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WO1996040614A1 - Modulateurs .x. de proteine kinase c - Google Patents

Modulateurs .x. de proteine kinase c Download PDF

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Publication number
WO1996040614A1
WO1996040614A1 PCT/US1996/009710 US9609710W WO9640614A1 WO 1996040614 A1 WO1996040614 A1 WO 1996040614A1 US 9609710 W US9609710 W US 9609710W WO 9640614 A1 WO9640614 A1 WO 9640614A1
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Prior art keywords
compounds
hydroxymethyl
phorbol
protein kinase
carbon
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PCT/US1996/009710
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English (en)
Inventor
Paul E. Driedger
James Quick
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Procyon Pharmaceuticals, Inc.
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Priority claimed from US08/472,871 external-priority patent/US5891870A/en
Priority claimed from US08/480,251 external-priority patent/US6080784A/en
Priority claimed from US08/480,191 external-priority patent/US5955501A/en
Application filed by Procyon Pharmaceuticals, Inc. filed Critical Procyon Pharmaceuticals, Inc.
Publication of WO1996040614A1 publication Critical patent/WO1996040614A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C271/34—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C271/38—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D245/06—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • Protein kinase C (also known as "calcium/phospholipid-dependent protein kinase", "PKC” or “C-kinase”) is a family of closely related enzymes; one or more members of the protein kinase C family are found in nearly all animal tissues and animal cells that have been examined. The identity of protein kinase C is generally established by its ability to phosphorylate certain proteins when adenosine triphosphate and phospholipid cofactors are present, with greatly reduced activity when these cofactors are absent. Protein kinase C is believed to phosphorylate only serine and/or threonine residues in the proteins that are substrates for protein kinase C. Additionally, some forms of protein kinase C require the presence of calcium ions for maximal activity.
  • Protein kinase C comprises a family of eleven or more closely related protein molecules [Parker, P.J. et al., Mol. Cell. Endocrin. 65: 1-11 (1989)]. Because of their high degree of relatedness they are referred to as “isozymes”, “isotypes” or “isoforms”.
  • genes for each of the isotypes above have been cloned from one or more animal and yeast species and the clones have been sequenced; the relatedness of the genes and their product polypeptides is thus well established. Beyond the ability of phospholipid and, for some isotypes, calcium to stimulate protein kinase C activity, members of the A-, B- and D-groups of the protein kinase C family are also substantially stimulated by certain 1,2-sn-diacylglycerols that bind specifically and stoichiometrically to a recognition site or sites on the enzyme.
  • This site is called the diacylglycerol binding site, and it is located on the amino-terminal portion of protein kinase C, the so-called “regulatory domain".
  • the carboxy-terminal portion of protein kinase C carries the site at which protein phosphorylation is effected, and this portion is therefore called the "kinase domain” or the "catalytic domain”.
  • the rate at which various protein kinase C family members carry out their enzymatic phosphorylation of certain substrates can be markedly enhanced by the presence of the cofactors such as phospholipids, diacylglycerols (except for the C-group) and, for some protein kinase C family members, calcium ions.
  • This stimulation of protein kinase C activity is referred to as protein kinase C "activation", and the activation of protein kinase C by the binding of diacylglycerols to the regulatory domain of protein kinase C is of particular importance in the normal and pathological functions of protein kinase C.
  • protein kinase C inhibitors are capable of inhibiting various cellular or tissue phenomena which are thought to be mediated by protein kinase C.
  • neurotransmitters and other biological control factors such as histamine, vasopressin, ⁇ - adrenergic agonists, dopamine agonists, muscarinic cholinergic agonists, platelet activating factor, cytokines, growth factors and many others [see Nishizuka, Y., Nature 308: 693-698 (1984) and Science 225: 1365-1370 (1984) for reviews].
  • diterpenes such as the phorbol esters
  • indole alkaloids indolactams
  • polyacetates such as the aplysiatoxins and oscillatoxins
  • certain derivatives of diaminobenzyl alcohol macrocyclic lactones of the bryostatin class
  • benzolactams such as (-)-BL-V8-310; these seven classes of compounds are collectively referred to herein as "phorboids”.
  • benzolactams shall be herein defined as a class of chemical compounds having at least two fused rings (the "primary rings") wherein the two vertices of fusion comprise adjacent carbon atoms.
  • One ring of this fused bicyclic structure contains six atoms, including the atoms common to the two primary rings, is aromatic in character and contains either six carbon atoms or, optionally, may have one or two nitrogen atoms in any position except the vertices at which the two primary rings are fused.
  • the other primary ring may be comprised of eight or nine atoms, including the atoms common to the two primary rings, is not aromatic, and, in the case of the parent
  • benzolactams from which the benzolactam portion of the present invention is derived carries a hydroxymethyl or 1-hydroxyethyl group.
  • the definition of benzolactam as used herein is also conditioned by functional constraints (see below under "Detailed Description of the Invention").
  • the phorbol esters have long been known as powerful tumor promoters, the teleocidins, aplysiatoxins, diacylglycerols and, though weak, the bryostatins are now known to have this activity, and it appears likely that additional classes of compounds will be found to have the toxic and tumor promoting activities associated with the capability to bind to the diacylglycerol site of protein kinase C and thus activate the enzyme.
  • Other toxicities of these agents when administered to animals include lung injury and profound changes in blood elements, such as leukopenia and neutropenia, among many others.
  • the phorboids depicted have diverse, dissimilar structural elements of both hydrophilic and hydrophobic nature, with one prominent exception, namely that each class of phorboid contains a hydroxymethyl or 1-hydroxyethyl group (indicated by the dashed-line boxes in each structure).
  • the phorboids depicted are among the most potent of their respective structural class, and among the seven classes the diterpenes, indolactams, polyacetates, bryostatins and benzolactams have members of especially high potency, in the range of low nanomolar affinities for protein kinase C.
  • phorboids are potent skin inflammatory agents, cause smooth muscle contraction in several tissues, alter immune system function and can be used to cause or mimic a wide variety of other normal or pathological biological responses.
  • the efficacy of the compound defined as the capability to elicit a full or partial biological result, such as complete displacement of a Iigand from its receptor site or the complete inhibition of inflammation or edema caused by a standard stimulus
  • the potency defined as that amount or concentration of drug that causes 50% of the full response (often abbreviated as the ED 50 ).
  • ED 50 the potency
  • the potency), and the modified compounds otherwise generally retain the same central biological characteristic (i.e. efficacy as a pharmaceutical or in a given biological assay or test).
  • central biological characteristic i.e. efficacy as a pharmaceutical or in a given biological assay or test.
  • members of such a class may also be differences between members of such a class as regards properties other than the central biological characteristic; for example, members of the class might differ in side effects or susceptibility to metabolism by an organism.
  • Aspirin for example, is often taken in multi-gram amounts per day for treatment of inflammation or arthritis, and detailed analyses of its mechanism of action in vitro show that a concentration in the millimolar range is required for certain therapeutic effects of aspirin.
  • steroid-based topical anti- inflammatory compounds such as fluocinolone acetonide are many thousand-fold more potent, and, beyond this, some oral contraceptive agents are prescribed in daily doses in the microgram range.
  • high potency is generally advantageous for a
  • the structures of the different classes of phorboids vary quite markedly from one to the other class, yet widespread testing of their biological activities has shown that these classes have essentially at least one common general target site, namely the diacylglycerol binding site on protein kinase C, and generally have very similar biological properties.
  • the numerous known phorboids of the diterpene, indolactam, diacylglycerol, polyacetate, bryostatin and benzolactam classes appear to have, with very minor exceptions, virtually identical efficacies as skin irritants and tumor promoters [Sugimura, T., Gann 73: 499-507 (1982)].
  • Typical exceptions involve: (i) a few compounds that have a short duration of irritant activity and/or manifest diminished tumor promoting activity [Hergenhahn, M. et al., Experentia 30: 1438-1440 (1974)], perhaps due to slightly different protein kinase C isotype selectivity, toxicity or secondary parameters such as differing metabolic destruction rates; (ii) the bryostatins, which, though having weak but detectable inflammatory and tumor-promoting activity, show other, non- correlating pharmacological properties [Sako, T. et al., Cancer Res. 47: 5445-5450 (1987)]; or (iii) certain short-chain diesters of phorbol which are tumor promotion inhibitors at low doses but fully efficacious tumor promoters when tested alone at higher
  • Example compounds can be found in the diterpene, indolactam, polyacetate and benzolactam classes that have nearly equal, very high potencies. At the same time there are compounds in each of these classes which embody significant structural changes that do not diminish efficacy but do result in potency decreases of 10-fold to 100,000-fold or more [see, for example, Driedger, P.E. and Blumberg, P., Cancer Res. 37: 3257-3265 (1977); idem, Cancer Res. 39: 714-719 (1979)]. Thus, all these compounds appear to be capable of achieving generally the same biological results, and merely differ in the amount which must be used to obtain a given result.
  • diacylglycerol binding site which is also referred to herein as the "phorboid binding site" on protein kinase C or on other biological molecules which have phorboid binding sites (see below).
  • phorboid binding site on protein kinase C or on other biological molecules which have phorboid binding sites (see below).
  • bryostatin 1 or bryostatin 2 the presence of the unmodified 1-hydroxyethyl group in typical bryostatins such as bryostatin 1 or bryostatin 2 is associated with substantially less skin-inflammatory and tumor-promoting activity than for the other classes of parent phorboids such as diterpenes, etc.
  • the inflammatory and tumor-promoting activity of bryostatin 1 and 2 are nonetheless still detectable, indicating an incomplete separation between these toxicities and other properties of the bryostatins.
  • the phorbol esters, indolactams, polyacetates, diaminobenzyl alcohols, bryostatins and benzolactams are generally found in plants, molds, and algae, or are synthetic in origin. Although they are found in many parts of the world, normal human contact with these classes of phorboids is thought to be low and of negligible medical significance.
  • the diacylglycerols are part of the functioning of virtually every type of animal cell, and the undesirable activation (and, alternatively as discussed below, the cessation of desirable activation) of protein kinase C by the diacylglycerols is thought to have a very widespread role in human diseases.
  • diacylglycerol binding site on protein kinase C would be valuable agents in the prevention and treatment of a wide variety of diseases in animals and humans.
  • protein kinase C inhibitors/antagonists as agents for the treatment of cancer has received much attention [Corda, D. et al., Trends in
  • the stimulation of one protein kinase C isotype or a limited subset of protein kinase C isotypes might lead to undesirable results such as the development of inflammation [Ohuchi, K. et al., Biochim. Biophys. Acta 925: 156-163 (1987)], the promotion of tumor formation [Slaga, T., Envir. Health Perspec. 50: 3-14 (1983)] or an increased rate of viral replication in cells (i.e., de novo infection of cells and/or expression, assembly and release of new viral particles) [Harada, S. et al., Virology 154: 249-258 (1986)].
  • protein kinase C isozymes might be responsible for the many beneficial effects observed when protein kinase C is stimulated by known protein kinase C activators in a variety of biological settings; such beneficial effects include the cessation of division of leukemic cells [Rovera, G., O'Brien, T. and Diamond, L., Science 204: 868-870 (1979)], multiplication of colonies of lymphocytes [Rosenstreich, D. and Mizel, S., J. Immunol. 123: 1749-1754 (1979)] and leucocytes [Skinnider, L. and McAskill, J., Exp.
  • diacylglycerol binding site-directed compounds may have utility on non-protein kinase C biological targets.
  • diacylglycerol binding site-bearing proteins are involved.
  • these compounds have potent skin inflammatory activity and are not desirable in human or animal medicine because of this toxicity.
  • the first type would be capable of selectively activating one or a few useful, but not other, deleterious, diacylglycerol binding site-bearing targets.
  • the second type would be capable of inhibiting, or antagonizing the stimulation of, one or more diacylglycerol binding site-bearing targets without blocking activity and/or activation of phorboid-activated target entities whose activation is physiologically harmless or desirable.
  • the physiology of protein kinase C includes, in certain cases, a phenomenon known as "down-regulation", manifested as the ability of protein kinase C activators of the phorboid class to initially stimulate protein kinase C at or shortly after the time of application of the phorboid, followed by a net, phorboid-induced metabolic lowering of total protein kinase C levels.
  • down-regulation manifested as the ability of protein kinase C activators of the phorboid class to initially stimulate protein kinase C at or shortly after the time of application of the phorboid, followed by a net, phorboid-induced metabolic lowering of total protein kinase C levels.
  • Patent 5,145,842 September 8, 1992 and related patents and patent applications including PCT WO 87/07599 (published December 17, 1987) and PCT WO 92/02484 (published February 20, 1992)], and diterpenes having polar substituents at position 13 as exemplified by phorbol 12-esters [Driedger, P.E., European Patent 0310622 (April 15, 1992) and related patents and applications], efforts to make medical use of the previously known phorboids themselves or to modify the structures of these known phorboids in medically useful ways, have generally not been successful in producing useful compounds with toxicity low enough for use in humans.
  • inflammatory and tumor-promoting compounds such as phorbol 12-tigliate 13-decanoate, mezerein, lyngbyatoxin and aplysiatoxin have anti-leukemic activity in mouse model tests [Sugimura, T., op cit.; Kupchan, S.M. and Baxter, R.L., Science 187: 652-653 (1975); Kupchan, S.M. et al., Science 191: 571-572 (1976); Territo, M.C. and Koeffler, HP., Br. J. Haematol 47, 479-483 (1981)].
  • the toxic and inflammatory diterpenes of the phorbol ester type have been reported to cause human cells to decrease their production of the 40-43 amino acid peptide family known as A ⁇ , amyloid peptide or BAP, which is thought to be a primary pathological cause of Alzheimer's disease [Buxbaum, J.D. et al., Proc. Acad. Sci. USA 87: 6003-6006 (1990); Demaerschalk, I. et al., Biochim. Biophys. Acta 1181: 214-218 (1993); Buxbaum, J.D. et al., Proc. Acad. Sci. USA 90: 9195-9198 (1993); Slack, B.E. et al., J. Biol. Chem. 268: 21097-21101 (1993); Hung, AY. et al., J. Biol. Chem. 268:
  • benzolactam phorboids improved compounds of the phorboid class having altered hydroxymethyl/l-hydroxyethyl groups.
  • the primary focus of the diterpenoid portion of this invention comprises novel compounds of the diterpenoid class of phorboids, designated herein as "13-polar diterpenoids".
  • Such 13-polar diterpenoids have the following defining characteristics (in addition to the basic definition of diterpene phorboids): (i) the usual hydroxymethyl or 1- hydroxyethyl group attached to carbon 6 [using common phorbol numbering] is intact, (ii) at least one substituent other than hydrogen or hydroxy is present at carbon 12, and (iii) at least one generally polar group, as exemplified without limitation by hydroxy, amino, thiol, hydroxymethyl, mercaptomethyl, aminomethyl, 2-hydroxyethyl, carboxy, unsubstituted carboxamido, unsubstituted aminocarbonyloxy or unsubstituted aminothiocarbonyloxy in the ⁇ or ⁇ configuration on carbon 13 or an oxo or thiono group is present at carbon 13.
  • the previously disclosed 13-polar diterpenoid compounds embodied at least one ester group and an intact cyclopropyl ring, making the compounds susceptible to degradation under esterolytic/basic and mildly acidic conditions, respectively.
  • the present invention provides, variously, compounds lacking one or another or both of the sensitive ester and cyclopropyl groups, with consequent improved stability in the presence of esterolytic conditions such as biological fluids, acidic conditions such as gastric fluids and chemical synthesis procedures, and/or basic conditions such as are routinely encountered in chemical synthesis.
  • Compounds of the present invention show novel profiles of differential affinity for the known classes of protein kinase C isotypes and other classes of proteins bearing diacylglycerol-type binding sites.
  • the present invention also provides new medical uses for phorbol 12-esters and other 13-polar diterpenoids, such as anti-cancer, anti-leukemia, anti-HIV and anti- Alzheimer's activity.
  • Patent 5,145,842 and related patents and patent applications including PCT WO 87/07599 and PCT WO 92/02484] showed that specific modifications of the latter chemical groupings yields non-skin inflammatory compounds that show anti-inflammatory activity in several test systems, whereas, except as noted above, any of a very wide variety of changes in other parts of the then-known parent phorboid structures, including but not limited to diterpenes, indole alkaloids, polyacetates, diaminobenzyl alcohol derivatives, aplysiatoxins and bryostatinoids, have very markedly less effect on the overall biological properties of the derivatives, other than changes in potency.
  • the benzolactam portion of this invention is based on the finding that the hydroxymethyl and 1-hydroxyethyl groups, which previously were thought to be required for biological activity of phorboids containing these groups, not only can be replaced by other substituents of very diverse nature, even though these new substituents are very substantially larger and of more diverse structure and heteroatom composition than the original hydroxymethyl/ 1-hydroxyethyl group, but also that the resulting compounds have improved chemical and biological properties over the previously discovered six classes of hydroxymethyl/1-hydroxyethyl-modified phorboids [Driedger, P.E. and Quick, J., U.S. Patent 5,145,842 and related patents and patent applications including PCT WO 87/07599 and PCT WO 92/02484].
  • Compounds of the benzolactam portion of the present invention show several unexpected advantages over previously disclosed hydroxymethyl/1-hydroxyethyl-modified phorboids.
  • compounds of the present invention show novel profiles of differential affinity for the known classes of protein kinase C isotypes and other classes of proteins bearing diacylglycerol-type binding sites.
  • Compounds of the present invention have improved potencies over hydroxymethyl/l-hydroxyethyl derivatives of other phorboid parent classes such as diacylglycerols and diaminobenzyl alcohols.
  • the hydroxymethyl/1- hydroxyethyl-modified benzolactam compounds of the present invention also provide novel properties in terms of biodistribution.
  • This invention provides compounds with a range of protein kinase C-modulatory properties.
  • this invention provides, among others, compounds generally able to stimulate many members of the protein kinase C family but which lack the inflammatory toxicity of previously known protein kinase C activators. Because protein kinase C activators can, with prolonged exposure, result in the down-regulation of certain protein kinase C isotypes in certain cells, tissues and organs, this invention also provides a means for blocking certain protein kinase C activities. This invention also provides new
  • This invention pertains to novel phorboid derivatives which variously block the toxic effects of the hydroxymethyl-containing phorboids, lack the toxic properties of previously available phorboids and show activity for applications as therapeutics.
  • the phorboid derivatives of the present invention embody very diverse structures and have utility as anti- inflammatory agents, as cancer cell and leukemic cell inhibitory agents, anti-asthmatic and anti-hypertensive agents, as modulators of human immune cell function, as anti-viral agents, as stimulators of the production of lymphokines such as interferon and the interleukins and as central nervous system pharmaceuticals for several pathological conditions.
  • the phorboid derivatives of the diterpenoid portion of the invention are generally represented by the formula:
  • I 0 represents a radical, formally derived from a phorbol- or daphnane-type diterpenoid parent compound, which compound:
  • a binds reversibly or irreversibly to a diacylglycerol-type receptor; and/or b. activates any form of the enzyme protein kinase C;
  • c. contains an hydroxymethyl or 1-hydroxyethyl group bonded to carbon 6; and d. contains at least one substituent other than hydrogen or hydroxy at carbon 12; and
  • D is a polar group attached to carbon 13.
  • the group, D may be further exemplified, without limitation, by hydroxy, amino, thioL hydroxymethyl, mercaptomethyl, aminomethyl, 2-hydroxyethyl, carboxy, unsubstituted carboxamido, unsubstituted aminocarbonyloxy, unsubstituted aminothiocarbonyloxy, ketonic or thionic groups.
  • Requirements for a polar group at position 13 may also be met by an amino group carrying 1-2 substituents or by guanidino or other such polar nitrogen containing groups.
  • the invention does not include 12-O-methylphorbol, 12-O-ethylphorbol or compounds of the exact phorbol structure with acyl groups at the 12-hydroxy group, also known as "phorbol 12-esters.”
  • diterpene portion of the invention provides compounds of the general formula (I):
  • a 1 and A 2 may be individually selected from hydrogen and a straight chain or branched chain, cyclic or acyclic, saturated, unsaturated and/or aromatic carbon- and/or heteroatom-containing substituent having not more than 34 carbon atoms, not more than 24 halogen atoms and not more than 6 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus, boron and sulfur or wherein A 1 and A 2 taken together complete a 5- or 6-membered carbocyclic or heterocyclic ring, optionally substituted by, respectively, up to six or up to eight straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or aromatic carbon- and/or heteroatom-containing groups, which groups may optionally form one or two additional rings by connection among themselves and/or to J 1 or A 4 and which taken together contain a total of not more than 30 carbon
  • J 1 , J 2 and S are as defined above; and wherein carbons (1 and 2) or (2 and 3) may optionally be joined by a double bond; carbons (5 and 6) or (6 and 7) may optionally be joined by a double bond; S may be bonded to carbon 5, 6 or 7;
  • R A1 represents not more than 6 identical or different substituents bonded independently via single and/or double bonds to carbons 1, 2 and/or 3, which substituents may optionally form one or two additional rings by connection among themselves and/or to J 1 or the substituents on the 6- membered ring and which may independently be halogen(s) and/or other groups, which halogens and groups taken together contain a total of not more than 30 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur;
  • R A3 represents not more than 6 identical or different substituents bonded independently via single and/or double bonds to carbons 5, 6 and/or 7, which substituents may
  • Illustrative examples of compounds of the I R type include, without limitation, derivatives of crotophorbolone, bisdehydrophorbol and 4,9,20-trihydroxy-15,16,17- trinortigliadien-(1,6)-dione-(3,13),
  • substituents may be bound to the A-ring or C-ring via heteroatom-free carbon linkages or, depending on the organism and tissue involved, the metabolism-resistant heteroatom linkages such as ether, dialkyl- or alkylarylphosphinate and derivatives, carbonate, carbamate, amides of certain types, sterically hindered ester, sulfur-for-oxygen analogs of the foregoing heteroatom linkages, and linkages comprising silyl-carbon bonds, silyl ethers, diradylsulfoxides, diradylsulfones, or amines at the secondary level of alkyl substitution or greater.
  • the metabolism-resistant heteroatom linkages such as ether, dialkyl- or alkylarylphosphinate and derivatives, carbonate, carbamate, amides of certain types, sterically hindered ester, sulfur-for-oxygen analogs of the foregoing heteroatom linkages, and linkages comprising silyl-carbon bonds, silyl ethers, dira
  • A-ring or C-ring substituents with metabolically labile linkages to the A- or C-rings would be preferred when compounds short in vivo half- lives are desired.
  • linkages include unhindered esters and phosphodiesters.
  • I R is illustrated by, but not limited to, structures carrying a substituted or unsubstituted cyclopropyl ring, forming I p
  • J 1 , J 2 , J 5 , J 6 , J 7 , J 8 , R A1 , R A3 and S are as defined for I R above, except that in I p J 5 is necessarily in the ⁇ configuration and may not be oxo or thiono; and wherein the R A5 and R A6 radicals may independently be hydrogen, halogen and/or other groups, which halogens and groups taken together contain a total of not more than 30 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur.
  • J 5 , J 6 , J 7 , J 8 , R A1 , R A3 and S are as defined above for I p ; and wherein either J 6 or J 7 is linked to carbon 12 via a carbon atom and the other of J 6 or J 7 is linked to carbon 12 via an oxygen atom.
  • benzolactam phorboid derivatives generally represented by the formula:
  • a binds reversibly or irreversibly to a diacylglycerol-type receptor; and/or b. activates any form of the enzyme protein kinase C;
  • c. contains an hydroxymethyl or 1-hydroxyethyl group bonded to a carbon atom
  • G is any group of 55 or fewer atoms selected from carbon, hydrogen, oxygen, nitrogen, halogen, sulfur, phosphorus, silicon, arsenic, boron and selenium either: i) singly or doubly bonded to the carbon atom of the parent compound in place of the hydroxymethyl or 1-hydroxyethyl group; or ii) singly or doubly bonded to a carbon atom immediately adjacent to the carbon atom to which the hydroxymethyl or 1-hydroxyethyl group is bound in the parent compound; and wherein the hydroxymethyl or 1-hydroxyethyl group of the parent compound is absent or has been replaced by G.
  • phorboid derivatives of the benzolactam portion of this invention are represented by the formula:
  • the formula depicts a radical P 0 , formally derived from a parent hydroxymethyl-containing phorboid compound, bonded to an S 0 -E 0 substituent.
  • P 0 represents a radical, formally derived from a compound which contains an hydroxymethyl (or the equivalent 1-hydroxyethyl) group rather than S 0 E 0 , and which binds reversibly or irreversibly to a diacylglycerol-type receptor and/or activates any form of the enzyme protein kinase C.
  • P 0 may be formally derived from a protein kinase C activator of the benzolactam class. These parent benzolactam phorboids contain an hydroxymethyl or
  • 1-hydroxyethyl group which is replaced by S 0 E 0 in the present invention and is shown in the present invention to be associated with the toxic biological activity of the parent benzolactam phorboids, such as skin inflammatory activity measured on the mouse ear.
  • S 0 -E 0 represents a substituent which is either:
  • S 0 can be a substituted or unsubstituted, saturated, unsaturated and/or aromatic, straight or branched, acyclic, ring-containing and/or ring-carrying chain of atoms which separates P 0 and E 0 by a linear count of not more than 12 atoms and contains and/or carries not more than 9 heteroatoms selected from oxygen, nitrogen, silicon, sulfur, phosphorus, arsenic, boron and selenium, and not more than 16 halogen atoms; provided that the total number of atoms does not exceed 35; and in some cases S 0 may be a single or double bond; and E 0 can be hydrogen, halogen or a saturated or singly or multiply unsaturated group containing up to 15 carbon atoms and optionally containing 1 to 12 halogen atoms and/or 1 to 6 heteroatoms selected from oxygen, nitrogen, silicon, sulfur, phosphorus, arsenic, boron and se
  • S 0 E 0 taken together may also be a hydrogen, halogen, thionic sulfur atom or ketonic oxygen atom or a hydroxy, amino, or thiol group singly or doubly bonded to the carbon atom of the parent compound P 0 in place of the hydroxymethyl or 1-hydroxyethyl group.
  • benzolactam portion of the present invention is represented as follows:
  • P x is a benzolactam-type parent structure as defined below, wherein S x is selected from seven different structural types as defined below and E 1 is as defined below.
  • B 7 -B 10 may optionally be nitrogen; represents 1-4 identical or different substituents located independently at
  • substituents may independently be hydrogen, halogen and/or other groups which, taken together, contain not more than 9 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur, the groups being optionally connected to one another and/or to to form 1-2 additional carbocyclic or heterocyclic rings; is selected from oxygen, sulfur wherein is hydrogen, hydroxy, methyl, ethyl, fluoro, n-propyl, allyl, or propargyl and is hydrogen, methyl, ethyl, halogen, trifluoromethyl or cyano; may be the same or may differ and each may independently be hydrogen, halogen, a substituent group, or may complete an additional ring connecting or connecting either such that taken together contain not more than 18 carbon atoms, not more than 12 halogen atoms, and not more than 8 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur; 7 is selected from oxygen, sulfur, sulfoxide, sulf
  • y may either be 0 or 1; and, Q L is hydrogens or is Q as defined below; provided that if S x E 1 is hydroxymethyl or 1-hydroxyethyl then S x E 1 may not be bound to carbon 5.
  • S x may represent any of a broad range of connecting chains or groups of atoms, designated S B , S 1 , S 2 , S 3 , S 4 , S 5 and S 6 .
  • these organic functional groups may be hydrophobic in nature, with few if any polar or heteroatoms present, may be extensively halogen-substituted, or may contain one or several polar atoms such as oxygen, nitrogen, silicon, phosphorus, arsenic, boron, selenium and/or sulfur in any of numerous chemical groupings.
  • Such functional groupings may even bear positive or negative charges at physiologic pH, and the values which are permissible for S x also may include combinations of hydrophobic, halogenated, hydrophilic and/or charged functional groups.
  • the resultant compounds in any case generally display, variously, the protein kinase C-modulatory, nontoxic agonist, and/or antagonistic properties, selectivities and therapeutic and other utilities described in this invention.
  • S B -S 6 may comprise the following values.
  • S B is a single or double bond.
  • S 1 is a chain of atoms of the formula:
  • a, b, d, e, and g may independently be from 0 to 3; c and f may independently be 0 or 1; the sum of (a + b + c + d + e + f + g) is at least 1 but not more than 12; and if c and f are both 1, then the sum of (d + e) must be at least 1; and X and X' are as defined below.
  • S 2 is a chain of atoms of the formula:
  • h, i, k, m, p, and q may be independently be from 0 to 3; j and n may independently be 0 or 1; if j and n are both 1 and 1 is 0, then the sum of (k + m) must be at least 1; if n is 1 and o is 0, then the sum of (p + q) must be at least 1; the sum of (1 + o) is 1-3; and the sum of (h + i + j + k + 21 + m + n + 2o + p + q) is at least 1 but not more than 12; and X, X', Y and Y 1 are as defined below.
  • S 3 is a chain of atoms of the formula:
  • r, s, u, y, a', and b' may independently be from 0 to 3; the sum of (t + z) is 0 or 1; the sum of (v + w + x) is 1; the sum of (y + z + a' + b') is at least 1; and the sum of (r + s + 2t + u + 2v + 3w + 4x + y + 2z + a' + b') is at least 1 but not more than 12; and Y, Y', Z 1 , Z 2 , and Z 3 are as defined below.
  • S 4 is a chain of atoms defined by:
  • c', d', e', h', and i' may independently be from 0 to 3; the sum of (f' + g') must be 1 or 2; f' and g' may independently be 0 or 1; and the sum of (c' + d' + e' + f' + g' + h' + i') is at least 1 but not more than 12; and M, M', and R Q are as defined below.
  • S 5 is a chain of atoms defined by:
  • j', k', m', q', and s' may independently be from 0 to 3; l' and r' may each be 0 or 1, but the sum of (l' + r') must be 1 or 2; n' and p' may each be 0 or 1, but the sum of (n' + p') must be 0 or 1; the value of o' may be 0-2; if the sum of (n' + p') is l and l' is 0, then q' must be at least 1; if the sum of (n' + p') is 1 and r' is 0, then m' must be at least 1; and the sum of (j' + k' + l' + m' + n' + o' + p' + q' + r' + s') is at least 1 but not more than 12; and Q, Q', X, X', and Y are as defined below.
  • S 6 is a chain of atoms defined by: wherein u', v', w', x', y', z', and m" may each be 0 or 1; t' and a" may each independently be 0-6; the sum of (t' + u' + v' + 2w' + x' + 2y' + z' + a") must be 0-8; b", d", e", f", h", j", k" and n" may each independently be 0 or 1; c", g", i", and l” may each independently be 0-3; if d" and j" are both 1, then the sum of (g" + i") must be at least 1; if either j" or k" is 1, then l" must be at least 1; if b" is 1, then the sum of (c" + g" + h" + i” + l") must be at least 1; if d" is
  • S 1 -S 6 through may be the same or different and each may be hydrogen, halogen or an acyclic substituent containing not more than 20 carbon atoms, not more than 16 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, sulfur, silicon, boron, arsenic, phosphorus and selenium; one substituent selected from
  • S 1 -S 6 is subject to the restriction that, for any given S 1 , S 2 , S 3 , S 4 , S 5 or S 6 , but excluding P x and E 1 : the total of carbon atoms is 25 or less; the total of halogen atoms is 16 or less; the total of oxygen atoms is 6 or less; the total of nitrogen atoms is 4 or less; the sulfur, silicon, boron and phosphorus atoms each total 3 or less; the arsenic and selenium atoms each total 1 or less; and the total of oxygen, nitrogen, silicon, boron, arsenic, phosphorus, selenium and sulfur atoms together is 8 or less.
  • the oxygen, nitrogen, sulfur, silicon and/or phosphorus atoms in may be situated in a variety of functional groups such as hydroxy, amino, hydroxylamine, tertiary amine oxide, Schiffs base, hydrazine, thiol, nitro, nitroso, oxime, azide, ether, acetal, ketal, thioether, aldehyde, keto, hydrazone, carboxy, mercaptocarbonyl, mercaptothionocarbonyl, sulfonate, sulfonyl, sulfoxide, phosphate, phosphonate, phosphate ester, phosphonate ester, phosphine, phosphine oxide,
  • thionophosphine phosphite, phosphonium, phosphorothioate, thionophosphate ester, thiophosphonate, thionophosphonate ester, silane, silanol, silanediol, fluorinated silane, ester, amide, cyano, hydrazide, carbonate, carbamate, urea, isourea, carboxamidine, imidate, guanidine, thioester, thioamide, thiocarbonate, dithiocarbonate, thiocarbamate,
  • the total of - OH groups is 3 or less, the total of -NH 2 groups is 2 or less, the total of -SH groups is 2 or less, and the total of -OH, -SH and -NH 2 groups is 4 or less.
  • X, X', X" may be the same or different and are selected from:
  • an acyclic substituent containing 1-20 carbon atoms, not more than 16 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, and sulfur, such that for any substituent the oxygen atoms total 4 or less, the nitrogen atoms total 4 or less, and the sulfur atoms total 2 or less; may independently be hydroxy; Q and Q' are as defined below; may optionally represent an additional bond to P x , thus completing an unsaturated linkage; and, one to four of the substituents may optionally
  • G 1 comprises the same or different values of G 1 , as defined below.
  • Y and Y' may be the same or different and are selected from: wherein each pair being cis or trans relative to one another, may be the same or different and each may be hydrogen or an acyclic substituent containing not more than 20 carbon atoms, not more than 16 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, and sulfur, such that for any substituent the oxygen atoms total 4 of less, the nitrogen atoms total 4 or less, and the sulfur atoms total 2 or less; y ⁇ may also independently be halogen; one or two of the substituents may optionally comprise the same or different values of G 1 , as defined below; and one of the substituents may be linked to either the atom in P x that carries the chain containing X, X', and/or X" or to an atom in P x adjacent thereto, to form a saturated, unsaturated or aromatic, carbocyclic or heterocyclic 4-8 membered ring defined as for the analogous -containing
  • the substituents are selected from hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy,
  • mercaptocarbonyl mercaptothionocarbonyl, sulfonate, sulfonyl, sulfoxide, ester, amide, cyano, carbonate, carbamate, urea, isourea, carboxamidine, guanidine, thioester, thioamide, thiourea, nitroguanidine, cyanoguanidine and xatthate.
  • substituents are generally selected from hydrogen, halogen in cases where a chemically stable structure results, and a radical containing about 1-12 carbon atoms and optionally containing 0-12 halogens and 0-6 heteroatoms selected from oxygen, nitrogen and sulfur.
  • the substituents comprise a range of saturated or unsaturated substituents as described below, wherein the terms alkyl, halogenated alkyl and acyl are taken to include alkenyl, alkynyl, alkenoyl and alkynoyl and their halogenated forms.
  • l individually may be -O-, -S-, or wherein may be hydrogen, C 1-4 alkyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, 2-acetoxyethyl, or 2-acetoxy-n-propyl; and l individually may be hydrogen or a substituent selected from C 1-4 alkyl; C 1-4 alkoxy; C 1- 4 alkylthio; phenoxy or thiophenoxy optionally substituted by methyl, hydroxy,
  • hydroxymethyl, thiol, carboxy, carboxymethyl, amino, methoxy, halogen, and/or nitro; or amino optionally mono- or disubstituted by C 1-4 alkyl or monosubstituted by cyano, nitro or phenyl optionally substituted by halogen, hydroxy, hydroxymethyl, thiol, carboxy, carboxymethyl, amino, and/or nitro may be hydrogen, a
  • C 1-6 acyl independently selected from C 1-6 acyl, C 1-6 halogenated acyl, C 2-6 monohydroxyacyl, and C 2-6 hydroxyalkyl;
  • may also be independently selected from C 1-6 hydroxyalkyl,
  • may also independently be C 2-6 hydroxyalkyl; one of the substituents f may be linked to
  • M and M' independently may be: k wherein may be the same or different and each may be hydrogen or a saturated or singly or multiply unsaturated, straight or branched, acyclic substituent containing 1-20 carbon atoms, not more than 16 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, and sulfur, in which the oxygen atoms total 4 or less, the nitrogen atoms total 4 or less, and the sulfur atoms total 2 or less, the heteroatoms being preferably situated in functional groups selected from hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy, ester, amide, cyano, nitroguanidine, and cyanoguanidine; may optionally comprise an additional bond to P x group, thus completing an
  • unsaturated linkage may optionally comprise the same or different values of G 1 , as defined below; may be linked to either the atom in P x that carries the chain containing M and/or M' or to an atom in P x adjacent thereto, to form a saturated, unsaturated or aromatic, carbocyclic or heterocyclic 4-8 membered ring defined as for the analogous -containing ring above.
  • Q-Q' independently may be: wherein R may be the same or different and each may have the values specified above for Q Q may optionally comprise the same or different values of G 1 , as defined below; may be linked to either the atom in P x that carries the chain containing Q and/or Q' or to an atom in P x adjacent thereto, to form a saturated, unsaturated or aromatic, carbocyclic or heterocyclic 4-8 membered ring defined as for the analogous p ⁇ -containing ring above.
  • R Q -R Q' are independently selected from:
  • R may be the same or different and each may be selected from halogen
  • G 1 may optionally comprise the same or different values of G 1 , as defined below;
  • Q and Q' are as defined above; one of Q and may be linked to either the atom in P x bonded to the chain that carries R Q or to an atom in P x adjacent thereto, to form a saturated, unsaturated or aromatic, carbocyclic or heterocyclic 4-8 membered ring defined as for the analogous -containing ring above.
  • the capping group E 0 that terminates the connecting chain also may be selected from any of a surprisingly broad array of chemical groupings, and these chemical groupings can be composed of a far larger number of atoms than is found in the hydroxymethyl or 1- hydroxyethyl group.
  • These chemical groupings may include, without limitation, hydrophobic entities such as alkyl, hydrogen, and halogenated alkyl, or may include, without limitation, quite hydrophilic organic functional groups, such as hydroxy, thiol, carboxy and carboxy esters, amines, etc.
  • organic functional groups spanning a wide range of properties, from ionized and very hydrophilic to very hydrophobic, can be formed from multi-atom groupings of elements selected from carbon, hydrogen, halogen, oxygen, nitrogen, silicon, phosphorus, arsenic, boron and selenium.
  • S 0 E 0 taken together should not be hydroxymethyl or 1-hydroxyethyl bonded in the usual position in the parent compounds, since such compounds correspond to the skin-inflammatory and often tumor- promoting parent natural products.
  • T 1 is selected from -O -, -S-, and -NH-;
  • T 3 , T 4 and T 4' are independently selected from -OH, -NH 2 , -SH, -N 3 , -NH-NH 2 , and in which may be hydrogen, C 1-3 alkyl or C 1-3 acyl; T 3 may also be hydrogen or halogen;
  • T 5 -T 5" are independently selected from hydrogen and hydroxy;
  • T 5 may also be halogen; is selected from hydrogen, halogen, hydroxy, nitro, nitroso, cyano, azide, -NH 2 , -NH-OH, -SH, -O-NH 2 , -NH-NH 2 ,
  • novel compounds of this invention may embody the structure P 7B .
  • substituents attached independently to carbons 8 and/or 9, which substituents may independently be hydrogen, halogen(s) and/or other groups which taken together, contain not more than 40 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur, the groups being optionally connected to one another to form 1-2 additional carbocyclic or heterocyclic rings.
  • substituents may independently be hydrogen, halogen(s) and/or other groups which taken together, contain not more than 40 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur, the groups being optionally connected to one another to form 1-2 additional carbocyclic or heterocyclic rings.
  • substituents may independently be hydrogen, halogen(s) and/or other groups which taken together, contain not more than 40 carbon atoms, not more than 24 halogen atoms and not more than 9 heteroatoms selected from oxygen, nitrogen, silicon
  • hydroxymethyl or 1-hydroxyethyl groups of the parent phorboids lead to diverse compounds with diverse biological properties, and different embodiments will be preferred for different utilities. If different protein kinase C isotypes and other proteins bearing phorboid-type binding sites have different biological functions, as has been extensively hypothesized and to some extent demonstrated in biological experiments, then the novel compounds of this invention with differing activity on different protein kinase C isotypes will obviously display a wide range of differing utilities.
  • the compounds of this invention are dispensed in unit dosage form comprising 0.001 to 1000 mg per unit dosage in a pharmaceutically acceptable carrier.
  • unit dosages in the range of 0.1 to 100 mg are preferred.
  • the compounds of this invention may also be incorporated in topical formulations in concentrations of about 0.001 to 10 weight percent, with concentrations of 0.01 to 10 weight percent being preferred.
  • the compounds of this invention are dispensed in unit dosage form comprising from about 0.001 to 3000 mg per unit dosage in a pharmaceutically acceptable carrier.
  • unit dosages in the range of 0.1 to 100 mg are preferred.
  • the compounds of this invention may also be incorporated in topical formulations in
  • the actual preferred amounts of active compound in a specific case will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, and the particular sites and organism being treated. Compounds of this invention having higher potencies should be used in generally smaller amounts, and compounds with lower potencies should be used in generally larger amounts. Dosages for a given host, whether a small animal such as a cat or a human patient, can be determined using conventional considerations, e.g., the host's weight or body surface area. In general, the compounds of the present invention are administered in unit doses of about 0.000015 to about 50 mg/kg of body weight, and quantities of about 0.01 to about 15 mg/kg of body weight are preferred.
  • the compounds of this invention variously block inflammation; show cytostatic and/or cytotoxic activity against diverse types of human cancer cells representative of several human cancers such as leukemia, carcinoma and melanoma; inhibit the ability of HIV to infect human cells; and induce production of thrombolytic activity.
  • the tests demonstrating the anti-HIV properties of these compounds [see Example 23] were carried out in widely validated and accepted cellular assays of HIV infectivity in human cells that are indicative of in vivo activity.
  • the anti-HIV properties of the compounds of this invention relate directly to the in vivo activities of standard anti-HIV reverse transcription inhibitors such as azidothymidine, dideoxyinosine, dideoxycytidine and non-nucleoside reverse transcription inhibitors, HIV-protease inhibitors and inhibitors of tat-gene function, which are fully active in the anti-HIV assay by which the compounds of this invention were tested.
  • the compounds of this invention also show selective effects as antagonists for protein kinase C in some cases, as noninflammatory agonists for protein kinase C in other cases, and as selective ligands for protein kinase C and/or for phorboid receptors.
  • compounds of the present invention can be used as agents for the abrogation of pathophysiological conditions and disease states such as inflammation, psoriasis, cancer, ulcer, hypertension, asthma, arthritis, autoimmune, nociperception, secretory disease, parasitic infections, amoebic infections, viral disease including HIV disease, Alzheimer's disease, multiple sclerosis, in prophylaxis against infection by any HIV form, and any other application in which pathological activity or pathological absence of activity of protein kinase C and/or other proteins bearing diacylglycerol-type binding sites is found.
  • the compounds of the present invention may also be used as agents for the induction of cardiac pre-conditioning effects.
  • enhancers proteins kinase C of the host cell.
  • enhancers known as AP-1 and NF- ⁇ B [see, for example: Marich, J.E. et al., "The phylogenetic relationship and complete nucleotide sequence of human papillomavirus Type 35", Virology 186: 770-776 (1992); Smith, R.L. et al., "Activation of second-messenger pathways rectivates latent Herpes Simplex virus in neuronal cultures", Virology 188: 311-318 (1992); Gdovin, S.L.
  • the compounds of this invention can also be used in combination with other therapeutic agents, for example for use in the treatment of viral infections.
  • a compound of this invention can be used in combination with a nucleoside analog such as azidothymidine or dideoxyinosine, a tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)- one derivative, other HIV reverse transcriptase inhibitors, HIV protease inhibitors, or HIV tat-gene function inhibitors for the prophylaxis against or treatment of HIV infections.
  • a method for treating a mammal infected with a virus comprises administering to a mammal in need of such treatment an antivirally effective quantity of a composition comprising an acceptable pharmaceutical carrier and an antivirally active compound or compounds or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of a compound, novel or known, of the formulae I 0 -D, I, I R , I P , I PP , P-G, P 0 -S 0 -E 0 , P 7 -S x -E 1 , P 7B -S x -E 1 or
  • P 7BL -S x -E 1 for the manufacture of a medicament for medical use, e.g., treating
  • Alzheimer's disease inflammatory conditions, viral infections and central nervous system disorders such as Alzheimer's disease.
  • composition containing a compound of the formulae I 0 -D, I, I R , I P , I PP , P-G, P 0 -S 0 -E 0 , P 7 -S x -E 1 , P 7B -S x -E 1 or P 7BL -S x -E 1 as defined and a pharmaceutically acceptable carrier.
  • the compounds of this invention may be used to achieve desired physiological results such as interferon release, interleukin induction, tumor necrosis factor production, immune system stimulation and/or reconstitution, insulin secretion,
  • the compounds of this invention also have very valuable application as experimental agents for research into the role of protein kinase C and/or phorboid receptors in important biological processes and in human and veterinary diseases.
  • their value extends to their use as pharmacological tools for in vitro and in vivo research, in a manner similar to the important roles that selective agonists and antagonists have played in the studies of the mechanism of action of adrenergic, dopaminergic, opiate, benzodiazepine, cholinergic, and serotoninergic receptor systems, among others.
  • the compounds can be used in in vitro diagnostics (e.g., in an assay for protein kinase C). They are also useful as intermediates in the production of other drugs, e.g., as described in the present invention and/or related inventions.
  • the compounds of this invention are generally administered to animals, including but not limited to fish, avians, and mammals including humans.
  • the pharmacologically active compounds of this invention can be processed in accordance with conventional methods of galenic pharmacy to produce medicinal agents for administration to patients, e.g., mammals including humans.
  • the compounds of this invention can be employed in admixture with conventional excipients and carriers, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral (e.g., oral) or topical application which do not deleteriously react with the active compounds.
  • suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcoholics, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds. They can also be combined where desired with other active agents, e.g., enzyme inhibitors, to reduce metabolic degradation.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and
  • injectable, sterile solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
  • Ampoules are convenient unit dosages.
  • Suitable enteral application particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules.
  • a syrup, elixir, or the like can be used wherein a sweetened vehicle is employed.
  • a preferred method of administration comprises oral dosing, with tablets, dragees, liquids, drops, or capsules.
  • oral route of administration either compounds of this invention lacking functional groups destroyed by acid, or tablets or capsules which protect the active compound from upper gastrointestinal acidity, are preferred.
  • Sustained or directed release compositions can be formulated, e.g., in liposomes or in compositions wherein the active compound is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, absorption onto charcoal, entrapment in human serum albumin microspheres, etc. It is also possible to freeze-dry the new compounds and use the lyophilizates obtained, for example, for the preparation of products for injection.
  • Another preferred route of administration comprises topical application, for which are employed nonsprayable forms, viscous to semi-solid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity compatible with topical application, preferably greater than water.
  • Suitable formulations include but are not limited to solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservatives, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure, etc.
  • sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier material, is packaged in a squeeze bottle or in admixture with a pressurized volatile, normally gaseous propellant, e.g., a freon.
  • a pressurized volatile, normally gaseous propellant e.g., a freon.
  • the compounds of this invention may also be delivered to subjects by means of an externally connected or internally implanted pumping device to give a controlled and/or sustained release of the therapeutic mixture, or by means of a patch of natural or synthetic fabric and/or polymer impregnated with the compounds in a suitable carrier and affixed to the skin to achieve transdermal release and absorption of the active compounds.
  • the compounds of this invention may also be modified by covalent attachment of metabolically modifiable groups, to form "prodrugs" which are released by cleavage in vivo of the metabolically removable groups.
  • metabolically modifiable groups For example, amine, hydroxy and/or thiol groups present in many compounds of this invention may be converted to prodrugs by covalent attachment of acyl or aminoacyl organic functional groups.
  • compounds of this invention containing carboxylic, sulfonic, phosphoric, phosphonic or related free acids, including those in which one or more oxygen atoms are replaced by sulfur may be converted to prodrugs by formation of their esters or amides by covalent attachment of alcohols, amines, amino acids and the like.
  • Compounds of this invention may also incorporate N-alkyldihydropyridine functional groups, which become localized to the central nervous system after administration to the subject and subsequent metabolic modification of the N-alkyldihydropyridine group in the central nervous system.
  • starting materials for obtaining compounds of the diterpene portion of this invention from natural sources or from total or partial synthesis may be altered in very diverse ways, consistent with this invention, to obtain compounds with novel and diverse primary biological/medicinal activities resulting from, and controlled by, the polar group attached to carbon 13; such properties include, for example, loss of skin inflammatory activity and appearance or retention of anti-inflammatory, anti-HIV, anti- Alzheimer's disease, anti-leukemic and cytokine-induction activities.
  • diterpene phorboids of this invention are available by total synthesis from common organic chemical starting materials. These syntheses provide a variety of approaches and associated flexibility in arriving at widely diverse functionalities on the parent nucleus [see Paquette, L. et al., J. Am. Chem. Soc. 106: 1446-1454 (1984); Rigby, J. and Moore, T., J. Org. Chem. 55: 2959-2962 (1990); Wender, P. et al., J. Am. Chem. Soc. 111: 8954-8957 (1989); Wender, P. et al., J. Am. Chem. Soc. 111: 8957-8958 (1989); and Wender, P. and McDonald, F., J. Am. Chem. Soc. 112: 4956-4958 (1990)].
  • Compounds of this invention may be obtained by semisynthetic procedures, starting from any of a variety of compounds from naturally occurring sources, using very routine synthetic strategies to protect sensitive hydroxy and keto groups at, for example, the 3, 4, 9 and/or 20 positions of the diterpenes (phorbol numbering) during subsequent steps aimed at modifying the C-ring.
  • oxygen atoms must be blocked before some types of chemical modifications may be accomplished on the other portions of the diterpene parents available easily from natural sources.
  • Many widely used and thoroughly characterized protecting groups for the oxygen atoms present as hydroxy groups are acyl, benzyl, trialkylsilane, benzyloxycarbonyl, 4'-methoxyphenyldiphenylmethyl and
  • trimethylsilylyethoxycarbonyl which are variously stable to or removed under acidic, basic or reducing conditions or with fluoride ion reagents. Carbonyl functions may be protected by conversion to acetals or ketals, or by reduction to the alcohol level followed by protection with standard protecting groups for the hydroxy group.
  • C-ring modifications in suitably protected crotophorbolone and bisdehydrophorbol compounds can include a wide range of very routine manipulations of keto and hydroxy groups, including oxidation, reduction, conversion to a thiono or amino group, alkylation, esterification, etherification, formation of carbamates, carbonates, iminoesters, thioureas, etc.
  • Standard techniques for removal of protecting groups then provide any of a very diverse selection of agents having the particular features taught in this invention, particularly with respect to the substitution patterns on carbons 12 and 13.
  • the use and removal of such groups is obvious and accessible to any worker with modest skill in the art of synthetic organic chemistry without undue experimentation.
  • Protection of reactive functional groups such as hydroxy and ketone moieties in regions other than the 12 and 13 positions in the diterpene series is accomplished using routine procedures in protecting group chemistry.
  • the 20-hydroxyl is protected with silyl, trityl, methoxytrityl groups, etc.
  • the 4-hydroxyl is protected with small silyl or acyl groups, or, in combination with a 3 ⁇ -hydroxy, ketal-type protecting groups such as an acetonide, phenyl boronate, etc.
  • the latter method also protects a 3-keto group, which, after synthetic manipulations in the 12 and 13 positions, can be regenerated by routine oxidation following acetonide hydrolysis, all under mild conditions.
  • the 13-hydroxyl group of standard diterpenes can be protected with silyl, acyl or acetal-type groups. Such protected intermediates as described above are then derivatized at 12- and/or 13- hydroxyls by standard chemical methods, such as reaction with isocyanates, isothiocyanates, chloro- or fluoroformates and the like.
  • a protected phorbol starting material with a free 12-hydroxyl and protected 13-hydroxyl may be oxidized to a 12-ketone, followed by further
  • crotophorbolone/bisdehydrophorbol class are similarly derivatized at hydroxyl in the 12/13 region.
  • Such starting materials are also converted to novel compounds via manipulation of e.g. a ketonic oxygen group at position 13, by such routine synthetic procedures as reduction to hydroxy, conversion to a thione group, reductive amination, alkylation of enols and enolates, etc.
  • the protecting groups at 13 and 20 may be sequentially removed by treatment with sodium carbonate or sodium methoxide followed by treatment with alcoholic trifluoroacetic acid to afford phorbol 12-(N-octadecy ⁇ )carbamate.
  • 12-(N-octadecyl)carbamate may be treated with other reagents such as
  • 13-O-isopropyldimethylsilylphorbol may be reduced by treatment with sodium borohydride in the presence of cerium(III) chloride and the resulting alcohol treated with
  • modified parent structures may be obtained which embody alterations at any of the numerous permitted substituent locations and which have useful biological activity as taught by the present invention.
  • modified diterpenoid structures may result from the use of modified starting materials, from modifications of one or more synthetic steps or from a combination of both, as applied to the examples in the synthetic organic and natural product literature cited above by workers of ordinary skill in synthetic organic chemistry.
  • starting materials for obtaining compounds of the benzolactam portion of this invention from synthesis may be altered in very diverse ways, consistent with this invention, to obtain compounds with novel and diverse primary biological/medicinal activities resulting from, and controlled by, the replacements for the hydroxymethyl/1-hydroxyethyl; such properties include, for example, loss of skin inflammatory activity and appearance or retention of anti-inflammatory, anti-HIV, anti- Alzheimer's disease, anti-leukemic and cytokine-induction activities.
  • Benzolactams having one or two nitrogens incorporated into the benzenoid portion of the basic fused bicyclic system are easily derived via total syntheses using starting benzenoid compounds having one or two nitrogen atoms already present in the aromatic nucleus.
  • Chemical manipulations of this type have been extensively developed in the routine practice of heterocyclic chemistry, for example in the field of nucleoside and nucleoside analog synthesis, and permit a wide variety of nitrogen heterocycles to be synthesized by routes of inherently high predictability. The ready adaptation of such approaches are obvious to synthetic chemical practitioners of ordinary skill in the pharmaceutical industry.
  • the hydroxymethyl group may be conveniently capped under very mild conditions by the treatment with a substituted or unsubstituted alkyl, aryl, or aralkyl isocyanate, optionally containing silicon or phosphorus atoms in a variety of functional groups, in the presence of a catalyst such as dibutyltin dilaurate or activated and displaced with a wide variety of nucleophiles.
  • a catalyst such as dibutyltin dilaurate or activated and displaced with a wide variety of nucleophiles.
  • the resulting compounds lack the toxic inflammatory activity of the phorboid from which they were derived, and have themselves anti-inflammatory utility.
  • nucleophiles may include, without limitation, reagents having carbon, hydrogen, oxygen, nitrogen, sulfur, phosphorus, silicon, arsenic, boron, and/or selenium atoms in their structures. Particular examples would be reaction with ammonia,
  • methylamine the sodium salt of dimethylphosphine, trimethylphosphite, triphenylphosphine, potassium sulfite, trimethylsilylmethyl-metal salts, lithium trimethylsilylacetylide, sodium cyanide, N-methyl-2-hydroxyethyl amine, 1[H]-tetrazole, or with the sodium salt of 2-mercaptoethanol, 3-mercaptoethanol, or of hydroxymethylphenol.
  • Many variations may be executed as described in standard textbooks of synthetic organic chemistry, such as J. March, Advanced Organic Chemistry, Third Edition, Wiley-Interscience, New York, 1985.
  • 11-O-methanesulfonyl-(2S,5S)-BL-V8-310 yields 11-deoxy-(2S,5S)-BL- V8-310 11-sulfonic acid upon treatment with sodium sulfite.
  • treatment of 11-O-methansulfbnyl-(2R,5S)-BL-V8-310 with the sodium salt of 4-t- butyldimethylsilyloxyphenol followed by treatment of the product with tetrabutylammonium fluoride in tetrahydrofuran affords 11-O-(4'-hydroxyphenyl)-(2R,2S)-BL-V8-310.
  • the hydroxy group of the hydroxymethyl of benzolactams may be replaced by a metal and then reacted with an electrophile, effectively replacing the hydroxy with a group derived from the electrophile.
  • the techniques for this replacement are obvious to workers with ordinary skill in organic synthesis, in that replacement of the hydroxymethyl hydroxy group by halogen in a suitably protected or modified benzolactam permits strong and/or hard nucleophiles to be generated by the use of metals or strong bases, and persons with ordinary skill in the art of organic chemistry will recognize that such nucleophiles can be contacted with a very diverse range of electrophilic reagents having carbon, hydrogen, oxygen, nitrogen, sulfur, phosphorus, silicon, arsenic, boron and/or selenium atoms in their structures to obtain hydroxymethyl-modified benzolactams.
  • the 14-O-methanesulfonyl derivative of an appropriate benzolactam may be converted to an iodo compound with sodium iodide in acetone.
  • the resulting iodide may be modified by halogen-metal exchange using appropriately active metals or metal-containing reagents such as magnesium, zinc, alkali metals, metal alkyl reagents and so on, to obtain carbanionic character at the carbon atom previously bearing the hydroxy group, as shown: *
  • Met is the metal ion, and PG 7 may be unnecessary (i.e. may be hydrogen or an anionic charge), may be benzyl (removable by hydrogenolysis) or may be a stable group, such as methyl or ethyl, intended to remain in the final bioactive synthetic product.
  • an electrophile such as, without limitation, an aldehyde, ketone, epoxide or oxetane then provides, after reaction and workup, compounds having one or more methylenes inserted between the original hydroxy group and the methylene to which it was attached.
  • This methodology is particularly advantageous for replacement of the hydroxy with a group containing silicon, phosphorus or other atoms by contacting the anionic metal derivative of the parent nucleus with electrophilic reagents having halogen or pseudohalogen groups, in addition to other functions chosen for biological specificity, bonded directly to the silicon or phosphorus atoms, affording compounds with useful biological activity.
  • the hydroxy group on the hydroxymethyl of benzolactams may be oxidized to an aldehyde and then reacted via condensation or addition chemistries to provide a very wide variety of modified benzolactams. Examples, without limitation, would be reactions with Wittig reagents, hydroxylamines, or Grignard reagents. Many variations may be executed as described in standard textbooks of synthetic organic chemistry, such as J. March, op cit. As an illustration, the aldehyde, 11-deoxy-11-oxo-epi-BL-V9-310, may be prepared by oxidation of the parent hydroxymethyl compound with periodinane among other oxidizing agents. This aldehyde may be treated with methyl
  • aldehydes may also be obtained by reduction of appropriate carboxylic acid derivatives by application of well-known techniques.
  • carboxylic acid derivatives may be prepared by modification of the published synthetic routes, which modifications are well understood by those with skill in the art of organic synthesis.
  • the carboxylic acid derivatives of the benzolactam phorboids may also be prepared by oxidation of the hydroxymethyl group of suitable benzolactam phorboids or of aldehydic derivatives of benzolactams by methods well-known in the art.
  • this carboxylic group may be activated for condensation reactions by any of a number of ordinary and well-known methods, e.g. by conversion to an acyl halide or to an active ester such as the
  • N-succinimidyl ester N-succinimidyl ester.
  • the resultant activated carboxyl may then be easily converted to simple or multifunctional ester, amide, or thioester derivatives by reaction with alcohols, amines, or thiols respectively, alone or in the presence of condensation catalysts.
  • the present invention also discloses broad and diverse alterations which are accommodated in the non-hydroxymethyl regions of the parent P 7 -type phorboids.
  • modifications of the benzolactam parents can be carried out before, after or in alternating fashion with respect to construction of the hydroxymethyl modifications, depending on obvious considerations of chemical stability of the various functional groups in intermediates being subjected to chemical modifications.
  • modified benzolactam parents may be obtained by carrying a modification through the de novo synthesis as described in the literature cited above.
  • modified parents of the benzolactam class may also be further modified at positions other than the hydroxymethyl group either before or after the modifications of hydroxymethyl group to produce embodiments of this invention.
  • the means for accomplishing these modifications are obvious to workers with ordinary skill in organic synthesis.
  • This anhydride was mixed with 1.6 g of 20-O-[diphenyl(4'-methoxyphenyl)- methyl]-13-O-isopropyldimethylsilylphorbol and then 15 mL of pyridine was added. After 18 h of stirring under nitrogen 100 mg of 4-dimethylaminopyridine was added followed 7 h later with 400 mg of dicyclohexylcarbodiimide. After another 22 h at room temperature approximately 10 mL of methanol was added followed by the concentration of the mixture in vacuo.
  • a mixture of 11-O-methanesulfonyl-(2S,5S)-BL-V8-310, sodium sulfite and sodium iodide in a 1:1 mixture of ethanol/water containing a small amount of acetic acid is stirred for a period of time at an elevated temperature. After that time the mixture is concentrated in vacuo and partitioned between ethyl acetate and brine to afford a residue which is purified by liquid chromatography to yield 11-deoxy-(2S,5S)-BL-V8-310 11-sulfonic acid.
  • a stock solution of 300 pmoles of the standard inflammatory compound phorbol 12- myristate 13-acetate (PMA) per 5 ⁇ L acetone was prepared. This solution was used to prepare four-fold dilutions of the agent to be tested, covering concentrations of the latter typically selected from a range of about 4.0 to about 1,200,000 pmoles per 5 ⁇ L. These solutions containing both PMA and the test agent were used to demonstrate the anti- inflammatory activity of the test compound by application of 5 ⁇ L to the insides of the ears of mice (one ear per mouse), followed by the observation of ear inflammation/erythema at intervals from 1 to 48 hours after application.
  • PMA phorbol 12- myristate 13-acetate
  • Human peripheral blood lymphocytes were isolated from the buffy coat fiactions of blood donations. The lymphocytes were then stimulated with 5 micrograms/ml of
  • the lymphocytes Prior to infection with HIV, the lymphocytes were washed and resuspended in mitogen-free medium. On day 0 the cells were infected with HIV and were cultured for four days in the presence or absence of graded concentrations of the test agent. On days 3 and 4 the supernatant levels of total viral RNA and viral core protein p24 were determined at each drug concentration and dose-response curves were used to determine the concentration of drug giving 50% inhibition of production of viral RNA and of p24 core protein.
  • RNA drug concentration is in brackets
  • anti-HIV ED 50 value for RNA [drug concentration is in brackets] for the following compound was determined from dose-response curves or by estimation from one or more experimental drug concentrations:
  • HIV-RNA 17% and 9% inhibition at 3 and 4 days, respectively; both at 10 ⁇ M];
  • Human RPMI-7272 melanoma cells were grown in the standard culture medium under normal incubation conditions. On day 1 the cells were cultured in the absence (control) or presence of graded concentrations of the test agent in separate tubes. On day 4 after 72 h of exposure the number of cells in each tube was measured and the number of cell doublings determined. The drug treated tubes were compared to the control tube to arrive at the ID 50 (the concentration of drug required to inhibit cell doublings by 50%) for the test agent.
  • HL-60 promyelocytic leukemia cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum. Cells (7,500) were seeded into 96-well microtiter plates and incubated overnight. Serial dilutions of the test agent (dissolved in DMSO and then diluted with culture medium) were added to the wells on day 1. The plates were incubated for 8 days to allow the control cultures to undergo at least 3 cell divisions. The cell growth was monitored by using the calorimetric MTT (tetrazolium) assay [Mosmann, T., J. Immunol. Meth. 65: 55-63 (1983)].
  • calorimetric MTT tetrazolium
  • the cells were washed with phosphate-buffered saline in the microtiter plate. DMSO was then added to each well and the dish was put on a shaker for 20 min. The optical density was measured at 540 nm and compared using the formula: (OD Test - OD Start)/(OD Control - OD Start) x 100.
  • the IC 50 was defined as the dmg concentration which leads to 50% of cells per well compared to control cultures (100%) at the end of the incubation period.
  • T-24 human bladder carcinoma cells were cultured in Eagle's minimal essential medium supplemented with 5% fetal bovine serum. Cells (1,000) were seeded into 96-well microtiter plates and incubated overnight. Serial dilutions of the test agent (dissolved in DMSO and then diluted with culture medium) were added to the wells on day 1. The plates were incubated for 5-6 days to allow the control cultures to undergo at least 3 cell divisions. After the incubation period, the cells were fixed with glutaraldehyde, washed with water and stained with 0.05% methylene blue. After washing the dye was eluted with 3% HCl.
  • the optical density per well was measured at 665 nm and compared using the formula: (OD Test - OD Start)/(OD Control - OD Start) x 100.
  • the IC 50 was defined as the drug concentration which leads to 50% of cells per well compared to control cultures (100%) at the end of the incubation period.
  • composition for a topical gel is the following:
  • the materials are mixed, homogenized and filled into containers each holding 1 gram of gel.

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Abstract

Cette invention concerne des composés possédant une activité anti-inflammatoire ainsi que d'autres activités. Ces composés sont dérivés de phorboïdes de types diterpène et benzolactame.
PCT/US1996/009710 1995-06-07 1996-06-07 Modulateurs .x. de proteine kinase c WO1996040614A1 (fr)

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US08/472,871 US5891870A (en) 1986-06-11 1995-06-07 Protein kinase C modulators Q
US08/480,251 1995-06-07
US08/480,251 US6080784A (en) 1986-06-11 1995-06-07 Protein kinase C modulators N
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997043268A1 (fr) * 1996-05-10 1997-11-20 Georgetown University Derives de benzodizocine a substitution 8-hydrocarbyle, leur preparation et leur utilisation comme modulateurs de la proteine kinase c (pkc)
WO2007009055A3 (fr) * 2005-07-13 2007-04-12 Salvia Sciences Inc Analogues et derives de prostratine et composes de phorbol relatifs
US8067632B2 (en) 2007-07-26 2011-11-29 The Board Of Trustees Of The Leland Stanford Junior University Process to produce prostratin and structural or functional analogs thereof
WO2023033128A1 (fr) * 2021-09-03 2023-03-09 国立大学法人京都大学 Procédé de production d'une protéine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5089517A (en) * 1990-08-03 1992-02-18 The Board Of Trustees Of The Leland Stanford Junior University Neuroprotection by indolactam v and derivatives thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5089517A (en) * 1990-08-03 1992-02-18 The Board Of Trustees Of The Leland Stanford Junior University Neuroprotection by indolactam v and derivatives thereof

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997043268A1 (fr) * 1996-05-10 1997-11-20 Georgetown University Derives de benzodizocine a substitution 8-hydrocarbyle, leur preparation et leur utilisation comme modulateurs de la proteine kinase c (pkc)
WO2007009055A3 (fr) * 2005-07-13 2007-04-12 Salvia Sciences Inc Analogues et derives de prostratine et composes de phorbol relatifs
US8022103B2 (en) 2005-07-13 2011-09-20 Salvia Sciences, Inc. Ester prodrugs of prostratin and related phorbol compounds
AU2006268148B2 (en) * 2005-07-13 2012-11-01 Salvia Sciences, Inc. Ester prodrugs of prostratin and related phorbol compounds
US8431612B2 (en) 2005-07-13 2013-04-30 Salvia Sciences, Inc. Ester prodrugs of prostratin and related phorbol compounds
US8067632B2 (en) 2007-07-26 2011-11-29 The Board Of Trustees Of The Leland Stanford Junior University Process to produce prostratin and structural or functional analogs thereof
US8536378B2 (en) 2007-07-26 2013-09-17 The Board Of Trustees Of The Leland Stanford Junior University Prostratin and structural or functional analogs thereof
WO2023033128A1 (fr) * 2021-09-03 2023-03-09 国立大学法人京都大学 Procédé de production d'une protéine

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