Deuterated idebenone

Abstract

The present invention in one embodiment provides a method of treating Leber's hereditary optic neuropathy, comprising administering to a subject in need of such treatment 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 method of treating Leber's hereditary optic neuropathy, comprising administering to a subject in need of such treatment a compound of Formula I, or a pharmaceutical composition comprising 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 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 deuterium; each Y.sup.9 is the same and is deuterium; and each Y.sup.10 is the same and is deuterium, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

2. The method of claim 1, wherein in the compound of Formula I, R.sup.1 is CH.sub.3.

3. The method of claim 1, wherein in the compound of Formula I, R.sup.1 is CD.sub.3.

4. The method of claim 1, wherein in the compound of Formula I, R.sup.2 is CH.sub.3.

5. The method of claim 1, wherein in the compound of Formula I, R.sup.2 is CD.sub.3.

6. The method of claim 1, wherein in the compound of Formula I, R.sup.3 is CH.sub.3.

7. The method of claim 1, wherein in the compound of Formula I, R.sup.3 is CD.sub.3.

8. The method of claim 1, wherein in the compound of Formula I, 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; and each Y.sup.7 is deuterium.

9. The method 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 Cmpd No. R.sup.1 R.sup.2 each Y.sup.10 each Y.sup.9 each Y.sup.8 107 CH.sub.3 CH.sub.3 D D D 115 CH.sub.3 CD.sub.3 D D D 123 CD.sub.3 CH.sub.3 D D D 131 CD.sub.3 CD.sub.3 D D D or a pharmaceutically acceptable salt thereof.

10. The method 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.8 207 CH.sub.3 CH.sub.3 D D D 215 CH.sub.3 CD.sub.3 D D D 223 CD.sub.3 CH.sub.3 D D D 231 CD.sub.3 CD.sub.3 D D D or a pharmaceutically acceptable salt thereof.

11. The method 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.3 300 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.

12. The method of claim 1, wherein in the compound of Formula I, the deuterium incorporation at each designated deuterium atom is at least 90%.

13. The method of claim 12, wherein the deuterium incorporation at each designated deuterium atom is at least 95%.

Description

EXAMPLE 1. EVALUATION OF METABOLIC STABILITY

(1) Microsomal Assay:

(2) Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, Kans.). -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl.sub.2), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.

(3) Determination of Metabolic Stability:

(4) 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.

(5) Data Analysis:

(6) The in vitro t.sub.1/2S 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
k=[slope of linear regression of % parent remaining(ln) vs incubation time]

(7) Data Analysis is Performed Using Microsoft Excel Software.

(8) 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.