Prodrugs of secondary amine compounds
The present invention relates to compounds of Formula I:
1. A method for sustained delivery of a secondary amine-containing parent drug to a patient comprising administering a compound of Formula I:
wherein:
R 1 is —C(O)OCH 2 OC(O)R 6 ;
R 6 is selected from C 13 -C 26 -alkyl, substituted C 13 -C 26 -alkyl, C 13 -C 26 -alkenyl, substituted C 13 -C 26 -alkenyl, C 13 -C 26 - alkynyl, substituted C 13 -C 26 -alkynl, C 13 -C 26 -cycloalkyl, substituted C 13 -C 26 -cycloalkyl, aryl-C 13 -C 26 -alkyl, substituted aryl-C 13 -C 26 -alkyl, C 1 -C 10 -aryl, substituted C 1 -C 10 -aryl, heteroaryl-C 13 -C 26 -alkyl, substituted heteroaryl-C 13 -C 26 -alkyl; optionally substituted C 13 -C 26 -alkylaryl, optionally substituted C 13 -C 26 -alkenylaryl and optionally substituted C 13 -C 26 -alkynylaryl; and
R 2 and R 3 , together with the nitrogen atom to which they are attached, form a secondary amine-containing parent drug, or a substituted secondary amine-containing parent drug.
2. The method according to claim 1 , wherein upon administration of a compound of Formula Ito the patient, release of the parent drug from the prodrug is sustained release.
3. The method according to claim 1 , wherein the compound of Formula I further comprises a biocompatible delivery system for delivering the prodrug wherein the system is capable of minimizing accelerated hydrolytic cleavage of the prodrug by minimizing exposure of the prodrug to water.
4. The method according to claim 1 , wherein the parent drug is present in the blood stream of the patient for a period selected from at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 4 days, at least one week, at least one month and at least 3 months.
5. The method according to claim 1 , wherein the administering step is by injection or oral delivery.
6. The method according to claim 1 , wherein said parent drug is selected from atenolol, atomoxetine, clozapine, desipramine, desloratadine (clarinex), diclofenac, doripenem, duloxetine, enalapril, ertapenem, fluoxetine, metoprolol, mecamylamine, meropenem, methylphenidate, dtmp (dextrorotary methylphenidate), olanzapine, paroxetine, pramipexole, rasagiline, (r)-rasagiline, salbutamol/albuterol, tamsulosin, varenicline (chantix), and vildagliptin.
7. The method according to claim 1 , wherein said parent drug is alprenolol, acebutolol, amidephrine, amineptine, amosulalol, amoxapine, amphetaminil, atenolol, atomoxetine, balofloxacin, bamethan, befunolol, benazepril, benfluorex, benzoctamine, betahistine, betaxolol, bevantolol, bifemelane, bisoprolol, brinzolamide, bufeniode, butethamine, camylofine, carazolol, carticaine, carvedilol, cephaeline, ciprofloxacin, clozapine, clobenzorex, clorprenaline, cyclopentamine, delapril, demexiptiline, denopamine, desipramine, desloratadine (clarinex), diclofenac, dimetofrine, dioxadrol, dobutamine, dopexamine, doripenem, dorzolamide, droprenilamine, duloxetine, eltoprazine, enalapril, enoxacin, epinephrine, ertapenem, esaprazole, esmolol, etoxadrol, fasudil, fendiline, fenethylline, fenfluramine, fenoldopam, fenoterol, fenproporex, flecainide, fluoxetine, formoterol, frovatriptan, gaboxadol, garenoxacin, gatifloxacin, grepafloxacin, hexoprenaline, imidapril, indalpine, indecainide, indeloxazine hydrochloride, isoxsuprine, ispronicline, labetalol, landiolol, lapatinib, levophacetoperane, lisinopril, lomefloxacin, lotrafiban, maprotiline, mecamylamine, mefloquine, mepindolol, meropenem, metapramine, metaproterenol, methoxyphenamine, dtmp (dextrorotary methylphenidate), methylphenidate, metipranolol, metoprolol, mitoxantrone, mivazerol, moexipril, moprolol, moxifloxacin, nebivolol, nifenalol, nipradilol, norfloxacin, nortriptyline, nylidrin, olanzapine, oxamniquine, oxprenolol, oxyfedrine, paroxetine, perhexiline, phenmetrazine, phenylephrine, phenylpropylmethylamine, pholedrine, picilorex, pimefylline, pindolol, pipemidic acid, piridocaine, practolol, pradofloxacin, pramipexole, pramiverin, prenalterol, prenylamine, prilocaine, procaterol, pronethalol, propafenone, propranolol, propylhexedrine, protokylol, protriptyline, pseudoephedrine, reboxetine, rasagiline, (r)-rasagiline, repinotan, reproterol, rimiterol, ritodrine, safinamide, salbutamol/albuterol, salmeterol, sarizotan, sertraline, silodosin, sotalol, soterenol, sparfloxacin, spirapril, sulfinalol, synephrine, tamsulosin, tebanicline, tianeptine, tirofiban, tretoquinol, trimetazidine, troxipide, varenicline (champix), vildagliptin, viloxazine, viquidil and xamoterol.
8. The method according to claim 1 , wherein the compound of Formula I is selected from:
9. The method according to claim 1 , wherein R 6 is selected from C 13 -C 25 -alkyl, substituted C 13 -C 25 -alkyl, C 13 -C 25 -alkenyl, substituted C 13 -C 25 -alkenyl, C 13 -C 25 -alkynyl, substituted C 13 -C 25 -alkynyl, C 13 -C 25 -cycloalkyl, and substituted C 13 -C 25 -cycloalkyl.
10. The method according to claim 1 , wherein R 6 is selected from C 17 -C 21 -alkyl, substituted C 17 -C 21 -alkyl, C 17 -C 21 -alkenyl, substituted C 17 -C 21 -alkenyl, C 17 -C 21 -alkynyl, substituted C 17 -C 21 -alkynyl, C 17 -C 21 -cycloalkyl, and substituted C 17 -C 21 -cycloalkyl.
11. The method according to claim 1 , wherein R 6 is selected from C 17 -alkyl, substituted C 17 -alkyl, C 17 -alkenyl, substituted-C 17 -alkenyl, C 17 -alkynyl, substituted C 17 -alkynyl, C 17 -cycloalkyl, and substituted C 17 -cycloalkyl.
12. The method according to claim 1 , wherein R 6 is selected from C 19 -alkyl, substituted C 19 -alkyl, C 19 -alkenyl, substituted C 19 -alkenyl, C 19 -alkynyl, substituted C 19 -alkynyl, C 19 -cycloalkyl, and substituted C 19 -cycloalkyl.
13. The method according to claim 1 , wherein R 1 is selected from
14. The method according to claim 1 , wherein the compound of Formula I is selected:
Com-
Com-
pound
pound
#
Structure
#
Structure
10.
62.
11.
63.
12.
64.
13.
65.
14.
66.
67.
68.
69.
70.
28.
29.
30.
37.
38.
39.
43.
84.
44.
85.
45.
86.
49.
50.
51.
93.
94.
95.
100.
99.
101.
105.
106.
107.
129.
130.
131.
132.
133.
134. and
15. The method of claim 1 , wherein R 6 is selected from C 15 -C 23 -alkyl, substituted C 15 -C 23 -alkyl, C 15 -C 23 -alkenyl, substituted C 15 -C 23 -alkenyl, C 15 -C 23 -alkynyl, substituted C 15 -C 23 -alkynyl, C 15 -C 23 -cycloalkyl, and substituted C 15 -C 23 -cycloalkyl.