# US 2012/0083528 A1 · Novel protein kinase modulators and therapeutic uses thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2012/0083528 A1 - Document ID: US20120083528A1 - Status: Published application - Kind: A1 - Application number: 13/293,546 - Filed: 2011-11-10 - Published: 2012-04-05 - Earliest claimed: 2006-12-04 - Assignees: Novotyr Therapeutics Ltd. - Inventors: Hadas Reuveni; Alexander Levitzki; Lilach Steiner; Revital Sasson; Iris Ben-David; Avi Weissberg - Web page: https://patentgrep.com/patent/US20120083528A1 ## CPC - A61K 31/277: having a ring, e.g. verapamil - A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide - A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) - A61P 17/06: Antipsoriatics - A61P 35/00: Antineoplastic agents - A61P 35/02: specific for leukemia - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention provides new tyrphostin derivatives acting as protein tyrosine kinase (PTK) inhibitors and receptor tyrosine kinase (RTK) inhibitors, and/or which directly or indirectly affect proteins in the PTK-mediated signal transduction pathway, methods of their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds and compositions, especially as chemotherapeutic agents for preventions and treatments of PTK and RTK related disorders such as metabolic, fibrotic, and cell proliferative disorders, in particular psoriasis and cancer. ## Claims ### Claim 1 A method of inhibiting signal transduction pathways mediated by a protein tyrosine kinase (PTK), comprising the step of contacting a cell comprising said PTK with an effective inhibitory amount of a compound represented by the structure of formula 1: wherein R1, R2, R5 and R6 are independently selected from H, C1-C4 alkyl, acyl and a functional group that gives rise to hydroxyl upon hydrolysis; R3 and R7 are independently selected from H, halogen, haloalkyl and OR8 wherein R8 is H, C1-C4 alkyl, acyl or a functional group that gives rise to hydroxyl upon hydrolysis; R4 is H or CN, including salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof; or a pharmaceutical composition comprising said compound, and a pharmaceutically acceptable carrier. ### Claim 2 (depends on 1) The method according to claim 1, wherein the compound of formula (1) directly or indirectly interacts with, affects or inhibits said PTK or a protein in said PTK-mediated pathway. ### Claim 3 (depends on 1) The method according to claim 1, wherein the protein tyrosine kinase is a receptor protein tyrosine kinase (RTK). ### Claim 4 (depends on 3) The method according to claim 3, wherein the receptor protein kinase (RTK) is selected from the group consisting of: a platelet-derived growth factor receptor (PDGFR), a fibroblast growth factor receptor (FGFR), a hepatocyte growth factor receptor (HGFR), an insulin receptor, an insulin-like growth factor-1 receptor (IGF-1R), an epidermal growth factor receptor (EGFR), a nerve growth factor receptor (NGFR), a vascular endothelial growth factor receptor (VEGFR), and a macrophage colony stimulating factor (M-CSFR). ### Claim 5 (depends on 4) The method according to claim 4, wherein the compound of formula (1) is an inhibitor of an insulin receptor or an insulin-like growth factor-1 receptor (IGF-1R), or wherein the compound of formula (1) directly or indirectly interacts with, affects or inhibits a substrate protein in the IGF-1R mediated pathway. ### Claim 6 (depends on 5) The method according to claim 5, wherein the substrate protein is Insulin Receptor Substrate 1 (IRS1), Insulin Receptor Substrate 2 (IRS2), or a combination thereof. ### Claim 7 (depends on 6) The method according to claim 6, wherein said compound of formula (1) leads to any one or more of (i) dissociation of IRS1 or IRS2 from the cell membrane; (ii) phosphorylation of IRS1 or IRS2; or (iii) degradation of IRS1 or IRS2, in any order. ### Claim 8 (depends on 1) The method according to claim 1, wherein R1, R2, R5 and R6 are each H. ### Claim 9 (depends on 1) The method according to claim 1, wherein R3 is selected from H, halogen, halomethyl and OH. ### Claim 10 (depends on 1) The method according to claim 1, wherein R7 is OH. ### Claim 11 (depends on 1) The method according to claim 1, wherein said compound is selected from the group consisting of: ### Claim 12 (depends on 11) The method according to claim 11, wherein the compound is represented by the structure of formula 7, 8, 9, 10, 11, 12, 13 or 14. ### Claim 13 A method for treating or preventing a protein tyrosine kinase (PTK) related disorder comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound represented by the structure of formula 1: wherein R1, R2, R5 and R6 are independently selected from H, C1-C4 alkyl, acyl and a functional group that gives rise to hydroxyl upon hydrolysis; R3 and R7 are independently selected from H, halogen, haloalkyl and OR8 wherein R8 is H, C1-C4 alkyl, acyl or a functional group that gives rise to hydroxyl upon hydrolysis; R4 is H or CN, including salts, hydrates, solvates, polymorphs; optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof; or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier. ### Claim 14 (depends on 13) The method according to claim 13, wherein the protein tyrosine kinase related disorder is a cell proliferative disorder, a fibrotic disorder, or a metabolic disorder. ### Claim 15 (depends on 14) The method according to claim 14, wherein the proliferative disorder is cancer or psoriasis. ### Claim 16 (depends on 15) The method according to claim 15, wherein the cancer is selected from prostate, ovarian, colon, lung, glioma, breast, brain, liver, melanoma, bladder, pancreatic, leukemia, lymphoma, Ewing sarcoma, osteosarcoma, gastric, and myeloma cancer. ### Claim 17 (depends on 13) The method according to claim 13, wherein said compound is selected from the group consisting of: ### Claim 18 A method for treating or preventing a protein tyrosine kinase (PTK) related disorder comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of: including salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof; or a pharmaceutical composition comprising said compound, and a pharmaceutically acceptable carrier. ### Claim 19 (depends on 18) The method according to claim 18, wherein the protein tyrosine kinase related disorder is a cell proliferative disorder, a fibrotic disorder, or a metabolic disorder. ### Claim 20 (depends on 19) The method according to claim 19, wherein the proliferative disorder is cancer.