Cyclopropyl modulators of p2y12 receptor

Abstract

The present invention relates to new cyclopropyl modulators of P2Y12 receptor activity, pharmaceutical compositions thereof, and methods of use thereof.

What is claimed is: 
     
         1 . A compound of Formula A or Formula B: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein each position represented as D has deuterium enrichment of no less than about 10%. 
     
     
         2 . The compound or salt thereof of  claim 1  wherein each position represented as D has deuterium enrichment of no less than about 50%. 
     
     
         3 . The compound or salt thereof of  claim 1  wherein each position represented as D has deuterium enrichment of no less than about 90%. 
     
     
         4 . The compound or salt thereof of  claim 1  wherein each position represented as D has deuterium enrichment of no less than about 98%. 
     
     
         5 . A method of treating a P2Y12 receptor-mediated disorder comprising administering to a patient in need thereof, a therapeutically effective amount of a compound or salt thereof as recited in  claim 1 . 
     
     
         6 . The method of  claim 5 , wherein said disorder is arterial thrombosis or coronary artery disease. 
     
     
         7 . The method of  claim 5 , further comprising administering an additional therapeutic agent. 
     
     
         8 . The method of  claim 7  wherein said additional therapeutic agent is an alpha adrenergic receptor antagonist, a beta adrenergic receptor antagonist, an angiotensin II receptor antagonist, an angiotensin-converting enzyme inhibitor, an anti-arrhythmic, an antithrombotic, an antiplatelet agent, a calcium channel blocker, a fibrate, or a HMG-CoA reductase inhibitor. 
     
     
         9 . The method of  claim 8  wherein said alpha adrenergic receptor antagonist is abanoquil, adimolol, ajmalicine, alfuzosin, amosulalol, arotinolol, atiprosin, benoxathian, buflomedil, bunazosin, carvedilol, CI-926, corynanthine, dapiprazole, DL-017, domesticine, doxazosin, eugenodilol, fenspiride, GYKI-12,743, GYKI-16,084, indoramin, ketanserin, L-765,314, labetalol, mephendioxan, metazosin, monatepil, moxisylyte (thymoxamine), naftopidil, nantenine, neldazosin, nicergoline, niguldipine, pelanserin, phendioxan, phenoxybenzamine, phentolamine, piperoxan, prazosin, quinazosin, ritanserin, RS-97,078, SGB-1,534, silodosin, SL-89.0591, spiperone, talipexole, tamsulosin, terazosin, tibalosin, tiodazosin, tipentosin, tolazoline, trimazosin, upidosin, urapidil, zolertine, 1-PP, adimolol, atipamezole, BRL-44408, buflomedil, cirazoline, efaroxan, esmirtazapine, fluparoxan, GYKI-12,743, GYKI-16,084, idazoxan, mianserin, mirtazapine, MK-912, NAN-190, olanzapine, phentolamine, phenoxybenzamine, piperoxan, piribedil, rauwolscine, rotigotine, SB-269,970, setiptiline, spiroxatrine, sunepitron, tolazoline, or yohimbine. 
     
     
         10 . The method of  claim 8 , wherein said beta adrenergic receptor antagonist is acebutolol, adaprolol, adimolol, afurolol, alprenolol, alprenoxime, amosulalol, ancarolol, arnolol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bormetolol, bornaprolol, brefonalol, bucindolol, bucumolol, bufetolol, buftiralol, bufuralol, bunitrolol, bunolol, bupranolol, burocrolol, butaxamine, butidrine, butofilolol, capsinolol, carazolol, carpindolol, carteolol, carvedilol, celiprolol, cetamolol, cicloprolol, cinamolol, cloranolol, cyanopindolol, dalbraminol, dexpropranolol, diacetolol, dichloroisoprenaline, dihydroalprenolol, dilevalol, diprafenone, draquinolol, dropranolol, ecastolol, epanolol, ericolol, ersentilide, esatenolol, esmolol, esprolol, eugenodilol, exaprolol, falintolol, flestolol, flusoxolol, hydroxycarteolol, hydroxytertatolol, ICI-118,551, idropranolol, indenolol, indopanolol, iodocyanopindolol, iprocrolol, isoxaprolol, isamoltane, labetalol, landiolol, levobetaxolol, levobunolol, levocicloprolol, levomoprolol, medroxalol, mepindolol, metalol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nafetolol, nebivolol, neraminol, nifenalol, nipradilol, oberadilol, oxprenolol, pacrinolol, pafenolol, pamatolol, pargolol, parodilol, penbutolol, penirolol, PhQA-33, pindolol, pirepolol, practolol, primidolol, procinolol, pronethalol, propafenone, propranolol, ridazolol, ronactolol, soquinolol, sotalol, spirendolol, SR 59230A, sulfinalol, TA-2005, talinolol, tazolol, teoprolol, tertatolol, terthianolol, tienoxolol, tilisolol, timolol, tiprenolol, tolamolol, toliprolol, tribendilol, trigevolol, xibenolol, or xipranolol. 
     
     
         11 . The method of  claim 8 , wherein said angiotensin II receptor antagonist is candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, or valsartan. 
     
     
         12 . The method of  claim 8 , wherein said angiotensin-converting enzyme inhibitor is captopril, enalapril, lisinopril, perindopril, ramipril, quinapril, benazepril, cilazapril, fosinopril, trandolapril, spirapril, delapril, moexipril, temocapril, zofenopril, or imidapril. 
     
     
         13 . The method of  claim 8 , wherein said anti-arrhythmic is quinidine, procainamide, disopyramide, sparteine, ajmaline, prajmaline, lorajmine, lidocaine, mexiletine, tocainide, aprindine, propafenone, flecainide, lorcainide, encainide, amiodarone, bretylium tosilate, bunaftine, dofetilide, ibutilidem, tedisamil, moracizine, or cibenzoline. 
     
     
         14 . The method of  claim 8 , wherein said antithrombotic is dicoumarol, phenindione, warfarin, phenprocoumon, acenocoumarol, ethyl biscoumacetate, clorindione, diphenadione, tioclomarol, heparin, antithrombin III, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, danaparoid, tinzaparin, sulodexide, bemiparin, ditazole, cloricromen, picotamide, clopidogrel, ticlopidine, acetylsalicylic acid, dipyridamole, carbasalate calcium, epoprostenol, indobufen, iloprost, abciximab, aloxiprin, eptifibatide, tirofiban, triflusal, beraprost, treprostinil, prasugrel, streptokinase, alteplase, urokinase, fibrinolysin, brinase, reteplase, saruplase, ancrod, drotrecogin alfa (activated), tenecteplase, protein C, desirudin, lepirudin, argatroban, melagatran, ximelagatran, bivalirudin, dabigatran etexilate, defibrotide, dermatan sulfate, fondaparinux, or rivaroxaban. 
     
     
         15 . The method of  claim 8 , wherein said antiplatelet agent is abciximab, eptifibatide, tirofiban, clopidogrel, prasugrel, ticlopidine, ticagrelor, beraprost, prostacyclin, iloprost, treprostinil, acetylsalicylic acid, aloxiprin, carbasalate calcium, indobufen, dipyridamole, picotamide, terutroban, cilostazol, dipyridamole, triflusal, cloricromen, or ditazole. 
     
     
         16 . The method as recited in  claim 8 , wherein said calcium channel blocker is amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine, benidipine, mibefradil, verapamil, gallopamil, diltiazem, fendiline, bepridil, lidoflazine, or perhexiline. 
     
     
         17 . The method of  claim 8 , wherein said fibrate is clofibrate, bezafibrate, aluminium clofibrate, gemfibrozil, fenofibrate, simfibrate, ronifibrate, ciprofibrate, etofibrate, or clofibride. 
     
     
         18 . The method of  claim 8 , wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin. 
     
     
         19 . The method of  claim 5 , further resulting in at least one effect which is:
 a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;   b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;   c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;   d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; or   e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.   
     
     
         20 . The method of  claim 5 , further resulting in at least two effects which are:
 a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;   b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;   c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;   d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; or   e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.   
     
     
         21 . The method of  claim 5 , wherein the method effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P 450 isoform in the subject, as compared to the corresponding non-isotopically enriched compound. 
     
     
         22 . The method of  claim 21 , wherein the cytochrome P 450  isoform is CYP2C8, CYP2C9, CYP2C19, or CYP2D6. 
     
     
         23 . The method of  claim 5 , wherein said compound is characterized by decreased inhibition of at least one cytochrome P 450  or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound. 
     
     
         24 . The method of  claim 23 , wherein said cytochrome P 450  or monoamine oxidase isoform is CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO A , or MAO B . 
     
     
         25 . The method of  claim 5 , wherein the method reduces a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound. 
     
     
         26 . The method of  claim 25 , wherein the diagnostic hepatobiliary function endpoint is alanine aminotransferase (“ALT”), serum glutamic-pyruvic transaminase (“SGPT”), aspartate aminotransferase (“AST,” “SGOT”), ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “γ-GTP,” “GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5′-nucleotidase, or blood protein.