Protein kinase C modulators N

A compound of the formula I:

• ##STR7## in the form of an individual isomer, an isomer mixture, a racemate or optical antipode, or a pharmaceutically acceptable salt thereof;
• wherein
• A.sup.1 and A.sup.2 may independently be selected from the group consisting of hydrogen, halogen and a straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing group having not more than 34 carbon atoms, not more than 24 halogen atoms and not more than 6 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus, boron and sulfur;
• or,
• A.sup.1 and A.sup.2 taken together may 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 or unsaturated 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.sup.1 or A.sup.4 and which, 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 the group consisting of oxygen, nitrogen, silicon, phosphorus, boron and sulfur;
• A.sup.3 is a three atom chain which carries S and completes a 7-membered carbocyclic ring substituted by 0-5 straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing groups, which, taken together, excluding S, contain not more than 12 carbon atoms, not more than 8 halogen atoms, and not more than 5 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus and sulfur;
• provided that, excluding S, the middle carbon atom of A.sup.3 is not substituted by hydroxymethyl or 1-hydroxyethyl;
• A.sup.4 completes a 6-membered carbocyclic ring connected in the .beta. configuration to carbon atom 9, substituted by 0-8 straight chain or branched chain, cyclic or acyclic, saturated or unsaturated or aromatic carbon- and/or heteroatom-containing groups, linked to A.sup.4 by single or double bonds, the group or groups optionally completing 1-2 additional rings by connections among themselves and/or 1-2 additional rings by connections to A.sup.1, A.sup.2, a ring formed by A.sup.1 and A.sup.2 together, and/or a bond to carbon 9, wherein said groups, taken together, include not more than 50 carbon atoms, not more than 24 halogen atoms, and not more than 15 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus, boron and sulfur;
• and wherein A.sup.4 carries at least one substituent which is not hydrogen and is not an hydroxyl at carbon 12 and carries a substituent selected from the group consisting of hydroxy, unsubstituted amino, thiol, hydroxymethyl, mercaptomethyl, aminomethyl, 2-hydroxyethyl, carboxy, unsubstituted carboxamido, unsubstituted aminocarbonyloxy group, each in the .alpha. configuration on carbon 13, and an oxo or thiono group on carbon 13;
• carbon atom 9 is bound to a moiety selected from the group consisting of hydrogen, hydroxy, acyloxy, orthoesteroxy, ether, silyl ether and a group attached to A.sup.4 ;
• J.sup.1 may be selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, amino, mono- or di(lower-alkyl)amino, methyl, ethyl, vinyl, ethynyl, propargyl, cyano, methoxy, ethoxy, trifluoromethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, acetoxy, propanoyloxy, acetyl, propanoyl, hydroxyacetyl, 2-hydroxypropanoyloxy, 3-hydroxypropanoyl, acetamido, propanamido, hydroxyacetamido, 2-hydroxypropanamido and 3-hydroxypropanamido each of which must be situated in the .beta. configuration, or J.sup.1 taken together with A.sup.1, A.sup.2, or a ring formed by A.sup.1 together with A.sup.2 may complete a 3- to 7-membered substituted or unsubstituted carbocyclic or heterocyclic ring, the substituents of which contain not more than 15 carbon atoms, not more than 10 halogens, and not more than 8 heteroatoms selected from the group consisting of oxygen, nitrogen, silicon, phosphorus, boron and sulfur;
• J.sup.2 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, allyl, propargyl, n-propyl and isopropyl;
• and
• S is bound to carbon 6 and is selected from the group consisting of hydroxymethyl, 1-hydroxyethyl and 2-hydroxy-2-propyl;
• provided that:
• said compound is not:
• a 12-n-alkanoyl ester, a 12-alkenoyl ester, a 12-(2'-methylbutanoate), 12-benzoate or a 12-(2'-methylamino)benzoate of a compound having the 20-carbon tigliane skeleton;
• phorbol 12-(12'-N-dansylaminododecanoate);
• 12-O-methylphorbol;
• 12-O-ethylphorbol;
• neophorbol;
• 12-deoxy-12-oxophorbol;
• 2-(benzoyloxy)-1,2,3,4,4a,4b,5a,6,6a,7,9a,9b-dodecahydro-3,6,6a,9b-tetrahy droxy-5a-(hydroxymethyl)-1,8-dimethyl-3-(1-methylethenyl)benz[7,8]azuleno[5 ,6-b]oxiren-4-yl ester of 2,4-decadienoic acid;
• tiglophorbol B;
• tiglophorbol;
• bisdehydrophorbol 12-acetate;
• or, bisdehydrophorbol 12-tetradecanoate.