EP0687249A1 - Balanoides - Google Patents

Balanoides

Info

Publication number
EP0687249A1
EP0687249A1 EP94909847A EP94909847A EP0687249A1 EP 0687249 A1 EP0687249 A1 EP 0687249A1 EP 94909847 A EP94909847 A EP 94909847A EP 94909847 A EP94909847 A EP 94909847A EP 0687249 A1 EP0687249 A1 EP 0687249A1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
phenyl
benzene
mmol
hydroxyphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94909847A
Other languages
German (de)
English (en)
Inventor
Steven Edward Hall
Lawrence M. Ballas
Palaniappan Kulanthaivel
Christie Boros
Jack B. Jiang
Gunnar Erik Jagdmann, Jr.
Yen-Shi Lai
Christopher K. Biggers
Hong Hu
Yali Hallock
Philip F. Hughes
Jean Marie Defauw
Michael Patrick Lynch
John William Crossley Lampe
David Steven Menaldino
Julia Marie Heerding
William P. Janzen
Sean Patrick Hollinshead
Jeffrey Bailey Nichols
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Sphinx Pharmaceuticals Corp
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sphinx Pharmaceuticals Corp, Eli Lilly and Co filed Critical Sphinx Pharmaceuticals Corp
Publication of EP0687249A1 publication Critical patent/EP0687249A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/54—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/52—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of six-membered aromatic rings being part of condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/09—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by at least two halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/04—Seven-membered rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/04—Seven-membered rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • the present invention relates to the field of treatments for inflammatory, cardiovascular, metabolic, nervous system, viral infectious, neoplastic and other diseases.
  • the invention provides compounds which can inhibit protein kinase C enzymes. More particularly, the present invention relates to novel compounds which are referred to herein as "balanoids”.
  • Protein kinase C is a family of calcium- and phospholipid-dependent serine/threonine-specific protein kinases which play an important role in cellular growth control, regulation, and differentiation. Protein kinase C is activated by diacylglycerol (DAG), a neutral lipid, and when activated will transfer the ⁇ -phosphate of MgATP to a serine or threonine residue on a substrate protein.
  • DAG diacylglycerol
  • the mechanisms of protein kinase C action have been described in U.S. Patent 4,816,450 issued March 28, 1989 to Bell et al ., which is incorporated herein by reference.
  • protein kinase C The activation of protein kinase C has been implicated in several human disease processes, including cancer tumors, inflammation and reperfusion injury. Accordingly, protein kinase C is a target for therapeutic agents useful in treating these conditions.
  • Cancer is a disease characterized in part by uncontrolled cell growth. Protein kinase C is directly involved in cellular growth control and is believed to be involved in tumor formation. Protein kinase C is fundamental to the processes involved in tumorigenicity, since it is the major high-affinity receptor for endogenous cellular DAGs as well as for several classes of tumor promoters. These tumor promoters also stimulate protein kinase C catalysis. Castagna et al . , (1982) J. Biol . Chem. 257:7847, reported direct activation of protein kinase C by tumor promoting phorbol esters.
  • Protein kinase C is the major, if not exclusive, intracellular receptor of phorbol esters, which are very potent tumor promoters. Phorbol esters and other tumor promoters bind to and activate protein kinase C. Since DAG and phorbol esters interact at the same site, DAGs have been suggested to be the "endogenous phorbol esters", analogous to the opiate receptor where the conservation of a high affinity receptor implied the existence of an endogenous analogue. DAG has been shown to increase the affinity of protein kinase C for Ca +2 and phospholipid and thus activates protein kinase C at cellular levels of these essential cofactors. Extracellular signals including hormones, growth factors, and neurotransmitters are known to stimulate phosphatidylinositol turnover resulting in the generation of IP 3 and DAG.
  • oncogenes encode altered forms of normal cellular proteins.
  • Several of the gene products appear related to growth factors or other elements involved in transmembrane signalling. These oncogene products appear to function by altering the level of critical second messengers.
  • Cells transformed with the oncogenes ras, sis , erbB , abl , and src have been shown to contain elevated levels of DAG which is then believed to activate protein kinase C.
  • Studies on ras transformed cells have shown protein kinase C activation to be concomitant with elevation of DAG.
  • Phorbol esters such as phorbol myristate acetate (PMA)
  • PMA phorbol myristate acetate
  • Synthetic DAGs mimic many of the effects of PMA in vitro and inhibitors of protein kinase C have been shown to block PMA-induced effects on cells.
  • protein kinase C may mediate the actions of certain oncogenes, such as ras , which cause intracellular increases in DAG and concomitant increases in protein kinase C.
  • protein kinase C activation of protein kinase C leads to the expression of c-myc, c-fos , c-cis , c-fms , nuclear protooncogenes which are important in cell transformation.
  • Overexpression of protein kinase C in NIH 3T3 cells causes altered growth regulation and enhanced tumorigenicity, and in rat fibroblasts leads to anchorage-independent growth in soft agar. Overexpression of protein kinase C in these cells resulted in tumor formation in animals receiving transplanted cells.
  • Protein kinase C inhibitors have been reported to potentiate the antitumor activity of chemotherapeutic agents such as cis-platin both in vitro and in vivo (Grunicke, et al . (1989) Adv. Enzyme Regul . 28:201; and German Offenlegungsschrift DE 3827974).
  • protein kinase C would be a potential target for therapeutic design because of its central role in cell growth (Tritton, T.R. and J.A. Hickman, (1990) Cancer Cells 2:5-102).
  • German Offenlegungsschrift DE 3827974 Al discloses therapeutic preparations comprising a protein kinase C inhibitor in combination with a lipid, a lipid analogue, a cytostatic agent or phospholipase inhibitor which are useful for cancer therapy.
  • Inflammation and reperfusion injury are common conditions for which there exists no definitive treatment despite extensive research. Appropriate treatments for these conditions are needed.
  • Protein kinase C inhibitors have been demonstrated to block platelet aggregation and release of neutrophil activating agents such as platelet activating factor (PAF) (Schachtele, et al . (1988) Biochem. Biophy. Res . Commun . 151:542; Hannun, et al . (1987) J. Biol . Chem . 262:13620; Yamada, et al . (1988) Biochem. Pharmacol . 37:1161). Protein kinase C inhibitors have also been shown to inhibit neutrophil activation, and chemotactic migration (Mclntyre, et al . (1987) J. Biol Chem.
  • PAF platelet activating factor
  • inhibitors of protein kinase C have the capability of blocking all three of the most significant mechanisms of pathogenesis associated with myocardial reperfusion injury. Protein kinase C is, accordingly, a drug target for therapeutic agents. Additionally, the inhibitory effect of protein kinase C inhibitors on keratinocytes, and on the oxidative burst in neutrophils, provides an anti-inflammatory effect.
  • the present invention relates to a novel class of compounds referred to herein as balanoids.
  • Compounds according to the present invention have the following formula:
  • A is: CH 2 , NR 1 , S, SO 2 or O;
  • B 1 is: NR 2 , O or CH 2 ;
  • B 2 is: CO, CS, or SO 2 ;
  • Z is: R 4 , aryl, heteroaryl, substituted aryl or substituted heteroaryl;
  • D is: NR, O or CH 2 ;
  • E is: R 5 , aryl, heteroaryl, substituted aryl or substituted heteroaryl;
  • F is: CO, CS, CH(OR 6 ), CH 2 , O, S or NR 6 ;
  • G is: R 7 , aryl, heteroaryl, substituted aryl, substituted heteroaryl or substituted cycloalkyl;
  • K is: hydrogen or lower alkyl
  • X is: CO, CS, CH 2 , CNR 8 or CCR 9 R 10 ;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are, independently, hydrogen, lower alkyl, aryl or JR 11 ;
  • R 5 is: lower alkyl or aryl
  • R 11 is: hydrogen, lower alkyl, aryl, alkamino, arylamino, aryloxy or alkoxy;
  • R 12 is: straight or branched alkyl, aryl
  • n is: 1-4;
  • n is: 1-4;
  • n up to 5;
  • A is NH
  • B 1 is O
  • B 2 is CO
  • Z is p-hydroxyphenyl
  • D is NH
  • X is CO
  • the present invention relates to pharmaceutically acceptable salts of the above compounds and to formulations comprising the above compounds in pharmaceutically acceptable carriers.
  • Prodrugs such as carbonates and esters of phenolic functional groups and other species metabolizable into compounds of the invention are also considered to be within the scope of the present invention.
  • the present invention relates to a method of inhibiting protein kinase C activity which comprises contacting protein kinase C with an inhibitory amount of a balanoid of the invention.
  • the present invention also relates to methods of treating an animal, preferably a mammal, that is suffering from a PKC-related disease, especially an inflammatory, cardiovascular and/or neoplastic diseases by administering an effective amount of a balanoid to the animal.
  • This invention is directed to a family of novel compounds denominated "balanoids".
  • Members of the family have been found to exhibit the ability to inhibit enzymes of the family of enzymes known as protein kinase C enzymes.
  • Selectivity in inhibitors among the isoforms of protein kinase C (PKC) has been shown for balanoids and it is believed that balanoids will be useful in the treatment of disease linked to PKC enzymes.
  • balanoids are further objects of the invention as are methods for testing for PKC-linked diseases.
  • the present invention relates to balanoids, and their pharmaceutically acceptable salts and formulations.
  • Compounds according to the present invention have been shown to inhibit protein kinase C.
  • PKC inhibitors are known to be useful in the treatment of cancer, inflammatory and reperfusion injury through their antiproliferative and anti-inflammatory activities in human neutrophils, human keratinocytes, and human tumor cells.
  • the present invention relates to methods of inhibiting protein kinase C activity which comprises contacting said protein kinase C with an effective amount of a balanoid or a pharmaceutically acceptable salt thereof.
  • Protein kinase C inhibitors are useful as anti-inflammatory, antitumor, and reperfusion injury agents through their antiproliferative and anti-inflammatory activities in human neutrophils, human keratinocytes, and human tumor cells.
  • the present invention relates to methods of treating animals, specifically mammals, suffering from inflammatory, cardiovascular and/or neoplastic diseases by administering an amount of a balanoid or a pharma- ceutically acceptable salt thereof to the animal. Human therapeutics are preferred.
  • the methods of the present invention comprise inhibiting protein kinase C activity by contacting protein kinase C with an inhibitory effective amount of a balanoid.
  • Balanoids been discovered to inhibit the activity of protein kinase C. Exposure of cells in vitro to balanoids results in the inhibition of PKC activity. Inhibition of PKC activity in cells impedes cellular activities associated with several disease conditions.
  • selectivity exhibited by Balanoids which permits selective inhibition of one or more isoforms (isozymes) of PKC to a greater degree than other isoforms. Such selectivity has long been desired and is indicative of great therapeutic usefulness.
  • the methods of the present invention are useful in the treatment of diseases which involve cellular growth, regulation and differentiation such as inflammatory, cardiovascular and neoplastic diseases.
  • PKC activity is associated with disease conditions such as cancer, inflammation and reperfusion injury.
  • the present invention relates to methods of treating a mammal suffering from cancer, inflammation such as the type associated with arthritis, reperfusion injury or other PKC-linked conditions.
  • the methods comprise administering to the mammal an effective amount of a balanoid or a pharmaceutically acceptable salt thereof which inhibits PKC activity connected with disease.
  • PKC phosphorylates certain molecules, referred to herein as phosphorylation acceptor molecules.
  • An appropriate assay is performed.
  • An exemplary and convenient assay is one in which radio labelled ATP is combined with a phosphorylation acceptor molecule in the presence of PKC and a balanoidal PKC inhibitor-candidate compound (hereinafter referred to as a "test compound").
  • test compound a balanoidal PKC inhibitor-candidate compound
  • Assay conditions such as pH, salt and cofactor conditions are preferably maintained to be similar to physiological levels in order to duplicate in vivo conditions.
  • the inhibitory activity of the test compound can be determined by incubating PKC, 32 P-ATP, phosphorylation receptor molecule and test compound and then measuring the level of phosphorylation activity by measuring the level of radioactive phosphorus present in the phosphorylation receptor molecule.
  • test compounds are investigated for cAMP dependent protein kinase (PKA) inhibitory activity.
  • PKA cAMP dependent protein kinase
  • the level of inhibitory activity is determined by measuring the level of phosphorylation of a phosphorylation acceptor molecule incubated with radiolabelled ATP and PKA.
  • Preferred PKC inhibitors are selective inhibitors and do not effect the activity of PKA.
  • a human tumor cell growth inhibition assay measures the growth of tumor cells in the presence PKC inhibitors by measuring the incorporation of radiolabelled amino acid in cells.
  • the human keratinocyte inhibition assay measures the proliferation of human epidermal keratinocytes in the same manner as tumor cell growth is measured. Hyperproliferation of keratinocytes is symptomatic of many disease conditions associated with inflammation.
  • the neutrophil superoxide anion release assay measures a PKC inhibitors ability to block the PMA-induced effects on cells. The ability of the PKC inhibitors to affect superoxide release by PMA stimulated neutrophils is determined by measuring cytochrome C reduction. Cytochrome C is measured by measuring optical density.
  • balanoids novel compounds according to the present invention.
  • Novel compounds according to the present invention can be expressed by the formula:
  • A is : CH 2 , NR 1 , S , SO 2 or O ;
  • Bi is : NR 2 , O or CH 2 ;
  • B 2 is : CO , CS , or SO 2 ;
  • Z is : R 4 , aryl , heteroaryl , substituted aryl or substituted heteroaryl ;
  • D is : NR , O or CH 2 ;
  • E is: R 5 , aryl, heteroaryl, substituted aryl or substituted heteroaryl;
  • F is: CO, CS, CH(OR 6 ), CH 2 , O, S or NR 6 ;
  • G is: R 7 , aryl, heteroaryl, substituted aryl, substituted heteroaryl or substituted cycloalkyl;
  • K is: hydrogen or lower alkyl
  • X is: CO, CS, CH 2 , CNR 8 or CCR 9 R 10 ;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are, independently, hydrogen, lower alkyl, aryl or JR 11 ;
  • R 5 is: lower alkyl or aryl
  • R 11 is: hydrogen, lower alkyl, aryl, alkamino, arylamino, aryloxy or alkoxy;
  • R 12 is: straight or branched alkyl, aryl
  • n is: 1-4;
  • n is: 1-4;
  • n up to 5;
  • A is NH
  • B 1 is O
  • B 2 is CO
  • Z is p-hydroxyphenyl
  • D is NH
  • X is CO
  • n is not 1.
  • Compounds according to the present invention include pharmaceutically acceptable salts of these compounds.
  • Prodrugs, such as those having carbonates and esters of phenolic groups are also within the scope of the invention.
  • Lower alkyl means a straight chain, branched or cyclic moiety having from 1 to 6 carbon atoms.
  • Compounds according to the present invention can have at position B 1 : NR 2 , O or CH 2 . It is preferred that B 1 be NR 2 or O. B 1 is more preferably NH or NCH 3 .
  • Compounds according to the present invention can have at position B 2 : CO, CS, or SO 2 . It is preferred that B 2 be CO or CS; B 2 is more preferably CO.
  • Compounds according to the present invention can have at position K: H, or lower alkyl, such as methyl, ethyl or propyl. It is preferred that K be H.
  • Compounds according to the present invention can have at position Z: R 4 , aryl, heteroaryl, substituted aryl or substituted heteroaryl.
  • Z is preferably hydroxy substituted aryl, ether substituted aryl, hydroxy substituted heteroaryl or ether substituted aryl.
  • Z is pyridine, pyrrole, oxazole, indole, purine, furan, thiophene, pyridazine, pyrimidine, pyrazine, imidazole, thiazole, isoxazole, pyrazole, isothiazole, benzene, methyl benzene, dimethyl benzene, trimethyl benzene, tetramethyl benzene, ethyl benzene, tetraethyl benzene, propyl benzene, tetrapropyl benzene, butyl benzene, tetrabutyl benzene, pentyl benzene, tetrapentyl benzene, methoxy benzene, dimethoxy benzene, trimethoxy benzene, tetramethoxy benzene, ethoxy benzene, diethoxy
  • Z is more preferably p-hydroxy phenyl, p- benzyloxy phenyl, p-benzoate phenyl, p-carboxy phenyl, 4-(2- hydroxyphenylcarbonyl)-3,5-dihydroxy phenyl, p-amino phenyl, 4- fluoro phenyl, 4-benzyloxy phenyl, p-methyl phenyl, p- benzyloxycarbonyl phenyl, p-nitrophenyl, 5-benzyloxy-2-indole, 5-hydroxy-2-indole, 3,4-dihydroxy phenyl, 2-benzyloxy phenyl, 2-hydroxyphenyl, phenyl, p-NHSO 2 CH 3 phenyl, p-methoxymethyleneoxy phenyl, p-acetoxy phenyl.
  • Z be substituted phenyl. It is most preferred that Z be p-hydroxy phenyl, p-halophenyl or 5-hydroxy indole.
  • Compounds according to the present invention can have at position D: NR 3 , O or CH 2 . It is preferred that D be NR 3 , or O. It is more preferred that D be O or NH.
  • Compounds according to the present invention can have at position E: R 4 , aryl, heteroaryl, substituted aryl or substituted heteroaryl.
  • E is preferably hydroxy substituted aryl, ether substituted aryl, hydroxy substituted heteroaryl or ether substituted aryl.
  • E may be pyridine, pyrrole, oxazole, indole, purine, furan, thiophene, pyridazine, pyrimidine, pyrazine, imidazole, thiazole, isoxazole, pyrazole, isothiazole, benzene, methyl benzene, dimethyl benzene, trimethyl benzene, tetramethyl benzene, ethyl benzene, tetraethyl benzene, propyl benzene, tetrapropyl benzene, butyl benzene, tetrabutyl benzene, pentyl benzene, tetrapentyl benzene, methoxy benzene, dimethoxy benzene, trimethoxy benzene, tetramethoxy benzene, ethoxy benzene, dieth
  • Compounds according to the present invention can have at position F: CO, CS, CH(OR 6 ), CH 2 , O, S or NR 6 . It is preferred that F be CO or CH 2 . It is most preferred that F be CO.
  • G can have at position G: R 4 , aryl, heteroaryl, substituted aryl, substituted heteroaryl or substituted cycloalkyl.
  • G is preferably hydroxy substituted aryl, carboxy substituted aryl, hydroxy substituted heteroaryl or carboxy substituted heteroaryl.
  • G may be pyridine, pyrrole, oxazole, indole, purine, furan, thiophene, pyridazine, pyrimidine, pyrazine, imidazole, thiazole, isoxazole, pyrazole, isothiazole, benzene, methyl benzene, dimethyl benzene, trimethyl benzene, tetramethyl benzene, ethyl benzene, tetraethyl benzene, propyl benzene, tetrapropyl benzene, butyl benzene, tetrabutyl benzene, pentyl benzene, tetrapentyl benzene, methoxy benzene, dimethoxy benzene, trimethoxy benzene, tetramethoxy benzene, ethoxy benzene, dieth
  • G is preferably 2-carboxy-6-hydroxy phenyl, 2-ethoxycarbonyl-6-hydroxy phenyl, 2-hydroxy phenyl, 2-benzyloxycarbonyl phenyl, 2-hydroxy naphthyl, 2,3,5,6,-tetramethyl phenyl, 2,6-dihydroxy phenyl, 2,6-dimethoxy phenyl, 2-carboxy cyclohexane, 2-hydroxy cyclohexane, 2-hydroxy-1-naphthyl, 2,6-dichloro phenyl, 2- methoxy-6-hydroxy phenyl, 2-carboxy-3-pyridine, 3-carboxy-2- pyridine, phenyl, 3,4-dihydroxy phenyl, 2-methoxycarbonyl-6- hydroxy phenyl, 2-butoxycarbonyl-6-hydroxy phenyl, 2-(2- methylpropyloxycarbonyl)-6-hydroxy phenyl, 2-nitrilo-6-hydroxy phenyl,
  • G be 2-carboxy-6-hydroxyphenyl, 2-hydroxy-6-(tetrazol-2- y)phenyl, 2,6-dihydroxy phenyl, 2-hydroxy-1-naphthyl, 2- methoxycarbonyl-6hydroxyphenyl, 2-cyano-6-hydroxy phenyl, and 2-hydroxy-6-(trifluoromethylsulfonamino) phenyl. It is most preferred that G be 2-carboxy-6-hydroxy benzene and its ester or acyl derivatives as well as 2-R-6-hydroxyphenyl where R is carboxylic acid surrogate such as tetrazole or N- sulfonylcarboxamide.
  • Compounds according to the present invention can have at position X: CO, CS, CNR 8 or CCR 9 R 10 . It is preferred that X be CO or CH 2 .
  • Compounds according to the present invention can have as R 1 , R 2 , R 3 , R*, R 6 , R 7 , R 8 , R 9 and R 10 , independently: hydrogen, lower alkyl, aryl or JR 11 wherein J is CO, CN or SO 2 and R 11 is lower alkyl, aryl, alkylamino, arylamino, aryloxy or alkoxy.
  • Compounds according to the present invention can have at position R 5 lower alkyl or aryl.
  • n 1-4. It is preferred that m be 1-2, preferably 1.
  • n is
  • n 1-3.
  • n plus m is less than or equal to 5. It is preferred that n plus m is less than or equal to 4.
  • atoms within the moieties defined by n and m may have substituents.
  • substituents may preferably include hydrocarbyl groups such as the lower alkyl groups, methyl, ethyl and propyl together with larger aliphatic and aromatic functions.
  • m and n may contain other functional species such as carbonyl, thiocarbonyl, hydroxy, amino, halo and others. Preferred species are carbonyl and thiocarbonyl.
  • Preferred compounds contain aryl groups in positions
  • Z, E and G are hydroxy substituted aryl, ether substituted aryl, hydroxy substituted heteroaryl, or ether substituted aryl.
  • E and G are preferably substituted aryls or substituted heteroaryls whereby the substitutions are located such that the two aryl rings are conformationally "crowded" out of plane with each other.
  • A is preferably NR 1 or CH 2 .
  • Pharmaceutically acceptable salts of these compounds may be used in accordance with the present invention.
  • Pharmaceutically acceptable salts include, but are not limited to sodium, trialkyl ammonium, potassium, calcium, zinc, lithium, magnesium, aluminum, diethanolamine, ethylenediamine, meglumine and acetate.
  • Preferred salts are sodium and potassium.
  • A is CH 2 , NR 1 , S, or O;
  • B1 is NR 2 , O, or CH 2 ;
  • B2 is CO or CS;
  • Z is R 4 , aryl, heteroaryl, substituted aryl or substituted heteroaryl or D is NR 3 , O or CH 2 ;
  • E is R 5 , aryl, heteroaryl, substituted aryl or substituted heteroaryl;
  • F is CO or CS;
  • G is R 7 , aryl, heteroaryl, substituted aryl or substituted heteroaryl;
  • X is CO or CS;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are, independently: hydrogen, lower alkyl or aryl;
  • R 5 is lower alkyl or aryl;
  • m is 1-4; and
  • n is 1-4; where n plus m is less than or equal to 5.
  • A is CH 2 , NR 1 , S, or O; B 1 is NR 2 or O; B 2 is CO or CS; Z is hydroxy substituted aryl, ether substituted aryl, hydroxy substituted heteroaryl, halo substituted aryl; D is NR 3 or O; E is hydroxy substituted aryl, ether substituted aryl, hydroxy substituted heteroaryl, acyloxy substituted aryl; F is CO or CS; G is hydroxy substituted aryl, ether substituted aryl, hydroxy substituted heteroaryl, carboxy substituted aryl; X is CO or CS; R 1 , R 2 and R 3 independently: hydrogen, lower alkyl or aryl; m is 1-2; and n is 1-3; where n plus m is less than or equal to 4.
  • A is NH, CH 2 or NR 1; Bl is NR 2 or O; B2 is CO or CS; Z is hydroxyphenyl or halophenyl; D is NR 3 , O or CH 2 ; E is 3,5- hydroxy benzene or 3,5-alkoxy benzene; F is CO or CH 2 ; G is 2- carboxy-benzene, 2-hydroxy benzene, 2,6-dihydroxy benzene, 2- methoxy benzene, 2,6-dimethoxy benzene, or 6-hydroxy benzene- 2-carboxylic acid; X is CO; R 1 , R 2 , or R 3 are, independently hydrogen, lower alkyl or aryl; m is 1; and n is 3.
  • A is NH or CH 2 ;
  • B1 is NH;
  • B2 is CO;
  • Z is p-hydroxyphenyl;
  • D is O;
  • E is 3,5-hydroxy benzene;
  • F is CO;
  • G is 2-carboxy-6- hydroxyphenyl, 2-hydroxy-6-(tetrazol-2-y)phenyl, 2,6-dihydroxy phenyl, 2-hydroxy-1-naphthyl, 2-methoxycarbonyl-6hydroxyphenyl, 2-cyano-6-hydroxy phenyl, and 2-hydroxy-6- (trifluoromethylsulfonamino)phenyl;
  • X is CO;
  • one stereoisomer is more biologically active than its enantiomer. It is envisioned that preferred stereoisomerism will be determined for active species and that such preferred compounds will be selected for therapeutic and other uses.
  • Prodrugs such as carbonates and carboxy esters of phenolic OH and NH groups can be prepared by the derivatization of OH and NH groups with acylating agents, such as methyl chloroformate, ethyl chloroformate, isobutyryl chloride, methoxypropionyl chloride, methyl chlorosuccinate, ethyl chlorosuccinate and benzoyl chloride, for example.
  • acylating agents such as methyl chloroformate, ethyl chloroformate, isobutyryl chloride, methoxypropionyl chloride, methyl chlorosuccinate, ethyl chlorosuccinate and benzoyl chloride, for example.
  • prodrugs of compounds which contain a carboxylic acid can be prepared by derivitazation with alkylating agents, such as methyl iodide or acetoxymethyl chloride.
  • Reaction Scheme I provides syntheses for producing compounds according to the present invention including the use of a cyclic carbonyl or a heterocyclic carbonyl such as the seven membered lactam shown as a starting material.
  • a lactam can be benzylated with base in tetrahydrofuran to protect the nitrogen functionality. It is then reacted with base and phenylselenyl chloride followed by sodium periodate to yield the unsaturated lactam. Oxidation with osmium tetroxide followed by benzoylation yields the hydroxy benzoate shown.
  • Scheme II provides a synthesis scheme for producing compounds according to the present invention including the use of an enol ether lactam such as the azepinone shown as a starting material.
  • an enolether lactam such as the azepinone shown as a starting material.
  • an enolether lactam can be benzylated with base in tetrahydrofuran to protect the nitrogen function. It is then hydrolyzed with acid and reacted with sodium nitrite in acetic acid to form the oxime. Catalytic hydrogenation in the presence of acetic anhydride gives the acetamide, which can be reduced with, for example, sodium borohydride and hydrolyzed to the syn (or anti) aminohydroxy lactam.
  • Reaction Scheme III provides methods for producing compounds according to the present invention including the use as a starting material of the previously mentioned syn aminohydroxy lactam.
  • Oxidation of the alcohol using, for example, oxalyl chloride, dimethylsulfoxide, and triethylamine (Swen oxidation) provides the Keto intermediate which is treated with HONH 2 -HCl followed by reduction using, for example, RaNi (Raney nickel) catalyst and hydrogen affords the amino-amide.
  • Reaction with a GFE carboxylic acid function followed by deprotection provides the family of diamides.
  • Scheme IV provides a synthesis scheme for producing compounds according to the present invention including the use as a starting material of a cyclic olefin as shown.
  • Epoxidation with peracetic acid followed by reaction with sodium azide affords the anti azido alcohol, which is O- protected and reduced to the aminoalcohol ether.
  • Reaction with a carboxylic acid substituted with a Z functionality yields the amide, which is O-deprotected and reacted with a GFE carboxylic function to provide the family of ester/amides.
  • Scheme V provides a syntheses for preparing compounds according to the present invention including a synthesis scheme for producing 6, 7 and 8 member cyclic and heterocyclic groups including B 1 and D with stereo specific attachment, including the use as a starting material of the unsaturated aldehyde.
  • tin-mediated condensation and subsequent cyclization of the aldehyde with an isothiocyanate affords the oxazolidine thione, which can be reduced with lithium aluminum hydride, ozonolyzed, and further reduced with, for example, sodium borohydride to the diol.
  • the reactions of Scheme VI provide a synthesis scheme for producing 6, 7, and 8 membered cyclic and heterocyclic groups including B 1 and D with stereo specific attachment including the use as a starting material of N-carbobenzyloxy asparagine.
  • CBZ-asparagine is reacted with bis(trifluoroacetoxy) iodobenzene to give the mono-protected diaminoacid, which is differentially protected with di-t-butyl dicarbonate and reduced with, for example, borane/tetrahydrofuran.
  • Oxidation to the aldehyde and condensation with an unsaturated organometallic affords the diprotected diamino alcohol, which gives the terminal tosyloxy compound after hydroboration/oxidation and treatment with toluene sulfonyl chloride.
  • Removal of the butoxycarbonyl is accomplished by acid treatment, for example, formic acid or trifluoroacetic acid, followed by removal of the amine- protecting group, which can be removed with hydrogen.
  • Scheme VII provides a syntheses for producing compounds according to the present invention including a synthesis scheme for producing 6, 7, and 8 member cyclic and heterocyclic groups including B 1 and D with stereo specific attachment including the use as a starting material of phthalimide alkyl aldehyde, for example, the aldehyde can be reacted with methyl isocyanoacetate in the present of gold ferrocene catalyst to give the oxazolidine, which is hydrolyzed to the diaminohydroxy ester salt with for example, hydrochloric acid. Base mediated cyclization affords the lactam, which can be reduced to an aminohydroxy compound.
  • Scheme VIII A provides a synthesis scheme for producing compounds according to the present invention including a synthesis scheme for producing 5 and 6 member cyclic and heterocyclic groups including B 1 and D with syn attachment including the se of the protected cyclic ketone as starting material.
  • the ketone is deprotonated and the enolate aminated to afford the butoxycarbonylamino ketone which can be stereo specifically reduced with, for example, sodium borohydride to the syn aminoalcohol.
  • Reactions with a carboxylic acid substituted with a Z functionality yields the amide.
  • Further reaction with a GFE carboxylic function followed by deprotection provides the family of syn ester/amides.
  • Scheme VIII B provides a synthesis scheme for producing compounds according to the present invention including a synthesis scheme for producing 5 and 6 member cyclic and heterocyclic groups including B 1 and D with anti attachment including the use as starting material of the syn hydroxyamide from Scheme VIII A.
  • the syn hydroxyamide can be inverted to anti hydroxyamide by treatment with carboxylic acid, such as acetic acid, in the present of triphenylphosphine and diethylazodicarboxylate followed by treatment with sodium methoxide. Reaction with a GFE carboxylic function followed by deprotection provides the family of anti ester/amides.
  • Scheme VIII C provides methods for producing compounds according to the present invention including a synthesis scheme for producing 5 and 6 member cyclic and heterocyclic groups including B 1 and D with anti attachment including the use as starting material of the syn hydroxyamide from Scheme VIII A.
  • the syn hydroxyamide can ba inverted to anti amino amide by treatment with trifluoromethane sulfonic anhydride and sodium azide followed by reduction with, for example, tin (II) chloride.
  • Reaction with a GFE carboxylic function followed by deprotection provides the family of anti diamides.
  • Scheme VIII D provides a synthesis scheme for producing compounds according to the present invention including a synthesis scheme for producing 5 and 6 member cyclic and heterocyclic groups including B 1 and D with syn attachment including the use as starting material of the anti hydroxyamide from Scheme VIII B.
  • the anti hydroxyamide can be inverted to syn amino amide by treatment with trifluoromethanesulfonic anhydride and sodium azide followed by reduction with, for example, tin (II) chloride. Reaction with a GFE carboxylic function followed by deprotection provides the family of syn diamides.
  • Scheme VIII E provides a synthesis scheme for producing compounds according to the present invention including producing 5 and 6 member cyclic and heterocyclic groups including B 1 and D with anti attachment including the use of the protected cyclic epoxide as starting material.
  • the epoxide is opened with ammonia to provide the anti aminoalcohol or with azide to provide the azido-alcohol.
  • Reduction of the latter with, for example, triphenylphosphine provides the amino alcohol.
  • Reaction with a carboxylic acid substituted with a Z functionality yields the anti hydroxyamide.
  • Further reaction with a GFE carboxylic function followed by deprotection provides the family of anti ester/amides.
  • Scheme VIII F provides a synthesis scheme for producing compounds according to the present invention including a synthesis scheme for producing 5 and 6 member cyclic and heterocyclic groups including B 1 and D with syn attachment including the use of the anti hydroxyamide from Scheme VIII E as starting material.
  • the anti hydroxyamide can be inverted to syn hydroxyamide by treatment with carboxylic acid, such as acetic acid in the presence of triphenylphosphine and diethyl azodicarboxylate followed by deprotection provides the family of syn ester/amides.
  • Scheme VIII G provides a synthesis scheme for producing compounds according to the present invention including a synthesis scheme for producing 5 and 6 member cyclic and heterocyclic groups including B 1 and D with syn attachment including the use of the anti hydroxyamide from Scheme VIII E as starting material.
  • the anti hydroxyamide can be inverted to syn amino amide by treatment with trifluoromethanesulfonic anhydride and sodium azide followed by reduction with, for example, tin (II) chloride. Reaction with a GFE carboxylic function followed by deprotection provides the family of syn diamides.
  • Scheme VIII H provides a synthesis scheme for producing compounds according to the present invention including a synthesis scheme for producing 5 and 6 member cyclic and heterocyclic groups including the use of the syn hydroxyamide from Scheme VIII F as starting material.
  • the syn hydroxyamide can be inverted to anti amino amide by treatment with trifluoromethanesulfonic anhydride and sodium azide followed by reduction with, for example, tin (II) chloride. Reaction with a GFE carboxylic function followed by deprotection provides the family of anti diamides.
  • Scheme IXA provides a synthesis scheme for producing intermediate GFE carboxylic acids including the use of 4- bromobenzoic acids as starting material.
  • a 4- bromobenzoic acid can be esterified by treatment with carbonyldiimidazole followed by an alcohol such as tert- butanol. The ester is treated with n-butyl lithium followed by an addition of N, N-dimethyl formamide to give the aldehyde ester, or by addition of carbon dioxide to give the acid ester, which is converted to the acid chloride ester with oxalyl chloride.
  • the ester can also be reacted with n-butyl lithium and a benzaldehyde to give the diphenyl carbinol, which is oxidized with, for example, chromic acid, and deprotected to provide GFE carboxylic acids.
  • the ester can be reacted with n- butyl lithium and benzoyl chloride to give the diphenyl ketone, which is deprotected to also provide GFE carboxylic acids.
  • Scheme IXB provides a synthesis scheme for producing intermediate GFE carboxylic acids including the use of either 4-bromobenzoic esters from scheme IXA or benzyl alcohols as starting material.
  • a 4-bromobenzoic ester can be treated with n-butyl lithium and phthalic anhydride to afford the 2'-carboxybenzophenone ester, which is protected with, for example, benzyl alcohol esterification at the 2' position and deprotected at the other ester position to provide GFE carboxylic acids.
  • the alcohol is coupled with the acid chloride and treated with one equivalent of nBuLi which provides, upon rearrangement, the hydroxy ketone.
  • Oxidation to the acid is effected in a two- step process using first pyridinium dichromate (PDC) or TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) followed by tetrabutylammonium permanganate (nBu 4 MnO 4 ) or sulfamic acid (NH 2 SO 3 H) and sodium chlorite (NaClO 2 ).
  • PDC pyridinium dichromate
  • TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy
  • nBu 4 MnO 4 tetrabutylammonium permanganate
  • NH 2 SO 3 H sulfamic acid
  • NaClO 2 sodium chlorite
  • Scheme IXC provides a synthesis scheme for producing GFE carboxylic acids including the use of bromobenzenes as starting material.
  • a bromobenzene can be treated with n-butyl lithium and the acid chloride ester from scheme IXA to afford the benzophenone ester, which is deprotected to provide GFE carboxylic acids.
  • the bromobenzene can also be treated with n-butyl lithium and the aldehyde ester from scheme IXA to give the diphenylcarbinol ester, which is either deprotected directly, oxidized with, for example, chromic acid and deprotected, or reduced with, for example, hydrogen and deprotected to provide the family of GFE carboxylic acids.
  • Scheme IXD provides a synthesis scheme for producing compounds according to the present invention including the use of halobenzenes, for example, bromobenzenes, and heterocyclic or cyclic compounds substituted with B 1 -B 2 -Z and DH, which are described in other schemes, as starting materials.
  • halobenzenes for example, bromobenzenes
  • heterocyclic or cyclic compounds substituted with B 1 -B 2 -Z and DH which are described in other schemes, as starting materials.
  • halobenzenes for example, bromobenzenes
  • heterocyclic or cyclic compounds substituted with B 1 -B 2 -Z and DH which are described in other schemes, as starting materials.
  • halobenzenes for example, bromobenzenes
  • heterocyclic or cyclic compounds substituted with B 1 -B 2 -Z and DH which are described in other schemes, as starting materials.
  • a bromobenzene can be
  • Scheme IXE provides a synthesis scheme for producing compounds according to the present invention including the use of aromatic or heteroaromatic halides protected, hetero- substituted aryl or heteroaryl acids or alcohols, and heterocyclic or cyclic compounds substituted with B 1 -B 2 -X and DH, which are described in other schemes, as starting materials.
  • a bromoaromatic can be reacted with a protected 4-hetero-substituted aryl acid or alcohol in the presence of transition metal catalyst, for example, copper, and base to afford protected GFE acid or alcohol, which can be deprotected and treated with, for example, phosphorous penta chlorides to provide GFEX chloride.
  • transition metal catalyst for example, copper
  • phosphorous penta chlorides to provide GFEX chloride.
  • This is reacted with heterocyclic or cyclic compounds substituted with B 1 -B 2 -Z and DH to provide another family of balanoids.
  • Scheme IX F provides a preferred method for the preparation of the GFE-CO 2 H.
  • Intermediate aldehyde is first protected, for example, as a cyclic acetal, which is then treated with nBuLi and DMF to afford aldehyde 1.
  • Aryl bromide is treated with n-butyl lithium and then aldehyde 1 to afford the alcohol.
  • Oxidation using, for example MnO 2 followed by acidic hydrolysis of the acetal gives the ketoaldehyde.
  • Oxidation to the acid using, for example, sodium chlorite and sulfamic acid, followed by the appropriate deprotection sequences affords GFE-CO 2 H.
  • Scheme IX G describes a preferred method for the preparation of GFE-CO 2 H where E is substituted with two OH or OR groups.
  • Protected bis-phenol is treated with n-butyl lithium followed by aldehyde (prepared in Scheme IX F) provides, after oxidation with, for example, MnO 2 the ketone intermediate.
  • the primary alcohol is oxidized, using, for example MnO 2 followed by sodium chlorite/hydrogen peroxide.
  • Hydrolysis of the acetal followed by treatment with MnO 2 , KCN, acetic acid and the alcohol R'-OH provides the desired GFE-CO 2 H.
  • a reducing agent such as sodium borohydride
  • balanoids where F is CHOH
  • a sulfurizing agent for example, phosphorus pentasulfide
  • Scheme XIA provides a synthesis scheme for producing compounds according to the present invention including the use of heterocyclic compounds substituted with B 1 -B 2 -Z and DXEFG where A is NH, described in other schemes, as starting materials.
  • a heterocyclic compound substituted with B 1 -B 2 -Z and DXEFG where A is NH can be treated with an alkylating agent, sulfonylating agent, or acylating agent, for example acetyl chloride, in the presence of base to provide the family of balanoids with a substanted nitrogen.
  • R 1 group can be appended at an earlier stage in the synthesis using appropriately protected intermediates.
  • heterocyclic intermediate can be treated with an alkylating agent, sulfonylating agent or acylating agent, in the presence of base to provide the intermediate where R 1 is not hydrogen.
  • an organometallic for example, the lithium salt of diethyl malonate
  • Scheme XIII provides syntheses for producing compounds according to the present invention including the use of GFE carboxylic acids and cyclic or heterocyclic compounds substituted with B 1 -B 2 -Z and DH or B,H and DXEFG, which are described in other schemes, as starting materials.
  • a GFE carbinol can be treated with mesyl chloride and an amine base, such as triethylamine, followed by treatment with an iodide source such as sodium iodide to afford a GFE methyl iodide.
  • This can be reacted with a cyclic or heterocyclic compound substituted with B 1 -B 2 -Z and DH in the presence of base such as sodium hydride to provide the family of balanoids in which X is CH 2 .
  • the cyclic or heterocyclic compound substituted with B,H and DXEFG can be reacted with a Z sulfonyl chloride, for example, benzenesulfonyl chloride, in the presence of base to provide the family of balanoids in which B 2 is SO 2 .
  • a Z sulfonyl chloride for example, benzenesulfonyl chloride
  • a cyclic diene such as cyclopentadiene can be treated with a peracid such as peracetic acid and the epoxide opened with an amino species, for example, (dibenzylamino) dimethyl aluminum, followed by butyldimethylsilyl chloride to obtain the protected amino alcohol.
  • This can be ozonolyzed and reduced to the diol, which is treated with tosyl chloride to give the chloro tosylate.
  • Treatment with bis(trimethyltin)oxide or preferably potassium superoxide and a crown ether, for example, 18-C-6, provides the chloroalcohol which is ring closed on treatment with a strong base, such as methyllithium or butyllithium to afford the protected heterocyclic compound, which is deprotected to heterocyclic compounds substituted with B ⁇ NHz and D OH and in which A is oxygen.
  • a strong base such as methyllithium or butyllithium
  • a cyclic diene such as cyclopentadiene can be treated with a peracid such as peracetic acid and the epoxide opened with an azide species, for example, sodium azide, followed by t- butyldimethylsilyl chloride to obtain the protected amino alcohol.
  • Compounds where A is SO 2 can be prepared from compounds where A is sulfur by treatment with an oxidizing agent, for example, peracetic acid, followed by deprotection to provide compounds wherein A is SO 2 (Scheme XIV C).
  • an oxidizing agent for example, peracetic acid
  • Z sulfonyl chlorides such as benzenesulfonyl chloride
  • Scheme XVI provides a synthesis scheme for producing compounds according to the present invention including the use of ketones, for example, acetophenone, and azepinediones, such as 1-benzylazepin-2,4-dione, as starting materials.
  • ketones for example, acetophenone, and azepinediones, such as 1-benzylazepin-2,4-dione
  • the ketone can be brominated with bromine in acetic acid and protected with ethylene glycol to afford the bromomethyl ketal, which is added to a base-treated solution of the azepinedione to give the alkylated azepinedione.
  • Scheme XVII provides a synthesis scheme for producing compounds according to the present invention including GFE carboxylic acids, which are described in other schemes, and cyclic or heterocyclic groups substituted with OH and B 1 B 2 Z, also described in other schemes, as starting materials.
  • GFE carboxylic acids which are described in other schemes, and cyclic or heterocyclic groups substituted with OH and B 1 B 2 Z, also described in other schemes, as starting materials.
  • a GFE carboxylic acid can be treated with oxalyl chloride and N,O-dimethylhydroxylamine to afford the methoxymethyl amide, which is reacted with a methyl organometallic to give the methyl ketone.
  • Scheme XVIII provides a synthetic scheme for compounds of the invention where K is not equal to H.
  • This intermediate is converted using the Scheme I to compounds of the invention.
  • Scheme XIX provides a synthetic scheme for compounds of the invention where the group G is substituted with an alkoxycarbonyl group.
  • Compounds wherein G is substituted with a carboxy group are treated with an alkylating agent, for example, methyl iodide, and a base such as sodium carbonate to provide the target compounds.
  • an alkylating agent for example, methyl iodide
  • Scheme XX provides a synthetic route for compounds of the invention where G and/or E residues are substituted with acyloxy groups.
  • Target compounds which possess one or more hydroxyl groups on G or E is treated with an acylating agent, for example, acetyl chloride, ethyl chloroformate, and the like, in the presence of a base such as pyridine or triethylamine to provide the target compounds.
  • an acylating agent for example, acetyl chloride, ethyl chloroformate, and the like, in the presence of a base such as pyridine or triethylamine to provide the target compounds.
  • Intermediate amide following protection of the D functionality, is treated with a strong base such as KOtBu or KH and an alkylating agent such as methyliodide or dimethylsulfate to provide the intermediate where B 1 is N-R.
  • a strong base such as KOtBu or KH
  • an alkylating agent such as methyliodide or dimethylsulfate
  • Scheme XXII describes the synthesis of compounds of the invention in which group G is substituted with a tetrazole ring.
  • Keto aldehyde (prepared as described in Scheme IX F) is treated with hydroxylamine hydrochloride in dimethylformamide to provide the nitrile. Following deprotection to the acid, it is coupled to provide target compounds wherein G is substituted with a nitrile group. Treatment with trimethylsilylazide and nBu 2 SnO followed by deprotection affords the target compounds.
  • Scheme XXIII provides a synthetic scheme for the preparation of compounds where D is N-R.
  • Amine intermediate (prepared as described in Scheme III) is converted to the trifluoroacetamide.
  • Treatment with a strong base, such as KOtBu and an alkylating agent such as methyl iodide or dimethylsulfate followed by cleavage of the trifluorocetamide provides the intermediate amine wherein D is N-R. This is converted to compounds of the invention using procedures outlined in Scheme III.
  • compositions incorporating compounds according to the present invention can be used to block PKC activity related to abnormal or undesirable cellular events and activity including tumorogeneis and cellular activity related to inflammation and reperfusion injury. Treatment of disorders and disease conditions can be performed by administration of effective amounts of pharmaceutical preparation that comprise compounds according to the present invention.
  • Compounds can be formulated for human and animal prophylactic and therapeutic applications by those having ordinary skill in the art. The range of amounts of a compound to be administered to mammals, particularly humans, to be effective in inflammatory, tumor or reperfusion injury therapy can routinely be determined by those having ordinary skill in the art.
  • the compounds and pharmaceutical compositions of the invention may be administered by any method that produces contact of the active ingredient with the agent's site of action in the body of a mammal or in a body fluid or tissue. These methods include but not limited to oral, topical, hypodermal, intravenous, intramuscular and intraparenteral methods of administration.
  • the compounds may be administered singly or in combination with other compounds of the invention, other pharmaceutical compounds such as chemotherapeutic compounds, or in conjunction with therapies such as radiation treatment.
  • the compounds of the invention are preferably administered with a pharmaceutically acceptable carrier selected on the basis of the selected route of administration and standard pharmaceutical practice.
  • the compounds of the invention are administered to mammals, preferably humans, in therapeutically effective amounts which are effective to inhibit protein kinase C, to inhibit tumor cell growth, inhibit inflammation of tissue, inhibit keratinocyte cell proliferation, inhibit oxidative burst from neutrophils or inhibit platelet aggregation.
  • the dosage administered in any particular instance will depend upon factors such as the pharmacodynamic characteristics of the compound of the invention, its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment, and the effect desired.
  • balanoids are useful in the treatment of disease conditions in which control of cellular growth, regulation and/or differentiation is desirable.
  • An effective amount of a balanoid can be administered to mammals who are suffering from inflammatory, cardiovascular or neoplastic diseases, particularly inflammation, reperfusion injury and cancer, in order to counter the disease at the cellular level.
  • the daily dosage of a compound of the invention will be in the range of from about 1 ⁇ g to about 100 mg per kg of body weight, preferably from about 1 ⁇ g to about 40 mg per kg body weight, more preferably from about 10 ⁇ g to about 20 mg per kg per day.
  • compositions of the invention may be administered in a single dosage, divided dosages or in sustained release forms. Persons of ordinary skill will be able to determine dosage forms and amounts with only routine experimentation based upon the considerations of this invention. Isomers of the compounds and pharmaceutical compositions, particularly optically active stereoisomers, are also within the scope of the present invention.
  • the compounds of the invention may be administered as a pharmaceutical composition orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions.
  • the compounds may also be administered parenterally in sterile liquid dosage forms or topically in a carrier.
  • the compounds of the invention may be formulated into dosage forms according to standard practices in the field of pharmaceutical preparations. See Remington 's Pharmaceutical Sciences , A. Osol, Mack Publishing Company, Easton, Pennsylvania.
  • Compounds of the invention may be mixed with powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, and stearic acid for insertion into gelatin capsules, or for forming into tablets. Both tablets and capsules may be manufactured as sustained release products for continuous release of medication over a period of hours. Compressed tablets can be sugar or film coated to mask any unpleasant taste and protect the tablet from the atmosphere or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, and stearic acid for insertion into gelatin capsules, or for forming into tablets. Both tablets and capsules may be manufactured as sustained release products for continuous release of medication over a period of hours. Compressed tablets can be sugar or film coated to mask any unpleasant taste and protect the tablet from the atmosphere or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration may contain coloring and flavoring to increase patient acceptance, in addition to a pharmaceutically acceptable diluent such as water, buffer or saline solution.
  • a pharmaceutically acceptable diluent such as water, buffer or saline solution.
  • a compound of the invention may be mixed with a suitable carrier or diluent such as water, an oil, saline solution, aqueous dextrose (glucose) and related sugar solutions, glycols such as propylene glycol or polyethylene glycols.
  • Solutions for parenteral administration contain preferably a water soluble salt of the compound of the invention.
  • Stabilizing agents, antioxidizing agents and preservatives may also be added.
  • Suitable antioxidizing agents include sodium bisulfite, sodium sulfite, and ascorbic acid, citric acid and its salts, and sodium EDTA.
  • Suitable preservatives include benzalkonium chloride, methyl-or propyl-paraben, and chlorbutanol.
  • ischemic-related myocardial damage can be attributed to polymorphonuclear leukocytes (neutrophils) which accumulate at the site of occlusion. Damage from the accumulated neutrophils may be due to the release of proteolytic enzymes from the activated neutrophils or the release of reactive oxygen intermediates (ROI).
  • ROI reactive oxygen intermediates
  • protein kinase C inhibitors as therapeutics for reperfusion injury is that they have been demonstrated to: 1) block platelet aggregation and release of neutrophil activating agents such as PAF; 2) block neutrophil activation, chemotactic migration, and adherence to activated or damaged endothelium; and 3) block neutrophil release of proteolytic enzymes and reactive oxygen intermediates.
  • neutrophil activating agents such as PAF
  • PAF neutrophil activating agents
  • syn-hexahydro-4-hydroxy-3-(4-phenylmethoxy)benzoyl- amino-1-phenylmethylazepine (0.170 g, 0.40 mmol) was dissolved in anhydrous methylene chloride (3 ml), treated with 4- dimethyl-aminopyridine (0.01 g) and triethylamine (0.12 ml, 1.2 mmol), and cooled in an ice bath under nitrogen. The acid chloride was removed from high vacuum and dissolved in anhydrous methylene chloride (2 ml), and was then added to the cooled solution. The mixture was allowed to warm to room temperature, stirred for one hour, and was partially concentrated in vacuo.
  • the catalyst Pd(OH) 2 on carbon (20%, moist, 20 mg) was added to a solution of trans-1-(4-benzoyloxybenzamido)-2-)4- benzoyl-3,5-dibenzyloxybenzoyloxy)cycloheptane (215 mg, 0.28 mmol) in methanol (8.4 ml). The mixture was stirred vigorously at room temperature under 1 atm H 2 contained in a balloon for sixteen hours.
  • the catalyst Pd(OH) 2 on carbon (20%, moist, 9 mg) was added to a solution of trans-1-(4-benzyloxybenzamido)-2-[4-(2- benzyloxybenzoyl)-3,5-dibenzyloxybenzoyloxy] cycloheptane (112 mg, 0.13 mmol) in methanol (3.9 ml) and ethyl acetate (1.3 ml). The mixture was stirred vigorously at room temperature under 1 atm H 2 contained in a balloon for seventeen hours. The solid catalyst was removed by filtration through Florisil ® .
  • the upper ester fraction (490 mg, 0.76 mmol) was dissolved in methanol (5 ml) and treated with 85% potassium hydroxide (97 mg, 1.52 mmol) dissoved in methanol (5 ml) and stirred for 16 h.
  • the mixture was treated with water (15 ml) and extracted with methylene chloride (2 x 25 ml).
  • the organic layer was concentrated and chromatographed (2.5 x 10 cm, ethyl acetate) to give the chiral alcohol (266 mg) as an oil.
  • the lower ester fraction (260 mg, 0.40 mmol) was dissolved in methanol (5 ml) and treated with 85% potassium hydroxide (53 mg, 0.8 mmol) dissoved in methanol (5 ml) and stirred for 48 h.
  • the mixture was treated with water (15 ml) and extracted with methylene chloride (2 x 25 ml) .
  • the organic layer was concentrated and chromatographed (2.5 x 10 cm, ethyl acetate) to give the chiral alcohol (154 mg) as an oil.
  • Balanol benzophenone (255 mg, 375 ⁇ mol) was dissolved in methylene chloride (3 ml) and treated with DMF (3 drops) followed by a 2M methylene chloride solution of oxalyl chloride (244 ⁇ L, 62 mg, 488 ⁇ mol). After stirring for 1 h, the mixture was concentrated and put under vacuum. The residue was dissolved in methylene chloride (5 ml) and added to chiral amidoalcohol (150 mg, 375 ⁇ mol), DMAP (5 mg), triethylamine (157 ⁇ L, 114 mg, 1.13 mmol) in methylene chloride (5 ml).
  • the reaction mixture was evaporated, and the residue was evaporated twice from 20 ml of methylene chloride.
  • the residue was dissolved in 5 ml of methylene chloride, and was added to a solution of 251 mg (0.583 mmol) of trans-N-benzyl-3-(4-benzyloxybenzamido) -4-hydroxyazepine, 122 ⁇ L (0.700 mmol) of diisopropyl ethylamine, and 4.1 mg of DMAP in 9 ml of methylene chloride at 0°C.
  • the product was chromatographed on a Dynamax ® -60 C18 column (41.4 mm ID X 30 cm length) using a linear gradient from 100% A (0.1% TFA and 5% acetonitrile in water) to 50% B (pure acetonitrile) over 60 m at 25 ml/min. The product elutes in 50 minutes. Removal of the volatiles provided Compound 511 as a yellow solid (99 mg, 38%), mp 165-168oC.
  • IR KBr (disc) cm -1 3397, 3274, 3121, 2874, 1796, 1776, 1680, 1633, 1606, 1544, 1510, 1461, 1426, 1369, 1344, 1202, 1142, 1109, 1054, 986, 910, 827, 802, 762, 723, 671.
  • the product was chromatographed on a Dynamax ® -60 C18 column (41.4 mm ID X 30 cm length) using a linear gradient from 100% A (0.1% TFA and 5% acetonitrile in water) to 50% B (pure acetonitrile) over 60 m at 25 ml/min. The product elutes in 58 minutes. Removal of the volatiles under reduced pressure provided Compound 513 as a yellow solid (185 mg, 75%), mp 157-160oC.
  • the mixture was stirred at -65 ⁇ 5°C for 30 min, then treated dropwise with a solution of syn-hexahydro-4-hydroxy-3- (4-phenylmethoxy)benzoylamino-1-phenylmethylazepine (0.645 g, 1.5 mmol) in anhydrous methylene chloride (1.5 ml) at a rate to keep the pot temperature below -55oC.
  • the mixture was stirred at 55+5oC for 2 h, then treated dropwise with triethylamine (1.5 ml) , warmed to room temperature over one hour, and diluted with methylene chloride (10 ml) .
  • the flask was fitted with a balloon and a balloon valve, purged with hydrogen, and placed under positive hydrogen pressure for 18 h, then evacuated of hydrogen and purged for several minutes with nitrogen.
  • the solution was carefully filtered through celite (wash filter pad with ethanol) and the filtrate was concentrated in vacuo to a yellow foam. This was dissolved in methanol (20 ml), diluted with deionized water (60 ml), and concentrated in vacuo to remove the methanol.
  • reaction mixture was allowed to warm to room temperature and stirred overnight (approximately 18 h) under a nitrogen atmosphere, after which it was diluted with 50 ml of methylene chloride, washed with saturated sodium bicarbonate solution (10 ml), water (10 ml), and brine (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 440 mg of the crude product. Chromatography on silica gel eluting with 4:1-hexane:ethyl acetate gave 399 mg (71%) of the coupled product as a light yellow solid, which was used directly in the next step.
  • the reaction flask was then purged with nitrogen gas and the solution diluted with chloroform (50 ml), filtered over celite, treated with 1 ml of trifluoroacetic acid, and concentrated in vacuo to give 87 mg of the crude product.
  • the material was purified by HPLC chromatography with a 21 x 250 mm C18 column (solvent A: 95:5 water/acetonitrile + 0.1% TFA; solvent B: 100% acetonitrile; gradient 0-50% B over 60 minutes, flow: 15 ml/min). The purified fractions were concentrated and lyophilized from water to give 67 mg (63%) of the title compound as a yellow fluffy solid.
  • the product was chromatographed on a Dynamax ® -60 C18 column (41.4 mm ID X 30 cm length) using a linear gradient from 100% A (0.1% TFA and 5% acetonitrile in water) to 100% B (pure acetonitrile) over 60 m at 25 ml/min. The product elutes in 58 minutes. Removal of the volatiles under reduced pressure provided Compound 518 as a white solid (62 mg, 26%), mp 134-137oC.
  • the dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and the volatiles were removed under reduced pressure.
  • the crude residue was purified using flash column chromatography (silica gel, 1 : 8 ethyl acetate / hexane) to provide the title compound as white solid (2.36 g, 88%), mp 54-57oC.
  • the solution was stirred in the cold for two hours.
  • the solution was poured into 150 ml of saturated ammonium chloride and 350 ml of ether.
  • the reaction mixture was stirred for thirty minutes.
  • the organic layer was separated, washed with 0.1 N hydrochloric acid, saturated brine and dried over magnesium sulfate.
  • the solvent was evaporated to yield 3.4 g (98 % ) of a clear oil.
  • tert-butyl 4-(2,6-dibenzyloxybenzoyl)-3,5- dibenzyloxybenzoate 360 mg, 0.51 mmol was placed in formic acid(10 ml). The resulting suspension was stirred for 20 min and intermittantly heated with a heat gun. The reaction was poured over water (300 ml) and stirred. The solids that precipitated were then filtered. Next, the solids were dissolved in ethyl acetate, and dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated in vacuo and recrystalized in hexane: ethyl acetate to yield a light yellow solid (Acid 175 mg).
  • reaction mixture was poured into 0.5N HCl (50 ml) after warming up to 0oC, extracted with EtOAc (100 ml), and washed with brine.
  • the crude material after concentration was purified on a silica gel column eluting with 8:1 Hexane:EtOAc to recover starting material aldehyde (0.5 g, 26%) and yield pure coupling product (1.0 g, 48%, based on 26% of recovered aldehyde).
  • the coupling product (1.0 g, 1.41 mmol) was dissolved in acetone (40 ml) and treated with Jones's reagent (ca. 2ml) at 5oC until the color of the reaction remained essentially the same color as the Jone's reagent. The reaction was then stirred at room temperature for 1hr. Acetone was removed in vacuo and residue was taken into EtOAc, washed with brine, dried over Na 2 SO 4 , and concentrated. The pure product was obtained as bright yellow foam from a short silica gel column eluting with 5:1/Hexane:EtOAc (997 mg, 100%).
  • the prior product (200 mg, 0.183 mmol) was dissolved in THF (20ml) and treated with few drops of TFA and 10% Pd(OH) 2 (120mg, 62 mol %). The mixture was subjected to hydrogenolysis at 50 psi for 30 hr. THF was removed in vacuo and the residue taken into MeOH. The MeOH solution was concentrated after filtering through a pad of celite and chromatographed on 41 x 300 mm C18 column (solvent A: 95:5 water/acetonitrile + 0.1% TFA; solvent B: 100% acetonitrile; gradient: 0-100% B over 60 min, flow: 25 ml/min). The pure fractions were evaporated to give two yellow solids.
  • Anti- hexahydro-4-hydroxy-3-(indole-5-carboxamido)-1- phenylmethylazepine (0.145g, 0.40 mmol) was suspended in anhydrous methylene chloride (1.0 ml), then treated with 4-dimethylaminopyridine (10mg), triethylamine (0.10 ml, 0.72 mmol), and the acid chloride solution prepared above. The mixture was stirred under nitrogen for 17h and concentrated in vacuo.
  • the flask was fitted with a baloon valve connected to a baloon containing hydrogen, then purged with hydrogen and placed under positive hydrogen pressure for 20h.
  • the flask was carefully purged with nitrogen and the solution filtered through celite (wash filter cake with ethanol), then the filtrate was concentrated in vacuo .
  • the residue was taken up in methanol (15 ml) and trifluoroacetic acid (0.5 ml), gravity filtered, and the filtrate was diluted with de-ionized water (75 ml). The mixture was partially concentrated in vacuo, and the aqueous solution was freeze-dried for 18h.
  • N,N-dimethylformamide (1 ml).
  • the solution was loaded onto a 41x250 mm C18 HPLC column and eluted as follows: A-0.1% TFA/95:5 water:acetonitrile, B-acetonitrile, 100% A to 50:50 A:B over 60 min collected at 25 ml/min.
  • Carbonyldiimidizole (0.11 g, 0.65 mmole) was added to a solution of 4-[((3-benzyloxycarbonyl)-2-pyridinyl)carbonyl]- 3,5-dibenzyloxybenzoic acid ( 0.25 g, 0.44 mmole) in 5 ml of methylene chloride and the solution was stirred at room temperature for sixty minutes under nitrogen. The solution was added to a solution of 0.19 g (0.44 mmole) of trans-N-benzyl-3- (4-benzyloxybenzamido)-4-hydroxyperhydroazepine, 0.12 ml triethylamine, and 5 mg DMAP in 8 ml of methylene chloride.
  • the solution was stirred at room temperature for twenty hours.
  • the solution was diluted with 30 ml of methylene chloride, washed with water, saturated brine and dried over magnesium sulfate.
  • the solvent was removed in vacuo.
  • the residue was chromatographed on silica gel eluting with a gradient of 5% - 10% - 20% ethyl acetate - hexane to yield 70 mg of a clear oil.
  • the preceeding compound (300 mg, 0.315 mmol) in EtOAc:MeOH (1:1, 25 ml) was treated with CF 3 COOH (37.76 mg. 25.5 ⁇ l, 0.33 mmol) and 20% Pd(OH) 2 on activated carbon (150 mg, 50% on weight basis).
  • the mixture was subjected to hydrogenolysis at 45 psi for 15 hr.
  • the crude product after filtration and concentration was taken into DMF (0.5 ml) and purified on C 18 -HPLC column eluting with 5%-50% acetonitrile in H 2 O containing 0.1% CF 3 COOH.
  • the title compound was obtained as white powder (118 mg, 62%). m.p. 204-206 (dec)°C; 1 HNMR
  • 3,5-Dibenzyloxy-4-[(3,4-dibenzyloxy)benzoyl]benzoic acid 500 mg, 0.768 mmol was dissolved in anhydrous dichloromethane (6 ml). Anhydrous dimethylformamide (0.10 ml) was then added to the solution followed by oxalyl chloride (2 N in dichloromethane, 0.50 ml, 0.99 mmol). This solution was stirred for 1 h and then concentrated in vacuo. The resulting yellow oil was placed under high vacuum for a period of 1 h to make sure all of the excess oxalyl chloride was removed.
  • Anti-3-(4-benzyloxybenzamido)-4-[3,5-benzyloxy-4-(3,4- dibenzyloxyphenylcarbonyl)benzoyloxy]- ⁇ -benzylazepine (240 mg, 0.23 mmol) and acetic acid were dissolved in methanol:ethyl acetate/2:1 in a 500 ml Parr bottle. Next, 5% palladium on activated carbon (45 mg) was added under nitrogen. The reaction mixture was placed on a Parr hydrogenator for 3 h. The mixture was then filtered over celite, and the filtrate was concentrated in vacuo to yield a yellow solid.
  • the reaction was stirred at room temperature for 18 h, then concentrated in vacuo, dissolved in a little methylene chloride, and passed through a short column of silica gel (eluted with 10% acetone/methylene chloride).
  • the early fractions containing chromophoric material were concentrated in vacuo and dissolved in ethanol/acetic acid/water (6:1:1, 12 ml), then treated with zinc powder (0.50 g, 7.5 mmol). After 30 min, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in 1.0 N sodium hydroxide (40 ml), and the aqueous mixture was extracted with methylene chloride (3 x 35 ml).
  • the mixture was stirred at -65 ⁇ 5°C for 30 min, then treated dropwise with a solution of syn-hexahydro-4-hydroxy-3- (4-phenylmethoxy)benzoylamino-1-phenylmethylazepine (0.645 g, 1.5 mmol) in anhydrous methylene chloride (1.5 ml) at a rate to keep the pot temperature below -55oC.
  • the mixture was stirred at 55 ⁇ 5oC for 2 h, then treated dropwise with triethylamine. (1.5 ml), warmed to room temperature over 1 h, and diluted with methylene chloride (10 ml).
  • the acid chloride was dissolved in methylene chloride (2.5 ml) and treated with 4-aminohexahydro-3-(4-phenylmethoxy)benzoylamino-1- phenylmethylazepine, 1:1 mixture of syn and anti isomers (0.14 g, 0.325 mmol) followed by 1.0 N sodium hydroxide (1.5 ml).
  • the biphasic mixture was rapidly stirred for 2 h and separated.
  • the aqueous layer was extracted with methylene chloride (2 x 7 ml), and the combined organic extracts and organic layer were washed with saturated aqueous sodium chloride (10 ml), dried (Na 2 SO 4 ), and concentrated in vacuo.
  • Methanesulfonyl chloride (2.67 ml, 34 mmol) was added dropwise to a stirred solution of the borohydride reduction product (4.01 g, 14 mmol) and Et 3 N (5.76 ml, 41 mmol) in CH 2 Cl 2 (40 ml) at 5oC. After 30 min. the cooling bath was removed and stirring was continued for 16h. The resultant mixture was diluted with CH 2 Cl 2 (20 ml), wa sh ed with 1 N HCl (3 x 30 ml), H 2 O (2 x 30 ml), brine (2 x 30 ml), dried (MgSO 4 ), and evaporated.
  • the white precipitate was collected, dried under vacuum, and dissolved in a mixture of MeOH (10 ml) and THF (8 ml). 1 N aq. NaOH (1 ml) was added and the mixture was stirred at room temperature for 4h. The volatile components were evaporated and the residue was dissolved in CH 2 Cl 2 (25 ml), washed with H 2 O (3 x 5 ml), dried (MgSO 4 ), and filtered. The filtrate was diluted with hexane (10 ml) and rotaevaporated at 0oC to ca. 5 ml. The precipitate was collected, washed with hexane, and dried under vacuum to give a white powder (382 mg, 67%).
  • Racemic balanol (preparation described in Compound 508; 100 mg, 147 ⁇ mol) was dissolved in methanol (1 ml) and treated with triethylamine (204 ⁇ l, 1.47 ⁇ mol) and dansyl chloride (39.5 mg, 146.5 ⁇ mol) in methylene chloride (1 ml). After stirring at room temperature for 3 h, the mixture was concentrated under vacuum to a yellow film.
  • Racemic balanol (preparation described in Compound 508; 100 mg, 147 ⁇ mol) was dissolved in methanol (1 ml) and treated with triethylamine (204 ⁇ l, 1.47 ⁇ mol) and 2-nitrobenzene sulfonyl chloride (48.7 mg, 219.7 ⁇ mol) in methylene chloride (1 ml). After stirring at room temperature for 3 h, the mixture was concentrated under vacuum to a yellow film.
  • Racemic balanol (preparation described in Compound 508; 100 mg, 147 ⁇ mol) was dissolved in methanol (1 ml) and treated with triethylamine (204 ⁇ l, 1.47 ⁇ mol) and 4-nitrobenzene sulfonyl chloride (48.7 mg, 219.7 ⁇ mol) in methylene chloride (1 ml). After stirring at room temperature for 3 h, the mixture was concentrated under vacuum to a yellow film.
  • trans-N- t-butoxycarbonyl-3-(4-benzyloxybenzamido)-4-hydroxypyrrolidine (1.26 mmol, 500 mg) in 12 ml anhydrous CH 2 Cl 2 under N 2 .
  • triethylamine 3.6 mmol, 0.5 ml
  • DMAP 150 mg
  • a solution of the acid chloride generated above in 10 ml anhydrous CH 2 Cl 2 was added via cannula. This was allowed to stir under N 2 at room temperature overnight. The reaction mixture was then diluted with CH 2 Cl 2 , washed with sat. NaHCO 3 , brine, then dried over MgSO 4 and concentrated in vacuo.
  • trans-N-t- butoxycarbonyl-3-(4-hydroxybenzamido)-4-[4-(2-hydroxy-6- carboxylbenzoyl)-3,5-dihydroxybenzoyloxy]pyrrolidine (0.15 mmol, 95 mg) in 5 ml DMF.
  • NaHCO 3 0.23 mmol, 19 mg
  • 1-iodo-2-methylpropane 0.75 mmol, 0.09 ml
  • the reaction mixture was diluted with EtOAc and washed with water 3 times.
  • the aqueous layer was back extracted with EtOAc and the organic layers combined and dried over MgSO 4 then concentrated in vacuo.
  • NaOAc (426 mg, 5.2 mmol) was dissolved in a solution of peroxyacetic acid in acetic acid (32 wt. %, 21.9 ml, 104 mmol) and the resultant solution was added dropwise over 30 min. to a mixture of cycloheptene (10 g, 104 mmol) and Na 2 CO 3 (44.1 g, 416 mmol) in CH 2 Cl 2 (100 ml) at 5oC. The mixture was allowed to stir at room temperature for 3h with occasional cooling using a water bath.
  • Tetrabutylammonium fluoride in THF (1M, 10 ml, 10 mmol) was added to a solution of the amide product from the previous reaction (3.8 g, 8.36 mmol) in THF and the resultant yellow solution was stirred at room temperature for 2h.
  • the mixture was poured into CH 2 Cl 2 (150 ml), washed with H 2 O (3 x 30 ml) and brine (2 x 30 ml), dried (MgSO 4 ), and concentrated to about 30 ml.
  • the precipitate was collected by filtration and washed with CH 2 Cl 2 (3 x 3 ml).
  • Palmitoyl chloride (10 mg, 0.038 mmol) was added to a stirred solution of Compound 589 (24 mg, 0.038 mmol) in pyridine (0.4 ml). The mixture was stirred at room temperature for 16h and TLC showed that the reaction was incomplete. More palmitoyl chloride (5 mg) was added and stirring was continued for 16h. The reaction mixture was evaporated to remove pyridine leaving a yellow syrup with some solid material which was shown to contain starting material by 1 H NMR. This material was dissolved in pyridine (0.4 ml) and treated with palmitoyl chloride (15 mg).
  • Oxalyl chloride in CH 2 Cl 2 (2 M, 0.39 ml, 0.78 mmol) was added dropwise to a solution of 4-(2-benzyloxy-6- benzyloxycarbonylbenzoyl)-3,5-dibenzyloxybenzoic acid (353 mg, 0.52 mmol) and a drop of DMF in CH 2 Cl 2 (2 ml) at 5°C.
  • the mixture was stirred at room temperature for 2h, then evaporated to remove the solvent and excess oxalyl chloride.
  • (+)-trans-3-(3,4-dihydroxybenzamido)-4-[4-(2-carboxy-6- hydroxybenzoyl)-3,5-dihydroxy]benzoyloxypyrrolidine trifluoroacetic acid salt (COMPOUND 675)
  • the acid chloride was then taken up in dichloromethane (20 ml) and canulated into a 0oC mixture of t-butyl anti-3-(4-benzyloxybenzamido)-4-hydroxy-N- pyrrolidinecarboxylate (2.08 g, 5.04 mol), triethyamine (2.1 ml, 15.1 mol), and dimethylaminopyridine (61 mg, 0.504 mol) in dichloromethane (30 ml). After 15 hours, the reaction mixture was diluted with dichloromethane (200 ml) and washed with water (100 ml).
  • Anti-Hexahydro-4-hydroxy-3-(4- phenylmethoxybenzoyl-N-methylamino)-1-phenylmethylazepine (0.18 g, 0.40 mmol) was dissolved in methylene chloride (1.5 mL) under nitrogen, then treated with 4-dimethylaminopyridine (30 mg), triethylamine (0.20 mL), and a solution of the above formed acid chloride in methylene chloride (1.5 mL) .
  • the bottle was carefully evacuated of hydrogen, the solution was filtered through celite, and the filter cake was washed with ethanol without allowing it to dry.
  • the filtrate was concentrated in vacuo and the residue was dissolved in DMF (0.4 mL) and loaded onto an HPLC column; conditions: A-0.1%TFA/5% MeC ⁇ /H 2 O, B-MeCN, 100% A to 50:50 A:B over 60 min, 15 mL/min, 21x250 cm C 18 column.
  • the solution was concentrated in vacuo, placed under high vacuum for one hour, then dissolved in methylene chloride (2mL) and combined with hexahydro-4-(methylamino)-3-(4-phenylmethoxy)benzoylamino-1- phenylmethylazepine (0.18 g, 0.40 mmol).
  • the mixture was treated with 1.0N sodium hydroxide (1.0 mL) and stirred for two hours, then diluted with methylene chloride (10mL) and water (4mL). The organic layer was separated and the aqueous solution was extracted with methylene chloride (10mL). The combined organic solution was dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the bottle was carefully evacuated of hydrogen, the solution was filtered through celite, and the filter cake was washed with ethanol without allowing it to dry.
  • the filtrate was concentrated in vacuo and the residue was dissolved in DMF (0.4 mL) and loaded onto an HPLC column; conditions: A-0.1%TFA/5% MeCN/H2O, B-MeCN, 100% A to 50:50 A:BB over 60 min, 15 mL/min, 21X250 cm C 18 column.
  • Carbonyldiimidizole (0.110 g, 0.672 mmole) was added to a solution of 4-[((2-(benzyloxycarbonyl)-3-pyridinyl) carbonyl]-3,5-dibenzyloxybenzoic acid (0.275 g, 0.448 mmole) in 3 mL of methylene chloride containing a trace (approximately 1 ⁇ L) of dimethyl formamide The solution was stirred at room temperature for sixty minutes under nitrogen.
  • the solution was added to a solution of 0.193 g (0.448 mmole) of trans-N-benzyl- 3-(4-benzyloxybenzamido)-4-hydroxyazepine, 0.1mL (0.672 mmole) of triethylamine, 5 mg of DMAP in 3 mL of methylene chloride.
  • the solution was stirred at room temperature under nitrogen for sixteen hours.
  • the solution was diluted with 30 mL of methylene chloride, washed with water, saturated brine and dried over magnesium sulfate. The solvent was removed in vacuo.
  • FIGURE AZ
  • the carbinol (690 mg, 1.09 mmol) was dissolved in acetone and treated with Jones reagent (ca. 2mL) at 5°C until the color of the reaction remained essentially the same color as the Jones reagent. The reaction was then stirred at room temperature for 1 hr. Acetone was removed in vacuo and residue was taken into EtOAc, washed with 3N NaOH and brine, dried over Na 2 SO 4 , and concentrated. The pure product, white oily solid, was obtained from flash chromatography eluting with 85:15/Hexane:EtOAc (420mg, 61%).
  • the Compound 613 (60 mg, 0.061 mmol) was dissolved in THF (7mL) and treated with a drop of TFA and Pd(OH) 2 /C (20mg, 30% by weight). The mixture was subjected to hydrogenolysis with a H 2 balloon overnight. THF was removed in vacuo and the residue taken into MeOH. The MeOH solution was concentrated after filtering through a pad of celite and chromatographed on 21 x 300 mm C18 column (solvent A: 95:5 water/acetonitrile 0.1% TFA; solvent B:100% acetonitrile; gradient: 0-100% B over 60 min, flow: 15 mL/min).
  • the dichloromethane layer was dried over magnesium sulfate, filtered, and the volatiles were removed under reduced pressure to give a crude white solid.
  • the solid was purified using flash column chromatography (silica gel, 9:1 hexane: ethyl acetate - 2:1 hexane : ethyl acetate) to provide Compound 607 as a white solid (175 mg, 51%).
  • the reaction mixture was allowed to stir while warming to room temperature over 2 h.
  • the reaction mixture was quenched with solid ammonium chloride and the volatiles were removed under reduced pressure.
  • the crude residue was diluted with ethyl acetate (400 mL) and washed with 0.5N HCl (100 mL).
  • the ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, and the volatiles were removed under reduced pressure.
  • the crude residue was purified using flash column chromatography (silica gel, 5% ethyl acetate / hexane - 10 % ethyl acetate / hexane) which provided a white solid of the title compound (96 mg, 34%).
  • the mixture was stirred at -65 ⁇ 5oC for 30 min, then treated dropwise with a solution of syn-hexahydro-4-hydroxy-3- (4-phenylmethoxy)benzoylamino-1-phenylmethylazepine (0.645 g, 1.5 mmol) in anhydrous methylene chloride (1.5 mL) at a rate to keep the pot temperature below -55oC.
  • the mixture was stirred at -55 ⁇ 5oC for 2 h, then treated dropwise with triethylamine (1.5 mL), warmed to room temperature over one hour, and diluted with methylene chloride (10 mL).
  • the flask was fitted with a balloon and a balloon valve, purged with hydrogen, and placed under positive hydrogen pressure for 22 h, then evacuated of hydrogen and purged for several minutes with nitrogen.
  • the solution was carefully filtered through celite (wash filter pad with ethanol) and the filtrate was concentrated in vacuo to a yellow foam. This was dissolved in a small amount of dimethyl formamide and loaded onto a C 18 HPLC column. Gradient elution (5% MeC ⁇ /H 2 O/0.1% TFA to 50%

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  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Neurology (AREA)
  • Molecular Biology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Nouvelle classe de composés thérapeutiques nommés balanoïdes. Lesdits composés possèdent une activité inhibitrice de la protéine kinase C et une sélectivité parmi les isoformes de la protéine kinase C. Les balanoïdes sont utiles pour traiter les maladies liées à la protéine kinase C chez les animaux, en particulier chez leshumains, et ils sont particulièrement indiqués pour traiter les maladies inflammatoires.
EP94909847A 1993-03-03 1994-03-02 Balanoides Withdrawn EP0687249A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US2584693A 1993-03-03 1993-03-03
US25846 1993-03-03
PCT/US1994/002283 WO1994020062A2 (fr) 1993-03-03 1994-03-02 Balanoides utilisables comme inhibiteurs de la proteine kinase c

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EP0687249A1 true EP0687249A1 (fr) 1995-12-20

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EP94909847A Withdrawn EP0687249A1 (fr) 1993-03-03 1994-03-02 Balanoides

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EP (1) EP0687249A1 (fr)
JP (1) JPH09503994A (fr)
AU (1) AU6252794A (fr)
CA (1) CA2157412A1 (fr)
IL (1) IL108849A0 (fr)
WO (1) WO1994020062A2 (fr)
ZA (1) ZA941478B (fr)

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US5583221A (en) * 1994-05-04 1996-12-10 Eli Lilly And Company Substituted fused and bridged bicyclic compounds as therapeutic agents
TW339325B (en) * 1995-07-05 1998-09-01 Hoffmann La Roche Novel azepane derivatives, process for the preparation thereof and pharmaceutical composition containing the same
US5902882A (en) * 1996-04-17 1999-05-11 Hoffmann-La Roche Inc. Assymetric synthesis of azepines
EP0802190A1 (fr) * 1996-04-17 1997-10-22 F. Hoffmann-La Roche Ag Procédé et intermédiaires pour la préparation d'azépines
US6914140B1 (en) 1996-04-17 2005-07-05 Hoffmann-La Roche Inc. Asymmetric synthesis process
MXPA01002173A (es) 1998-08-28 2003-07-14 Scios Inc Inhibidores de p38-alfa cinasa.
DZ3083A1 (fr) * 1999-02-19 2004-06-02 Smithkline Beecham Corp Composés nouveaux inhibiteurs de protéases, procédé pour leur préparation et compositions pharmaceutiques les conentant.
AU3507700A (en) 1999-06-01 2000-12-18 University Of Texas Southwestern Medical Center, The Method of treating hair loss using diphenylether derivatives
MXPA01012494A (es) 1999-06-01 2002-07-02 Univ Texas Southwestern Med Ct Metodo para tratar perdida capilar con el uso de compuestos sulfonil tiromimeticos.
US6680344B1 (en) 1999-06-01 2004-01-20 The University Of Texas Southwestern Medical Center Method of treating hair loss using diphenylmethane derivatives
US6541477B2 (en) 1999-08-27 2003-04-01 Scios, Inc. Inhibitors of p38-a kinase
WO2001028987A1 (fr) 1999-10-15 2001-04-26 Du Pont Pharmaceuticals Company Amines benzyle cycloalkyle comme modulateurs de l'activite du recepteur de la chimiokine
TWI290136B (en) 2000-04-05 2007-11-21 Daiichi Seiyaku Co Ethylenediamine derivatives
EP1343751A2 (fr) 2000-12-20 2003-09-17 Bristol-Myers Squibb Company Derives cycliques en tant que modulateurs de l'activite des recepteurs de chimiokines
CZ20032258A3 (cs) 2001-02-23 2004-01-14 Merck & Co., Inc. N-substituované nearylové heterocyklické sloučeniny
WO2002080928A1 (fr) 2001-04-03 2002-10-17 Merck & Co., Inc. Antagonistes de nmda/nr2b nonaryl-heterocyclo amidyle n-substitues
EP1405852B9 (fr) * 2001-06-20 2013-03-27 Daiichi Sankyo Company, Limited Derives de diamine
US7365205B2 (en) 2001-06-20 2008-04-29 Daiichi Sankyo Company, Limited Diamine derivatives
CN100545160C (zh) * 2001-08-09 2009-09-30 第一制药株式会社 二胺衍生物
MXPA04001977A (es) 2001-09-13 2004-06-07 Hoffmann La Roche Antagonistas v de receptor ccr-3.
WO2003075853A2 (fr) 2002-03-08 2003-09-18 Bristol-Myers Squibb Company Derives cycliques servant de modulateurs de l'activite du recepteur de la chimiokine
US6887864B2 (en) * 2002-03-12 2005-05-03 Hoffmann-La Roche Inc. Azepane derivatives
WO2015188130A1 (fr) * 2014-06-05 2015-12-10 The University Of Kansas Analogues du marmelin et méthodes d'utilisation dans le traitement du cancer
CN111801322B (zh) 2017-10-31 2024-03-15 迈阿密大学 用于治疗中枢和周边神经系统病症的激酶抑制剂

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EP0664706A1 (fr) * 1991-08-22 1995-08-02 Sphinx Pharmaceuticals Corporation Inhibition de proteine-kinase c et nouveau compose appele balanol

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Also Published As

Publication number Publication date
JPH09503994A (ja) 1997-04-22
IL108849A0 (en) 1994-06-24
WO1994020062A3 (fr) 1996-08-15
ZA941478B (en) 1995-09-05
CA2157412A1 (fr) 1994-09-15
AU6252794A (en) 1994-09-26
WO1994020062A2 (fr) 1994-09-15

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