| Treatment of t-helper cell type 2-mediated immune diseases by retinoid antagonists -> Monitor Keywords |
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  Treatment of t-helper cell type 2-mediated immune diseases by retinoid antagonistsUSPTO Application #: 20060183737Title: Treatment of t-helper cell type 2-mediated immune diseases by retinoid antagonists Abstract: Retinoids with retinoid receptor antagonistic activity, pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters thereof, have been found efficacious in treating T-helper cell type 2 (Th2)-mediated immune diseases, such as immunoglobulin E (IgE)-mediated allergic diseases. (end of abstract) Agent: George W. Johnston Hoffmann-laroche Inc. - Nutley, NJ, US Inventors: Werner Bollag, Michael Klaus, Paola Panina-Bordignon, Francesco Sinigaglia USPTO Applicaton #: 20060183737 - Class: 514219000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Seven-membered Consisting Of Two Nitrogens And Five Carbon Atoms, Polycyclo Ring System Having The Seven-membered Hetero Ring As One Of The Cyclos The Patent Description & Claims data below is from USPTO Patent Application 20060183737. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of patent application Ser. No. 11/131,062, filed May 17, 2005, which is a divisional of Ser. No. 10/353,523, filed Jan. 29, 2003, which is a divisional of Ser. No. 09/631,655, Aug. 3, 2000, now U.S. Pat. No. 610,742, which is a divisional of Ser. No. 09/189,189, Nov. 10, 1998, now U.S. Pat. No. 6,133,309. BACKGROUND OF THE INVENTION [0002] 1. Field [0003] The present invention relates a method for using retinoid antagonists, such as retinoids with selective Retinoic Acid Receptor ("RAR") antagonistic activity, Retinoid X Receptor ("RXR") antagonistic activity or mixed RAR-RXR antagonistic activity, to treat T-helper cell type 2. ("Th2")-mediated immune diseases. Th2-mediated immune diseases include immunoglobulin E ("IgE")-mediated allergic diseases. The present invention also relates.to using retinoid antagonists to prepare medicaments for treating Th2-mediated immune diseases. [0004] 2. Description [0005] Retinoids are a class.of compounds structurally related to vitamin A and include natural and synthetic compounds. Retinoids are clinically useful in the treating dermatological and oncological diseases. [0006] Retinoid activity is thought to be mediated by the nuclear retinoid receptors RAR.alpha., .beta., .gamma. and RXR.alpha., .beta., .gamma., belonging to the superfamily of steroid, thyroid hormone vitamin D, peroxisome proliferator-activated receptors [Pfahl et al., Vitamins and Hormones, 49: 327-382 (1994)]. Retinoids with receptor agonistic activity bind to and activate receptors, whereas retinoids with receptor antagonistic activity bind to receptors but do not activate them. [0007] Experimentally, retinoids with retinoid receptor agonistic activity have been shown to be active in model systems for treating dermatological and oncological diseases and in models for treating immunological diseases. Retinoids with retinoid receptor agonistic activity have been shown active in treating adjuvant arthritis [Brinckerhoffet al., Science, 221: 756-758 (1983)] and experimental allergic encephalomyelitis [Massacesi et al., J. Clin. Invest. 88: 1331-1337(1991); Racke et al., J.Immunol., 154, 450-458 (1995)], animal models for rheumatoid arthritis and multiple sclerosis, respectively. Both diseases are considered to belong to Th1-mediated immune diseases. [0008] Experimentally, retinoids with retinoid receptor antagonistic activity (retinoid antagonists) have been shown effective in counteracting many properties of retinoids with retinoid receptor-agonistic activity (retinoid agonists), such as inhibiting cell proliferation, inducing cell differentiation, inducing apoptosis and inhibiting angiogenesis [Bollag et al., Int. J. Cancer, 70: 470-472 (1997)]. Retinoid antagonists also suppress toxic side effects of retinoid agonists, such as the signs and symptoms of the hypervitaminosis A syndrome and teratogenesis [Standeven et al., Toxicol. Appl. Pharmacol., 138: 169-175 (1996); Eckhardt and Schmitt, Toxicol. Letters, 70: 299-308 (1994)]. Therefore, they may be useful clinically in preventing or treating adverse events caused by retinoid agonists. [0009] Retinoid antagonists have been proposed for clinical use in the prevention and treatment of retinoid-induced toxicity and side effects, particularly of the so-called hypervitaminosis A syndrome. Retinoid antagonists have also been proposed to be used in combination with retinoid receptor agonists or other nuclear receptor agonists for preventing and treating preneoplastic or neoplastic lesions, vitreo-retinopathy, and retinal detachment. In addition, retinoid antagonists may be useful as single agents, based on their anti-proliferative effect, for treatment of certain neoplasms insensitive to retinoid receptor agonists [WO 97/09297]. [0010] The subject invention provides for the first time a method for using retinoid antagonists in the treatment of Th2-mediated immune diseases, such as IgE-mediated allergic diseases and diseases mediated by the Th2-related cytokines. SUMMARY OF THE INVENTION [0011] The subject invention provides a method of treating a T-helper cell type 2-mediated immune disease or a disease mediated by T-helper cell type 2-related cytokines. This method comprises administering to a subject having a T-helper cell type 2-mediated immune disease or a disease mediated by T-helper cell type 2-related cytokines an effective amount of a compound selected from the group consisting of retinoid antagonists, pharmaceutically acceptable salts of retinoid antagonists, and pharmaceutically acceptable hydrolyzable esters of such retinoid antagonists and their salts. DETAILED DESCRIPTION OF THE INVENTION [0012] The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting. [0013] In the scope of the present invention the term "retinoid antagonists" is used for retinoids or compounds with RAR, RXR or mixed RAR-RXR antagonistic activity. It includes compounds with receptor neutral antagonistic activity (neutral antagonists), receptor inverse agonistic activity (inverse agonists) and negative hormone activity (negative hormones) [Klein et al., J. biol Chem., 271: 22692-22696 (1996)]. [0014] In the scope of the present invention the term "retinoid antagonists" encompass compounds of formulas I-XVI depicted below: [0015] a) RAR a-antagonists of formulas: [0016] wherein R.sup.1 is C.sub.5-10-alkyl, and R.sup.2 and R.sup.3 independently of each other are hydrogen or fluorine; such compounds are described in U.S. Pat. No. 5,391,766 and J. Med. Chem., 40: 2445 (1997); [0017] b) RAR .alpha.,.beta. antagonists of formulas: [0018] wherein R.sup.4 is diamantyl, X is O or NH, R.sup.5 is phenyl or benzyl, and [0019] wherein optionally either ring A or ring B is present; such compounds are described in Med. Chem. Res., 1: 220 (1991); Biochem. Biophys. Res. Com., 231: 243 (1997); and J. Med. Chem., 37: 1508 (1994); [0020] c) RAR .beta.,.gamma. antagonists of formula [0021] wherein R.sup.6 and R.sup.7 independently of each other hydroxy, C.sub.1-4-alkoxy, optionally branched C.sub.1-5-alkyl or adamantyl; such compounds are described in J. Med. Chem. 38: 4993 (1995); [0022] d) RAR .gamma. antagonists of formulas: [0023] such compounds are described in Cancer Res., 55: 4446 (1995); [0024] e) RAR .alpha., .beta., .gamma. antagonists of formulas: [0025] wherein Y is --CH.sub.2-- or sulfur and Z is --CH.dbd. or nitrogen, and R.sup.8 is hydrogen or C.sub.1-4-alkyl; such compounds are described in J. Med. Chem. 38: 3163 and 4764 (1995); J. Biol. Chem., 271: 11897 and 22692 (1996); [0026] f) RXR antagonists of formulas: [0027] wherein the dotted bond is optional; and, when the dotted bond is present, R.sup.9 is methyl and R.sup.10 is hydrogen; and, when the dotted bond is absent, R.sup.9 and R.sup.10 taken together are rethylene to form a cis-substituted cyclopropyl ring; R.sup.11 is C.sub.1-4-alkoxy; such compounds are described in EP Patent Appl. No. 97 107 843.1; J. Med. Chem., 39: 3229 (1996); and Nature, 383: 450 (1996). [0028] In accordance with this invention, it has thus been found that administration of retinoid antagonists, pharmaceutically acceptable salts, and pharmaceutically acceptable hydrolyzable esters thereof, are efficacious in treating patients with T-helper cell type 2 (Th2)-mediated diseases. It has also been found that the administration of retinoid antagonists is efficacious in treating patients with diseases mediated by Th2-related cytokines, such as interleukin-4 (IL4) and IL-5. [0029] The invention, therefore, in one aspect, relates to the use of retinoid antagonists, their pharmaceutically acceptable salts or pharmaceutically acceptable hydrolyzable esters, for the manufacture of a medicament for the treatment of T-helper cell type 2 (Th2)-mediated immune diseases. In another aspect the invention relates to the use of retinoid antagonists, their pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof for the manufacture of a medicament for the treatment of disease mediated by Th2-related cytokines, such as IL-4 and IL-5. [0030] The invention also relates to a method for treating patients having T-helper cell type 2 (Th2)-mediated immune diseases comprising administering to said human patient a compound selected from the group of retinoid antagonists, pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters thereof, said compound being administered in an amount effective to treat said disease. The term "treatment" or "treating" includes preventive and/or therapeutic treatment. [0031] As used herein, the term "T-helper cell type 2-mediated immune diseases" relates to diseases involving immunoglobulin E (IgE) and mast cells due to the development and activation of allergen-specific Th2 cells and it encompasses allergic diseases, such as atopic dermatitis, other dermatological diseases associated with atopy; allergic rhinitis or hay fever, allergic bronchial asthma in its acute or chronic, mild or severe forms, with or without acute or chronic bronchitis. Elevated serum levels of immunoglobulin E (IgE) and hypereosinophilia can be associated with these diseases. Retinoid antagonists are effective in all those immune diseases which are linked with an increase of Th2 cell activity and an increased secretion of the related cytokines, such as IL4 and IL-5. The therapeutic effect of retinoid antagonists is due to a decrease in Th2 cell activity, a decreased secretion of the related cytokines, such as IL-4 and IL-5, and/or an increase in Th1 cell activity due to the enhancement of IL-12 production by activated myelomono-cytic cells. [S. Romagnani, Ann. Rev. Immunol., 12: 227-257 (1994); Romagnani, ed., Th1 and Th2 Cells in Health and Disease. Chem. Immunol., Karger, Basel, 63: 187-203 (1996); Abbas et al., Nature, 383: 787-793 (1996)]. [0032] The efficacy of the retinoid antagonists in accordance with the present invention can be shown by their ability to either upregulate Th1 cell activity or induce/stimulate the production of cytokines, such as IL-12, IFN.gamma., TNF; and/or down-regulate Th2 cell activity, or inhibit the production of cytokines, such as IL-4 and IL-5. [0033] Retinoid antagonists are active in the treatment of allergic bronchial asthma. The hallmarks of inflammation associated with asthmatic disease are the presence of activated eosinophils, an increased sensitivity of the airways (hyperresponsiveness), edema, mucus hypersecretion and cough. This inflammatory process is mediated by the generation and activation of Th2-type cells. The ability of retinoid antagonists to promote a Th1-type response and thereby to suppress the Th2-type response is thought to be the mechanism underlying the efficacy of these compounds in allergic lung inflammation/asthma. Retinoid antagonists are acting on Th1-type cells, in inhibiting the signs and symptoms of allergic lung inflammation/asthma [Gavett et al., J. Exp. Med., 182: 1527-1536 (1995); Kips et al., Am. J. Respir. Crit. Care Med., 153: 535-539 (1996)]. They are active in antigen/allergen (e.g. ovalbumin)-sensitized and challenged animals. Retinoid antagonists, given either systemically or topically by aerosol, are efficacious in attenuating, inhibiting or reversing bronchoconstriction, airway edema and mucus hypersecretion, airway inflammation, accumulation of eosinophils and neutrophils in the broncho-alveolar tissue and broncho-alveolar lavage respectively, as well as airway hyperresponsiveness to non-specific stimuli. Continue reading... Full patent description for Treatment of t-helper cell type 2-mediated immune diseases by retinoid antagonists Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Treatment of t-helper cell type 2-mediated immune diseases by retinoid antagonists 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. Each week you receive an email with patent applications related to your keywords. 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