OPIOID KETAL COMPOUNDS AND USES THEREOF
This invention relates to opioid ketal compounds of Formula (I), Formula (II), or Formula (III): or a pharmaceutically acceptable salts thereof, wherein R 1 is H or CH 3 , R 2 is H or OH, n is 0, 1, 2 or 3, R 3 and R 4 are independently H or optionally substituted C 1 -C 4 alkyl, or when n is 0, then R 3 and R 4 and the carbon atoms to which they are attached together form six, or seven membered ring, which is optionally mono or disubstituted by C 1 -C 4 alkyl. The invention also relates to oxycodone ketal compounds of Formula (IV) or (V): or a pharmaceutically acceptable salts thereof. The invention also relates to the use of such compounds for the treatment, prevention, or amelioration of pain.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is H or CH 3 ,
R 2 is H or OH,
n is 0, 1, 2 or 3,
R 3 and R 4 are independently H or optionally substituted C 1 -C 4 alkyl, or
when n is 0, then R 3 and R 4 and the carbon atoms to which they are attached together form a five, six, or seven membered ring, which is optionally mono or disubstituted by C 1 -C 4 alkyl, and wherein the carbon atoms labeled * and ** are independently in the R or S configuration.
2 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 , R 2 is H, n is 1, and R 3 and R 4 are each CH 3 .
3 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the carbon atom labeled * and the carbon atom labeled ** are both in the R configuration.
4 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the carbon atom labeled * and the carbon atom labeled ** are both in the S configuration.
5 . The compound of claim 1 , in which the carbon atom labeled * is in the R configuration and the carbon atom labeled ** is in the S configuration.
6 . The compound of claim 1 , in which the carbon atom labeled * is in the S configuration and carbon atom labeled ** is in the R configuration.
7 . A mixture, comprising at least two stereoisomers of the compound or salt according to claim 2 , wherein the stereoisomers are compounds in which the carbon atom labeled * and the carbon atom labeled ** are independently in the R or S configurations.
8 . (canceled)
9 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 , R 2 is H or OH, n is 2, and R 3 and R 4 are each CH 3 .
10 . (canceled)
11 . (canceled)
12 . A mixture, comprising at least two stereoisomers of the compound or salt according to claim 9 , wherein R 2 is H and the stereoisomers are compounds in which the carbon atom labeled * and the carbon atom labeled ** are independently in the R or S configurations.
13 - 17 . (canceled)
18 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H, R 2 is H, n is 1, and R 3 and R 4 are each CH 3 .
19 - 22 . (canceled)
23 . A mixture, comprising two or more stereoisomers of the compound or salt according to claim 18 , wherein the stereoisomers are compounds in which the carbon atom labeled * and the carbon atom labeled ** are independently in the R or S configurations.
24 . (canceled)
25 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 , R 2 is H, n is 0, and R 3 and R 4 together with the carbon atoms to which they are attached form a six membered carbon ring.
26 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 , R 2 is OH, n is 1, and R 3 and R 4 are independently —CH 2 CH 3 and CH 2 CH 2 CH 3 , and the carbon atoms labeled * and the carbon atom labeled ** are independently in the R or S configurations.
27 . A compound of Formula II or Formula III:
or a pharmaceutically acceptable salt thereof.
28 . A pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof, or a mixture of compounds or the pharmaceutically acceptable salts thereof, according to claim 1 , and a pharmaceutically acceptable carrier.
29 . (canceled)
30 . A method of treating, ameliorating or preventing pain in a mammal, comprising orally administering to a mammal in need of such treatment, amelioration or prevention a therapeutically effective amount of the compound or a mixture of compounds according to claim 1 , or a molar equivalent of a pharmaceutically acceptable salt thereof.
31 . (canceled)
32 . (canceled)
33 . A method of slowing the onset of activity of an opioid in a mammal in need of opioid therapy, comprising orally administering to the mammal a therapeutically effective amount of a compound or a mixture of compounds according to claim 1 , or a pharmaceutically acceptable salt thereof.
34 . A method of achieving opioid therapy in a mammal in need thereof, comprising orally administering to the mammal a therapeutically effective amount of the compound or a mixture of compounds according to claim 1 .
35 . A method of preparing a compound of Formula I according to claim 1 , comprising reacting an opioid with a diol under conditions necessary to obtain a compound of Formula I.
36 - 42 . (canceled)
43 . A compound of Formula IV or Formula V:
or a pharmaceutically acceptable salt thereof.
44 . The compound according to claim 43 which has the Formula IV.
45 . The compound according claim 44 , wherein the carbon atoms labeled * are both in the R configuration.
46 . The compound according to claim 44 , wherein the carbon atoms labeled * are both in the S configuration.
47 . The compound according to claim 44 , wherein one carbon atom labeled * is in the R configuration, and the oilier carbon atom labeled * is in the S configuration.
48 . The compound according to claim 43 , which has the formula V.
49 . The compound of claim 48 , wherein the carbon atom labeled * is in the R configuration.
50 . The compound of claim 48 , wherein the carbon atom labeled * is in the S configuration.
51 . A mixture comprising at least two isomers selected from the group consisting of:
and the pharmaceutically acceptable salts thereof.
52 . The mixture according to claim 51 , comprising the isomers IVC and IVD, or the pharmaceutically acceptable salts thereof.
53 . The mixture according to claim 51 , wherein the isomer IVC is present in a molar amount greater than isomer IVD.
54 . The mixture according to claim 51 , wherein the isomer DM is present in a molar amount greater than isomer IVC.
55 . The mixture according to claim 51 , comprising isomers IVA, IVB, IVC, and IVD or the pharmaceutically acceptable salts thereof.
56 . The mixture according to claim 51 , wherein the isomers IVC and IVD together are present in an aggregate molar amount greater than isomers IVA and IVB together.
57 . A mixture comprising at least two isomers selected from the group consisting of
and the pharmaceutically acceptable salts thereof.
58 . A mixture according to claim 57 , comprising isomers VA, VB, VC, and VD or the pharmaceutically acceptable salts thereof.
59 . A pharmaceutical composition, comprising a compound according to claim 43 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
60 . A pharmaceutical composition, comprising a mixture according to claim 51 , or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
61 . (canceled)
62 . A method of treating, ameliorating or preventing pain in a mammal, comprising orally administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound according to claim 43 , or molar equivalent of a pharmaceutically acceptable salt thereof.
63 . (canceled)
64 . (canceled)
65 . A method of slowing the onset of activity of an opioid in a mammal in need of opioid therapy, comprising orally administering to the mammal a therapeutically effective amount of a compound according to claim 43 .
66 . A method of achieving opioid therapy in a mammal in need thereof, comprising orally administering to the mammal a therapeutically effective amount of a compound according to claim 43 .
67 . The method of claim 66 , wherein at least about 40% of the compound is hydrolyzed to opioid within about 2 hours at 37° C. in 0.1 N HCl.
68 . The method of claim 66 , wherein about 100% of the compound is hydrolyzed to opioid within about 4 hours at 37° C. in 0.1 N HCl.
69 . A method of achieving opioid therapy in a mammal in need thereof, comprising orally administering to the mammal a therapeutically effective amount of a mixture according to claim 51 .
70 . The method of claim 69 , wherein at least about 40% of the mixture is hydrolyzed to opioid within about 2 hours at 37° C. in 0.1 N HCl.
71 . The method of claim 69 , wherein about 100% of the mixture is hydrolyzed to opioid within about 2 hours at 37° C. in 0.1 N HCl.
72 . A method of preparing a compound of Formula IV according to claim 44 , comprising reacting oxycodone with 2,4-pentanediol, optionally in the presence of an acid catalyst, and optionally in the presence of a solvent, to obtain the compound of Formula IV.
73 - 75 . (canceled)
76 . A method of preparing a compound of Formula V according to claim 48 , comprising reacting oxycodone with 1,3-butanediol, optionally in the presence of an acid catalyst, and optionally in the presence of a solvent, to obtain the compound of Formula V.
77 - 79 . (canceled)
80 . A method of treating, ameliorating or preventing pain in a mammal, comprising orally administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound or g mixture according to claim 51 .
81 - 92 . (canceled)
93 . A controlled release dosage form comprising two or more stereoisomers of one or more compounds according to claim 1 or a pharmaceutically acceptable salt thereof.
94 . A method of treating, ameliorating or preventing pain in a mammal, comprising orally administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a mixture according to claim 57 , or molar equivalent of a pharmaceutically acceptable salt thereof.