Griseolic acid derivatives, and their use as enzyme inhibitors
First Claim
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1. A griseolic acid compound of the formula:
- ##STR9## wherein;
A represents a group of formula;
##STR10## R1, R2, R5 and R6 are the same or different and each represents a hydrogen or halogen atom, the azido group, or a group of formula --OR9, --NR10 R11 or --SR9 ;
R3 represents a hydrogen or halogen atom or a C1 -C20 aliphatic acyloxy or a (C6 -C20 aromatic)acyloxy or C1 -C6 alkoxy group;
R4 represents a hydrogen or halogen atom;
orR3 and R4 together represent an extra carbon-carbon bond between the carbon atoms to which they are attached;
orR3 and R2 together represent an oxygen atom bridging the carbon atoms to which they are attached;
R7 represents an optionally substituted C1 -C6 alkyl, C3 -C6 alkenyl or aralkyl group (wherein the alkyl moiety has from 1 to 6 carbon atoms), the substituents being selected from halogen atoms, C1 -C4 alkoxy groups, (C1 -C4 alkoxy)carbonyl groups and (where R7 is substituted aralkyl) C1 -C4 alkyl groups;
R8 represents an oxygen or sulfur atom or the imino group;
R9 represents hydrogen, a C1 -C6 alkyl group, a heterocyclic group (having 5 or 6 ring atoms, of which from 1 to 3 are oxygen, nitrogen or sulfur, and being unsubstituted or having from 1 to 3 C1 -C4 alkyl or alkoxy substituents), a tri(C1 -C4 alkyl)silyl group, an alkylsulfonyl group, a haloalkylsulfonyl group, a benzenesulphonyl optionally substituted with a C1 -C3 alkyl group, a C1 -C20 aliphatic acyl group or a C6 -C20 aromatic acyl group;
R10 and R11 are the same or different and each represents hydrogen, hydroxy, a C1 -C6 alkyl group, a C1 -C6 hydroxyalkyl group, a C1 -C6 aminoalkyl group, an aralkyl group, an aryl group, a C1 -C6 alkoxy group, the amino group, a C1 -C20 aliphatic acyl group or a C6 -C20 aromatic acyl group;
or R10 and R11, together with the nitrogen atom to which they are attached, represent a 5- or 6-membered heterocyclic group having at least one other hetero-atom selected from oxygen, and nitrogen atoms and optionally having one C1 -C4 alkyl substituent;
and pharmaceutically acceptable salts and esters thereof;
but excluding 7'"'"'(R)-griseolic acid itself and salts thereof.
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Abstract
Griseolic acid derivatives of formula (I): ##STR1## wherein A represents: ##STR2## have enzyme-inhibitory activity, especially against cAMP PDE and cGMP PDE. When formulated as compositions with appropriate carriers or diluents, they may be used for the treatment of a variety of organic disorders and show toxicities less than griseolic acid itself.
21 Citations
38 Claims
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1. A griseolic acid compound of the formula:
- ##STR9## wherein;
A represents a group of formula;
##STR10## R1, R2, R5 and R6 are the same or different and each represents a hydrogen or halogen atom, the azido group, or a group of formula --OR9, --NR10 R11 or --SR9 ;R3 represents a hydrogen or halogen atom or a C1 -C20 aliphatic acyloxy or a (C6 -C20 aromatic)acyloxy or C1 -C6 alkoxy group; R4 represents a hydrogen or halogen atom;
orR3 and R4 together represent an extra carbon-carbon bond between the carbon atoms to which they are attached;
orR3 and R2 together represent an oxygen atom bridging the carbon atoms to which they are attached; R7 represents an optionally substituted C1 -C6 alkyl, C3 -C6 alkenyl or aralkyl group (wherein the alkyl moiety has from 1 to 6 carbon atoms), the substituents being selected from halogen atoms, C1 -C4 alkoxy groups, (C1 -C4 alkoxy)carbonyl groups and (where R7 is substituted aralkyl) C1 -C4 alkyl groups; R8 represents an oxygen or sulfur atom or the imino group; R9 represents hydrogen, a C1 -C6 alkyl group, a heterocyclic group (having 5 or 6 ring atoms, of which from 1 to 3 are oxygen, nitrogen or sulfur, and being unsubstituted or having from 1 to 3 C1 -C4 alkyl or alkoxy substituents), a tri(C1 -C4 alkyl)silyl group, an alkylsulfonyl group, a haloalkylsulfonyl group, a benzenesulphonyl optionally substituted with a C1 -C3 alkyl group, a C1 -C20 aliphatic acyl group or a C6 -C20 aromatic acyl group; R10 and R11 are the same or different and each represents hydrogen, hydroxy, a C1 -C6 alkyl group, a C1 -C6 hydroxyalkyl group, a C1 -C6 aminoalkyl group, an aralkyl group, an aryl group, a C1 -C6 alkoxy group, the amino group, a C1 -C20 aliphatic acyl group or a C6 -C20 aromatic acyl group;
or R10 and R11, together with the nitrogen atom to which they are attached, represent a 5- or 6-membered heterocyclic group having at least one other hetero-atom selected from oxygen, and nitrogen atoms and optionally having one C1 -C4 alkyl substituent;and pharmaceutically acceptable salts and esters thereof; but excluding 7'"'"'(R)-griseolic acid itself and salts thereof. - View Dependent Claims (2, 3, 4, 5, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)
- ##STR9## wherein;
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6. A compound selected from the group consisting of:
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dibenzhydryl N6,O2'"'"',O7'"'"' -tripropionylgriseolate; disodium N6,O2'"'"',O7'"'"' -tribenzoylgriseolate; N6 -benzoylgriseolic acid; O2'"'"' -benzoylgriseolic acid; O7'"'"' -benzoylgriseolic acid; 6-desamino-6-hydroxygriseolic acid; 6-desamino-6-mercaptogriseolic acid; N6,O2'"'"',O7'"'"' -tribenzoylgriseolic acid; 7'"'"'-deoxygriseolic acid; 6-desamino-7'"'"'-deoxy-6-hydroxygriseolic acid; 2'"'"'(S)-chloro-2'"'"'-deoxygriseolic acid; 2'"'"'(S)-bromo-2'"'"'-deoxygriseolic acid; '"'"' -deoxygriseolic acid; bis(1-pivaloyloxyethyl)griseolate; bis(5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl)griseolate; bis(1-pivaloyloxyethyl) 6-desamino-6-hydroxygriseolate; bis(5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl) 6-desamino-6-hydroxygriseolate; 7'"'"'(S)-griseolic acid; 8-mercaptogriseolic acid; 8-methoxygriseolic acid; 8-bromogriseolic acid; 8-aminogriseolic acid; 7'"'"'(S)-acetoxy-7'"'"'-deoxygriseolic acid; dibenzhydryl 4'"'"',7'"'"'-anhydro-5'"'"'α
-bromo-4'"'"'α
-hydroxygriseolate;2'"'"'(S)-azido-2'"'"'-deoxygriseolic acid; and N6 -methylgriseolic acid.
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7. A pharmaceutical composition comprising an effective amount of at least one active compound in admixture with a pharmaceutically acceptable carrier or diluent, wherein the active compound is selected from griseolic acid compounds of the formula:
- ##STR11## wherein;
A represents a group of formula;
##STR12## R1, R2, R5 and R6 are the same or different and each represents a hydrogen or halogen atom, the azido group, or a group of formula --OR9, --NR10 R11 or --SR9 ;R3 represents a hydrogen or halogen atom or a C1 -C20 aliphatic acyloxy or a (C6 -C20 aromatic) acyloxy or C1 -C6 alkoxy group; R4 represents a hydrogen or halogen atom;
orR3 and R4 together represent an extra carbon-carbon bond between the carbon atoms to which they are attached;
orR3 and R2 together represent an oxygen atom bridging the carbon atoms to which they are attached; R7 represents an optionally substituted C1 -C6 alkyl, C3 -C6 alkenyl or aralkyl group (wherein the alkyl moiety has from 1 to 6 carbon atoms), the substituents being selected from halogen atoms, C1 -C4 alkoxy groups, (C1 -C4 alkoxy)carbonyl groups and (where R7 is substituted aralkyl) C1 -C4 alkyl groups; R8 represents an oxygen or sulfur atom or the imino group; R9 represents hydrogen, a C1 -C6 alkyl group, a heterocyclic group (having 5 or 6 ring atoms, of which from 1 to 3 are oxygen, nitrogen or sulfur, and being unsubstituted or having from 1 to 3 C1 -C4 alkyl or alkoxy substituents), a tri(C1 -C4 alkyl)silyl group, an alkylsulfonyl group, a haloalkylsulfonyl group, a benzenesulphonyl optionially substituted with a C1 -C3 alkyl group, a C1 -C20 aliphatic acyl group or a C6 -C20 aromatic acyl group; R10 and R11 are the same or different and each represents hydrogen, hydroxy, a C1 -C6 alkyl group, a C1 -C6 hydroxyalkyl group, a C1 -C6 aminoalkyl group, an aralkyl group, an aryl group, a C1 -C6 alkoxy group, the amino group, a C1 -C20 aliphatic acyl group or a C6 -C20 aromatic acyl group;
or R10 and R11, together with the nitrogen atom to which they are attached, represent a 5- or 6-membered heterocyclic group having at least one other hetero-atom selected from oxygen, and nitrogen atoms and optionally having one C1 -C4 alkyl substituent;and pharmaceutically acceptable salts and esters thereof; but excluding 7'"'"'(R)-griseolic acid itself and salts thereof. - View Dependent Claims (8, 9, 10, 11, 12)
- ##STR11## wherein;
Specification