Inhibitors of the enzyme UDP-glucose: N-acyl-sphingosine glucosyltransferase
This invention relates to novel inhibitors of UDP-glucose: N-acyl-sphingosine glucosyltransferase and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering inhibitors of UDP-glucose: N-acyl-sphingosine glucosyltransferase.
1. A method of treating a condition selected from Tay-Sach's disease, Gaucher's disease, Fabry's disease, diabetes, fatty liver disease, polycystic kidney disease, and lupus in a subject in need of such treatment, the method comprising the step of administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
each Y 1 is the same and is hydrogen or deuterium;
each Y 2 is the same and is hydrogen or deuterium;
Y 3 is hydrogen or deuterium;
Y 4 is hydrogen or deuterium;
each Y 5 is the same and is hydrogen or deuterium;
each Y 6 is the same and is hydrogen or deuterium;
each Y 7 is the same and is hydrogen or deuterium;
R 1 is —(CD 2 ) 6 CD 3 ; and wherein
each designated deuterium atom has a deuterium incorporation of at least 90%, and wherein any atom not designated as deuterium is present at its natural isotopic abundance.
2. The method of claim 1 , wherein for the compound of Formula I, each Y 1 is hydrogen.
3. The method of claim 1 , wherein for the compound of Formula I, each Y 1 is deuterium.
4. The method of claim 1 , wherein for the compound of Formula I, each Y 2 is hydrogen.
5. The method of claim 1 , wherein for the compound of Formula I, each Y 2 is deuterium.
6. The method of claim 1 , wherein for the compound of Formula I, each Y 3 is hydrogen.
7. The method of claim 1 , wherein for the compound of Formula I, each Y 3 is deuterium.
8. The method of claim 1 , wherein for the compound of Formula I, each Y 4 is hydrogen.
9. The method of claim 1 , wherein for the compound of Formula I, each Y 4 is deuterium.
10. The method of claim 1 , wherein for the compound of Formula I, each Y 7 is hydrogen.
11. The method of claim 1 , wherein for the compound of Formula I, each Y 7 is deuterium.
12. The method of claim 1 , wherein for the compound of Formula I, each Y 5 is the same as each Y 6 .
13. The method of claim 1 , wherein the compound of Formula I is selected from any one of the compounds in the table below:
each Y 1 =
each
each
each
each
Compound
Y 2
Y 3 = Y 4
Y 5
Y 6
Y 7
R 1
102
H
H
H
H
H
—(CD 2 ) 6 —CD 3
105
D
H
H
H
H
—(CD 2 ) 6 —CD 3
108
H
D
H
H
H
—(CD 2 ) 6 —CD 3
111
H
H
H
H
D
—(CD 2 ) 6 —CD 3
114
H
H
H
D
D
—(CD 2 ) 6 —CD 3
117
H
H
D
D
D
—(CD 2 ) 6 —CD 3
182
D
D
H
H
H
—(CD 2 ) 6 —CD 3
185
D
H
H
H
D
—(CD 2 ) 6 —CD 3
120
D
H
H
D
D
—(CD 2 ) 6 —CD 3
123
D
H
D
D
D
—(CD 2 ) 6 —CD 3
126
H
D
H
H
D
—(CD 2 ) 6 —CD 3
129
H
D
H
D
D
—(CD 2 ) 6 —CD 3
132
H
D
D
D
D
—(CD 2 ) 6 —CD 3
135
D
D
H
H
D
—(CD 2 ) 6 —CD 3
138
D
D
H
D
D
—(CD 2 ) 6 —CD 3
141
D
D
D
D
D
—(CD 2 ) 6 —CD 3
or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound of Formula I is selected from any one of the compounds in the table below:
each Y 1 =
each
each
each
Compound
each Y 2
Y 3
Y 4
Y 5
Y 6
Y 7
R 1
144
H
D
H
H
H
H
—(CD 2 ) 6 —CD 3
145
D
D
H
H
H
H
—(CD 2 ) 6 —CD 3
146
H
D
H
H
H
D
—(CD 2 ) 6 —CD 3
147
H
D
H
H
D
D
—(CD 2 ) 6 —CD 3
158
H
D
H
D
D
D
—(CD 2 ) 6 —CD 3
159
D
D
H
H
H
D
—(CD 2 ) 6 —CD 3
150
D
D
H
H
D
D
—(CD 2 ) 6 —CD 3
151
D
D
H
D
D
D
—(CD 2 ) 6 —CD 3
152
H
D
H
H
D
H
—(CD 2 ) 6 —CD 3
153
H
D
H
D
D
H
—(CD 2 ) 6 —CD 3
154
D
D
H
H
D
H
—(CD 2 ) 6 —CD 3
155
D
D
H
D
D
H
—(CD 2 ) 6 —CD 3
158
H
H
D
H
H
H
—(CD 2 ) 6 —CD 3
159
D
H
D
H
H
H
—(CD 2 ) 6 —CD 3
160
H
H
D
H
H
D
—(CD 2 ) 6 —CD 3
161
H
H
D
H
D
D
—(CD 2 ) 6 —CD 3
162
H
H
D
D
D
D
—(CD 2 ) 6 —CD 3
163
D
H
D
H
H
D
—(CD 2 ) 6 —CD 3
164
D
H
D
H
D
D
—(CD 2 ) 6 —CD 3
165
D
H
D
D
D
D
—(CD 2 ) 6 —CD 3
166
H
H
D
H
D
H
—(CD 2 ) 6 —CD 3
167
H
H
D
D
D
H
—(CD 2 ) 6 —CD 3
168
D
H
D
H
D
H
—(CD 2 ) 6 —CD 3
169
D
H
D
D
D
H
—(CD 2 ) 6 —CD 3
or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein for the compound of Formula I, each Y 5 is deuterium; each Y 6 is hydrogen; and the compound is selected from any one of the compounds in the table below:
each Y 1 =
each Y 3 =
Compound
each Y 2
each Y 4
Y 7
R 1
171
H
H
H
—(CD 2 ) 6 —CD 3
172
D
H
H
—(CD 2 ) 6 —CD 3
173
H
H
D
—(CD 2 ) 6 —CD 3
174
D
H
D
—(CD 2 ) 6 —CD 3
176
H
D
H
—(CD 2 ) 6 —CD 3
177
D
D
H
—(CD 2 ) 6 —CD 3
178
H
D
D
—(CD 2 ) 6 —CD 3
179
D
D
D
—(CD 2 ) 6 —CD 3
or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein for the compound of Formula I, the deuterium incorporation at each designated deuterium atom is at least 95%.
17. The method of claim 1 , wherein for the compound of Formula I, the deuterium incorporation at each designated deuterium atom is at least 97%.