Macrocyclic diterpenes for treating conditions associated with protein kinase c

Abstract

The present invention relates generally to chemical agents useful in the treatment and prophylaxis of inflammatory conditions or in the amelioration of symptoms resulting from or facilitated by an inflammatory condition in a mammalian animal including human and primate, non-mammalian animal and avian species. More particularly, the present invention provides a chemical agent of the macrocyclic diterpene family obtaining from a member of the Euphorbiaceae family of plants or botanical or horticultural relatives thereof or derivatives or chemical analogues or chemically synthetic forms of the agents for use in the treatment or prophylaxis of an inflammatory condition or in the amelioration of symptoms resulting from or facilitated by an inflammatory condition in a mammal, animal or avian species. The present invention further contemplates a method for the prophylaxis or treatment of mammalian, animal or avian subjects for inflammatory conditions including chronic or transitory inflammatory conditions or for ameliorating the symptoms of an inflammatory condition by the topical or systemic administration of a macrocyclic diterpene obtainable from a member of the Fuphorbiaceae family or botanical or horticultural relatives thereof or a derivative, chemical analogue or chemically synthetic form of the agent. The chemical agent of the present invention may be in the form of a purified compound, mixture of compounds, a precursor form of one or more of the compounds capable of chemical transformation into a therapeutically active agent or be in the form of a chemical fraction, sub-fraction or preparation or extract of the plant.

1 - 118 . (canceled) 
   
   
       119 . A method for the treatment or prophylaxis of an inflammatory condition in a subject, said method comprising administering to said subject a symptom-ameliorating effective amount of a chemical agent obtainable from a species of  Euphorbia  or derivative or chemical analog thereof which chemical agent is a macrocyclic diterpene selected from compounds of the ingenane, pepluane, paraliane and jatrophane wherein said ingenane is represented by formulae VIII 
     
       
         
         
             
             
         
       
     
     wherein:
 R 24 , R 25  and R 26  are independently selected from hydrogen, hydroxy, R 27 , R 28 , F, Cl, Br, I, CN, OR 27 , SR 27 , NR 27 R 28 , N(═O) 2 , NR 27 OR 28 , ONR 27 R 28 , SOR 27 , SO 2 R 27 , SO 3 R 27 , SONR 27 R 28 , SO 2 NR 27 R 28 , SO 3 NR 21 R 28 , P(R 27 ) 3 , P(═O)(R 27 ) 3 , Si(R 27 ) 3 , B(R 27 ) 2 , (C═X)R 29  or X(C═X)R 29  where X is selected from sulfur, oxygen and nitrogen; 
 R 27  and R 28  are each independently selected from C 1 -C 20  alkyl (branched and/or straight chained), C 1 -C 20  aryalkyl, C 3 -C 8  cycloalkyl, C 6 -C 14  aryl, C 1 -C 14  heteroaryl, C 1 -C 14  heterocycle, C 2 -C 10  alkenyl (branched and/or straight chained), C 2 -C 10  alkynyl (branched and/or straight chained), C 1 -C 10  heteroarylalkyl, C 1 -C 10  alkoxyalky, C 1 -C 10  haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C 1 -C 10  alkyl which is unsubstituted or substituted by CN, OR 27 , SR 27 , NR 27 R 28 , N(═O) 2 , NR 27 OR 28 , ONR 27 R 28 , SOR 27 , SO 2 R 27 , SO 3 R 27 , SONR 27 R 28 , SO 2 NR 27 R 28 , SO 3 NR 27 R 28 , P(R 27 ) 3 , P(═O)(R 27 ) 3 , Si(R 27 ) 3 , and B(R 27 ) 2 ; and 
 R 29  is selected from R 27 , R 28 , CN, COR 27 , CO 2 R 27 , OR 27 , SR 27 , NR 27 R 28 , N(═O) 2 , NR 27 OR 29 , ONR 27 R 28 , SOR 27 , SO 2 R 27 , SO 3 R 27 , SONR 27 R 28 , SO 2 NR 27 R 28 , SO 3 NR 27 R 28 , P(R 27 ) 3 , P(═O)(R 27 ) 3 , Si(R 27 ) 3 , and B(R 27 ) 2 . 
 
   
   
       120 . The method according to  claim 119  wherein R 24  is H. 
   
   
       121 . The method according to  claim 119  wherein R 24  is OAcetyl. 
   
   
       122 . A method according to  claim 119  wherein R 24  is OH. 
   
   
       123 . A method according to  claim 119  wherein R 25  and R 26  are OH. 
   
   
       124 . The method according to  claim 119  wherein the PKC-related condition is alcoholism, Alzheimer's disease, asthma, atherosclosis, dermatitis, autoimmune disease, bipolar disorder, blood disorder, cardiac hypertrophy, depression, diabetes, hypertension, hyperplastic dermatosis, multiple sclerosis, myocardial ischemia, osteoarthritis, psoriasis, rheumatoid arthritis, transplantation, or latent virus. 
   
   
       125 . The method according to  claim 119  wherein the species of  Euphorbia  is selected from  Euphorbia aaron - rossii, Euphorbia abbreviata, Euphorbia acuta, Euphorbia alatocaulis, Euphorbia albicaulis, Euphorbia algomarginata, Euphorbia aliceae, Euphorbia alta, Euphorbia anacampseros, Euphorbia andromedae, Euphorbia angusta, Euphorbia anthonyi, Euphorbia antiguensis, Euphorbia apocynifolia, Euphorbia arabica, Euphorbia ariensis, Fuphorbia arizonica, Euphorbia arkansana, Euphorbia arteagae, Euphorbia arundelana, Euphorbia astroites, Euphorbia atrococca, Euphorbia baselicis, Euphorbia batabanensis, Euphorbia bergeri, Euphorbia bermudiana, Euphorbia bicolor, Euphorbia biformis, Euphorbia bifurcata, Euphorbia bilobata, Euphorbia biramensis, Euphorbia biuncialis, Euphorbia blepharostipula, Euphorbia blodgetti, Euphorbia boerhaavioides, Euphorbia boliviana, Euphorbia bracei, Euphorbia brachiata, Euphorbia brachycera, Euphorbia brandegee, Euphorbia brittonii, Euphorbia caesia, Euphorbia calcicola, Euphorbia campestris, Euphorbia candelabrum, Euphorbia capitellata, Euphorbia carmenensis, Euphorbia carunculata, Euphorbia cayensis, Euphorbia celastroides, Euphorbia chalicophila, Euphorbia chamaerrhodos, Euphorbia chamaesula, Euphorbia chiapensis, Euphorbia chiogenoides, Euphorbia cinerascens, Euphorbia clarionensis, Euphorbia colimae, Euphorbia colorata, Euphorbia commutata, Euphorbia consoquitlae, Euphorbia convolvuloides, Euphorbia corallifera, Euphorbia creberrima, Euphorbia crenulata, Euphorbia cubensis, Euphorbia cuspidata, Euphorbia cymbiformis, Euphorbia darlingtonii, Euphorbia defoliata, Euphorbia degeneri, Euphorbia deltoidea, Euphorbia dentata, Euphorbia depressa Euphorbia dictyosperma, Euphorbia dicryosperma, Euphorbia dioeca, Euphorbia discoidalis, Euphorbia dorsiventralis, Euphorbia drumondii, Euphorbia duclouxii, Euphorbia dussii, Euphorbia eanophylla, Euphorbia eggersii, Euphorbia eglandulosa, Euphorbia elala, Euphorbia enalla, Euphorbia eriogonoides, Euphorbia eriophylla, Euphorbia esculaeformis, Euphorbia espirituensis, Fuphorbia esula, Euphorbia excisa, Euphorbia exclusa, Euphorbia exstipitata, Euphorbia exstipulata, Euphorbia fendleri, Euphorbia filicaulis, Euphorbia fillformis, Euphorbia florida, Euphorbia fruticulosa, Euphorbia garber, Euphorbia gaumerii, Euphorbia gerardiana, Euphorbia geyeri, Euphorbia glyptosperma, Euphorbia gorgonis, Euphorbia gracidior, Euphorbia gracillima, Euphorbia gradyi, Euphorbia graminea, Euphorbia graminiea Euphorbia grisea, Euphorbia guadalajarana, Euphorbia guanarensis, Euphorbia gymnadenia, Euphorbia haematantha, Euphorbia hedyotoides, Euphorbia heldrichii, Euphorbia helenae, Euphorbia helleri, Euphorbia helwigii, Euphorbia henricksonii, Euphorbia heterophylla, Fuphorbia hexagona, Euphorbia hexagonoides, Euphorbia hinkleyorum, Euphorbia hintonii, Euphorbia hirtula, Euphorbia hirta, Euphorbia hooveri, Euphorbia humistrata, Euphorbia hypericifolia, Euphorbia inundata, Euphorbia involuta, Euphorbia jaliscensis, Euphorbia jejuna, Euphorbia johnston, Euphorbia juttae, Euphorbia knuthii, Euphorbia lasiocarpa, Euphorbia lata, Euphorbia latazi, Euphorbia latericolor, Euphorbia laxiflora Euphorbia lecheoides, Euphorbia ledienii, Euphorbia leucophylla, Euphorbia lineata, Euphorbia linguiformis, Euphorbia longecornuta, Euphorbia longepetiolata, Euphorbia longeramosa, Euphorbia longinsulicola, Euphorbia longipila, Euphorbia lupulina, Euphorbia lurida, Euphorbia lycioides, Euphorbia macropodoides, macvaughiana, Euphorbia manca, Euphorbia mandoniana, Euphorbia mangleti, Euphorbia mango, Euphorbia marylandica, Euphorbia mayana, Euphorbia melanadenia, Euphorbia melanocarpa, Euphorbia meridensis, Euphorbia mertonii, Euphorbia mexiae, Euphorbia microcephala, Euphorbia microclada, Euphorbia micromera, Euphorbia misella, Euphorbia missurica, Euphorbia montana, Euphorbia montereyana, Euphorbia multicaulis, Euphorbia multiformis, Euphorbia multinodis, Euphorbia multiseta, Euphorbia muscicola, Euphorbia neomexicana, Euphorbia nephradenia, Euphorbia niqueroana, Euphorbia oaxacana, Euphorbia occidentalis, Euphorbia odontodenia, Euphorbia olivacea, Euphorbia olowaluana, Euphorbia opthalmica, Euphorbia ovata, Euphorbia pachypoda, Euphorbia pachyrhiza, Euphorbia padifolia, Euphorbia palmeri, Fuphorbia paludicola, Euphorbia parciflora, Euphorbia parishii, Euphorbia parryi, Euphorbia paxiana, Euphorbia pediculifera, Euphorbia peplidion, Euphorbia peploides, Euphorbia peplus, Euphorbia pergamena, Euphorbia perlignea, Euphorbia petaloidea, Euphorbia petaloidea, Euphorbia petrina, Euphorbia picachensis, Euphorbia pilosula, Euphorbia pilulifera, Euphorbia pinariona, Euphorbia pinetoruni, Euphorbia pionosperma, Euphorbia platysperma, Euphorbia plicata, Euphorbia poeppigii, Euphorbia poliosperma, Euphorbia polycarpa, Euphorbia polycnemoides, Euphorbia polyphylla, Euphorbia portoricensis, Euphorbia portulacoides Euphorbia portulana, Euphorbia preslii, Euphorbia prostrata, Euphorbia pteroneura, Euphorbia pycnanthema, Euphorbia ramosa, Euph orbia rapulum, Euphorbia remyi, Euphorbia retroscabra, Euphorbia revoluta, Euphorbia rivularis, Euphorbia robusta, Euphorbia romosa, Euphorbia rubida, Euphorbia rubrosperma, Euphorbia rupicola, Euphorbia sanmartensis, Euphorbia saxatilis  M. Bieb,  Euphorbia schizoloba, Euphorbia sclerocyathium, Euphorbia scopulorum, Euphorbia senilis, Euph orbia serpyllifolia, Euphorbia serrula, Euphorbia setiloba Fngelm, Euphorbia sonorae, Euphorbia soobyi, Euphorbia spars/flora, Euphorbia sphaerosperma, Euphorbia syphilitica, Euphorbia spruceana, Euphorbia subcoerulea, Euphorbia stellata, Euphorbia submammilaris, Euphorbia subpeltata, Euphorbia subpubens, Euphorbia  subren/forme,  Euphorbia subtrifoliata, Euphorbia succedanea, Euphorbia tamaulipasana, Euphorbia telephioides, Euphorbia tenuissima, Euphorbia tetrapora, Euphorbia tirucalli Euphorbia tomentella, Euphorbia tomentosa, Euphorbia torralbasii, Euphorbia tovariensis, Euphorbia trachysperma, Euphorbia tricolor, Euphorbia troyana, Euphorbia tuerckheimii, Euphorbia turczaminowii, Euphorbia umbellulata, Euphorbia undulata, Euphorbia vermiformis, Euphorbia versicolor, Euphorbia villifera, Euphorbia violacea, Euphorbia whitei, Euphorbia xanti Engelm, Euphorbia xylopoda  Greenm.,  Euphorbia yayalesia  Urb.,  Euphorbia yungasensis, Euphorbia zeravschanica  and  Euphorbia zinnuiflora.    
   
   
       126 . The method according to  claim 119  wherein the chemical agent is a jatrophane or an acetylated jatrophane or a pharmaceutically acceptable salt of these. 
   
   
       127 . The method according to  claim 126  wherein the jatrophane is jatrophane 2. 
   
   
       128 . The method according to  claim 119  wherein said chemical agent is a pepluane or an acetylated pepluane or a pharmaceutically acceptable salt of these. 
   
   
       129 . The method according to  claim 119  wherein said chemical agent is a paraliane or an acetylated paraliane or a pharmaceutically acceptable salt of these. 
   
   
       130 . The method according to  claim 119  wherein said chemical agent is an angeloyl-substituted ingenane or a derivative thereof represented by Formula VI or a pharmaceutically acceptable salt of these. 
   
   
       131 . The method according to  claim 119  wherein said chemical agent is 5,859,10,14-pentaacetoxy-3-benzoyloxy-15-hydroxypepluane (pepluane), 2,3,5,7,15-pentaacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17), 11E-diene (jatrophane 1).2,5,7,8,9,14-hexaacetoxy-3-benzoyloxy-55-hydroxytjatropha-6(17), 11E-diene (jatrophane 2), 2,5,14-triacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy-9-nicotinoyloxyjatropha-6(17), 11E-diene (jatrophane 3), 2,5,9,14-t etraacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isohbutyroyloxyjatropha-6(17), 11 E-diene) (jatrophane 4), 2,5,7,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-9-nicotinoyloxyjatropha-6(17), 11 E-diene (jatrophane 5), 2,5,7,9,14-pentaacetoxy-3-benzoyloxy-8,15-dihydroxyjatropha-6(17), 11E-diene (jatrophane 6), or a pharmaceutically acceptable salt of any of these. 
   
   
       132 . The method according to  claim 119  wherein said compound is 20-O-acetyl-ingenol-3-angelate or a derivative thereof represented by Formula VI or a pharmaceutically acceptable salt of these. 
   
   
       133 . The method according to  claim 119  wherein said chemical agent is ingenol-3-angelate, or a pharmaceutically acceptable salt of these. 
   
   
       134 . The method according to  claim 119  wherein said chemical agent is 20-hydroxy-ingenol-3-angelate or a pharmaceutically acceptable salt of these. 
   
   
       135 . The method according to  claim 119  wherein said subject is human.