In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. The N.sup.2 -(p-Tolysulfonyl)-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.sup.2 -dansyl-L-arginine esters or amides (U.S. Pat. No. 3,978,045) and many N.sup.2 -arylsulfonyl-L-argininamides. Moreover, another compound which has proven to be particularly useful for the treatment of thrombosis in mammals is 1-[5-[Aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8-qui nolinyl)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.