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  Sulfonamide-substituted chalcone derivatives and their use to treat diseasesUSPTO Application #: 20070093453Title: Sulfonamide-substituted chalcone derivatives and their use to treat diseases Abstract: or its pharmaceutically acceptable salt or ester, wherein the substituents are defined in the application. The invention relates to compounds, pharmaceutical compositions and methods of using compounds of the general formula (end of abstract) Agent: King & Spalding LLP - Atlanta, GA, US Inventors: Kimberly J. Worsencroft, Liming Ni, Zhihong Ye, Charles Q. Meng, M. David Weingarten, Jacob E. Simpson, James A. Sikorski USPTO Applicaton #: 20070093453 - Class: 514063000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Silicon Containing Doai The Patent Description & Claims data below is from USPTO Patent Application 20070093453. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. provisional patent application Ser. No. 60/476,708 filed Jun. 6, 2003. FIELD OF THE INVENTION [0002] The present invention is in the field of novel chalcone derivatives, pharmaceutical compositions and methods for treating a variety of diseases and disorders, including inflammation and cardiovascular disease. BACKGROUND OF THE INVENTION [0003] Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of inflammatory conditions, autoimmune disorders and bacterial and viral infections. Leukocyte recruitment to endothelium is mediated in part by the inducible expression of adhesion molecules on the surface of endothelial cells that interact with counterreceptors on immune cells. Endothelial cells determine which types of leukocytes are recruited by selectively expressing specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. VCAM-1 binds to the integrin VLA-4 expressed on lymphocytes, monocytes, macrophages, eosinophils, and basophils but not neutrophils. This interaction facilitates the firm adhesion of these leukocytes to the endothelium. VCAM-1 is an inducible gene that is not expressed, or expressed at very low levels, in normal tissues. VCAM-1 is upregulated in a number of inflammatory diseases, including arthritis (including rheumatoid arthritis), asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease. [0004] U.S. Pat. Nos. 5,750,351; 5,807,884; 5,811,449; 5,846,959; 5,773,231, and 5,773,209 to Medford, et al., as well as the corresponding WO 95/30415 to Emory University indicate that polyunsaturated fatty acids ("PUFAs") and their hydroperoxides ("ox-PUFAs"), which are important components of oxidatively modified low density lipoprotein (LDL), induce the expression of VCAM-1, but not intracellular adhesion molecule-1 (ICAM-1) or E-selectin in human aortic endothelial cells, through a mechanism that is not mediated by cytokines or other noncytokine signals. This is a fundamental discovery of an important and previously unknown biological pathway in VCAM-1 mediated immune responses. As non-limiting examples, linoleic acid, linolenic acid, arachidonic acid, linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide (15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1 or E-selectin. Saturated fatty acids (such as stearic acid) and monounsaturated fatty acids (such as oleic acid) do not induce the expression of VCAM-1, ICAM-1 or E-selectin. [0005] Chalcone (1,3-bis-aromatic-prop-2-en-1-ones) compounds are natural products related to flavonoids. WO 99/00114 (PCT/DK98/00283) discloses the use of certain chalcones, 1,3-bis-aromatic-propan-1-ones (dihydrochalcones), and 1,3-bisaromatic-prop-2-yn-1-ones for the preparation of pharmaceutical compositions for the treatment of prophylaxis of a number of serious diseases including i) conditions relating to harmful effects of inflammatory cytokines, ii) conditions involving infection by Helicobacter species, iii) conditions involving infections by viruses, iv) neoplastic disorders, and v) conditions caused by microorganisms or parasites. [0006] U.S. Pat. No. 4,085,135 to Kyogoku et al. discloses a process for preparation of 2'-(carboxymethoxy)-chalcones having antigastric and anti duodenal activities with low toxicity and high absorptive ratio in the body. [0007] European Patent No 307762 assigned to Hofmann-La Roche discloses substituted phenyl chalcones. [0008] Herencia, et al., in Synthesis and Anti-inflammatory Activity of Chalcone Derivatives, Bioorganic & Medicinal Chemistry Letters 8 (1998) 1169-1174, discloses certain chalcone derivatives with anti-inflammatory activity. [0009] Hsieh, et al., Synthesis and Antiinflammatory Effect of Chalcones, J. Pharm. Pharmacol. 2000, 52; 163-171 describes that certain chalcones have potent antiinflammatory activity. [0010] Zwaagstra, et al., Synthesis and Structure-Activity Relationships of Carboxylated Chalcones: A Novel Series of CysLT.sub.1 (LT.sub.4) Receptor Antagonists; J. Med. Chem., 1997, 40, 1075-1089 discloses that in a series of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2', 3', 4', or 5' carboxylated chalcones, certain compounds are CysLT.sub.1 receptor antagonists. [0011] JP 63010720 to Nippon Kayaku Co., LTD discloses that chalcone derivatives of the following formula (wherein R.sup.1 and R.sup.2 are hydrogen or alkyl, and m and n are 0-3) are 5-lipoxygenase inhibitors and can be used in treating allergies. [0012] JP 06116206 to Morinaga Milk Industry Co. Ltd, Japan, discloses chalcones of the following structure as 5-lipoxygenase inhibitors, wherein R is acyl and R.sup.1-R.sup.5 are hydrogen, lower alkyl, lower alkoxy or halo, and specifically that in which R is acyl and R.sup.1-R.sup.5 are hydrogen. [0013] U.S. Pat. No. 6,046,212 to Kowa Co. Ltd. discloses heterocyclic ring-containing chalcones of the following formula as antiallergic agents. [0014] Reported bioactivies of chalcones have been reviewed by Dimmock, et al., in Bioactivities of Chalcones, Current Medicinal Chemistry 1999, 6, 1125-1149; Liu, et al., Antimalarial Alkoxylated and Hydroxylated Chalones: Structure-Activity Relationship Analysis, J. Med. Chem. 2001, 44, 4443-4452; Herencia et al, Novel Anti-inflammatory Chalcone Derivatives Inhibit the Induction of Nitric Oxide Synthase and Cyclooxygenase-2 in Mouse Peritoneal Macrophages, FEBS Letters, 1999, 453, 129-134; and Hsieh et al., Synthesis and Anti-inflammatory Effect of Chalcones and Related Compounds, Pharmaceutical Research, 1998, Vol. 15, No. 1, 39-46. [0015] U.S. patent application Ser. No. 09/866,348, filed Jun. 20, 2001 and Ser. No. 10/324,987, filed Dec. 19, 2002 both assigned to AtheroGenics, Inc., and herein incorporated by reference, disclose particular derivatives of chalcones suitable to treat diseases mediated by VCAM-1. [0016] Given that VCAM-1 is a mediator of chronic inflammatory disorders, it is a goal of the present work to identify new compounds, compositions and methods that can inhibit the expression of VCAM-1. A more general goal is to identify selective compounds and methods for suppressing the expression of redox sensitive genes or activating redox sensitive genes that are suppressed. An even more general goal is to identify selective compounds, pharmaceutical compositions and methods of using the compounds for the treatment of inflammatory diseases. [0017] It is therefore an object of the present invention to provide new compounds for the treatment of disorders mediated by VCAM-1. [0018] It is also an object to provide new pharmaceutical compositions for the treatment of diseases and disorders mediated by the expression of VCAM-1. [0019] It is a further object of the invention to provide compounds, compositions, and methods of treating disorders and diseases mediated by VCAM-1, including cardiovascular and inflammatory diseases. [0020] Another object of the invention is to provide compounds, compositions, and method of treating cardiovascular and inflammatory diseases. [0021] It is another object of the invention to provide compounds, compositions and methods to treat arthritis. Continue reading... Full patent description for Sulfonamide-substituted chalcone derivatives and their use to treat diseases Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Sulfonamide-substituted chalcone derivatives and their use to treat diseases patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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