DEUTERATED IDEBENONE

Abstract

The present invention in one embodiment provides a compound of Formula I:

##STR00001##

or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula I are as defined in the specification.

Claims

1. A compound of Formula I: ##STR00012## or a pharmaceutically acceptable salt thereof, wherein: each of R.sup.1, R.sup.2 and R.sup.3 is independently selected from CH.sub.3, CH.sub.2D, CHD.sub.2 and CD.sub.3; each Y.sup.1 is the same and is hydrogen or deuterium; each Y.sup.2 is the same and is hydrogen or deuterium; each Y.sup.3 is the same and is hydrogen or deuterium; each Y.sup.4 is the same and is hydrogen or deuterium; each Y.sup.5 is the same and is hydrogen or deuterium; each Y.sup.6 is the same and is hydrogen or deuterium; each Y.sup.7 is the same and is hydrogen or deuterium; each Y.sup.8 is the same and is hydrogen or deuterium; each Y.sup.9 is the same and is hydrogen or deuterium; and each Y.sup.10 is the same and is hydrogen or deuterium; provided that if each Y.sup.1 is hydrogen; each Y.sup.2 is hydrogen; each Y.sup.3 is hydrogen; each Y.sup.4 is hydrogen; each Y.sup.5 is hydrogen; each Y.sup.6 is hydrogen; each Y.sup.7 is hydrogen; each Y.sup.8 is hydrogen; each Y.sup.9 is hydrogen; each Y.sup.10 is hydrogen; R.sup.2 is CH.sub.3; and R.sup.3 is CH.sub.3; then R.sup.1 is CH.sub.2D or CHD.sub.2.

2. The compound of claim 1, wherein each of R.sup.1, R.sup.3 and R.sup.2 is independently selected from CH.sub.3 and CD.sub.3.

3. The compound of claim 1, wherein each Y.sup.10 is deuterium.

4. The compound of claim 1, wherein each Y.sup.10 is hydrogen.

5. The compound of claim 1, wherein each Y.sup.9 is hydrogen.

6. The compound of claim 1, wherein each Y.sup.9 is deuterium.

7. The compound of claim 1, wherein each Y.sup.8 is hydrogen.

8. The compound of claim 1, wherein each Y.sup.8 is deuterium.

9. The compound of claim 1, wherein R.sup.1 is CH.sub.3.

10. The compound of claim 1, wherein R.sup.1 is CD.sub.3.

11. The compound of claim 1, wherein R.sup.2 is CH.sub.3.

12. The compound of claim 1, wherein R.sup.2 is CD.sub.3.

13. The compound of claim 1, wherein R.sup.3 is CH.sub.3.

14. The compound of claim 1, wherein R.sup.3 is CD.sub.3.

15. The compound of claim 1, wherein each Y.sup.1 is deuterium; each Y.sup.2 is deuterium; each Y.sup.3 is deuterium; each Y.sup.4 is deuterium; each Y.sup.5 is deuterium; each Y.sup.6 is deuterium; each Y.sup.7 is deuterium; each Y.sup.8 is deuterium; each Y.sup.9 is deuterium; and each Y.sup.10 is deuterium.

16. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds (Cmpd) set forth in the table below, wherein each Y.sup.1 is hydrogen; each Y.sup.2 is hydrogen; each Y.sup.3 is hydrogen; each Y.sup.4 is hydrogen; each Y.sup.5 is hydrogen; each Y.sup.6 is hydrogen; each Y.sup.7 is hydrogen; and R.sup.3 is CH.sub.3: TABLE-US-00004 TABLE Exemplary Embodiments of Formula I Cmpd No. R.sup.1 R.sup.2 each Y.sup.10 each Y.sup.9 each Y.sup.8 101 CH.sub.3 CH.sub.3 H H D 102 CH.sub.3 CH.sub.3 H D H 103 CH.sub.3 CH.sub.3 H D D 104 CH.sub.3 CH.sub.3 D H H 105 CH.sub.3 CH.sub.3 D H D 106 CH.sub.3 CH.sub.3 D D H 107 CH.sub.3 CH.sub.3 D D D 108 CH.sub.3 CD.sub.3 H H H 109 CH.sub.3 CD.sub.3 H H D 110 CH.sub.3 CD.sub.3 H D H 111 CH.sub.3 CD.sub.3 H D D 112 CH.sub.3 CD.sub.3 D H H 113 CH.sub.3 CD.sub.3 D H D 114 CH.sub.3 CD.sub.3 D D H 115 CH.sub.3 CD.sub.3 D D D 117 CD.sub.3 CH.sub.3 H H D 118 CD.sub.3 CH.sub.3 H D H 119 CD.sub.3 CH.sub.3 H D D 120 CD.sub.3 CH.sub.3 D H H 121 CD.sub.3 CH.sub.3 D H D 122 CD.sub.3 CH.sub.3 D D H 123 CD.sub.3 CH.sub.3 D D D 124 CD.sub.3 CD.sub.3 H H H 125 CD.sub.3 CD.sub.3 H H D 126 CD.sub.3 CD.sub.3 H D H 127 CD.sub.3 CD.sub.3 H D D 128 CD.sub.3 CD.sub.3 D H H 129 CD.sub.3 CD.sub.3 D H D 130 CD.sub.3 CD.sub.3 D D H 131 CD.sub.3 CD.sub.3 D D D or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

17. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds (Cmpd) set forth in the table below, wherein each Y.sup.1 is hydrogen; each Y.sup.2 is hydrogen; each Y.sup.3 is hydrogen; each Y.sup.4 is hydrogen; each Y.sup.5 is hydrogen; each Y.sup.6 is hydrogen; each Y.sup.7 is hydrogen; and R.sup.3 is CD.sub.3: TABLE-US-00005 Cmpd No. R.sup.1 R.sup.2 each Y.sup.10 each Y.sup.9 each Y.sup.8 200 CH.sub.3 CH.sub.3 H H H 201 CH.sub.3 CH.sub.3 H H D 202 CH.sub.3 CH.sub.3 H D H 203 CH.sub.3 CH.sub.3 H D D 204 CH.sub.3 CH.sub.3 D H H 205 CH.sub.3 CH.sub.3 D H D 206 CH.sub.3 CH.sub.3 D D H 207 CH.sub.3 CH.sub.3 D D D 208 CH.sub.3 CD.sub.3 H H H 209 CH.sub.3 CD.sub.3 H H D 210 CH.sub.3 CD.sub.3 H D H 211 CH.sub.3 CD.sub.3 H D D 212 CH.sub.3 CD.sub.3 D H H 213 CH.sub.3 CD.sub.3 D H D 214 CH.sub.3 CD.sub.3 D D H 215 CH.sub.3 CD.sub.3 D D D 216 CD.sub.3 CH.sub.3 H H H 217 CD.sub.3 CH.sub.3 H H D 218 CD.sub.3 CH.sub.3 H D H 219 CD.sub.3 CH.sub.3 H D D 220 CD.sub.3 CH.sub.3 D H H 221 CD.sub.3 CH.sub.3 D H D 222 CD.sub.3 CH.sub.3 D D H 223 CD.sub.3 CH.sub.3 D D D 224 CD.sub.3 CD.sub.3 H H H 225 CD.sub.3 CD.sub.3 H H D 226 CD.sub.3 CD.sub.3 H D H 227 CD.sub.3 CD.sub.3 H D D 228 CD.sub.3 CD.sub.3 D H H 229 CD.sub.3 CD.sub.3 D H D 230 CD.sub.3 CD.sub.3 D D H 231 CD.sub.3 CD.sub.3 D D D or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

18. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds (Cmpd) set forth in the table below, wherein each Y.sup.1 is deuterium; each Y.sup.2 is deuterium; each Y.sup.3 is deuterium; each Y.sup.4 is deuterium; each Y.sup.5 is deuterium; each Y.sup.6 is deuterium; each Y.sup.7 is deuterium; each Y.sup.8 is deuterium; each Y.sup.9 is deuterium; and each Y.sup.10 is deuterium: TABLE-US-00006 Cmpd No. R.sup.1 R.sup.2 R.sup.2 300 CH.sub.3 CH.sub.3 CH.sub.3 301 CH.sub.3 CH.sub.3 CD.sub.3 302 CH.sub.3 CD.sub.3 CH.sub.3 303 CH.sub.3 CD.sub.3 CD.sub.3 304 CD.sub.3 CH.sub.3 CH.sub.3 305 CD.sub.3 CH.sub.3 CD.sub.3 306 CD.sub.3 CD.sub.3 CH.sub.3 307 CD.sub.3 CD.sub.3 CD.sub.3 or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

19. The compound of claim 1, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

20. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

21. A method of reducing oxidative toxicity in mitochondria, comprising contacting mitochondria with a compound of claim 1.

22. A method of treating a condition that is Duchenne's muscular dystrophy or multiple sclerosis, comprising administering to a subject in need of such treatment a compound of claim 1.

23. The method of claim 22, wherein the condition is primary progressive multiple sclerosis.

Description

EXAMPLE 1. EVALUATION OF METABOLIC STABILITY

[0118] Microsomal Assay:

[0119] Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, Kans.). -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl2), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.

[0120] Determination of Metabolic Stability:

[0121] 7.5 mM stock solutions of test compounds are prepared in DMSO. The 7.5 mM stock solutions are diluted to 12.5-50 M in acetonitrile (ACN). The 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl.sub.2. The diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate. A 10 L aliquot of the 12.5-50 M test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution. The final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25-1.0 M test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl.sub.2. The reaction mixtures are incubated at 37 C., and 50 L aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 L of ice-cold ACN with internal standard to stop the reactions. The plates are stored at 4 C. for 20 minutes after which 100 L of water is added to the wells of the plate before centrifugation to pellet precipitated proteins. Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio-systems API 4000 mass spectrometer. The same procedure is followed for the non-deuterated counterpart of the compound of Formula I or Formula II and the positive control, 7-ethoxycoumarin (1 M). Testing is done in triplicate.

[0122] Data Analysis:

[0123] The in vitro tins for test compounds are calculated from the slopes of the linear regression of % parent remaining (ln) vs incubation time relationship.

in vitro t.sub.1/2=0.693/k

[0124] k=[slope of linear regression of % parent remaining (ln) vs incubation time]

[0125] Data analysis is performed using Microsoft Excel Software.

[0126] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention.