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  Ship 1 modulatorsUSPTO Application #: 20080090909Title: Ship 1 modulators Abstract: The present invention includes the use of pelorol, related compounds and pharmaceutical compositions thereof as modulators of SHIP 1 activity. This invention also provides novel terpene compounds capable of modulating SHIP 1 activity and methods of synthesis thereof. (end of abstract)
Agent: Bozicevic, Field & Francis LLP - East Palo Alto, CA, US Inventors: Raymond Andersen, David E. Williams, Alice Mui, Christopher Ong, Gerald Krystal, Lu Yang USPTO Applicaton #: 20080090909 - Class: 514569000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Radical -xh Acid, Or Anhydride, Acid Halide Or Salt Thereof (x Is Chalcogen) Doai, Carboxylic Acid, Percarboxylic Acid, Or Salt Thereof (e.g., Peracetic Acid, Etc.), Benzene Ring Nonionically Bonded, Polycyclo Ring System The Patent Description & Claims data below is from USPTO Patent Application 20080090909. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to SHIP 1, a negative regulator of cell proliferation and survival and immune cell activation. BACKGROUND OF THE INVENTION [0002] SH.sub.2-containing inositol 5-phosphatase (SHIP 1), selectively hydrolyzes the 5-phosphate from inositol 1,3,4,5-tetraphosphate (IP4) and phosphatalidylinositol 3,4,5-triphosphate (PIP3). U.S. Pat. No. 6,238,903 discloses that SHIP 1 is an enzyme regulator of signaling pathways that control gene expression, cell proliferation, differentiation, activation, and metabolism, particularly of the Ras and phospholipid signaling pathways. SHIP 1 plays an important role in cytokine and immune receptor signal tansduction. SHIP 1 disrupted (SHIP 1-/-) mice exhibit a myeloproliferative phenotype characterized by overproduction of granulocytes and macrophages.sup.1. SHIP 1-/- mast cells are more prone to IgE and Steel factor induced degranulation, while SHIP 1-/- B cells are resistant to negative regulation by Fc RIIB. SHIP 1 is also involved in the pathogenesis of chronic myelogenous leukemia.sup.2. [0003] Compounds that specifically modulate the activity of SHIP 1 would be useful in the treatment of cell proliferation, hematopoietic and immune disorders, as well as for manipulating SHIP 1 mediated pathways during investigatory and drug discovery testing. To date, no structure of a small molecule SHIP 1 specific modulator has been disclosed. [0004] A sesquiterpene compound termed pelorol may be obtained from various marine sponge species, including Petrosaspongia metachromia and Dactylospongia elegans. Kwak et al. and Goclik et al. each disclosed the structure of pelorol and its extraction from different marine sponges..sup.4,5 Pelorol was reported as having weak antitrypanosomal and antiplasmodial effects.sup.5. The precise structure of pelorol is as follows, with Me representing a methyl group and relative configuration of chiral atoms (C-5, 8, 9 and 10) shown. [0005] Some reduced and substituted chrysene derivatives similar to pelorol and having the characteristic gem substituted non-aromatic ring of pelorol are known as intermediates or derivatives in the preparation of various polycyclic polyprenols found in shale.sup.6-12, in the preparation of taxodione.sup.13, and in the compound 1,2,3,4,4a,4b,5,6,10b,11,12,12a-dodecahydro-1,1-dimethyl-chrysene.sup.14. None of these chrysene derivatives are known to have biological activity. SUMMARY OF THE INVENTION [0006] This invention is based on the discovery that pelorol and related compounds are capable of modulation of SHIP 1 activity. [0007] Some embodiments of this invention provide novel compounds of Formula I and salts thereof. Compounds of Formula I have the structure: wherein; [0008] R.sub.1 and R.sub.2 are independently selected from the group consisting of: --CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2OH, --CH.sub.2OR', --CHO, --CO.sub.2H, and --CO.sub.2R'; [0009] R.sub.3 and R.sub.4 are independently selected from the group consisting of: H, --CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2OH, --CH.sub.2OR', --CHO, --CO.sub.2H, and --CO.sub.2R'; [0010] Q is selected from the group consisting of: --CH.sub.2--, --CY.sub.1Y.sub.2--, --CH.sub.2CH.sub.2--, --CH.dbd.CH--, --C.sub.1Y.sub.2CY.sub.3Y.sub.4--, --CH.sub.2CH.sub.2CH.sub.2--, --CH.dbd.CHCH.sub.2--, --CH.dbd.CHCY.sub.1Y.sub.2--, and --C.sub.1Y.sub.2CY.sub.3Y.sub.4CY.sub.5Y.sub.6--; where Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5, and Y.sub.6 are independently selected from the group consisting of: H, F, Br, Cl, I, OH, OR', and SH; or any one group of Y.sub.1/Y.sub.2, Y.sub.3/Y.sub.4, and Y.sub.5/Y.sub.6 may be .dbd.O; or Y.sub.1/Y.sub.3 may form an epoxide; and, at least one of Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5 and Y.sub.6 when present, is not H; [0011] X.sub.1, X.sub.2, X.sub.3, and X.sub.4 are independently selected from the group consisting of: H, R, OH, --OR, --CO.sub.2H, --CO.sub.2R', F, Br, Cl, I, --CN, --SO.sub.3H, --OSO.sub.3H, NO.sub.2, NH.sub.2, --NHR, and --NR.sub.2; where R is a linear, branched, or cyclic, saturated or unsaturated one to ten carbon alkyl group that is unsubstituted or is substituted with one or more of: OH, .dbd.O, SH, F, Br, Cl, I, NH.sub.2, --NHR', --NR'.sub.2, NO.sub.2, --CO.sub.2H, --CO.sub.2R', and epoxide; [0012] and R' is a linear, branched, or cyclic, saturated or unsaturated one to ten carbon alkyl group that is unsubstituted or substituted with one or more of: OH, .dbd.O, SH, F, Br, Cl, I, NH.sub.2, --NHR'', --NR''.sub.2, NO.sub.2 and --CO.sub.2H where R'' is a linear, branched, or cyclic, saturated or unsaturated one to ten carbon alkyl group. [0013] Novel compounds of Formula I of this invention do not include the precise structures of previously described gem substituted chrysene derivatives. These previously described compounds include pelorol and compounds having the following structures in which Me is methyl: [0014] Alternately defined, this invention excludes such previously known specific compounds of Formula I in which each of R.sub.1-R.sub.4 are methyl; Q is --CH.sub.2CH.sub.2--; and, X.sub.1-X.sub.4 is according to any one of the following definitions: [0015] (a) X.sub.1 and X.sub.2=OH, X.sub.3=H, and X.sub.4=--COOCH.sub.3; [0016] (b) X.sub.1, X.sub.2, X.sub.3 and X.sub.4=H; [0017] (c) X.sub.1, X.sub.2, and X.sub.4=H, and X.sub.3=CH.sub.3; [0018] (d) X.sub.1, X.sub.3, and X.sub.4=H, and X.sub.2=CH.sub.3; [0019] (e) X.sub.2, X.sub.3, and X.sub.4=H, and X.sub.1=CH.sub.3; and [0020] (f) X.sub.1 and X.sub.4=H, X.sub.2 and X.sub.3=OCH.sub.3. Also excluded is a compound of Formula I in which R.sub.1 and R.sub.2=CH.sub.3; R.sub.3 and R.sub.4=H; Q=--CH.sub.2CH.sub.2--; and each of X.sub.1-X.sub.4 is H. Continue reading... Full patent description for Ship 1 modulators Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Ship 1 modulators 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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