Building IP: CELG Patent Grant re "Arylmethoxy isoindoline derivatives and ..."
United States Patent
Man , et al.
August 16, 2022
Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
Provided are 4'-arylmethoxy isoindoline compounds, and pharmaceutically acceptable salts, solvates, clathrates, stereoisomers, and prodrugs thereof. Methods of use, and pharmaceutical compositions of these compounds are disclosed.
Man; Hon-Wah (Princeton, NJ), Chen; Roger Shen-Chu (Edison, NJ), Muller; George W. (Rancho Santa Fe, CA), Ruchelman; Alexander L. (Cream Ridge, NJ), Khalil; Ehab M. (Yorktown, VA), Zhang; Weihong (Highland Park, NJ)
<> Gant, "Using deuterium in drug discovery: leaving the label in the drug," J. Med. Chem., 57:3595-3611 (2014). cited by applicant . Mullard, "Deuterated drugs draw heavier backing," Nature Rev. Drug Dis., 15:219-221 (2016). cited by applicant . Bioactivity Lenalidomide, "Bioactivity Data for Compound lenalidomide (CID 216326)," p. 1, retrieve online <http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?cid_216326>. Retrieved on Jun. 22, 2015. cited by applicant . Braga and Grepioni, "Making crystals from crystals: a green route to crystal engineering and polymorphism," Chem. Commun., 3635-3645 (2005). cited by applicant . Brown et al., "A clinical study assessing the tolerability and biological effects of infliximab, a TNF-.alpha. inhibitor, in patients with advanced cancer," Ann. Oncol., 19(7):1340-1346 (2008). cited by applicant . Grever et al., "The National Cancer Institute: Cancer drug discovery and development program," Semin. Oncol., 19(6):622-638 (1992). cited by applicant . Hideshima et al., "Current therapeutic uses of lenalidomide in multiple myeloma," Expert Opin. Investig. Drugs, 15(2):171-179 (2006). cited by applicant . Kiran, "Cancer Treatment, "Chapter 1, pp. 1-18 (2011). cited by applicant . Latli, "Synthesis of deuterium, tritium, and carbon-14 labeled BIRB 796, a p38 MAP kinase inhibitor," J. Label Compd. Radiopharm., 47:847-856 (2004). cited by applicant . Latli, "Synthesis of deuterium, tritium, and carbon-14 labeled BIRB 796, a p38 MAP kinase inhibitor," CAPLUS, 142:411280 (2004). cited by applicant . Nakamura et al., "Mono- and Dihydroxylated Metabolites of Thalidomide: Synthesis and TNF-.alpha. Production-Inhibitory Activity," Chem. Pharm, Bull., 54(12):1709-1714 (2006). cited by applicant . National Cancer Institute, "Targeted cancer therapies," retrieved online <http:www.cancer.gov/cancertopics/factsheet/Therapy/targeted>. Retrieved on Aug. 13, 2014, 6 pages. cited by applicant . National Cancer Institute, "What is Cancer?," retrieved online <http://www.cancer.gov/cancertopics/cancerlibrary/what-is-cancer>. Retrived on Aug. 11, 2014, 3 pages. cited by applicant . Peyrin-Biroulet et al., "Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials," Clin. Gasroenterol. Hepatol., 6(6):644-653 (2008). cited by applicant . Seddon, "Pseudopolymorph: a polemic," Crystal Growth Design, 4(6):1087 (2004). cited by applicant . Szlosarek et al., "Tumour necrosis factor-.alpha. as a tumour promoter," Eur. J. Cancer, 42(6):745-750 (2006). cited by applicant . Wade, "Deuterium isotope effects on noncovalent interactions between molecules," Chemico-Biological Interactions, 117:191-217 (1999). cited by applicant . WHO, "Cancer classification," retrieved on <http://training.seer.cancer.gov/module_ . . . ase/unit3_categories2_by_histology.html>. Retrieved on Jan. 26, 2005, 3 pages. cited by applicant . Wikipedia, "Lenalidomide," retrieved online <http://en.wikipedia.org/wiki/Lenalidomide>. Retrieved on Jan. 14, 2015, pp. 1-5. cited by applicant . Wiltshire et al., "Synthesis of labeled forms of cipemastat," CAPLUS, 134:311151 (2001). cited by applicant . Wiltshire et al., "The Synthesis of labelled forms of cipemastat," J. Labelled Cpd. Rapiopharm., 4:149-164 (2001). cited by applicant . Witzig et al., "A comprehensive review of lenalidomide therapy for B-cell non-Hodgkin lymphoma," Ann. Oncol., 1-10 (2015). cited by applicant . Wu and Zhou, "TNF-.alpha./NF-.kappa.B/snail pathway in cancer cell migration and invasion," Br. J. Cancer, 102(4):639-644 (2010). cited by applicant . Zhou et al., "The TNF-alpha-238 polymorphism and cancer risk: a meta-analysis, " PloS One, 6(7):e22092 (2011). cited by applicant . Kotla et al., "Mechanism of action of lenalidomide in hematological malignancies," J. Hematol. Oncol., 2:36 (2009). cited by applicant . Muller et al., "Structural modifications of thalidomide produce analogs with enhanced tumor necrosis factor inhibitory activity," J. Med. Chem., 39(17):3238-3240 (1996). cited by applicant.
Primary Examiner: Reese; Heidi Attorney, Agent or Firm:Jones Day
Parent Case Text
This application is a divisional application of U.S. application Ser. No. 16/195,550, filed Nov. 19, 2018, which is a divisional application of U.S. application Ser. No. 15/786,334, filed Oct. 17, 2017, now U.S. Pat. No. 10,189,814, which is a divisional application of U.S. application Ser. No. 15/040,980, filed Feb. 10, 2016, now U.S. Pat. No. 9,822,094, which is a divisional application of U.S. application Ser. No. 13/952,386, filed Jul. 26, 2013, now U.S. Pat. No. 9,309,219, which is a divisional application of U.S. application Ser. No. 13/025,105, filed Feb. 10, 2011, now U.S. Pat. No. 8,518,972, which claims priority to U.S. Provisional Application No. 61/303,618, filed Feb. 11, 2010, the entirety of each of which is incorporated herein by reference.
What is claimed is:
1. A compound of formula (III): ##STR00379## or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: X is CH.sub.2; R.sup.5, R.sup.6 and R.sup.7 are each independently hydrogen, halogen, nitro, carbamoyl, amino, --SO.sub.2R.sup.8, --CONR.sup.9R.sup.10, --(C.sub.1-C.sub.6)alkyl or --(C.sub.1-C.sub.6)alkoxy, said alkyl or alkoxy may be optionally substituted with one or more halogen, amino, hydroxyl, or NR.sup.9R.sup.10; R.sup.8 is: (C.sub.1-C.sub.6)alkyl, optionally substituted with (C.sub.1-C.sub.6)alkyl or (C.sub.6-C.sub.10)aryl; amino, optionally substituted with (C.sub.1-C.sub.6)alkyl or (C.sub.6-C.sub.10)aryl; or 6 to 10 membered heterocycle, optionally substituted with (C.sub.1-C.sub.6)alkyl or (C.sub.6-C.sub.10)aryl; R.sup.9 and R.sup.10 are each independently hydrogen, 6 to 10 membered aryl, --COO--(C.sub.1-C.sub.6)alkyl, --(C.sub.0-C.sub.6)alkyl-CHO, --(C.sub.0-C.sub.6)alkyl-COOH, --(C.sub.0-C.sub.6)alkyl-(5 to 10 membered heterocycle), --(C.sub.1-C.sub.6)alkyl-OH, --(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.6)cycloalkyl; and R.sup.9' and R.sup.10' are each independently hydrogen or (C.sub.1-C.sub.6)alkyl; with the proviso that all of R.sup.5-R.sup.7 cannot be hydrogen; and with the proviso that if one of R.sup.5-R.sup.7 is hydrogen and the remaining two of R.sup.5-R.sup.7 are both chloride, then the two chloride atoms cannot be on 3 and 4 position of the phenyl ring.
2. The compound of claim 1, wherein one of R.sup.5-R.sup.7 is hydrogen, and the remaining two of R.sup.5-R.sup.7 are each independently halogen, (C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkyl.
3. The compound of claim 1, wherein two of R.sup.5-R.sup.7 are hydrogen and the remaining one of R.sup.5-R.sup.7 is halogen, (C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkyl.
4. The compound of claim 1, which is a compound of formula (III): ##STR00380## or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: X is CH.sub.2; R.sup.5 is hydrogen; R.sup.6 is hydrogen or --(C.sub.1-C.sub.6)alkoxy; R.sup.7 is --SO.sub.2R.sup.8, --CONR.sup.9R.sup.10, --(C.sub.1-C.sub.6)alkyl or --(C.sub.1-C.sub.6)alkoxy, said alkyl or alkoxy is substituted with one or more NR.sup.9R.sup.10; R.sup.8 is 6 to 10 membered heterocycle, optionally substituted with (C.sub.1-C.sub.6)alkyl or (C.sub.6-C.sub.10)aryl; R.sup.9 is hydrogen, --COO--(C.sub.1-C.sub.6)alkyl, --(C.sub.0-C.sub.6)alkyl-CHO, or (C.sub.1-C.sub.6)alkyl; and R.sup.10 is 6 to 10 membered aryl, --(C.sub.0-C.sub.6)alkyl-(5 to 10 membered heterocycle), or (C.sub.3-C.sub.6)cycloalkyl.
5. The compound of claim 4, wherein R.sup.7 is --SO.sub.2R.sup.8 or --CONR.sup.9R.sup.10.
6. The compound of claim 4, wherein R.sup.7 is --(C.sub.1-C.sub.6)alkyl substituted with one or more NR.sup.9R.sup.10.
7. The compound of claim 1, which is: ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
8. A pharmaceutical composition comprising a compound of claim 1 and one or more excipients.
9. A method of treating, managing or preventing a disease or disorder comprising administering to a patient a compound of claim 1, wherein the disease or disorder is cancer, a disorder associated with angiogenesis, pain, macular degeneration or a related syndrome, a skin disease, a pulmonary disorder, an asbestos-related disorder, a parasitic disease, an immunodeficiency disorder, a CNS disorder, CNS injury, atherosclerosis or a related disorder, dysfunctional sleep or a related disorder, an infectious disease, hemoglobinopathy or a related disorder, or a TNF.alpha. related disorder.
Provided herein are 4'-arylmethoxy isoindoline derivatives. Pharmaceutical compositions comprising the compounds and methods for treating, preventing and managing various disorders using the compounds and compositions are also disclosed.
2.1 Pathobiology of Cancer and Other Diseases
Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance. Roitt, I., Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).
There is an enormous variety of cancers which are described in detail in the medical literature. Examples include cancer of the lung, colon, rectum, prostate, breast, brain, and intestine. The incidence of cancer continues to climb as the general population ages, as new cancers develop, and as susceptible populations (e.g., people infected with AIDS or excessively exposed to sunlight) grow. However, options for the treatment of cancer are limited. For example, in the case of blood cancers (e.g., multiple myeloma), few treatment options are available, especially when conventional chemotherapy fails and bone-marrow transplantation is not an option. A tremendous demand therefore exists for new methods and compositions that can be used to treat patients with cancer.
Many types of cancers are associated with new blood vessel formation, a process known as angiogenesis. Several of the mechanisms involved in tumor-induced angiogenesis have been elucidated. The most direct of these mechanisms is the secretion by the tumor cells of cytokines with angiogenic properties. Examples of these cytokines include acidic and basic fibroblastic growth factor (a,b-FGF), angiogenin, vascular endothelial growth factor (VEGF), and TNF-.alpha.. Alternatively, tumor cells can release angiogenic peptides through the production of proteases and the subsequent breakdown of the extracellular matrix where some cytokines are stored (e.g., b-FGF). Angiogenesis can also be induced indirectly through the recruitment of inflammatory cells (particularly macrophages) and their subsequent release of angiogenic cytokines (e.g., TNF-.alpha., b-FGF).
A variety of other diseases and disorders are also associated with, or characterized by, undesired angiogenesis. For example, enhanced or unregulated angiogenesis has been implicated in a number of diseases and medical conditions including, but not limited to, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, rubeosis (neovascularization of the angle), viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases and conditions include, but are not limited to: diabetic retinopathy; retinopathy of prematurity; corneal graft rejection; neovascular glaucoma; retrolental fibroplasia; arthritis; and proliferative vitreoretinopathy.
Accordingly, compounds that can control angiogenesis or inhibit the production of certain cytokines, including TNF-.alpha., may be useful in the treatment and prevention of various diseases and conditions.
2.2 Methods of Treating Cancer
Current cancer therapy may involve surgery, chemotherapy, hormonal therapy and/or radiation treatment to eradicate neoplastic cells in a patient (see, e.g., Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). Recently, cancer therapy could also involve biological therapy or immunotherapy. All of these approaches pose significant drawbacks for the patient. Surgery, for example, may be contraindicated due to the health or age of a patient or may be unacceptable to the patient.
Additionally, surgery may not completely remove neoplastic tissue. Radiation therapy is only effective when the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy can also often elicit serious side effects. Hormonal therapy is rarely given as a single agent. Although hormonal therapy can be effective, it is often used to prevent or delay recurrence of cancer after other, treatments have removed the majority of cancer cells. Biological therapies and immunotherapies are limited in number and may produce side effects such as rashes or swellings, flu-like symptoms, including fever, chills and fatigue, digestive tract problems or allergic reactions.
With respect to chemotherapy, there are a variety of chemotherapeutic agents available for treatment of cancer. A majority of cancer chemotherapeutics act by inhibiting DNA synthesis, either directly, or indirectly by inhibiting the biosynthesis of deoxyribonucleotide triphosphate precursors, to prevent DNA replication and concomitant cell division. Gilman et al., Goodman and Gilman's: The Pharmacological Basis of Therapeutics, Tenth Ed. (McGraw Hill, New York).
Despite availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous side effects including severe nausea, bone marrow depression, and immunosuppression. Additionally, even with administration of combinations of chemotherapeutic agents, many tumor cells are resistant or develop resistance to the chemotherapeutic agents. In fact, those cells resistant to the particular chemotherapeutic agents used in the treatment protocol often prove to be resistant to other drugs, even if those agents act by different mechanism from those of the drugs used in the specific treatment. This phenomenon is referred to as pleiotropic drug or multidrug resistance. Because of the drug resistance, many cancers prove or become refractory to standard chemotherapeutic treatment protocols.
Other diseases or conditions associated with, or characterized by, undesired angiogenesis are also difficult to treat. However, some compounds such as protamine, heparin and steroids have been proposed to be useful in the treatment of certain specific diseases. Taylor et al., Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S. Pat. Nos. 5,001,116 and 4,994,443.
Still, there is a significant need for safe and effective methods of treating, preventing and managing cancer and other diseases and conditions, including for diseases that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicities and/or side effects associated with the conventional therapies.
Provided herein are 4'-arylmethoxy isoindoline compounds, and pharmaceutically acceptable salts, solvates (e.g., hydrates), prodrugs, clathrates, or stereoisomers thereof.
Also provided are methods of treating and managing various diseases or disorders. The methods comprise administering to a patient in need of such treatment or management a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, prodrug, clathrate, or stereoisomer thereof.
Further provided are methods of preventing various diseases and disorders, which comprise administering to a patient in need of such prevention a prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, prodrug, clathrate, or stereoisomer thereof.
Also provided herein are pharmaceutical compositions, single unit dosage forms, dosing regimens and kits which comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate, prodrug, clathrate, or stereoisomer thereof.