Claims for Patent: 9,585,884
✉ Email this page to a colleague
Summary for Patent: 9,585,884
Title: | Pyrimidinone inhibitors of lipoprotein-associated phospholipase A2 |
Abstract: | The present invention relates to new pyrimidinone inhibitors of lipoprotein-associated phospholipase A2 activity, pharmaceutical compositions thereof, and methods of use thereof. ##STR00001## |
Inventor(s): | Rao; Tadimeti (San Diego, CA), Zhang; Chengzhi (San Diego, CA) |
Assignee: | Auspex Pharmaceuticals, Inc. (La Jolla, CA) |
Application Number: | 14/107,953 |
Patent Claims: | 1. A method of treating a disorder which is a primary coronary disorder, a secondary coronary disorder, an acute coronary heart disorder, atherosclerosis, peripheral
vascular atherosclerosis, or cerebrovascular atherosclerosis, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I: ##STR00222## or a pharmaceutically acceptable salt thereof,
wherein: R.sub.1-R.sub.38 are, independently, hydrogen or deuterium; and at least one of R.sub.1-R.sub.38 is deuterium and, independently, has deuterium enrichment of no less than about 10%; wherein the treatment alleviates one or more of the symptoms
associated with the disorder.
2. The method as recited in claim 1 wherein at least one of R.sub.1-R.sub.38 independently has deuterium enrichment of no less than about 50%. 3. The method as recited in claim 1 wherein at least one of R.sub.1-R.sub.38 independently has deuterium enrichment of no less than about 90%. 4. The method as recited in claim 1 wherein at least one of R.sub.1-R.sub.38 independently has deuterium enrichment of no less than about 98%. 5. The method as recited in claim 1 wherein said compound is: ##STR00223## ##STR00224## ##STR00225## ##STR00226## ##STR00227## ##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232## ##STR00233## ##STR00234## ##STR00235## ##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309## ##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317## ##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332## ##STR00333## ##STR00334## ##STR00335## ##STR00336## ##STR00337## ##STR00338## ##STR00339## ##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407## ##STR00408## ##STR00409## ##STR00410## ##STR00411## ##STR00412## ##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423## ##STR00424## ##STR00425## ##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430## ##STR00431## ##STR00432## ##STR00433## ##STR00434## ##STR00435## ##STR00436## ##STR00437## ##STR00438## wherein each position represented as D has deuterium enrichment of no less than about 10%. 6. The method as recited in claim 5 wherein each position represented as D has deuterium enrichment of no less than about 50%. 7. The method as recited in claim 5 wherein each position represented as D has deuterium enrichment of no less than about 90%. 8. The method as recited in claim 5 wherein each position represented as D has deuterium enrichment of no less than about 98%. 9. The method as recited in claim 5 wherein said compound is: ##STR00439## ##STR00440## ##STR00441## ##STR00442## ##STR00443## ##STR00444## ##STR00445## ##STR00446## ##STR00447## ##STR00448## ##STR00449## 10. The method as recited in claim 9 wherein said compound is: ##STR00450## 11. The method as recited in claim 9 wherein said compound is: ##STR00451## 12. The method as recited in claim 9 wherein said compound is: ##STR00452## 13. The method as recited in claim 9 wherein said compound is: ##STR00453## 14. The method as recited in claim 9 wherein said compound is: ##STR00454## 15. The method as recited in claim 9 wherein said compound is: ##STR00455## 16. The method as recited in claim 1 further comprising administration an additional therapeutic agent. 17. The method as recited in claim 16, wherein said additional therapeutic agent is an alpha adrenergic receptor antagonist, angiotensin II receptor antagonist, angiotensin-converting enzyme inhibitor, anti-arrhythmic, antithrombotic, antiplatelet agent, beta adrenergic receptor antagonist, calcium channel blocker, fibrate, or HMG-CoA reductase inhibitor. 18. The method as recited in claim 17, 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, and yohimbine. 19. The method as recited in claim 17, wherein said angiotensin II receptor antagonist is candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan. 20. The method as recited in claim 17, wherein said angiotensin-converting enzyme inhibitor is captopril, enalapril, lisinopril, perindopril, ramipril, quinapril, benazepril, cilazapril, fosinopril, trandolapril, spirapril, delapril, moexipril, temocapril, zofenopril, or imidapril. 21. The method as recited in claim 17, 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. 22. The method as recited in claim 17, 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. 23. The method as recited in claim 17, 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. 24. The method as recited in claim 17, wherein said beta-adrenergic 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. 25. The method as recited in claim 17, 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. 26. The method as recited in claim 17, wherein said fibrate is clofibrate, bezafibrate, aluminium clofibrate, gemfibrozil, fenofibrate, simfibrate, ronifibrate, ciprofibrate, etofibrate, or clofibride. 27. The method as recited in claim 17, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin. 28. The method as recited in claim 1, 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. 29. The method as recited in claim 1, 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. 30. The method as recited in claim 1, wherein the method effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P.sub.450 isoform in the subject, as compared to the corresponding non-isotopically enriched compound. 31. The method as recited in claim 30, wherein the cytochrome P.sub.450 isoform is CYP2C8, CYP2C9, CYP2C19, or CYP2D6. 32. The method as recited in claim 1, wherein said compound is characterized by decreased inhibition of at least one cytochrome P.sub.450 or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound. 33. The method as recited in claim 32, wherein said cytochrome P.sub.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.sub.A, or MAO.sub.B. |
Details for Patent 9,585,884
Applicant | Tradename | Biologic Ingredient | Dosage Form | BLA | Approval Date | Patent No. | Expiredate |
---|---|---|---|---|---|---|---|
Bausch Health Us, Llc | IPRIVASK | desirudin | For Injection | 021271 | 04/04/2003 | ⤷ Try a Trial | 2029-07-28 |
Microbix Biosystems Inc. | KINLYTIC | urokinase | For Injection | 021846 | 01/16/1978 | ⤷ Try a Trial | 2029-07-28 |
Genentech, Inc. | ACTIVASE | alteplase | For Injection | 103172 | 11/13/1987 | ⤷ Try a Trial | 2029-07-28 |
>Applicant | >Tradename | >Biologic Ingredient | >Dosage Form | >BLA | >Approval Date | >Patent No. | >Expiredate |
Make Better Decisions: Try a trial or see plans & pricing
Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.