US 20050215635A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0215635 A1 Rafi et al. (43) Pub. Date: Sep. 29, 2005 (54) DIARYLHEPTANOID COMPOUNDS AND Publication Classification USES THEREOF (76) Inventors: M. Mohamed Rafi, Highland Park, NJ (51) Int. Cl." .......................... A61K 31/22; A61K 31/12 (US); Zhihua Liu, Howell, NJ (US); (52) U.S. Cl. ............................................ 514/546; 514/690 Robert T. Rosen, Monroe Township, NJ (US); Sharon L. Rosen, legal representative, (US); Chi-Tang Ho, (57) ABSTRACT East Brunswick, NJ (US) Correspondence Address: JONES DAY The present invention relates to diarylheptanoid compounds 222 EAST 41ST ST and compositions comprising a diarylheptanoid compound. NEW YORK, NY 10017 (US) The present invention also relates to methods for preventing or treating various diseases and disorders by administering (21) Appl. No.: 11/075,275 to a Subject in need thereof one or more diarylheptanoid compounds. In particular, the invention relates to methods (22) Filed: Mar. 8, 2005 for preventing or treating cancer or an inflammatory disorder Related U.S. Application Data by administering to a Subject in need thereof one or more diarylheptanoid compounds. The present invention further (60) Provisional application No. 60/551,182, filed on Mar. relates to articles of manufacture comprising one or more 8, 2004. diarylheptanoid compounds. Patent Application Publication Sep. 29, 2005 Sheet 1 of 6 US 2005/0215635 A1 Figure 1 Fraction 2 Fraction 1 Fraction 3 Patent Application Publication Sep. 29, 2005 Sheet 2 of 6 US 2005/0215635 A1 Figure 2 Control HMP (6.25 uM) HMP (12.5 uM) HMP (25 uM) Patent Application Publication Sep. 29, 2005 Sheet 3 of 6 US 2005/0215635 A1 Figure 3 COX-2 3-Actin iNOS B-Actin Patent Application Publication Sep. 29, 2005 Sheet 4 of 6 US 2005/0215635 A1 Figure 4A iNOS COX-2 Controls LPS (0.5 ug/ml) H.LPS+HMP (12.5 uM) is LPS+HMP (25 uM) Patent Application Publication Sep. 29, 2005 Sheet 5 of 6 US 2005/0215635 A1 Figure 5 O -- + HMP (25 uM) -- -- -- -- + LPS (0.5ug/ml) A 0 15 30 60 30 60 Time (min) pp44/42 p44/42 11 24. 1 Yse 2 O Control LPS-15 min LPS-30 min LPS-60 min LPSHMP- LPSHMP 30 min 6O min Patent Application Publication Sep. 29, 2005 Sheet 6 of 6 US 2005/0215635 A1 Figure 6 A 16 B 14 8 O. 17 Control LPS LPS+HMP (25 LPS+HMP - uM) (12.5 uM) US 2005/0215635 A1 Sep. 29, 2005 DARYLHEPTANOD COMPOUNDS AND USES The inflammatory response is characterized by increased THEREOF blood flow, increased capillary permeability, and the influx 0001. This application is entitled to and claims priority to of phagocytic cells. These events result in Swelling, redness, U.S. provisional Ser. No. 60/551,182, filed Mar. 8, 2004, warmth (altered heat patterns), and pus formation at the site which is incorporated by reference herein in its entirety. of injury or infection. 0007. A delicate well-balanced interplay between the 1. FIELD OF THE INVENTION humoral and cellular immune elements in the inflammatory 0002 The present invention relates to diarylheptanoid response enables the elimination of harmful agents and the compounds and compositions comprising a diarylheptanoid initiation of the repair of damaged tissue. When this deli compound. The present invention also relates to methods for cately balanced interplay is disrupted, the inflammatory preventing or treating various diseases and disorders by response may result in considerable damage to normal tissue administering to a Subject in need thereof one or more and may be more harmful than the original insult that diarylheptanoid compounds. In particular, the invention initiated the reaction. In these cases of uncontrolled inflam relates to methods for preventing or treating a cell prolif matory responses, clinical intervention is needed to prevent erative disorder or an inflammatory disorder by administer tissue damage and organ dysfunction. DiseaseS Such as ing to a Subject in need thereof one or more diarylheptanoid rheumatoid arthritis, Osteoarthritis, Crohn's disease, asthma, compounds. The present invention further relates to kits allergies or inflammatory bowel disease, are characterized comprising one or more diarylheptanoid compounds. by chronic inflammation. 0008 Current treatments for inflammatory disorders 2. BACKGROUND OF THE INVENTION involve Symptomatic medications and immunosuppressive agents to control Symptoms. For example, nonsteroidal 2.1 Cancer and Neoplastic Disease anti-inflammatory drugs (NSAIDs) Such as aspirin, ibupro 0.003 Cancer is the second leading cause of death in the fen, fenoprofen, naproxen, tolmetin, Sulindac, meclofe United States. The American Cancer Society estimated that namate Sodium, piroXicam, flurbiprofen, diclofenac, in 2001, there would be 1.3 million new cases of cancer and Oxaprozin, nabumetone, etodolac, and ketoprofen have anal that cancer would cause 550,000 deaths. Overall rates have gesic and anti-inflammatory effects. However, NSAIDs are declined by 1% per year during the 1990s. There are 9 believed not to be capable of altering progression of the million Americans alive who have ever had cancer. NIH disease. (Tierney et al. (eds), Current Medical Diagnosis & estimates the direct medical costs of cancer as S60 billion. Treatment, 37 ed., Appleton & Lange (1998), p793). More 0004 Currently, cancer therapy involves Surgery, chemo over, NSAIDS frequently cause gastrointestinal Side effects. therapy and/or radiation treatment to eradicate neoplastic Corticosteroids are another class of drugs that are commonly cells in a patient (see, for example, Stockdale, 1998, “Prin used to control inflammatory Symptoms. Corticosteroids, ciples of Cancer Patient Management”, in Scientific Ameri like NSAIDs, do not alter the natural progression of the disease, and thus, clinical manifestations of active disease can. Medicine, vol. 3, Rubenstein and Federman, eds., commonly reappear when the drug is discontinued. Low Chapter 12, Section IV). All of these approaches pose doses of immunosuppressive agents Such as cytotoxic agents Significant drawbacks for the patient. are also commonly used to in treatment of inflammatory 0005. Despite the availability of a variety of chemothera disorders. Many cytotoxic agents, frequently causes Stoma peutic agents, traditional chemotherapy has many draw titis, erythema, Slopecia, nausea, vomiting, diarrhea, and backs (see, for example, Stockdale, 1998, “Principles Of damage to major organs Such kidney and liver. The long Cancer Patient Management” in Scientific American Medi term usage of immunosuppressive agents usually leaves the cine, Vol. 3, Rubenstein and Federman, eds., ch. 12, Sect. patient defenseless to infections. 10). Almost all chemotherapeutic agents are toxic, and chemotherapy can cause significant, and often dangerous, 0009 New treatment and preventative modalities for Side effects, including Severe nausea, bone marrow depres inflammatory disorders are constantly being Sought. In par Sion, immunosuppression, etc. Additionally, many tumor ticular, any new modalities that reduces the dosage and/or cells are resistant or develop resistance to chemotherapeutic frequency of administration of agents currently being used, agents through multi-drug resistance. Therefore, there is a or is capable of making a currently used treatment and/or Significant need in the art for novel compounds and com prevention more effective is constantly being Sought. positions, and methods that are useful for treating cancer or 0010. The use of herbal therapy or alternative medicine is neoplastic disease with minimal or no side effects. Further, becoming an increasingly attractive approach for the treat there is a need for cancer treatments that provide cancer ment of various inflammatory disorders. The majority of cell-specific therapies with increased Specificity and naturally occurring phenolics in different plants possess decreased toxicity. tremendous antioxidative and anti-inflammatory activities (Surh et al., 2001). Anti-inflammatory properties of various 2.2 Inflammatory Disorders phytochemicals are mediated through the inhibition of pro 0006 Inflammation plays a fundamental role in host duction of cytokines (IL-1 B, TNF-C., IL-6, IL-12, IFN-Y), defenses and the progression of immune-mediated diseases. nitric oxide (NO), prostaglandins and leukotriens. Antioxi The inflammatory response is initiated in response to injury dants Such as (-)-epigallocatechin-3-gallate (EGCG) (Lin (e.g., trauma, ischemia, and foreign particles) and infection and Lin, 1997), resveratrol (Tsai et al., 1999) and naturally (e.g., bacterial or viral infection) by a complex cascade of occurring flavonoids including apigenin and kaempferol events, including chemical mediators (e.g., cytokines and (Liang et al., 1999) have been reported to suppress NO prostaglandins) and inflammatory cells (e.g., leukocytes). production through inhibition of nuclear factor-kappa B US 2005/0215635 A1 Sep. 29, 2005 (NF-kB). Earlier studies have shown that ginger and its 3. SUMMARY OF THE INVENTION constituents are potent inhibitors of immune cell activation and cytokine Secretion and used for the treatment of cancer 0013 The present invention provides methods of using (Ageel et al., 1989). Pharmacologically, ginger (Zingiber diarylheptanoid compounds in the prevention, treatment or Oficinale), Similar to other plants, possess very complex management of various disorders. The present invention mixture of compounds. This plant contains Several hundred provides certain novel diarylheptanoid