By a News Reporter-Staff News Editor at Life Science Weekly — The University of British Columbia (Vancouver, BC, CA) has been issued patent number 8765994, according to news reporting originating out of Alexandria, Virginia, by NewsRx editors (see also The University of British Columbia).
The patent’s inventors are Andersen, Raymond (Vancouver, CA); Williams, David E. (Vancouver, CA); Mui, Alice (Burnaby, CA); Ong, Christopher (Vancouver, CA); Krystal, Gerald (Vancouver, CA); Yang, Lu (San Diego, CA).
This patent was filed on August 19, 2011 and was published online on July 1, 2014.
From the background information supplied by the inventors, news correspondents obtained the following quote: “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 (PIPS). 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.
“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.
“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.
“##STR00001##
“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.”
Supplementing the background information on this patent, NewsRx reporters also obtained the inventors’ summary information for this patent: “This invention is based on the discovery that pelorol and related compounds are capable of modulation of SHIP 1 activity.
“Some embodiments of this invention provide novel compounds of Formula I and salts thereof. Compounds of Formula I have the structure:
“##STR00002## wherein;
“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’;
“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’;
“Q is selected from the group consisting of: –CH.sub.2–, –CY.sub.1Y.sub.2–, –CH.sub.2CH.sub.2–, –CH.dbd.CH–, –CY.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 –CY.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;
“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;
“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.
“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:
“##STR00003##
“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:
“(a) X.sub.1 and X.sub.2.dbd.OH, X.sub.3=H, and X.sub.4.dbd.–COOCH.sub.3;
“(b) X.sub.1, X.sub.2, X.sub.3 and X.sub.4=H;
“© X.sub.1, X.sub.2, and X.sub.4=H, and X.sub.3.dbd.CH.sub.3;
“(d) X.sub.1, X.sub.3, and X.sub.4=H, and X.sub.2.dbd.CH.sub.3;
“(e) X.sub.2, X.sub.3, and X.sub.4=H, and X.sub.1.dbd.CH.sub.3; and
“(f) X.sub.1 and X.sub.4.dbd.H, X.sub.2 and X.sub.3.dbd.OCH.sub.3.
“Also excluded is a compound of Formula I in which R.sub.1 and R.sub.2.dbd.CH.sub.3; R.sub.3 and R.sub.4.dbd.H; Q=–CH.sub.2CH.sub.2–; and each of X.sub.1-X.sub.4 is H.
“Some embodiments of this invention provide a pharmaceutical composition comprising one or more compounds of Formula I or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. Such compositions may comprise previously known compounds of Formula I which have not been known as biologically active compounds suitable for pharmaceutical use.
“Some embodiments of this invention provide a method of treatment or prevention of an immune, inflammatory, or neoplastic disorder or condition, comprising administering to a patient in need of such treatment or prevention, an effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this invention.
“Some embodiments of this invention provide the use of a compound of Formula I or pharmaceutically acceptable salt thereof for modulation of SHIP 1 activity and for preparation of agents for the modulation of SHIP 1 activity. Such modulation may be in vitro or in vivo. Agents for in vivo use include a pharmaceutical composition of this invention as well as agents adapted for in vitro use. The modulation may be for a treatment or prevention of an immune, inflammatory, or neoplastic condition or disorders as described above.
“Some compounds of Formula I may be prepared in whole or in part by fractionating biological extracts or by derivatizing available compounds. Alternately, compounds of Formula I may be prepared by total synthesis.
“Some embodiments of this invention provide a method of making a compound of Formula IA
“##STR00004## in which R.sub.1-R.sub.4, X.sub.1, X.sub.3, and X.sub.4 are as defined for Formula I, L’ is a C.sub.1-C.sub.4 saturated or unsaturated alkyl linking group; and A is an activating group; comprising reacting a compound of Formula IIA or IIB:
“##STR00005## in which L is absent or is a C.sub.1-C.sub.3 saturated or unsaturated alkyl linking group and E and E’ are electrophilic reactive groups; with a compound of Formula III
“##STR00006## in which Nu is a group that renders the compound of Formula III nucleophilic at Nu, followed by optional reduction and by hydrolysis, to produce a compound of Formula IV
“##STR00007## and condensing the compound of Formula IV to produce a compound of Formula IA.
“L’ in compounds of Formula IA may optionally be changed or derivatized to form a desired component Q of Formula I. For example, component L’ in compounds of Formula IA produced by the preceding method may have different degrees of saturation or different substituents as compared to Q in a compound of Formula I. In order to reduce the number of atoms in the ring, a compound having an unsaturated L’ group could be subjected to oxidizing and reduction steps to reduce the size of the ring in Formula I comprising Q. In addition, functionalities such as ketone, hydroxyl, or other groups may be added to L’ to form a desired Q component.
“Preferred electrophilic reactive groups for E are lactone, ester, and thioester. A preferred group for E’ is carboxyl. More preferably, compounds of Formulas IIA and IIB are as follows.
“##STR00008##
“Even more preferably, compounds of Formulas IIA and IIB are as follows:
“##STR00009##
“A preferred Nu in compounds of Formula III is lithium which may be substituted onto the ring for a halogen such as bromine. Preferably, A in the compound of Formula III is an activating group such as –OMe or NHAc (Me=methyl and Ac=acetyl) which group may be subsequently converted to a desired substituent for X.sub.2 in compounds of Formula I. Substitutents may also be protected, where appropriate with a protecting group such as TBS.”
For the URL and additional information on this patent, see: Andersen, Raymond; Williams, David E.; Mui, Alice; Ong, Christopher; Krystal, Gerald; Yang, Lu. Ship 1 Modulators. U.S. Patent Number 8765994, filed August 19, 2011, and published online on July 1, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=\%2Fnetahtml\%2FPTO\%2Fsrchnum.htm&r=1&f=G&l=50&s1=8765994.PN.&OS=PN/8765994RS=PN/8765994
Keywords for this news article include: Chrysenes, Hydrocarbons, Phenanthrenes, Cell Proliferation, The University of British Columbia.
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