Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-22
2001-08-21
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S311000, C546S165000, C546S166000, C546S178000
Reexamination Certificate
active
06277863
ABSTRACT:
TECHNICAL FIELD
The field of this invention is the extended lifetime of physiologically active agents ini a mammalian host, more specifically, the extended lifetime of inhibitors of thrombin activity in a mammalian host.
BACKGROUND
In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. The N
2
-(p-tolysulfbnyt)-L-arginine esters are one type of agent which can be used and these have been found to be effective in dissolving blood clots (see U.S. Pat. No. 3,622,615, issued Nov. 23, 1971). Another family of compounds which have been found to be particularly useful as highly specific inhibitors of thrombin for the control of thrombosis is the N
2
-dansyl-L-arginine esters or amides (U.S. Pat. No. 3,978,045) and many N
2
-arylsulfonyl-L-argiminamides. Moreover, another compound which has proven to be particularly useful for the treatment of thrombosis in mammals is 1-[5-[Aminoiminomethyl)aminol]-1-oxo-2-[[(1,2,3,4-tetraydro-3-methyl-8-quinolinyl)sulfonyl]-amino]pentyl]-4-methyl-2-piperidinecarboxylic acid, a compound which is commonly known as argatroban.
Although the above described compounds have proven useful for the treatment of disorders associated with abnormal thrombosis via inhibition of thrombin activity in vivo, their therapeutic utility is somewhat limited due to the fact that many of these compounds are quickly degraded and/or removed from the host's vascular system after administration. As such, for continuous thrombin inhibitory activity over extended periods of time, the above described thrombin inhibitors must be administered as a large bolus given at periodic time intervals or by providing depots comprising the drug. Unfortunately, however, administration of large boluses at periodic time intervals often results in subtherapeutic doses of the drug for extended periods of time followed by doses which may greatly exceed the desired therapeutic level. The latter may often involve serious adverse side effects. Moreover, although various pumps and biodegradable and non-biodegradable capsules have been devised for the delivery of drug over an extended period of time, these devices may have a variety of shortcomings in their profile of drug delivery, for example, often resulting in an inflammatory response and/or being subject to interference in their release of active drug.
There is, therefore, an interest in providing improved therapies associated with thrombin inhibition.
SUMMARY OF THE INVENTION
Novel compounds are provided comprising chemically reactive intermediates which can react with available reactive functionalities on blood components to form covalent linkages, where the resulting covalently-bound conjugates are found to have thrombin inhibition activity. Specifically, the compounds of the present invention are chemically reactive derivatives of the known thrombin inhibitor 1-[5-[Aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]-amino]pentyl]-4-methyl-2-piperidinecarboxylic acid, a compound also known as argatroban. The derivatized argatroban molecules of the present invention comprise an active thrombin inhibitor portion and become covalently linked through a chemically reactive group to reactive functionalities on various blood components. The conjugated thrombin inhibitor molecules thereby have extended lifetimes in the bloodstream, as compared to the unconjugated parent drug, and are, therefore, capable of maintaining thrombin inhibitory activity for extended periods of time as compared to the urconjugated parent drug.
Also provided herein are compositions comprising the derivatized thrombin inhibitor molecules described above combined with pharmaceutically acceptable carriers and methods for inhibiting thrombin activity in vivo comprising administering to the bloodstream of a mammalian host the novel compounds of the present invention.
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Ezrin Alan M.
Krantz Alexander
Song Yonghong
ConjuChem Inc.
Morrison & Foerster / LLP
Seaman D. Margaret
LandOfFree
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