sclerosis and other motoneuron diseases. Use of inhibitors of Rho kinases after Claim 11 for the regenerative treatment of ischemia, a Stroke, of epilepsy, Huntington's disease, AIDS dementia Complex and of prion diseases. Use of inhibitors of Rho kinases after one of the claims 1-7 to Treatment of neurological and neurodegenerative diseases of the peripheral nervous system. Use of inhibitors of Rho kinases after Claim 14 for the treatment of lesions peripheral nerves. Use of inhibitors of Rho kinases after Claim 14 or 15 for the treatment of paralysis phenomena, by Injuries to peripheral nerves were caused. Use of inhibitors of Rho-kinases for treatment of memory and memory deficits based on the increase induced by these inhibitors the cerebral circulation. Use of compounds according to any one of claims 1-17, wherein the inhibitors are compounds of the formulas (III), (IV), (V) and (VI):