Deuterated CFTR potentiators
This invention relates to compounds of Formula I: 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 a CFTR potentiator.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is independently hydrogen or deuterium;
each of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is independently CH 3 or CD 3 ;
provided that if each of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is CH 3 , then at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is deuterium, wherein the isotopic enrichment for each designated deuterium atom is at least 90%.
2. The compound of claim 1 , wherein X 1 , X 2 , X 3 , and X 4 are each hydrogen.
3. The compound of claim 2 , wherein X 6 and X 7 are each hydrogen.
4. The compound of claim 2 , wherein Y 1 , Y 2 , and Y 3 are the same.
5. The compound of claim 2 , wherein Y 4 , Y 5 , and Y 6 are the same.
6. The compound of claim 1 , wherein X 5 is deuterium.
7. The compound of claim 3 , wherein at least one of C(Y 1 )(Y 2 )(Y 3 ) and C(Y 4 )(Y 5 )(Y 6 ) is C(CD 3 ) 3 .
8. The compound of claim 7 , wherein Y 1 , Y 2 , and Y 3 are CD 3 .
9. The compound of claim 8 , wherein Y 4 , Y 5 , and Y 6 are CD 3 .
10. The compound of claim 1 , wherein the compound of Formula I is any one of the compounds of the table below,
Cmpd #
X 1
X 2
X 3
X 4
X 5
X 6
X 7
Y 1
Y 2
Y 3
Y 4
Y 5
Y 6
100
D
D
D
D
D
D
D
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
101
H
H
H
H
D
H
H
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
102
H
H
H
H
D
H
H
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
103
H
H
H
H
D
H
H
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
104
H
H
H
H
D
H
H
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
105
H
H
H
H
H
H
H
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
106
H
H
H
H
H
H
H
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
107
H
H
H
H
H
H
H
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
11. The compound of claim 1 , wherein the compound of Formula I is any one of the compounds of the table below,
Cmpd #
X 1
X 2
X 3
X 4
X 5
X 6
X 7
Y 1
Y 2
Y 3
Y 4
Y 5
Y 6
110
H
H
H
H
H
D
D
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
111
H
H
H
H
D
D
D
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
112
H
H
H
H
D
D
D
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
113
H
H
H
H
D
D
D
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
114
H
H
H
H
D
D
D
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
115
H
H
H
H
H
D
D
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
116
H
H
H
H
H
D
D
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
117
D
D
D
D
D
D
D
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
118
D
D
D
D
D
D
D
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
119
D
D
D
D
D
H
H
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
120
D
D
D
D
D
H
H
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
121
H
H
H
H
H
H
D
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
122
H
H
H
H
H
H
D
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
123
H
H
H
H
H
H
D
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
12. The compound of claim 1 , wherein the compound of Formula I is any one of the compounds of the table below,
Cmpd #
X 1
X 2
X 3
X 4
X 5
X 6
X 7
Y 1
Y 2
Y 3
Y 4
Y 5
Y 6
124
H
H
H
H
H
D
H
CD 3
CD 3
CD 3
CD 3
CD 3
CD 3
125
H
H
H
H
H
D
H
CD 3
CD 3
CD 3
CH 3
CH 3
CH 3
126
H
H
H
H
H
D
H
CH 3
CH 3
CH 3
CD 3
CD 3
CD 3
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
13. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
14. A method of treating cystic fibrosis in a subject comprising administering to the subject a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, wherein the compound of Formula I has the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein
each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is independently hydrogen or deuterium;
each of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is independently CH 3 or CD 3 ;
provided that if each of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is CH 3 , then at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is deuterium, wherein the isotopic enrichment for each deuterium atom in Formula I is at least is 90%.
15. A method of treating COPD in a subject comprising administering to the subject a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, wherein the compound of Formula I has the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein
each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is independently hydrogen or deuterium;
each of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is independently CH 3 or CD 3 ;
provided that if each of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is CH 3 , then at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is deuterium, wherein the isotopic enrichment for each deuterium atom in Formula I is at least is 90%.
16. The compound of claim 1 , wherein the isotopic enrichment for each designated deuterium atom is at least 95%.
17. The method of claim 14 , wherein, for the compound of Formula I, the isotopic enrichment for each designated deuterium atom is at least 95%.
18. The method of claim 15 , wherein, for the compound of Formula I, the isotopic enrichment for each designated deuterium atom is at least 95%.