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US 7,662,987 B2Granted
Methods for synthesis of acyloxyalkyl compounds
AssigneeXenoPort, Inc.
InventorsLaxminarayan Bhat, Mark A. Gallop
Life of this patent
Estimating the term…
Abstract
Disclosed herein are methods for synthesizing 1-(acyloxy)-alkyl prodrug derivatives of drugs through oxidation of 1-acyl-alkyl derivatives of drugs under anhydrous reaction conditions. The methods typically proceed stereospecifically, in high yield, do not require the use of activated intermediates and/or toxic compounds and are readily amenable to scale-up.
Claims51
A method of synthesizing a 1-(acyloxy)-alkyl compound of Formula (II), comprising contacting a compound of Formula (I) with an anhydrous oxidant,
- wherein:
- n is 0 or 1;
- X is O or a bond;
- Y is —NRR′, —OR, wherein:
- —NRR′ is selected from the group consisting of acebutalol, albuterol, alprenolol, atenolol, bunolol, bupropion, butopamine, butoxamine, carbuterol, cartelolol, colterol, deterenol, dexpropanolol, diacetolol, dobutamine, exaprolol, exprenolol, fenoterol, fenyripol, labotolol, levobunolol, metolol, metaproterenol, metoprolol, nadolol, pamatolol, penbutalol, pindolol, pirbuterol, practolol, prenalterol, primidolol, prizidilol, procaterol, propanolol, quinterenol, rimiterol, ritodrine, solotol, soterenol, sulfiniolol, sulfinterol, sulictidil, tazaolol, terbutaline, timolol, tiprenolol, tipridil, tolamolol, thiabendazole, albendazole, albutoin, alendronate, alinidine, alizapride, amiloride, aminorex, aprinocid, cambendazole, cimetidine, cisapride, clonidine, cyclobenzadole, delavirdine, efegatrin, etintidine, fenbendazole, fenmetazole, flubendazole, fludorex, gabapentin, icadronate, lobendazole, mebendazole, metazoline, metoclopramide, methylphenidate, mexiletine, neridronate, nocodazole, oxfendazole, oxibendazole, oxmetidine, pamidronate, parbendazole, pramipexole, prazosin, pregabalin, procainamide, ranitidine, tetrahydrazoline, tiamenidine, tinazoline, tiotidine, tocainide, tolazoline, tramazoline, xylometazoline, dimethoxyphenethylamine, N—[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1-yl]acetyl-3(R)-methyl-β-alanine, adrenolone, aletamine, amidephrine, amphetamine, aspartame, bamethan, betahistine, carbidopa, clorprenaline, chlortermine, dopamine, L-Dopa, ephrinephrine, etryptamine, fenfluramine, methyldopamine, norepinephrine, tocainide, enviroxime, nifedipine, nimodipine, triamterene, pipedemic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-napthyridine-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazinyl)-3-quinolinecarboxylic acid, amifostine, baclofen, clonidine, ciprofloxacin, daunorubicin, doxorubicin, gentamycin, kanamycin, levodopa, meropenem, metazoline, neomycin, tobramycin, trovafloxacin, and vigabatrin;
- wherein a hydrogen atom of a primary or secondary amino group is replaced with a covalent bond;
- and
- —OR is selected from the group consisting of allylestrenol, cingestol, dehydroepiandrosteron, dienostrol, diethylstilbestrol, dimethisteron, ethyneron, ethynodiol, estradiol, estron, ethinyl estradiol, ethisteron, lynestrenol, mestranol, methyl testosterone, norethindron, norgestrel, norvinsteron, oxogeston, quinestrol, testosterone, tigestol, dofexazepam, hydroxyzin, lorazepam oxazepam, acetophenazine, carphenazine, fluphenazine, perphenyzine, piperaetazine, aclarubicin, cytarabine, decitabine, daunorubicin, dihydro-5-azacytidine, doxorubicin, epirubicin, estramustin, etoposide, fludarabine, gemcitabine, 7-hydroxychlorpromazin, nelarabine, neplanocin A, pentostatin, podophyllotoxin, tezacitabine, troxacitabine, vinblastin, vincristin, vindesin, buserilin, gonadoliberin, icatibrant, leuprorelin acetate, terphenadine, diflunisal, naproxol, paracetamol, salicylamide, salicyclic acid, azidamphenicol, azithromycin, camptothecin, cefamandol, chloramphenicol, clarithromycin, clavulanic acid, clindamycin, demeclocyclin, doxycyclin, erythromycin, gentamycin, imipenem, latamoxef, metronidazole, neomycin, novobiocin, oleandomycin, oxytetracyclin, tetracycline, thiamenicol, tobramycin, acyclovir, d4C, ddC, DMDC, Fd4C, FddC, FMAU, FTC, 2′-fluoro-ara-dideoxyinosine, ganciclovir, lamivudine, penciclovir, SddC, stavudine, 5-trifluoromethyl-2′-deoxyuridine, zalcitabine and zidovudine, EB-1053, etidronate, ibandronate, olpadronate, residronate, YH-529, zolendronate, ciprokiren, enalkiren, ritonavir, saquinavir, terlakiren, arbaprostil, carboprost, misoprostil, prostacydin, 8-hydroxychlorimipramine, 2-hydroxyimipramine, sotarol, fenoldopam, biperidine, procyclidin, trihexyphenidal, cromolyn, betamethasone, budenosid, chlorprednison, clobetasol, clobetasone, corticosteron, cortisone, cortodexon, dexamethason, flucortolon, fludrocortisone, flumethasone, flunisolid, fluprednisolon, flurandrenolide, flurandrenolon acetonide, hydrocortisone, meprednisone, methylpresnisolon, paramethasone, prednisolon, prednisol, triamcinolon, triamcinolon acetonide, apomorphine, buprenorphine, butorphanol, codein, cyclazocin, hydromorphon, ketobemidon, levallorphan, levorphanol, metazocin, morphine, nalbuphin, nalmefen, naloxon, nalorphine, naltrexon, oxycodon, oxymorphon, pentazocin, mazindol, pseudoephidrine, hydroxydion, propofol, acebutolol, albuterol, alprenolol, atenolol, betazolol, bucindolol, cartelolol, celiprolol, cetamolol, labetalol, levobunelol, metoprolol, metipranolol, nadolol, oxyprenolol, pindolol, propanolol, timolol, adrenalin, metaraminol, midodrin, norfenefrin, octapamine, oxedrin, oxilofrin, oximetazolin, phenylefrin, bamethan, clenbuterol, fenoterol, hexoprenalin, isoprenalin, isoxsuprin, orciprenalin, reproterol, salbutamol, terbutalin, carbuterol, dyphillin, etophyllin, fenoterol, pirbuterol, rimiterol, terbutalin, digitoxin, dobutamin, etilefrin, prenalterol, amphotericin B, chlorphenesin, nystatin, perimycin, acenocoumarol, dicoumarol, phenprocoumon, warfarin, bamethan, dipyrimadol, diprophyllin, isoxsuprin, vincamin, xantinol nicotinate, compactin, eptastatin, mevinolin, simvastatin, bromperidol, dithranol, ergotamine, ivermectin, metronidazole, secnizadole, nandrolon, propafenon, quinadine, quetiapine, serotonin, silybin, adenosine, cromolyn, cytarabine, decitabine, didanosine, docetaxel, gemcitabine, norgestrel, paclitaxel, pentostatin, and vinblastine;
- wherein a hydrogen atom of a hydroxyl group is replaced with a covalent bond;
- R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, and a substituted or unsubstituted 5 to 9 membered mono- or bicyclic heterocyclic ring having one or two S, O, or N heteroatoms;
- or R1 and either R2 or R3, together with the atoms to which R1 and R2 or R3 are attached, form a cycloalkyl, substituted cycloalkyl, or a substituted or unsubstituted 5 to 9 membered mono- or bicyclic heterocyclic ring having one or two S, O, or N heteroatoms, which is optionally fused to an aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, or a substituted or unsubstituted 5 to 9 membered mono- or bicyclic heterocyclic ring having one or two S, O, or N heteroatoms;
- and
- R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, and a substituted or unsubstituted 5 to 9 membered mono- or bicyclic heterocyclic ring having one or two S, O, or N heteroatoms;
- or optionally, R2 and R3 together with the atom to which they are attached, form a cycloalkyl, substituted cycloalkyl, or a substituted or unsubstituted 5 to 9 membered mono- or bicyclic heterocyclic ring having one or two S, O, or N heteroatoms.
11 more elements
A method of synthesizing a 1-(acyloxy)-alkyl compound of Formula (II), comprising contacting a compound of Formula (I) with an anhydrous oxidant,
- wherein:
- n is 0;
- X is O;
- Y is —C(O)R, —P(O)(OR′)R or —P(O)(OR)(OR′) wherein:
- Y is —C(O)R and the compound of Formula (I) is formed by reacting an α-hydroxyketone of formula HO—C(R2)(R3)—C(O)—R1 with a compound containing a carboxylic acid functional group of formula R—COOH or an acyl chloride derivative of a compound containing a carboxylic acid functional group of the formula R—C(O)—Cl;
- wherein the compound of fonnula R—COOH is selected from the group consisting of alecapril, captopril, 1-[4-carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxvlic acid, enalaprilic acid, lisinopril,
- N-cyclopentyl—N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]glycine, pivopril, quinaprilat, (2R, 4R)-2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid, (S) benzamido-4-oxo-6-phenylhexenovl-2-carboxypyrrolidine, [2S-1[R*(R*))]]2α, 3 αβ, 7 αβ]-1 [2-[[1-carboxy-3-phenyipropyl]-amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic acid, [3S-1[R*(R*))]],
- 3R*]-2-[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isociuinolone carboxylic acid, tiopronin, cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazuflur, cefazolin, cefbuperazone, cefixime, cefmenoxime, cefinetazole, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotefan, cefotiam, cefoxitin, cefpimizole, cefpirome, cefpodoxime, cefroxadine, cefsulodin, celbiramide, ceftazidime, ceftezole, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile, cephalexin, cephaloglycin, cephaloridine, cephalosporin, cephanone, cephradine, latamoxef, amoxycillin, ampicillin, apalcillin, azidocillin, azlocillin, benzylpencillin, carbenicillin, carfecillin, carindacillin, cloxacillin, cyclacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, methicillin, mezlocillin, nafcillin, oxacillin, phenethicillin, piperazillin, sulbenicllin, temocillin, ticarcillin, argatroban, melagatran, napsagatran, zanamivir, BCX-1 812, acametacin, alciofenac, alminoprofen, aspirin (acetylsalicylic acid), 4-biphenylacetic acid, bucloxic acid, carprofen, cinchofen, cinmetacin, clometacin, clonixin, diclenofac, diflunisal, etodolac, fenbufen, fenclofenac, fenclosic acid, fenoprofen, ferobufen, flufenamic acid, flufenisal, flurbiprofin, fluprofen, flutiazin, ibufenac, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, lonazolac, loxoprofen, meclofenamic acid, mefenamic acid, 2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid, naproxen, nifluminic acid, O—(carbamoylphenoxy)acetic acid, oxoprozin, pirprofen, prodolic acid, salicylic acid, salicylsalicylic acid, sulindac, suprofen, tiaprofenic acid, tolfenamic acid, tolmetin, zopemirac, ciprostene, 16-deoxy-16-hydroxy-16-vinyl prostaglandin E2, 6,16-dimethylprostaglandin E2, epoprostostenol, meteneprost, nileprost, prostacyclin, prostaglandin E1, prostaglandin E2, prostaglandin F2α, thromboxane A2, acrosoxacin, cinoxacin, ciprofloxacin, enoxacin, flumequine, naladixic acid, norfioxacin, ofloxacin, oxolinic acid, pefloxacin, pipemidic acid, piromidic acid, aztreonam, imipenem, meropenem, a carbopenem antibiotic, acametacin, argatroban, BCX-140, BCX-1812, cefotaxime, ceftazidime, cefiriaxone, cromolyn, foscarnet, lamifiban, melagatran, meropenem, and zanamivir;
- Y is —P(O)(OR′)R and the compound of Formula (I) is formed by reacting an α-hydroxyketone of formula HO—C(R2)(R3)—C(O)—R1 or an α-haloketone of formula Cl—C(R2)(R3)—C(O)—R1 with a compound containing a phosphonic acid functional group of the formula HO—P(O)(OR′)R;
- wherein the compound of the formula HO—P(O)(OR′)R is selected from the group consisting of adefovir, alendronate, AR-C69931MX, BMS-187745, ceronapril, CGP-24592, CGP-37849, CGP-39551, CGP-40116, cidofovir, clodronate, EB-1053, etidronate, fanapanel, foscarnet, fosfomycin, fosinopril, fosinoprilat, ibandronate, midafotel, neridronate, olpadronate, pamidronate, residronate, tenofovir, tiludronate, WAY- 126090, YH-529, and zolendronate;
- Y is —P(O)(OR′)(OR) and the compound of Formula (I) is formed by reacting an α-hydroxyketone of formula HO—C(R2)(R3)—C(O)—R1 or an α-haloketone of formula Cl—C(R2)(R3)—C(O)—R1 with a compound containing a phosphoric acid functional group of formula HO—P(O)(OR′)(OR);
- wherein the compound of formula HO—P(O)(OR′)(OR) is selected from the group consisting of bucladesine, choline alfoscerate, citocoline, fludarabine phosphate, fosopamine, GP-668, perifosine, triciribine phosphate, 3TC, acyclovir, AZT, BVDU, ddC, ddI, FMAU, FTC, ganciclovir, gemeitabine, H2G, lamivudine, and penciclovir;
- R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, and a substituted or unsubstituted 5 to 9 membered mono- or bicyclic heterocyclic ring having one or two S, O, or N heteroatoms;
- or R1 and either R2 or R3, together with the atoms to which R1 and R2 or R3 are attached, form a cycloalkyl, substituted cycloalkyl;
- or a substituted or unsubstituted 5 to 9 membered mono- or bicyclic heterocyclic ring having one or two S, O, or N heteroatoms, which is optionally fused to an aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, or a substituted or unsubstituted 5 to 9 membered mono- or bicyclic heterocyclic ring having one or two S, O, or N heteroatoms;
- and
- R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, and a substituted or unsubstituted 5 to 9 membered mono- or bicyclic heterocyclic ring having one or two S, O, or N heteroatoms, or optionally, R2 and R3together with the atom to which they are attached, form a cycloalkyl, substituted cycloalkyl, or a substituted or unsubstituted 5 to 9 membered mono- or bicyclic heterocyclic ring having one or two S, O, or N heteroatoms.
14 more elements
Dependencies are inferred from the claim text.