Imidazole derivatives as protective agents in reperfusion injury and severe inflammatory responses
First Claim
1. A method for inhibiting or treating reperfusion injury in a mammalian organism in need of such treatment, said method comprising administering to said mammal an amount of an imidazole derivative effective in the inhibition or treatment of reperfusion injury, said imidazole derivative having the formula:
- ##STR6## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
X is a heteroatom selected from the group consisting of oxygen and sulfur;
Q is selected from the group consisting of --(CH2)--n, --(CH)--n ##STR7## and m=0 or 1p=0 or 1 n=1-18x=y=0-3s=1-3t=1-3with the proviso that when p=0 then m=1 and the imidazole rings are joined together by a single bond to make a fused tricyclic ring, and when m=0 then p=1.
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Abstract
Compounds of the formula ##STR1## wherein the substituents are as defined in the disclosure. The compounds are particularly useful for inhibiting damage to a variety of mammalian tissue that are jeopardized, for example, during runaway inflammatory conditions due to the damaging presence of singlet oxygen, the hydroxyl radical, cytokines and growth factors. The compounds are also useful in inhibiting damage to cardiac and central nervous system tissues during reperfusion.
14 Citations
53 Claims
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1. A method for inhibiting or treating reperfusion injury in a mammalian organism in need of such treatment, said method comprising administering to said mammal an amount of an imidazole derivative effective in the inhibition or treatment of reperfusion injury, said imidazole derivative having the formula:
- ##STR6## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
X is a heteroatom selected from the group consisting of oxygen and sulfur;
Q is selected from the group consisting of --(CH2)--n, --(CH)--n ##STR7## and m=0 or 1p=0 or 1 n=1-18 x=y=0-3 s=1-3 t=1-3 with the proviso that when p=0 then m=1 and the imidazole rings are joined together by a single bond to make a fused tricyclic ring, and when m=0 then p=1. - View Dependent Claims (2, 3, 4, 5, 6)
- ##STR6## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
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7. A method of controlling at least one of ventricular tachycardia, ventricular fibrillation, and ultrastructural damage to or infarction of coronary and cardiac tissue, comprising the step of providing to said tissue an amount of an imidazole derivative effective to prevent tachycardia or fibrillation, ultrastructural damage to or infarction of said tissues, said imidazole derivative having the formula:
- ##STR8## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
X is a heteroatom selected from the group consisting of oxygen and sulfur;
Q is selected from the group consisting of --(CH2)--n, --(CH)--n ##STR9## and m=0 or 1p=0 or 1 n=1-18 x=y=0-3 s=1-3 t=1-3 with the proviso that when p=0 then m=1 and the imidazole rings are joined together by a single bond to make a fused tricyclic ring, and when m=0 then p=1. - View Dependent Claims (8, 9, 10, 11, 12)
- ##STR8## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
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13. A method for treating runaway inflammatory responses in a mammalian organism in need of such treatment, said method comprising administering to said mammal an effective amount of an imidazole derivative having the formula:
- ##STR10## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
X is a heteroatom selected from the group consisting of oxygen and sulfur;
Q is selected from the group consisting of --(CH2)--n, --(CH)--n ##STR11## and m=0 or 1p=0 or 1 n=1-18 x=y=0-3 s=1-3 t=1-3 with the proviso that when p=0 then m=1 and the imidazole rings are joined together by a single bond to make a fused tricyclic ring, and when m=0 then p=1. - View Dependent Claims (14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
- ##STR10## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
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25. A method of preventing, controlling, or ameliorating the growth of undesired or abnormal tissue that occurs in a mammal following surgical procedures, said method comprising the step of administering a therapeutically effective amount of an imidazole derivative having the formula:
- ##STR12## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
X is a heteroatom selected from the group consisting of oxygen and sulfur;
Q is selected from the group consisting of --(CH2)--n, --(CH)--n ##STR13## and m=0 or 1p=0 or 1 n=1-18 x=y=0-3 s=1-3 t=1-3 with the proviso that when p=0 then m=1 and the imidazole rings are joined together by a single bond to make a fused tricyclic ring, and when m=0 then p=1. - View Dependent Claims (26, 27, 28, 29, 30, 31, 32)
- ##STR12## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
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33. A method of ameliorating damage to mammalian central nervous system tissue, cells, or vessels, comprising the step of administering to a mammalian subject in need thereof an effective amount of an imidazole derivative having the formula:
- ##STR14## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
X is a heteroatom selected from the group consisting of oxygen and sulfur;
Q is selected from the group consisting of --(CH2)--n, --(CH)--n ##STR15## and m=0 or 1p=0 or 1 n=1-18 x=y=0-3 s=1-3 t=1-3 with the proviso that when p=0 then m=1 and the imidazole rings are joined together by a single bond to make a fused tricyclic ring, and when m=0 then p=1. - View Dependent Claims (34, 35, 36, 37, 38)
- ##STR14## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
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39. A method of protecting mammalian tissue and cells from damaging oxygen species by administering to a mammalian subject in need thereof an effective amount of an imidazole derivative to scavenge at least one of singlet oxygen and hydroxyl radicals, said imidazole derivative having the formula:
- ##STR16## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
X is a heteroatom selected from the group consisting of oxygen and sulfur;
Q is selected from the group consisting of --(CH2)--n, --(CH)--n ##STR17## and m=0 or 1p=0 or 1 n=1-18 x=y=0-3 s=1-3 t=1-3 with the proviso that when p=0 then m=1 and the imidazole rings are joined together by a single bond to make a fused tricyclic ring, and when m=0 then p=1.
- ##STR16## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
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40. A method of improving mammalian vasomotor tone by administering to a mammal an amount of an imidazole derivative sufficient to protect the endothelial dependent relaxation factor (EDRF/nitric oxide) cycle, said imidazole derivative having the formula:
- ##STR18## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
X is a heteroatom selected from the group consisting of oxygen and sulfur;
Q is selected from the group consisting of --(CH2)--n, --(CH)--n ##STR19## and m=0 or 1p=0 or 1 n=1-18 x=y=0-3 s=1-3 t=1-3 with the proviso that when p=0 then m=1 and the imidazole rings are joined together by a single bond to make a fused tricyclic ring, and when m=0 then p=1. - View Dependent Claims (41, 42, 43, 44, 45)
- ##STR18## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
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46. A pharmaceutical composition useful for inhibiting damage to jeopardized tissue during reperfusion in a mammal which comprises:
- (a) a compound of the formula ##STR20## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
X is a heteroatom selected from the group consisting of oxygen and sulfur;
Q is selected from the group consisting of --(CH2)--n, --(CH)--n ##STR21## and m=0 or 1p=0 or 1 n=1-18 x=y=0-3 s=1-3 t=1-3 with the proviso that when p=0 then m=1 and the imidazole rings are joined together by a single bond to make a fused tricyclic ring, and when m=0 then p=1;
(b) a therapeutic agent selected from the group consisting of urokinase, streptokinase, tissue plasminogen activator and superoxide dismutase; and
(c) a pharmaceutically acceptable inert carrier.
- (a) a compound of the formula ##STR20## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
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47. A therapeutic composition for treating reperfusion injury and injury due to severe inflammatory responses in a mammal which comprises:
- (a) a compound of the formula ##STR22## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
X is a heteroatom selected from the group consisting of oxygen and sulfur;
Q is selected from the group consisting of --(CH2)--n, --(CH)--n ##STR23## and m=0 or 1p=0 or 1 n=1-18 s=1-3 t=1-3 with the proviso that when p=0 then m=1 and the imidazole rings are joined together by a single bond to make a fused tricyclic ring, and when m=0 then p=1; and
(b) a carrier which is a biomaterial or a delivery device for direct or indirect delivery to tissue or cells in need of treatment. - View Dependent Claims (48)
- (a) a compound of the formula ##STR22## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
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49. A compound of the formula:
- ##STR24## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
X is a heteroatom selected from the group consisting of oxygen and sulfur;
Q is selected from the group consisting of --(CH)--n ##STR25## and m=0 or 1p=0 or 1 n=1-18 s=1-3 t=1-3 with the proviso that when p=0 then m=1 and the imidazole rings are joined together by a single bond to make a fused tricyclic ring, and when m=0 then p=1. - View Dependent Claims (50, 51, 52, 53)
- ##STR24## wherein R1 and R2 are selected from the group consisting of hydrogen and normal, secondary, branched and tertiary C1-18 alkyl groups;
Specification