Protein kinase c. modulators. d.

A compound, in the form of an individual isomer, an isomer mixture, a racemate or optical antipode, or a pharmaceutically acceptable salt thereof, of the formula:

• P.sub.o -S.sub.o -E.sub.o
• wherein P.sub.o represents a radical, formally derived from a parent aromatic heterocyclic compound of the indole, indene, benzofuran or benzothiophene class, which compound:
• a. .fwdarw.binds reversibly or irreversibly to a diacylglycerol-type receptor;
• and/or
• b. .fwdarw.activates any form of the enzyme protein kinase C;
• and
• c. .fwdarw.contains an hydroxymethyl or 1-hydroxy-ethyl group bonded to a carbon atom;
• and
• wherein S.sub.o -E.sub.o represents a moiety which is 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 S.sub.o is 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.sub.o and E.sub.o by a linear count of at least two but not more than 12 atoms and contains 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
• wherein E.sub.o comprises 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 selenium, or wherein S.sub.o E.sub.o taken together may be a hydrogen, halogen, thionic sulfur atom or ketonic oxygen atom or a hydroxy, amine, or thiol group singly or doubly bonded to the carbon atom of the parent compound P.sub.o in place of the hydroxymethyl or 1-hydroxyethyl group;
• provided that if P.sub.o is a substituted or unsubstituted indolactam radical having a bond at carbon 9 in place of the hydroxymethyl and S.sub.o E.sub.o is bonded to carbon 9 thereof, then S.sub.o E.sub.o may not comprise --COOMe, --COOEt or --CH.sub.2 --R.sub.e.sup.e, in which R.sub.e.sup.e is C.sub.1 -C.sub.12 saturated or unsaturated linear or branched alkoxy, --OCH.sub.2 OCH.sub.3, C.sub.1 -C.sub.12 linear or branched alkanoyloxy, bromoacetoxy, benzoyloxy, azidobenzoyloxy, 3,5-(CH.sub.3).sub.2 -C.sub.6 H.sub.3 COO--, methanesulfonyloxy, toluenesulfonyloxy, dansyloxy, (tetrahydro-2H-pyran-2-yl)oxy, or (C.sub.1 -C.sub.6 linear or branched alkyl).sub.n (phenyl).sub.3-n silyloxy, wherein n is 0-3.

A compound of the formula:

• P.sub.2 -S.sub.4 -E.sub.1
• wherein P.sub.2 is a radical of the formula:
• ##STR25## in the form of an individual isomer, an isomer mixture, a racemate or optical antipode, or a pharmaceutically acceptable salt thereof,
• wherein
• B.sup.1 completes a 6-membered carbocyclic aromatic ring, optionally substituted by halogen and/or straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or aromatic carbon-and/or heteroatom-containing 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 and/or to B.sub.2 to form 1-3 additional rings;
• B.sup.2 is selected from oxygen, sulfur, sulfoxide, sulfone, monofluoromethylene, difluoromethylene, and a carbon or nitrogen atom optionally substituted by a straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or aromatic carbon- and/or heteroatom-containing groups having not more than 20 carbon atoms, not more than 24 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur, and B.sup.2 may be linked to B.sup.1 or K.sub.1 to form an additional carbocyclic or heterocyclic ring;
• B.sup.3 is a 2-carbon chain optionally substituted by halogen and/or one or more straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or carbon- and/or heteroatom-containing groups, which groups taken together but excluding S.sub.4 E.sub.1, contain not more than 12 carbon atoms, not more than 6 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, and sulfur;
• provided that, including S.sub.4 E.sub.1, the carbon atoms of B.sup.3 bonded to K.sup.2 as defined below does not carry --CH.sub.2 OH or --CHCH.sub.3 OH;
• K.sup.1 is hydrogen, halogen or a straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or aromatic carbon- and/or heteroatom-containing group containing not more than 30 carbon atoms, not more than 18 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur, and K.sup.1 may be linked to B.sup.2 or B.sup.3 or to both B.sup.2 and B.sup.3 to form one or more additional carbocyclic and/or heterocyclic rings;
• K.sup.2 is selected from oxygen, sulfur --NK.sup.6 -- or --CK.sup.6 K.sup.7 -- wherein K.sup.6 is hydrogen, hydroxy, methyl, ethyl, fluoro, n-propyl, allyl, or propargyl, and K.sup.7 is hydrogen, methyl, ethyl, halogen, trifluoromethyl or cyano;
• K.sup.3 and K.sup.4 may be the same or may differ and may each be hydrogen, halogen or a straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or aromatic carbon- and/or heteroatom-containing group, such that K.sup.3 and K.sup.4 taken together contain not more than 18 carbon atoms, not more than 24 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur;
• K.sup.5 is selected from oxygen, sulfur, sulfoxide, sulfone or --NK.sup.8 --, --NOK.sup.8 -- or --CK.sup.8 K.sup.9 -- wherein K.sup.8 is hydrogen or a straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or aromatic carbon-and/or heteroatom-containing group containing not more than 30 carbon atoms, not more than 24 halogen atoms, and not more than 8 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur, and K.sup.9 is hydrogen, methyl, ethyl, n-propyl, hydroxy, halogen, allyl, propargyl, cyano, or trifluoromethyl;
• S.sub.4 is a chain of atoms defined by:
• ##STR26## wherein 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;
• R.sub.4.sup.1 through R.sub.4.sup.12 may be the same or different and each may be hydrogen, halogen or a saturated or singly or multiply unsaturated, straight or branched, 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, nitrogen, and sulfur atoms must be situated in functional groups selected from hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy, ester, amide, cyano, carbonate, carbamate, urea, isourea, carboxamidine, guanidine, thioester, thioamide, thiocarbonate, thiocarbamate, thiourea, nitroguanidine, cyanoguanidine, and xanthate;
• R.sub.4.sup.1 or R.sub.4.sup.2 may optionally be an additional bond completing an unsaturated linkage to the P.sub.2 moiety;
• one or two of the substituents R.sub.4.sup.1 -R.sup.10 may optionally comprise the same or different values for G.sup.1, as defined below;
• R.sub.4.sup.11 or R.sub.4.sup.12 may optionally be an additional bond to E.sub.1, thereby completing an unsaturated linkage;
• one of the substituents R.sub.4.sup.1 -R.sub.4.sup.12 may be linked to either the atom in P.sub.2 that carries that S.sub.4 chain or to an atom in P.sub.2 adjacent thereto, to form a saturated, unsaturated, or aromatic, carbocyclic or heterocyclic 4-8 membered ring optionally containing 1-4 identical or different hetero ring members selected from O, S, SO, SO.sub.2, CO, .dbd.N--, and NH, the ring being optionally substituted on any carbon and/or NH members by 1-8 identical or different substituents selected from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, COCH.sub.3, CH.dbd.O, acetoxy, amino, mono- or dialkylamino totalling 1-4 carbon atoms inclusive, acetamido, N-methylacetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy;
• M, M', and R.sup.Q are as defined below;
• provided that, for all substituents R.sub.4.sup.1 through R.sub.4.sup.12 and all constituents M, M' and R.sup.Q taken together, but excluding any atoms of the P.sub.2 moiety:
• 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 total of sulfur atoms is 3 or less;
• the total of oxygen, nitrogen, silicon, phosphorus and sulfur atoms together is 8 or less;
• the total of --OH groups is 3 or less;
• the total of --NH.sub.2 groups is 2 or less;
• the total of --SH groups is 2 or less;
• the total of --OH, --SH, and --NH.sub.2 groups together is 4 or less;
• M and M' independently may be:
• ##STR27## wherein R.sub.M.sup.1 and R.sub.M.sup.2 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 situated in functional groups selected from hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy, ester, amide, cyano, nitroguanidine, and cyanoguanidine;
• R.sub.M.sup.1 may optionally comprise an additional bond to P.sub.2 group, thus completing an unsaturated linkage;
• R.sub.M.sup.1 or R.sub.M.sup.2 may optionally comprise the same or different values for G.sup.1, as defined below;
• R.sub.M.sup.1 or R.sub.M.sup.2 may be linked to either the atom in P.sub.2 that carries the chain containing M and/or M' or to an atom in P.sub.2 adjacent thereto, to form a saturated, unsaturated, or aromatic, carbocyclic 4-8 membered ring optionally containing 1-4 identical or different hetero ring members selected from O, S, CO, .dbd.N--, and NH, the ring being optionally substituted on its carbon and/or NH members by 1-8 identical or different substituents selected from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxy-ethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, COCH.sub.3, CH.dbd.O, acetoxy, amino, mono- or dialkylamino totalling 1-4 carbon atoms inclusive, acetamido, N-methylacetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy;
• Q-Q'" independently may be:
• ##STR28## wherein R.sub.Q.sup.1 and R.sub.Q.sup.2 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, 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, the heteroatoms being situated in functional groups selected from hydroxy, amino, thiol, nitro, ether, thioether, carboxy, ester, amide, cyano, nitroguanidine, and cyanoguanidine;
• R.sub.Q.sup.1 and/or R.sub.Q.sup.2 may optionally comprise the same or different values for G.sup.1, as defined below;
• R.sub.Q.sup.1 may be linked to either the atom in P.sub.2 that carries the chain containing Q and/or Q' or to an atom in P.sub.2 adjacent thereto, to form a saturated, unsaturated, or aromatic, carbocyclic 4-8 memebered ring optionally containing 1-4 identical or different hetero ring members selected from O, S, CO, .dbd.N-, and NH, the ring being optionally substituted on its carbon and/or NH members by 1-8 identical or different substituents selected from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, CH.dbd.O, acetoxy, amino mono- or dialkylamino totalling 1-4 carbon atoms inclusive, acetamido, N-methylacetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy;
• R.sup.Q is selected from:
• ##STR29## wherein R.sub.Q.sup.3 and R.sub.Q.sup.4 may be the same or different and each may be hydrogen, halogen or a saturated or singly or multiply unsaturated, straight or branched, 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, nitrogen, and sulfur atoms must be situated in functional groups selected from hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy, ester, amide, cyano, carbonate, carbamate, urea, isourea, carboxamidine, guanidine, thioester, thioamide, thiocarbonate, thiocarbamate, thiourea, nitroguanidine, cyanoguanidine, and xanthate;
• R.sub.Q.sup.3 and R.sub.Q.sup.4 may optionally comprise the same or different values for G.sup.1, as defined below;
• Q and Q' are as defined above;
• one of R.sub.Q.sup.3 and R.sub.Q.sup.4 may be linked to either the atom in P.sub.2 bonded to the chain that carries R.sup.Q or to an atom in P.sub.2 adjacent thereto, to form a saturated, unsaturated, or aromatic, carbocyclic or heterocyclic 4-8 membered ring optionally containing 1-4 identical or different hetero ring members selected from O, S, SO, SO.sub.2, CO, .dbd.N-, and NH, the ring being optionally substituted on any carbon and/or NH members by 1-8 identical or different substituents selected from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, COCH.sub.3, CH.dbd.O, acetoxy, amino, mono- or dialkylamino totalling 1-4 carbon atoms inclusive, acetamido, N-methylacetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy;
• G.sup.1 comprises a group containing 1-3 fused or separate, saturated, unsaturated, or aromatic, carbocyclic or heterocyclic 4-8 membered rings, each ring optionally containing 1-4 identical or different hetero ring members selected from O, S, SO, SO.sub.2, CO, .dbd.N-, and NH, each ring being optionally substituted on its carbon and/or NH members by 1-8 identical or different substituents selected from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, COCH.sub.3, CH.dbd.O, acetoxy, amino, mono- or dialkylamino totalling 1-4 carbon atoms inclusive, acetamido, N-methyl acetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy, and wherein separate rings may be connected to one another and/or to the atom bearing G.sup.1 by a bond or by an intervening substituted or unsubstituted, linear or branched chain containing not more than 8 carbon atoms, not more than 8 halogens, and not more than 4 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur;
• and
• wherein E.sub.1 is selected from .dbd.O, .dbd.S, .dbd.NH, .dbd.NOH, .dbd.N--NH.sub.2, hydrogen, halogen, --OH, --SH, --NH.sub.2, --NH--NH.sub.2, --N.sub.3, --CN, --NO, --NO.sub.2, --NHOH, --ONH.sub.2, or is selected from:
• ##STR30## wherein T.sup.1 is selected from --O--, --S--, and --NH--;
• T.sup.2 is selected from .dbd.O, .dbd.S, and .dbd.N--R.sub.E.sup.6 in which R.sub.E.sup.6 may be hydrogen, hydroxy, cyano, or nitro;
• T.sup.2' is selected from .dbd.O and .dbd.S;
• T.sup.3, T.sup.4 and T.sup.4' are independently selected from --OH, --NH.sub.2, --SH, --N.sub.3, --NH--NH.sub.2, and --NH--OR.sub.E.sup.7, in which R.sub.E.sup.7 may be hydrogen, C.sub.1-3 alkyl, or C.sub.1-3 acyl;
• T.sup.3 may also be hydrogen;
• T.sup.5 -T.sup.5" are independently selected from hydrogen and hydroxy;
• R.sub.E.sup.1 is selected from hydrogen, halogen, hydroxy, nitro, nitroso, cyano, azide, --NH.sub.2, --NH--OH, --SH, --O--NH.sub.2, --NH--NH.sub.2, --T.sup.1 --C(.dbd.T.sup.2)--T.sup.3, --C(.dbd.T.sup.2)--T.sup.3, --SiT.sup.5 T.sup.5' T.sup.5", --T.sup.1 --S(.dbd.O)(.dbd.T.sup.2)--T.sup.4, --S(.dbd.O)(.dbd.T.sup.2)--T.sup.4, --T.sup.1 --P(--T.sup.4)--T.sup.4', --P(--T.sup.4)--T.sup.4', --T.sup.1 --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4, and --P(T.sup.2')(--T.sup.3)--T.sup.4 ;
• R.sub.E.sup.2 and R.sub.E.sup.3 are individually selected from hydrogen, --C(.dbd.T.sup.2)--T.sup.3, cyano, nitro, azide, halogen and a C.sub.1 -C.sub.15 straight or branched chain, saturated, unsaturated and/or aromatic-containing alkyl moiety optionally containing not more than 10 halogen atoms and not more than 4 heteroatoms selected from oxygen, nitrogen and sulfur;
• if R.sub.E.sup.1 is cyano or --C(.dbd.T.sup.2)--T.sup.3, then R.sub.E.sup.2 or R.sub.E.sup.3 may optionally be selected from --SiT.sup.5 T.sup.5' T.sup.5", --T.sup.1 --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4, and --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4 ;
• and
• R.sub.E.sup.4 and R.sub.E.sup.5 are individually selected from hydrogen, halogen, cyano, nitro, --C(.dbd.T.sup.2)--T.sup.3, --T.sup.1 --C(.dbd.T.sup.2)--T.sup.3, --CR.sub.E.sup.1 R.sub.E.sup.2 R.sub.E.sup.3, --SiT.sup.5 T.sup.5' T.sup.5", --S(.dbd.O)(.dbd.T.sup.2)--T.sup.4, and --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4 ;
• provided that P.sub.2 S.sub.4 E.sub.1 may not comprise (-)-1,10,14-N,N,O-trimethylindolactam V;
• and
• provided that if, in P.sub.2 S.sub.4 E.sub.1,
• B.sup.2 is --NH--, --N-(C.sub.1 -C.sub.12 linear or branched alkyl or alkanolyl)--, --N-COOCH.sub.2 C.sub.6 H.sub.5 -- or --N-COOC(CH.sub.3).sub.3 --, and
• B.sup.3 is --CH.sub.2 CH--, and
• K.sup.1 is hydrogen, and
• K.sup.2 is --NH--, and
• K.sup.4 is hydrogen, and
• K.sup.5 is --NH-- or --N(C.sub.1 -C.sub.3 -alkyl)--, then
• (i) if S.sub.4 E.sub.1 is bonded to the carbon atom in B.sup.3 that is adjacent to K.sup.2, then S.sub.4 E.sub.1 may not be --COOMe or --COOEt;
• and
• (ii) if S.sub.4 is a single bond directed to the carbon atom in B.sup.3 that is adjacent to K.sup.2, and E.sub.1 is --CH.sub.2 --R.sub.e.sup.e,
• then R.sub.e.sup.e is not C.sub.1 -C.sub.12 linear or branched alkanoyloxy, methanesulfonyloxy, or bromoacetoxy.

An anti-inflammatory composition for treatment of a mammal comprising:

• a physiologically acceptable pharmaceutical carrier;
• and
• an anti-inflammatory amount of a compound, in the form of an individual isomer, an isomer mixture, a racemate or optical antipode, or a pharmaceutically acceptable salt thereof, of the formula:
• P-G
• wherein P represents a radical, formally derived from a parent aromatic heterocyclic compound of the indole, indene, benzofuran or benzothiophene class, which compound:
• a. binds reversibly or irreversibly to a diacylglycerol-type receptor;
• and/or
• b. activates any form of the enzyme protein kinase C;
• and
• c. contains an hydroxymethyl or 1-hydroxyethyl group bonded to a carbon atom;
• and
• wherein 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.

An anti-inflammatory composition for treatment of a mammal comprising:

• a physiologically acceptable pharmaceutical carrier;
• and
• an anti-inflammatory amount of a compound, in the form of an individual isomer, an isomer mixture, a racemate or optical antipode, or a pharmaceutically acceptable salt thereof, of the formula:
• P.sub.o -S.sub.o -E.sub.o
• wherein P.sub.o represents a radical, formally derived from a parent aromatic heterocyclic compound of the indole, indene, benzofuran or benzothiophene class, which compound:
• a. binds reversibly or irreversibly to a diacylglycerol-type receptor;
• and/or
• b. activates any form of the enzyme protein kinase C;
• and
• contains an hydroxymethyl or 1-hydroxy-ethyl group bonded to a carbon atom;
• and
• wherein S.sub.o -E.sub.o represents a moiety which is 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 S.sub.o is 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.sub.o and E.sub.o by a linear count of at least two but not more than 12 atoms and contains 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
• wherein E.sub.o comprises 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 selenium, or wherein S.sub.o E.sub.o taken together may be a hydrogen, halogen, thionic sulfur atom or ketonic oxygen atom or a hydroxy, amine, or thiol group singly or doubly bonded to the carbon atom of the parent compound P.sub.o in place of the hydroxymethyl or 1-hydroxyethyl group.

An anti-inflammatory composition for treatment of a mammal comprising:

• a physiologically acceptable pharmaceutical carrier;
• and
• a compound of the formula:
• P.sub.2 -S.sub.4 -E.sub.1
• wherein P.sub.2 is a radical of the formula:
• ##STR35## in the form of an individual isomer, an isomer mixture, a racemate or optical antipode, or a pharmaceutically acceptable salt thereof in a quantity of between about 0.01-1000 mg per unit dosage,
• wherein
• B.sup.1 completes a 6-membered carbocyclic aromatic ring, optionally substituted by halogen and/or straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or aromatic carbon- and/or heteroatom-containing 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 and/or to B.sub.2 to form 1-3 additional rings;
• B.sup.2 is selected from oxygen, sulfur, sulfoxide, sulfone, monofluoromethylene, difluoromethylene, and a carbon or nitrogen atom optionally substituted by a straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or aromatic carbon- and/or heteroatom-containing groups having not more than 20 carbon atoms, not more than 24 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur, and B.sup.2 may be linked to B.sup.1 or K.sub.1 to form an additional carbocyclic or heterocyclic ring;
• B.sup.3 is a 2-carbon chain optionally substituted by halogen and/or one or more straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or carbon- and/or heteroatom-containing groups, which groups taken together but excluding S.sub.4 E.sub.1, contain not more than 12 carbon atoms, not more than 6 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, and sulfur;
• provided that, including S.sub.4 E.sub.1, the carbon atom of B.sup.3 bonded to K.sup.2 as defined below does not carry --CH.sub.2 OH or --CHCH.sub.3 OH;
• K.sup.1 is hydrogen, halogen or a straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or aromatic carbon- and/or heteroatom-containing group containing not more than 30 carbon atoms, not more than 18 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur, and K.sup.1 may be linked to B.sup.2 or B.sup.3 or to both B.sup.2 and B.sup.3 to form one or more additional carbocyclic and/or heterocyclic rings;
• K.sup.2 is selected from oxygen, sulfur --NK.sup.6 -- or --CK.sup.6 K.sup.7 -- wherein K.sup.6 is hydrogen, hydroxy, methyl, ethyl, fluoro, n-propyl, allyl, or propargyl, and K.sup.7 is hydrogen, methyl, ethyl, halogen, trifluoromethyl or cyano;
• K.sup.3 and K.sup.4 may be the same or may differ and may each be hydrogen, halogen or a straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or aromatic carbon- and/or heteroatom-containing group, such that K.sup.3 and K.sup.4 taken together contain not more than 18 carbon atoms, not more than 24 halogen atoms, and not more than 6 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur;
• K.sup.5 is selected from oxygen, sulfur, sulfoxide, sulfone or --NK.sup.8 --, --NOK.sup.8 -- or --CK.sup.8 K.sup.9 -- wherein K.sup.8 is hydrogen or a straight chain or branched chain, cyclic or acyclic, saturated, unsaturated, and/or aromatic carbon- and/or heteroatom-containing group containing not more than 30 carbon atoms, not more than 24 halogen atoms, and not more than 8 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur, and K.sup.9 is hydrogen, methyl, ethyl, n-propyl, hydroxy, halogen, allyl, propargyl, cyano, or trifluoromethyl;
• S.sub.4 is a chain of atoms defined by:
• ##STR36## wherein 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;
• R.sub.4.sup.1 through R.sub.4.sup.12 may be the same or different and each may be hydrogen, halogen or a saturated or singly or multiply unsaturated, straight or branched, 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, nitrogen, and sulfur atoms must be situated in functional groups selected from hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy, ester, amide, cyano, carbonate, carbamate, urea, isourea, carboxamidine, guanidine, thioester, thioamide, thiocarbonate, thiocarbamate, thiourea, nitroguanidine, cyanoguanidine, and xanthate;
• R.sub.4.sup.1 or R.sub.4.sup.2 may optionally be an additional bond completing an unsaturated linkage to the P.sub.2 moiety;
• one or two of the substituents R.sub.4.sup.1 -R.sup.10 may optionally comprise the same or different values for G.sup.1, as defined below;
• R.sub.4.sup.11 or R.sub.4.sup.12 may optionally be an additional bond to E.sub.1, thereby completing an unsaturated linkage;
• one of the substituents R.sub.4.sup.1 -R.sub.4.sup.12 may be linked to either the atom in P.sub.2 that carries that S.sub.4 chain or to an atom in P.sub.2 adjacent thereto, to form a saturated, unsaturated, or aromatic, carbocyclic or heterocyclic 4-8 membered ring optionally containing 1-4 identical or different hetero ring members selected from O, S, SO, SO.sub.2, CO, .dbd.N--, and NH, the ring being optionally substituted on any carbon and/or NH members by 1-8 identical or different substituents selected from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, COCH.sub.3, CH.dbd.O, acetoxy, amino, mono- or dialkylamino totalling 1-4 carbon atoms inclusive, acetamido, N-methylacetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy;
• M, M', and R.sup.Q are as defined below;
• provided that, for all substituents R.sub.4.sup.1 through R.sub.4.sup.12 and all constituents M, M' and R.sup.Q taken together, but excluding any atoms of the P.sub.2 moiety:
• 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 total of sulfur atoms is 3 or less;
• the total of oxygen, nitrogen, silicon, phosphorus and sulfur atoms together is 8 or less;
• the total of --OH groups is 3 or less;
• the total of --NH.sub.2 groups is 2 or less;
• the total of --SH groups is 2 or less;
• the total of --OH, --SH, and --NH.sub.2 groups together is 4 or less;
• M and M' independently may be:
• ##STR37## wherein R.sub.M.sup.1 and R.sub.M.sup.2 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 situated in functional groups selected from hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy, ester, amide, cyano, nitroguanidine, and cyanoguanidine;
• R.sub.M.sup.1 may optionally comprise an additional bond to P.sub.2 group, thus completing an unsaturated linkage;
• R.sub.M.sup.1 or R.sub.M.sup.2 may optionally comprise the same or different values for G.sup.1, as defined below;
• R.sub.M.sup.1 or R.sub.M.sup.2 may be linked to either the atom in P.sub.2 that carries the chain containing M and/or M' or to an atom in P.sub.2 adjacent thereto, to form a saturated, unsaturated, or aromatic, carbocyclic 4-8 membered ring optionally containing 1-4 identical or different hetero ring members selected from O, S, CO, .dbd.N--, and NH, the ring being optionally substituted on its carbon and/or NH members by 1-8 identical or different substituents selected from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxy-ethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCH.sub.3, COOH, COOCH.sub.3, COCH.sub.3, CH.dbd.O, acetoxy, amino, mono- or dialkylamino totalling 1-4 carbon atoms inclusive, acetamido, N-methylacetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy;
• Q-Q"' independently may be:
• ##STR38## wherein R.sub.Q.sup.1 and R.sub.Q.sup.2 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, 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, the heteroatoms being situated in functional groups selected from hydroxy, amino, thiol, nitro, ether, thioether, carboxy, ester, amide, cyano, nitroguanidine, and cyanoguanidine;
• R.sub.Q.sup.1 and/or R.sub.Q.sup.2 may optionally comprise the same or different values for G.sup.1, as defined below;
• R.sub.Q.sup.1 may be linked to either the atom in P.sub.2 that carries the chain containing Q and/or Q' or to an atom in P.sub.2 adjacent thereto, to form a saturated, unsaturated, or aromatic, carbocyclic 4-8 membered ring optionally containing 1-4 identical or different hetero ring members selected from O, S, CO, .dbd.N--, and NH, the ring being optionally substituted on its carbon and/or NH members by 1-8 identical or different substiuents selected from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, CH.dbd.O, acetoxy, amino mono- or dialkylamino totalling 1-4 carbon atoms inclusive, acetamido, N-methylacetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy;
• R.sup.Q is selected from:
• ##STR39## wherein R.sub.Q.sup.3 and R.sub.Q.sup.4 may be the same or different and each may be hydrogen, halogen or a saturated or singly or multiply unsaturated, straight or branched, 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, nitrogen, and sulfur atoms must be situated in functional groups selected from hydroxy, amino, thiol, nitro, azide, ether, thioether, aldehyde, keto, carboxy, ester, amide, cyano, carbonate, carbamate, urea, isourea, carboxamidine, guanidine, thioester, thioamide, thiocarbonate, thiocarbamate, thiourea, nitroguanidine, cyanoguanidine, and xanthate;
• R.sub.Q.sup.3 and R.sub.Q.sup.4 may optionally comprise the same or different values for G.sup.1, as defined below;
• Q and Q' are as defined above;
• one of R.sub.Q.sup.3 and R.sub.Q.sup.4 may be linked to either the atom in P.sub.2 bonded to the chain that carries R.sup.Q or to an atom in P.sub.2 adjacent thereto, to form a saturated, unsaturated, or aromatic, carbocyclic or heterocyclic 4-8 membered ring optionally containing 1-4 identical or different hetero ring members selected from O, S, SO, SO.sub.2, CO, .dbd.N--, and NH, the ring being optionally substituted on any carbon and/or NH members by 1-8 identical or different substituents selected from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, COCH.sub.3, CH.dbd.O, acetoxy, amino, mono- or dialkylamino totalling 1-4 carbon atoms inclusive, acetamido, N-methylacetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy;
• G.sup.1 comprises a group containing 1-3 fused or separate, saturated, unsaturated, or aromatic, carbocyclic or heterocyclic 4-8 membered rings, each ring optionally containing 1-4 identical or different hetero ring members selected from O, S, SO, SO.sub.2, CO, .dbd.N--, and NH, each ring being optionally substituted on its carbon and/or NH members by 1-8 identical or different substituents selected from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, cyano, azide, nitro, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, CF.sub.3, OCF.sub.3, SH, SCH.sub.3, SOCH.sub.3, SCF.sub.3, COOH, COOCH.sub.3, COCH.sub.3, CH.dbd.O, acetoxy, amino, mono- or dialkylamino totalling 1-4 carbon atoms inclusive, acetamido, N-methyl acetamido, carboxamido, N-alkylated carboxamido containing 1-4 carbon atoms inclusive, hydroxyacetyl and hydroxyacetoxy, and wherein separate rings may be connected to one another and/or to the atom bearing G.sup.1 by a bond or by an intervening substituted or unsubstituted, linear or branched chain containing not more than 8 carbon atoms, not more than 8 halogens, and not more than 4 heteroatoms selected from oxygen, nitrogen, silicon, phosphorus and sulfur;
• and
• wherein E.sub.1 is selected from .dbd.O, .dbd.S, .dbd.NH, .dbd.NOH, .dbd.N--NH.sub.2, hydrogen, halogen, --OH, --SH, --NH.sub.2, --NH--NH.sub.2, --N.sub.3, --CN, --NO, --NO.sub.2, --NHOH, --ONH.sub.2, or is selected from:
• ##STR40## wherein T.sup.1 is selected from --O--, --S--, and --NH--;
• T.sup.2 is selected from .dbd.O, .dbd.S, and .dbd.N--R.sub.E.sup.6 may be hydrogen, hydroxy, cyano, or nitro;
• T.sup.2' is selected from .dbd.O and .dbd.S;
• T.sup.3, T.sup.4 and T.sup.4' are independently selected from --OH, --NH.sub.2, --SH, --N.sub.3, --NH--NH.sub.2, and --NH--OR.sub.E.sup.7, in which R.sub.E.sup.7 may be hydrogen, C.sub.1-3 alkyl, or C.sub.1-3 acyl;
• T.sup.3 may also be hydrogen;
• T.sup.5 -T.sup.5" are independently selected from hydrogen and hydroxy;
• R.sub.E.sup.1 is selected from hydrogen, halogen, hydroxy, nitro, nitroso, cyano, azide, --NH.sub.2, --NH--OH, --SH, --O--NH.sub.2, --NH--NH.sub.2, --T.sup.1 --C(.dbd.T.sup.2)--T.sup.3, --C(.dbd.T.sup.2)--T.sup.3, --SiT.sup.5 T.sup.5' T.sup.5", --T.sup.1 --S(.dbd.O)(.dbd.T.sup.2)--T.sup.4, --S(.dbd.O)(.dbd.T.sup.2)--T.sup.4, --T.sup.1 --P(--T.sup.4)--T.sup.4', --P(--T.sup.4), --T.sup.1 --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4, and --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4 ;
• R.sub.E.sup.2 and R.sub.E.sup.3 are individually selected from hydrogen, --C(.dbd.T.sup.2)--T.sup.3, cyano, nitro, azide, halogen and a C.sub.1 -C.sub.15 straight or branched chain, saturated, unsaturated and/or aromatic-containing alkyl moiety optionally containing not more than 10 halogen atoms and not more than 4 heteroatoms selected from oxygen, nitrogen and sulfur;
• if R.sub.E.sup.1 is cyano or --C(.dbd.T.sup.2)--T.sup.3, then R.sub.E.sup.2 or R.sub.E.sup.3 may optionally be selected from --SiT.sup.5 T.sup.5' T.sup.5", --T.sup.1 --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4, and --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4 ;
• and
• R.sub.E.sup.4 and R.sub.E.sup.5 are individually selected from hydrogen, halogen, cyano, nitro, --C(.dbd.T.sup.2)--T.sup.3, --T.sup.1 --C(.dbd.T.sup.2)--T.sup.3, --CR.sub.E.sup.1 R.sub.E.sup.2 R.sub.E.sup.3, --SiT.sup.5 T.sup.5' T.sup.5", --S(.dbd.O)(.dbd.T.sup.2)--T.sup.4, and --P(.dbd.T.sup.2')(--T.sup.3)--T.sup.4.