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Aryl-carbaldehyde oxime derivatives and their use as estrogenic agentsRelated 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 Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Bicyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Quinolines (including Hydrogenated)Aryl-carbaldehyde oxime derivatives and their use as estrogenic agents description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070043077, Aryl-carbaldehyde oxime derivatives and their use as estrogenic agents. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application is a continuation of U.S. application Ser. No. 10,845,687, filed May 13, 2004, and claims benefit to U.S. Provisional Application Ser. No. 60/471,238, filed May 16, 2003, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0002] This invention relates to aryl-carbaldehyde oxime derivatives, and in certain aspects to (hydroxy-phenyl)-aryl-carbaldehyde oxime derivatives, their uses as estrogenic agents, and methods of their preparation. BACKGROUND OF THE INVENTION [0003] The pleiotropic effects of estrogens in mammalian tissues have been well documented, and it is now appreciated that estrogens affect many organ systems [Mendelsohn and Karas, New England Journal of Medicine 340: 1801-1811 (1999), Epperson, et al., Psychosomatic Medicine 61: 676-697 (1999), Crandall, Journal of Womens Health & Gender Based Medicine 8: 1155-1166 (1999), Monk and Brodaty, Dementia & Geriatric Cognitive Disorders 11: 1-10 (2000), Hurn and Macrae, Journal of Cerebral Blood Flow & Metabolism 20: 631-652 (2000), Calvin, Maturitas 34: 195-210 (2000), Finking, et al., Zeitschrift fur Kardiologie 89: 442-453 (2000), Brincat, Maturitas 35: 107-117 (2000), Al-Azzawi, Postgraduate Medical Journal 77: 292-304 (2001)]. Estrogens can exert effects on tissues in several ways. Probably, the most well characterized mechanism of action is their interaction with estrogen receptors leading to alterations in gene transcription. Estrogen receptors are ligand-activated transcription factors and belong to the nuclear hormone receptor superfamily. Other members of this family include the progesterone, androgen, glucocorticoid and mineralocorticoid receptors. Upon binding ligand, these receptors dimerize and can activate gene transcription either by directly binding to specific sequences on DNA (known as response elements) or by interacting with other transcription factors (such as API), which in turn bind directly to specific DNA sequences [Moggs and Orphanides, EMBO Reports 2: 775-781 (2001), Hall, et al., Journal of Biological Chemistry 276: 36869-36872 (2001), McDonnell, Principles Of Molecular Regulation. p 351-361(2000)]. A class of "coregulatory" proteins can also interact with the ligand-bound receptor and further modulate its transcriptional activity [McKenna, et al., Endocrine Reviews 20: 321-344 (1999)]. It has also been shown that estrogen receptors can suppress NF.epsilon.B-mediated transcription in both a ligand-dependent and independent manner [Quaedackers, et al., Endocrinology 142: 1156-1166 (2001), Bhat, et al., Journal of Steroid Biochemistry & Molecular Biology 67: 233-240 (1998), Pelzer, et al., Biochemical & Biophysical Research Communications 286: 1153-7 (2001)]. [0004] Estrogen receptors can also be activated by phosphorylation. This phosphorylation is mediated by growth factors such as EGF and causes changes in gene transcription in the absence of ligand [Moggs and Orphanides, EMBO Reports 2: 775-781 (2001), Hall, et al., Journal of Biological Chemistry 276: 36869-36872 (2001)]. [0005] A less well-characterized means by which estrogens can affect cells is through a so-called membrane receptor. The existence of such a receptor is controversial, but it has been well documented that estrogens can elicit very rapid non-genomic responses from cells. The molecular entity responsible for transducing these effects has not been definitively isolated, but there is evidence to suggest it is at least related to the nuclear forms of the estrogen receptors [Levin, Journal of Applied Physiology 91: 1860-1867 (2001), Levin, Trends in Endocrinology & Metabolism 10: 374-377 (1999)]. [0006] Two estrogen receptors have been discovered to date. The first estrogen receptor was cloned about 15 years ago and is now referred to as ER.alpha. [Green, et al., Nature 320: 134-9 (1986)]. The second was found comparatively recently and is called ER.beta. [Kuiper, et al., Proceedings of the National Academy of Sciences of the United States of America 93: 5925-5930 (1996)]. Early work on ER.beta. focused on defining its affinity for a variety of ligands and, indeed, some differences with ER.alpha. were seen. The tissue distribution of ER.beta. has been well mapped in the rodent and it is not coincident with ER.alpha.. Tissues such as the mouse and rat uterus express predominantly ER.alpha., whereas the mouse and rat lung express predominantly ER.beta. [Couse, et al., Endocrinology 138: 4613-4621 (1997), Kuiper, et al., Endocrinology 138: 863-870 (1997)]. Even within the same organ, the distribution of ER.alpha. and ER.beta. can be compartmentalized. For example, in the mouse ovary, ER.beta. is highly expressed in the granulosa cells and ER.alpha. is restricted to the thecal and stromal cells [Sar and Welsch, Endocrinology 140: 963-971 (1999), Fitzpatrick, et al., Endocrinology 140: 2581-2591 (1999)]. However, there are examples where the receptors are coexpressed and there is evidence from in vitro studies that ER.alpha. and ER.beta. can form heterodimers [Cowley, et al., Journal of Biological Chemistry 272: 19858-19862 (1997)]. [0007] The most potent endogenous estrogen is 17.beta.-estradiol. A large number of compounds have been described that either mimic or block the activity of 17.beta.-estradiol. Compounds having roughly the same biological effects as 17.beta.-estradiol are referred to as "estrogen receptor agonists". Those which block the effect of 17.beta.-estradiol, when given in combination with it, are called "estrogen receptor antagonists". In reality there is a continuum between estrogen receptor agonist and estrogen receptor antagonist activity and indeed some compounds behave as estrogen receptor agonists in some tissues but estrogen receptor antagonists in others. These compounds with mixed activity are called selective estrogen receptor modulators (SERMS) and are therapeutically useful agents (e.g. EVISTA) [McDonnell, Journal of the Society for Gynecologic Investigation 7: S10-S15 (2000), Goldstein, et al., Human Reproduction Update 6: 212-224 (2000)]. The precise reason why the same compound can have cell-specific effects has not been elucidated, but the differences in receptor conformation and/or in the milieu of coregulatory proteins have been suggested. [0008] It has been known for some time that estrogen receptors adopt different conformations when binding ligands. However, the consequence and subtlety of these changes only recently has been revealed. The three dimensional structures of ER.alpha. and ER.beta. have been solved by co-crystallization with various ligands and clearly show the repositioning of helix 12 in the presence of an estrogen receptor antagonist which sterically hinders the protein sequences required for receptor-coregulatory protein interaction [Pike, et al., Embo 18: 4608-4618 (1999), Shiau, et al., Cell 95: 927-937 (1998)]. In addition, the technique of phage display has been used to identify peptides that interact with estrogen receptors in the presence of different ligands [Paige, et al., Proceedings of the National Academy of Sciences of the United States of America 96: 3999-4004 (1999)]. For example, a peptide was identified that distinguished between ER.alpha. bound to the full estrogen receptor agonists 17.beta.-estradiol and diethylstilbesterol. A different peptide was shown to distinguish between clomiphene bound to ER.alpha. and ER.beta.. These data indicate that each ligand potentially places the receptor in a unique and unpredictable conformation that is likely to have distinct biological activities. [0009] As mentioned above, estrogens affect a panoply of biological processes. In addition, where gender differences have been described (e.g. disease frequencies, responses to challenge, etc), it is possible that the explanation involves the difference in estrogen levels between males and females. SUMMARY OF THE INVENTION [0010] The instant invention relates to aryl-carbaldehyde oxime derivatives, particularly those that find use as estrogenic agents. In one aspect, the invention relates to aryl-carbaldehyde derivatives of the formula: [0011] wherein: [0012] R.sup.1 is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; [0013] R.sup.2 and R.sup.3, together, form a fused aryl or heteroaryl ring; [0014] R.sup.4 is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; [0015] R.sup.5 is hydrogen, lower alkyl, or --C(O)R.sup.6; and [0016] R.sup.6 is lower alkyl; or a pharmaceutically acceptable salt thereof. In some preferred embodiments, R.sup.5 is H. [0017] In another aspect, the invention is directed to a pharmaceutical composition comprising at least one of the above compounds as well as a pharmaceutically acceptable carrier. [0018] In yet other aspects, the invention is drawn to the use of the above compounds in the treatment or prevention of diseases including but not limited to inflammatory bowel diseases such as Crohn's disease and colitis. DETAILED DESCRIPTION OF THE INVENTION [0019] This invention provides aryl-carbaldehyde oxime derivatives. These compounds, which preferably act as estrogenic agents, are useful for the treatment and prevention of diseases such as inflammatory bowel diseases (including Crohn's disease and colitis). In one aspect, the invention is directed to compounds of formula I: [0020] wherein: [0021] R.sup.1 is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; [0022] R.sup.2 and R.sup.3, together, form a fused aryl or heteroaryl ring; [0023] R.sup.4 is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; [0024] R.sup.5 is hydrogen, lower alkyl, or --C(O)R.sup.6; and [0025] R.sup.6 is lower alkyl; [0026] or a pharmaceutically acceptable salt thereof. In some preferred embodiments, R.sup.5 is H. [0027] In certain preferred embodiments, R.sup.1 is halogen, R.sup.2 and R.sup.3 together form a 5 or 6 membered fused ring, such as phenyl, furan, thiophene, and R.sup.4 is H or halogen. [0028] Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable aids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, such as alkali metal salts (for example, sodium, lithium, or potassium) alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group, when a compound of this invention contains an acidic moiety. [0029] The term "aryl" means a carbocyclic aromatic ring of 6 to 10 carbon atoms including, for example, phenyl. The term "heteroaryl" means a 5 or 6 membered aromatic ring containing 1 or more heteroatoms, eg 1 to 3, selected from oxygen, nitrogen and sulfur. Aryl and heteroaryl groups may be optionally substituted. Continue reading about Aryl-carbaldehyde oxime derivatives and their use as estrogenic agents... Full patent description for Aryl-carbaldehyde oxime derivatives and their use as estrogenic agents Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Aryl-carbaldehyde oxime derivatives and their use as estrogenic agents 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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