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Selective rxr ligandsRelated 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, Oxygen Containing Hetero Ring, The Hetero Ring Is Five-membered, Polycyclo Ring System Having The Hetero Ring As One Of The Cyclos, Bicyclo Ring System Having The Hetero Ring As One Of The CyclosSelective rxr ligands description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070099991, Selective rxr ligands. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention generally relates to compounds interacting with retinoid binding proteins, and more particularly to compounds that interact selectively with retinoid X receptors ("RXRs") as well as methods for their production and therapeutic use. BACKGROUND OF THE INVENTION [0002] Retinoids, both natural and synthetic, are derivatives of vitamin A. Retinoids have been recognized to induce a broad spectrum of biological effects. Thus, retinoid therapy ranges from therapeutic treatments for dermatological conditions, such as acne and psoriasis, to the treatment of metabolic disorders. In addition, RXR selective compounds are believed to be useful for the treatment and prevention of skin diseases, actinic keratoses, arsenic keratoses, inflammatory and non- inflammatory acne, psoriasis, ichthyoses, keratinization and hyperproliferative skin disorders, eczema, atopic dermatitis, Darrier's disease, lichen planus, steroid atrophy, topical microbial infections, skin photodamage, type II diabetes, eye disease, retinal detachment, dry eye, corneopathies, cardiovascular disease, dyslipidemias, post-angioplasty restenosis, HPV infections, genital warts, inflammatory disease, ileitis, colitis, Crohn's disease, neurodegeneration, Alzheimer's disease, Parkinson's disease, stroke, pituitary dysfunction, growth hormone deficiency, hair loss, organ rejection, immune disorders, wounds, as well as a variety of cancerous and pre-cancerous conditions, such as acute promyleocytic leukemia, cutaneous T-cell lymphoma, epithelial cancers, squamous cell carcinoma, and breast cancer, as well as in the treatment of hyperthyroidism, dyslipidemia, and hypertension. See, e.g, WO 9712853, WO 0026173, WO 9321146, WO 9504036, WO 0020397, WO 0020370, WO 9845242, EP 0790228, EP 0933350, WO 9908992, WO 9420093, WO 9417796, WO 9639374, EP 0933350, WO 9710819, WO 9963980, WO 9958487, WO 995848, WO 0001679 and Vuligonda et al., Bioorg. Med. Chem. Lett., 9:589-594 (1999). [0003] Retinoids regulate the activity of two distinct nuclear receptor families, the retinoic acid receptors ("RAR") and the retinoid X receptors ("RXR"). As with the RAR subfamily (currently including .alpha., .beta., and .gamma. isoforms), the RXR subfamily (currently including .alpha., .beta., and .gamma. isoforms) are recognized as ligand-induced transcription factors. [0004] Nevertheless, RARs and RXRs diverge in their primary structure and have only a 27% homology in the ligand binding domains. Thus, these structural differences provide for relative degrees of responsiveness among different retinoids. For example, certain retinoids have been identified that show selective binding to RXRs, but only a weak affinity for RARs. See, e.g., Lala et al., Nature, 83, 450-453 (1996). Furthermore, RARs and RXRs have distinct differences in their tissue distribution. RARs are expressed at high levels in visceral tissues, whereas RXR.alpha. is most abundant in the liver, kidney, lung, muscle, and intestine. Thus, while the subfamilies are related, each elicits distinct physiological responses apart from the other. Therefore, retinoids that are selective for either RARs or RXRs would provide for the independent control of the physiological responses mediated by the particular receptors. In addition, RXR dimerizes with many nuclear receptors (e.g., RAR, LXR, VDR, FXR, PPAR, and TR), as well as with itself to form a homodimer. Thus, retinoids that preferentially affect the RXR receptor, may additionally exhibit selectivity for specific heterodimer pairs as well. SUMMARY OF THE INVENTION [0005] The present invention includes novel retinoid compounds that have selectivity as RXR agonists on one or more isoforms of RXR, namely, RXR.alpha., RXR.beta., or RXR.gamma.. The present compounds, and pharmaceutical compositions incorporating these compounds, therefore, are effective in treating conditions mediated by RXRs. Among other physiological responses, the compounds of the present invention reduce blood glucose and maintain body weight, and, thus, are useful for the treatment of diabetes (particularly type II diabetes, or NIDDIM) and obesity. The present invention also includes methods of producing the compounds and methods for the therapeutic use of these novel retinoids and their pharmaceutical compositions. [0006] The present invention includes compounds of Formula I: including salts, solvates, and physiologically functional derivatives thereof, wherein the broken lines represent optional double bonds; X is CR.sup.1 or N, where R.sup.1 is halogen, H, or CH.sub.3; Z is O, S, or NH; M is N, C, or CR.sup.2, when M is N, the A ring is non-aromatic, when M is C, the A ring is aromatic, when M is CR.sup.2, then R.sup.2 is H or --Y(CH.sub.2).sub.nR.sup.6, and the A ring is non-aromatic; Y is O or CH.sub.2; when n is 0 to 6, R.sup.6 is H, alkyl, or CF.sub.3, but when n is 2 to 5, R.sup.6 is H, alkyl, CF.sub.3, SO.sub.2NHR.sup.23, NHSO.sub.2R.sup.23 or NR.sup.23R.sup.24, where R.sup.23 is alkyl, aryl optionally substituted, heteroaryl optionally substituted or combined with R.sup.24 to form a ring of 3-7 atoms; and R.sup.24 is H, alkyl, cycloalkyl or combined with R.sup.23 to form a ring of 3 to 7 atoms; G is CO.sub.2R.sup.7, SO.sub.3R.sup.7, PO.sub.3R.sup.7, CONHOH, or where the broken line represents an optional double bond; J is CHO, CO.sub.2R.sup.7, SO.sub.3R.sup.7, PO.sub.3R.sup.7, CONHOH, or J forms a thiazolidinedione ring with R.sup.8; R.sup.7 is H or alkyl; R.sup.8 and R.sup.9 are independently H, halogen, alkyl, or CF.sub.3; y and z are each 0, 1, or 2; Q is CR.sup.4, CR.sup.4R.sup.5, O, NR.sup.10, or S, where R.sup.4 and R.sup.5 are independently H or alkyl, provided that when Q is CR.sup.4, the A ring is aromatic; R.sup.10 is alkyl, COR.sup.11, CONHR.sup.11, CO.sub.2R.sup.11, CONR.sup.11R.sup.12, SO.sub.2R.sup.11, aryl, or cycloalkyl; R.sup.11 and R.sup.12 are independently alkyl or cycloalkyl; R.sup.3 is wherein D is CR.sup.13R.sup.14, O, S, NR.sup.15, CHOH, CO, SO, SO.sub.2, where R.sup.13 and R.sup.14 are independently H, alkyl, or cycloalkyl; and where R.sup.15 is H, alkyl, or cycloalkyl; R.sup.16 and R.sup.17 independently are H, C.sub.1-4 alkyl, cycloalkyl, or together form a carbocyclic ring having from 3 to 7 atoms; R.sup.18 is H, OR.sup.6, halogen, CF.sub.3, alkenyl, SR.sup.16, C.sub.1-4 alkyl, CO.sub.2R.sup.16, COR.sup.11, or NR.sup.16R.sup.17, where R.sup.16 and R.sup.17 are as above defined; m is 0 or 1; or R.sup.3 is where R.sup.18 is as defined above; or R.sup.3 is where M2 is C or N, provided however that the optional double bond represented by the broken line is optionally present only when M2 is C; each R.sup.19 is, independently, H or alkyl; y and z are as defined above; or R.sup.3 is where each R.sup.18 is, independently, as defined above; and M3 is C--(R.sup.16).sub.3 or N--(R.sup.16).sub.2, when M3 is N--(R.sup.16).sub.2, an R.sup.16 may combine with an R.sup.18 to form a 5- or 6-membered ring. [0007] Preferably when either R.sup.4 or R.sup.5 or both are alkyl, said alkyl is C.sub.1-5 alkyl; when R.sup.6 is alkyl, said alkyl is C.sub.1-6 alkyl; when R.sup.7 is alkyl, said alkyl is C.sub.1-5 alkyl; when either R.sup.8 or R.sup.9 or both are alkyl, said alkyl is C.sub.1-3 alkyl; when R.sup.10 is alkyl, said alkyl is C.sub.1-6 alkyl; when either R.sup.11 or R.sup.12 or both are alkyl, said alkyl is C.sub.1-5 alkyl; when either R.sup.13 or R.sup.14 or both are alkyl, said alkyl is C.sub.1-3 alkyl; when R.sup.15 is alkyl, said alkyl is C.sub.1-4 alkyl; when either R.sup.16 or R.sup.17 or both are alkyl, said alkyl is C.sub.1-4 alkyl; when R.sup.18 is alkenyl, said alkenyl is C.sub.1-4 alkenyl; when R.sup.18 is alkyl, said alkyl is C.sub.1-4 alkyl; when R.sup.19 is alkyl, said alkyl is C.sub.1-4 alkyl; when R.sup.23 is alkyl, said alkyl is C.sub.1-6 alkyl; and when R.sup.24 is alkyl, said alkyl is C.sub.1-7 alkyl. [0008] Preferably, X is CH, Z is O, Q is CH.sub.2, M is CH, G is J is CO.sub.2H, y and z are each 1, R.sup.8 and R.sup.9 are H; the double bond exists, and the olefin geometry is trans. [0009] In one embodiment preferably R.sup.3 is where D is CR.sup.13R.sup.14; R.sup.13, R.sup.14, R.sup.16, and R.sup.17 are each methyl; and R.sup.18 is H. [0010] Particularly preferred compounds of formula (I) include: (2E)-3[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)tetrahydr- o-1-benzofuran-2-yl]-2-propenoic acid; (2E)-3-[4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-4,5,6- ,7-tetrahydro-1-benzofuran-2-yl]-2-propenoic acid; (2E)-3-[4-(3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaleny- l)-4,5,6,7-tetrahydro-1-benzofuran-2-yl]-2-propenoic acid; (2E)-3-[4-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-2-naphthaleny- l)-4,5,6,7-tetrahydro-1-benzofuran-2-yl]-2-propenoic acid; (2E)-3-[6-methyl-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthaleny- l)-4,5,6,7-tetrahydro[2,3-c]pyridin-2-yl]-2-propenoic acid; (2E)-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-benzo- furan-2-yl]-2-propenoic acid; (2E)-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-4,5,6,7- -tetrahydro-1-benzothien-2-yl]-2-propenoic acid; (2E)-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-4,5,6,7- -tetrahydro-1,3-benzoxazol-2-yl]-2-propenoic acid; (2E)-3-(4-{[(2,6,6-trimethylcyclohexen-1-yl)methyl]amino}benzofuran-2-yl)- -2-propenoic acid; (2E)-3[4-(4-Isopropoxy-1-naphthalenyl)tetrahydro-1-benzofuran-2-yl]-2-pro- penoic acid; (2E)-3-{4-[4-Dimethylamino)-3-ethylphenyl]-4,5,6,7-tetrahydro-1-benzofura- n-2-yl}-2-propenoic acid; Continue reading about Selective rxr ligands... 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