4-hydroxybutyric acid analogs
This invention relates to novel derivatives of 4-hydroxybutyric acid and prodrugs thereof, and pharmaceutically acceptable salts of the foregoing. This invention also provides pharmaceutical compositions comprising a compound of this invention and the use of such compositions in methods of treating narcolepsy, fibromyalgia, other disorders or conditions that are beneficially treated by improving nocturnal sleep or by administering sodium oxybate.
1. A compound of the Formula B:
or a pharmaceutically acceptable salt thereof, wherein:
A 1 is hydrogen, deuterium, —CH 2 —C(O)OR 2′ or —CH(R 1′ )—C(O)OR 2′;
R 1′ is C 1-6 alkyl, C 2-10 alkoxyalkyl, phenyl, —(C 1-3 alkyl)-(C 3-6 cycloalkyl), or C 3-6 cycloalkyl, wherein R 1′ is optionally substituted with C 1-3 alkyl, C 1-3 alkoxy, phenyl, —O—(CH 2 CH 2 O) n —CH 3 , wherein n is 1, 2, or 3;
R 2′ is hydrogen; deuterium; —C 1-4 alkyl optionally substituted with phenyl; —(C 3-6 cycloalkyl) optionally substituted with phenyl or methyl; —CH 2 —(C 3-6 cycloalkyl) wherein the C 3-6 cycloalkyl is optionally substituted with phenyl; phenyl; or biphenyl;
X 1 is hydrogen, deuterium, —C(O)-indanyl, —C(O)-indenyl, —C(O)-tetrahydronaphthyl, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkenyl, —C(O)—C 1-6 alkynyl, —C(O)—C 1-3 alkyl optionally substituted with C 3-6 cycloalkyl, or —C(O)—C 3-6 cycloalkyl optionally substituted with C 1-6 alkyl, phenyl or naphthyl; and
each Y is independently selected from hydrogen and deuterium,
provided that:
(i) when A 1 is hydrogen or deuterium, at least one Y is deuterium; and
(ii) when X 1 is hydrogen or deuterium, each Y 2 is deuterium, and each Y 3 is deuterium, then A 1 is not hydrogen or deuterium; and wherein
each designated deuterium atom has a deuterium incorporation of at least 90%.
2. The compound of claim 1 , selected from:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , selected from any one of:
HO—CH 2 —CH 2 —CD 2 -C(O)—O − Na + ;
HO—CH 2 —CD 2 -CD 2 -C(O)—O − Na + ; and
HO—CH 2 —CD 2 -CH 2 —C(O)—O − Na + .
5. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
6. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
7. The composition of claim 6 , additionally comprising a second therapeutic agent selected from a dual serotonin-norepinephrine reuptake inhibitor and an alpha2-delta subunit calcium channel modulator.
8. The composition of claim 7 , wherein the second therapeutic agent is selected from duloxetine, milnacipran, venlafaxine, pregabalin, gabapentin, and prodrugs thereof.
9. A method of treating a disease or disorder selected from abnormal nocturnal sleep, narcolepsy, fibromyalgia, other diseases or disorders beneficially treated by improving nocturnal sleep or by administering sodium oxybate comprising the step of administering to a patient in need thereof an effective amount of a composition of claim 6 .
10. The method of claim 9 comprising the additional step of co-administering to the patient in need thereof a second therapeutic agent selected from a dual serotonin-norepinephrine reuptake inhibitor and an alpha2-delta subunit calcium channel modulator.
11. The method of claim 10 , wherein the second therapeutic agent is selected from duloxetine, milnacipran, venlafaxine, pregabalin, gabapentin, and prodrugs thereof.
12. A method of selectively inhibiting polysynaptic reflexes without significantly affecting monosynaptic reflexes in a patient in need thereof comprising the step of administering to the patient an effective amount of a composition of claim 6 .
13. The compound of claim 1 , wherein each designated deuterium atom has a deuterium incorporation of at least 95%.
14. The compound of claim 1 , wherein each designated deuterium atom has a deuterium incorporation of at least 97%.
15. The compound of claim 1 , wherein at least one Y is deuterium.
16. The compound of claim 15 , wherein:
R 2 ′ is hydrogen, —C 1-4 alkyl, —C 3-6 cycloalkyl, —CH 2 —(C 3-6 cycloalkyl), phenyl or benzyl.
17. The compound of claim 1 , wherein A 1 is —CH(R 1′ )—C(O)OR 2′ , the compound being represented by Formula B-II:
B-II, or a pharmaceutically acceptable salt thereof, wherein
each Y 1 is the same;
each Y 2 is the same;
and each Y 3 is the same.
18. The compound of claim 17 , wherein the chiral carbon atom bearing R 1′ has an (S) configuration, the compound being represented by Formula (S)-B-II:
(S)-B-II, or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein A 1 is —CH 2 —C(O)OR 2′ and each Y 3 is hydrogen, the compound having the structure shown in Formula B-III:
B-III, or a pharmaceutically acceptable salt thereof, wherein:
each Y 1 is the same;
each Y 2 is the same;
and each Y 3 is the same.
20. The compound of claim 19 , wherein at least one pair of Y are deuterium.
21. The compound of claim 19 selected from any one of the compounds set forth in the table below:
Compound #
X
Each Y 1
Each Y 2
R 2
100
H
H
H
CH 3
101
H
H
H
C 2 H 5
102
H
H
H
CH 2 C 6 H 5
103
H
D
H
CH 3
104
H
D
H
C 2 H 5
105
H
D
H
CH 2 C 6 H 5
106
H
H
D
CH 3
107
H
H
D
C 2 H 5
108
H
H
D
CH 2 C 6 H 5
109
Ac
H
H
CH 3
110
Ac
H
H
C 2 H 5
111
Ac
H
H
CH 2 C 6 H 5
112
Ac
D
H
CH 3
113
Ac
D
H
C 2 H 5
114
Ac
D
H
CH 2 C 6 H 5
115
Ac
H
D
CH 3
116
Ac
H
D
C 2 H 5
117
Ac
H
D
CH 2 C 6 H 5
118
H
H
H
H
or a pharmaceutically acceptable salt of any of the foregoing.
22. The compound of claim 1 , wherein each Y is independently selected from hydrogen and deuterium, provided that each Y 1 is the same, each Y 2 is the same, and each Y 3 is the same, and at least one pair of Y is deuterium.