SYNERGISTIC ANTICOAGULANT COMPOSITION

Abstract

A composition is provided that, when utilized in combination with a coumarin anticoagulant, greatly improves the anticoagulant effects of the anticoagulant in mammalian subjects. The composition is a compound having a naphthohydroquinone ring system substantially similar to the ring system of the reduced form of vitamin K.sub.1 and has the general formula:

##STR00001##

where n is 1 or 2, where R.sub.1 and R.sub.4 are hydrogen or acyl, R.sub.2 is a hydrogen or saturated or unsaturated alkyl group with up to 6 carbons, and R.sub.3 is a hydrogen or saturated or unsaturated alkyl group with up to 6 carbons, or R.sub.2 and R.sub.3 are part of a cyclic or polycyclic ring system.

Claims

1. A compound comprising the following structure: ##STR00005## wherein R is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; and wherein R.sup.1 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and R.sup.4 hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or wherein R.sup.1 and R.sup.2 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or wherein R.sup.1 and R.sup.4 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl).

2. A compound comprising the following structure: ##STR00006## wherein R is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; and wherein R.sup.1 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); or wherein R.sup.1 and R.sup.2 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); or wherein R.sup.1 and R.sup.4 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy).

3. A compound comprising the following structure: ##STR00007## wherein R.sup.1 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester); or wherein R.sup.1 and R.sup.2 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester); or wherein R.sup.1 and R.sup.4 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester).

4. A compound comprising the following structure: ##STR00008## wherein R.sup.1 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester); or wherein R.sup.1 and R.sup.2 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester); or wherein R.sup.1 and R.sup.4 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester).

5. A method for enhancing the effectiveness of an anti-coagulant composition comprising the step of administering the anticoagulant composition in conjunction with an effective amount of a composition comprising the following structure: ##STR00009## wherein R is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; and wherein R.sup.1 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and R.sup.4 hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or wherein R.sup.1 and R.sup.2 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or wherein R.sup.1 and R.sup.4 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); and wherein the anticoagulant composition is a coumarin-based anticoagulant or metabolite thereof with the general structure ##STR00010## wherein R.sup.7 is a substituted alkyl group with up to 6 carbons; and A is a group chosen from an alcohol, an ester, an ether, an ester, or a ketone; and wherein R.sup.8 is a substituted alkyl group with up to 6 carbons; and B is a an aryl group (phenyl, biphenyl, furyl, 4-bromo-4,1-biphenyl); or wherein R.sup.7 and R.sup.8 constitute a cycloalkyl group with up to 7 carbons; and A is a group chosen from an alcohol, an ester, an ether, an ester, or a ketone; and B is a an aryl group (phenyl, biphenyl, furyl, 4-bromo-4,1-biphenyl); and wherein X is hydrogen or hydroxy; and wherein Y is hydrogen or hydroxy.

6. A method for enhancing the effectiveness of an anti-coagulant composition comprising the step of administering the anticoagulant composition in conjunction with an effective amount of a composition comprising the following structure: ##STR00011## wherein R is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; and wherein R.sup.1 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and R.sup.4 hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); or wherein R.sup.1 and R.sup.2 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); or wherein R.sup.1 and R.sup.4 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyl dimethylsilyl, dim ethyl phenyl silyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyl dimethylsilyloxy, triethylsilyloxy, dim ethyl phenylsilyloxy); and wherein the anticoagulant composition is a coumarin-based anticoagulant or metabolite thereof with the general structure ##STR00012## wherein R.sup.7 is a substituted alkyl group with up to 6 carbons; and A is a group chosen from an alcohol, an ester, an ether, an ester, or a ketone; and wherein R.sup.8 is a substituted alkyl group with up to 6 carbons; and B is a an aryl group (phenyl, biphenyl, furyl, 4-bromo-4,1-biphenyl); or wherein R.sup.7 and R.sup.8 constitute a cycloalkyl group with up to 7 carbons; and A is a group chosen from an alcohol, an ester, an ether, an ester, or a ketone; and B is a an aryl group (phenyl, biphenyl, furyl, 4-bromo-4,1-biphenyl); and wherein X is hydrogen or hydroxy; and wherein Y is hydrogen or hydroxy.

7. A method for enhancing the effectiveness of an anti-coagulant composition comprising the step of administering the anticoagulant composition in conjunction with an effective amount of a composition comprising the following structure: ##STR00013## wherein R.sup.1 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester); or wherein R.sup.1 and R.sup.2 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester); or wherein R.sup.1 and R.sup.4 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.5 is hydrogen or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester); and wherein the anticoagulant composition is a coumarin-based anticoagulant or metabolite thereof with the general structure ##STR00014## wherein R.sup.7 is a substituted alkyl group with up to 6 carbons; and A is a group chosen from an alcohol, an ester, an ether, an ester, or a ketone; and wherein R.sup.8 is a substituted alkyl group with up to 6 carbons; and B is a an aryl group (phenyl, biphenyl, furyl, 4-bromo-4,1-biphenyl); or wherein R.sup.7 and R.sup.8 constitute a cycloalkyl group with up to 7 carbons; and A is a group chosen from an alcohol, an ester, an ether, an ester, or a ketone; and B is a an aryl group (phenyl, biphenyl, furyl, 4-bromo-4,1-biphenyl); and wherein X is hydrogen or hydroxy; and wherein Y is hydrogen or hydroxy.

8. A method for enhancing the effectiveness of an anti-coagulant composition comprising the step of administering the anticoagulant composition in conjunction with an effective amount of a composition comprising the following structure: ##STR00015## wherein R.sup.1 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester); or wherein R.sup.1 and R.sup.2 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.4 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester); or wherein R.sup.1 and R.sup.4 comprise a substituted or unsubstituted, saturated or unsaturated ,-alkylene group with up to four carbons; and wherein R.sup.2 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or rialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein R.sup.3 is hydrogen or saturated or unsaturated alkyl with up to 6 carbons; or alkoxy with up to 3 carbons; or trialkylsilyl (trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl); or trialkylsilyloxy (trimethylsilyloxy, tert-butyldimethylsilyloxy, triethylsilyloxy, dimethylphenylsilyloxy); and wherein X is a heteroatomic group (alcohol, ester, amine, amide, sulfonamide, halide, sulfonate ester); and wherein the anticoagulant composition is a coumarin-based anticoagulant or metabolite thereof with the general structure ##STR00016## wherein R.sup.7 is a substituted alkyl group with up to 6 carbons; and A is a group chosen from an alcohol, an ester, an ether, an ester, or a ketone; and wherein R.sup.8 is a substituted alkyl group with up to 6 carbons; and B is a an aryl group (phenyl, biphenyl, furyl, 4-bromo-4,1-biphenyl); or wherein R.sup.7 and R.sup.8 constitute a cycloalkyl group with up to 7 carbons; and A is a group chosen from an alcohol, an ester, an ether, an ester, or a ketone; and B is a an aryl group (phenyl, biphenyl, furyl, 4-bromo-4,1-biphenyl); and wherein X is hydrogen or hydroxy; and wherein Y is hydrogen or hydroxy.

9. The composition in claim 5, wherein the anticoagulant is a coumarin-based anticoagulant.

10. The composition in claim 6, wherein the anticoagulant is a coumarin-based anticoagulant.

11. The composition in claim 7, wherein the anticoagulant is a coumarin-based anticoagulant.

12. The composition in claim 8, wherein the anticoagulant is a coumarin-based anticoagulant.

13. The composition in claim 5, wherein the anticoagulant is warfarin.

14. The composition in claim 6, wherein the anticoagulant is warfarin.

15. The composition in claim 7, wherein the anticoagulant is warfarin.

16. The composition in claim 8, wherein the anticoagulant is warfarin.

17. The composition in claim 5, wherein the anticoagulant is a second-generation coumarin anticoagulant.

18. The composition in claim 6, wherein the anticoagulant is a second-generation coumarin anticoagulant.

19. The composition in claim 7, wherein the anticoagulant is a second-generation coumarin anticoagulant.

20. The composition in claim 8, wherein the anticoagulant is a second-generation coumarin anticoagulant.

21. The composition in claim 7, wherein the adjuvant composition is obtained by hydrolysis of the composition in claim 5 and wherein the anticoagulant is a coumarin-based anticoagulant.

22. The composition in claim 8, wherein the adjuvant composition is obtained by hydrolysis of the composition in claim 6 and wherein the anticoagulant is a coumarin-based anticoagulant.

23. The composition in claim 7, wherein the adjuvant composition is obtained by hydrolysis of the composition in claim 5 and wherein the anticoagulant is warfarin.

24. The composition in claim 8, wherein the adjuvant composition is obtained by hydrolysis of the composition in claim 6 and wherein the anticoagulant is warfarin.

25. The composition in claim 7, wherein the adjuvant composition is obtained by hydrolysis of the composition in claim 5 and wherein the anticoagulant is a second-generation coumarin anticoagulant.

26. The composition in claim 8, wherein the adjuvant composition is obtained by hydrolysis of the composition in claim 6 and wherein the anticoagulant is a second-generation coumarin anticoagulant.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0079] FIG. 1 depicts a general schematic illustrating the vitamin K cycle;

[0080] FIG. 2 depicts a general schematic illustrating oxygenation of warfarin to 7-hydroxywarfarin by cytochrome P450 polymorph CYP 2C9;

[0081] FIG. 3 depicts a general schematic illustrating reactions of UWEC-K2 under conditions of acid and base hydrolysis;

[0082] FIG. 4 depicts a general schematic illustrating a putative model that rationalizes the reversal of the anticoagulant activity of warfarin in the presence of UWEC-K2;

[0083] FIG. 5 depicts a general schematic illustrating generation of a naphthoquinone-based free radical by oxidation of the cyclopropyl ketone;

[0084] FIG. 6 depicts a general schematic illustrating possible coupling of a free radical derived from a cyclo-propyl ketone with 7-hydroxywarfarin; and

[0085] FIG. 7 depicts a general schematic illustrating possible inhibition of CYP 2C9 by a conjugate of 7-hydroxywarfarin formed in situ.

DETAILED DESCRIPTION OF THE INVENTION

[0086] The invention consists of a two-component synergistic mixture of a cyclopropyl ketone and a coumarin anticoagulant or its metabolite. The compound designated UWEC-K2 is prepared from the Diels-Alder adduct of 1,4-naphthoquinone and cyclopentadiene by the method of Lewis, et al. See Lewis, D. E.; Caldwell, M. D. Synergistic anticoagulant composition. U.S. Pat. No. 8,765,982 B2 (Jul. 1, 2014), hereby incorporated by reference. The treatment of UWEC-K2 with potassium carbonate in methanol for a short period (not more than 30 minutes) results in the formation of the cyclopropyl ketone. The cyclopropyl ketone in FIG. 3 has been derived from the starting diketone by a somewhat different route. See Marchand, A. P.; Dong, E. Z.; Bott, S. G. Synthesis and acid- and base-promoted ring opening of polycarbocyclic oxiranes. Tetrahedron 1998, 54(18), 4459-4570, hereby incorporated by reference. The approach described herein does not require the use of the strong bases or extended reaction times required by the March and method, and does not require chromatography.

[0087] The epoxide is essential for UWEC-K2 activity. In one model, it is postulated that the synergistic anticoagulant activity involves the transesterification of warfarin sodium by UWEC-K2. This process will lead to ring opening of the epoxide to give the cyclopropyl ketone, which makes the otherwise unfavorable equilibrium for the acetyl transfer irreversible (UWEC-K1 does not exhibit this type of biological activity). It is postulated that the products of the transesterification (warfarin acetate and the cyclopropyl ketone) are not anticoagulants, which then provides a reasonable rationalization of the observation that the anticoagulant activity of warfarin (and the anticoagulant activity of UWEC-K1) is reversed (FIG. 4).

[0088] It follows from this that the hydrolysis of the warfarin acetate at a later time may lead to the generation of a bolus of warfarin that leads to the much higher levels of anticoagulation observed previously. See Stromich, J. J.; Weber, A. K.; Mirzaei, Y. R. ; Caldwell, M. D.; Lewis, D. E. Bioorg. Med. Chem. Lett. 2010, 20, 1928-1932, hereby incorporated by reference. Warfarin acetate is also more lipophilic than warfarin itself, which may increase its half-life in the animal, also rendering it a more potent anticoagulant.

[0089] Another model that rationalizes the observed synergistic anticoagulant activity involves an intriguing possibility based on the typical activity of cytochrome P.sub.450. In particular, if the cyclopropyl ketone is bound in the active site of the cytochrome, then CYP 2C9 could oxidize this to a free radical that undergoes the normal cyclopropylcarbinyl to homoallyl radical isomerization to generate a naphthoquinone and a simple alkyl radical (FIG. 5).

[0090] What is particularly enticing is the fact that this free radical could easily react with warfarin or, much more interestingly, 7-hydroxywarfarin, to give a coupled product that may well be a super inhibitor of CYP 2C9 (FIG. 6).

[0091] The available evidence about this enzyme is that it has a large active site that can exist on an open form and a closed form. The X-ray crystal structures show that both active sites can accommodate a second molecule in addition to the warfarin. We suggest that the opening to the active site, however, is such that only one molecule at a time may enter, and that once the UWEC-K2 metabolite and the 7-hydroxywarfarin enter the active site of the enzyme, they actually become covalently bonded to each other. This results in a molecule that is too big to exit the active site, and thus leads to inactivation of the enzyme (FIG. 7). Since CYP 2C9 provides the most important pathway for deactivating warfarin in vivo, this may provide a new way for the control of warfarin anticoagulation.

[0092] The initial reversal of warfarin anticoagulation by UWEC-K2 may be rationalized in terms of the cyclopropyl ketone binding to the active site of CYP 2C9, and making warfarin and 7-hydroxywarfarin bind much more tightly, thus reducing the available warfarin in circulation, making the anticoagulation by warfarin ineffective. Once the CYP 2C9 active site is saturated, however, the effective warfarin concentration will rise, and anticoagulation will increase.

[0093] Alternatively, the final conjugate, formed in the active site of CYP 2C9 by coupling of warfarin (or 7-hydroxywarfarin) with the naphthoquinone radical may be a super inhibitor of CYP 2C9. This should gradually lead to a dramatic rise in warfarin anticoagulation because the inactivation of warfarin by CYP 2C9 is prevented as the amount of uninhibited CYP 2C9 decreases. One would assume that there is some threshold level of inhibition required to see the increased effectiveness of warfarin as an anticoagulant.

[0094] One especially puzzling result of early in vivo testing of UWEC-K2 was the observation that when the diets were mixed using a small amount of alcohol to add the UWEC-K2 to the soybean oil, the resultant tests were negative for the anticoagulation enhancement. It is difficult to see how so small a change could have such a large effect, but we now believe that the ethanol may have activated esterases to cleave more of the UWEC-K2 in the stomach, with the result that less of the UWEC-K2 entered the duodenum unaltered. Under these conditions, less UWEC-K2 would also enter the liver, where it is metabolized to the active adjuvant.

[0095] As can be appreciated, the results described in the above examples support the utility of the composition described and claimed herein that, when utilized in combination with a coumarin anticoagulant, improves the anticoagulant effects of the anticoagulant in mammalian subjects. Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration from the specification and practice of the invention disclosed herein. All references cited herein for any reason, including all journal citations and U.S./foreign patents and patent applications, if present, are specifically and entirely incorporated herein by reference. It is understood that the invention is not confined to the specific compositions, materials, methods, formulations, manufacturing conditions, etc., herein illustrated and described, but embraces such modified forms thereof as come within the scope of the following claims.