Piperidine and hexahydropyridazine thrombin inhibitors

Details Piperidine and hexahydropyridazine thrombin inhibitors Piperidine and hexahydropyridazine thrombin inhibitors

1997-01-16

1998-02-03

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514210, 514319, 514330, 544224, 546206, 548953, A61K 31445, A61K 3150, C07D21108, C07D23704

Patent

active

057144850

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

Thrombin is a serine protease present in blood plasma in the form of a precursor, prothrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the solution plasma protein, fibrinogen, into insoluble fibrin.
Edwards et al. J. Amer. Chem. Soc. (1992) vol. 114, pp. 1854-63, describes peptidyl a-ketobenzoxazoles which are reversible inhibitors of the serine proteases human leukocyte elastase and porcine pancreatic elastase.
European Publication 363 284 describes analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.
Australian Publication 86245677 also describes peptidase inhibitors having an activated electrophilic ketone moiety such as fluoromethylene ketone or a-keto carboxyl derivatives.
Thrombin inhibitors described in prior publications contain sidechains of arginine and lysine. These structures show low selectivity for thrombin over other trypsin-like enzymes. Some of them show toxicity of hypotension and liver toxicity.


SUMMARY OF THE INVENTION

These compounds show selectivity for thrombin over trypsin and other trypsin-like enzymes and have oral bioavailability. Trypsin-like enzymes (such as trypsin, thrombin, factor xa, kallikrein, plasmin, urokinase, and plasminogen activator) are serine dependent enzymes that catalyze hydrolysis at arginyl and lysyl peptide bonds.
The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents. The compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
The invention also includes a composition for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
The invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention.
Some abbreviations that may appear in this application are as follows.


ABBREVIATIONS



______________________________________ Designation Protecting Group BOC (Boc) t-butyloxycarbonyl CBZ (Cbz) benzyloxycarbonyl(carbobenzoxy) TBS (TBDMS) t-butyl-dimethylsilyl Activating Group HBT (HOBT or HOBt) 1-hydroxybenzotriazole hydrate Designation Coupling Reagent BOP reagent benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphinic chloride EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride Other (BOC).sub. O (BOC.sub.2 O) di-t-butyl dicarbonate n-Bu.sub.4 N+F-- tetrabutyl ammonium fluoride nBuLi (n-Buli) n-butyllithium DMF dimethylformamide Et.sub.3 N triethylamine EtOAc ethyl acetate TFA trifluoroacetic acid DMAP dimethylaminopyridine DME dimethoxyethane LDA lithium diisopropylamide THF tetrahydrofuran Amino Acid IIe Isoleucine Phe Phenylalanine Pro Proline Ala Alanine Val Valine ______________________________________


DETAILED DESCRIPTION OF THE INVENTION

Compounds of the invention have the following structure: ##STR2## wherein R.sup.1 and R.sup.2 are independently heterocyclic ring system any ting of which may be saturated or unsaturated, and which consists

REFERENCES:
patent: 2277409 (1942-03-01), Murray
Balasaubramanian et al., J. Med. Chem., vol. 36, pp. 300-303 "Active Site-Directed Synthetic Thrombin Inhibitors: Synthesis, in Vitro . . . " (1993).
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