Deuterated baricitinib
The present invention in one embodiment provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula I are as defined in the specification.
1. A method of treating alopecia and other hair loss disorders in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein:
each of Y 1a , Y 1b , Y 2a , and Y 2b is hydrogen or each of Y 1a , Y 1b , Y 2a , and Y 2b is deuterium;
X 1 and X 2 are the same and are selected from hydrogen and deuterium;
Z 1 and Z 2 are the same and are selected from hydrogen and deuterium; and
R is selected from —CH 3 , —CH 2 D, —CHD 2 , and —CD 3 ;
provided that when Y 1a , Y 1b , Y 2a , Y 2b , X 1 and X 2 are each hydrogen, and R is —CH 3 , then at least one of Z 1 or Z 2 is deuterium.
2. The method of claim 1 , wherein in the compound of Formula Ia, X 1 and X 2 are hydrogen.
3. The method of claim 1 , wherein in the compound of Formula Ia, each of Y 1a and Y 1b is hydrogen and each of Y 2a and Y 2b is hydrogen.
4. The method of claim 1 , wherein in the compound of Formula Ia, each of Y 1a and Y 1b is deuterium and each of Y 2a and Y 2b is deuterium.
5. The method of claim 1 , wherein in the compound of Formula Ia, R is —CH 3 or —CD 3 .
6. The method of claim 1 , wherein in the compound of Formula Ia, each of Z 1 and Z 2 is hydrogen.
7. The method of claim 1 , wherein in the compound of Formula Ia, each of Z 1 and Z 2 is deuterium.
8. The method of claim 1 , wherein the compound of Formula Ia is selected from any one of the compounds set forth in the table below:
Cmpd #
Y 1a = Y 1b
Y 2a = Y 2b
Z 1 = Z 2
X 1 = X 2
R
100
D
D
D
H
CH 3
101
D
D
D
H
CD 3
102
D
D
D
D
CH 3
103
D
D
D
D
CD 3
108
H
H
D
H
CH 3
109
H
H
D
H
CD 3
110
H
H
D
D
CH 3
111
H
H
D
D
CD 3
112
D
D
H
H
CH 3
113
D
D
H
H
CD 3
114
D
D
H
D
CH 3
115
D
D
H
D
CD 3
120
H
H
H
H
CD 3
121
H
H
H
D
CH 3
122
H
H
H
D
CD 3
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , comprising the additional step of co-administering methotrexate to the subject.
10. A method of treating lupus in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein:
each of Y 1a , Y 1b , Y 2a , and Y 2b is hydrogen or each of Y 1a , Y 1b , Y 2a , and Y 2b is deuterium;
X 1 and X 2 are the same and are selected from hydrogen and deuterium;
Z 1 and Z 2 are the same and are selected from hydrogen and deuterium; and
R is selected from —CH 3 , —CH 2 D, —CHD 2 , and —CD 3 ;
provided that when Y 1a , Y 1b , Y 2a , Y 2b , X 1 and X 2 are each hydrogen, and R is —CH 3 , then at least one of Z 1 or Z 2 is deuterium.
11. The method of claim 10 , wherein in the compound of Formula Ia, X 1 and X 2 are hydrogen.
12. The method of claim 10 , wherein in the compound of Formula Ia, each of Y 1a and Y 1b is hydrogen and each of Y 2a and Y 2b is hydrogen.
13. The method of claim 10 , wherein in the compound of Formula Ia, each of Y 1a and Y 1b is deuterium and each of Y 2a and Y 2b is deuterium.
14. The method of claim 10 , wherein in the compound of Formula Ia, R is —CH 3 or —CD 3 .
15. The method of claim 10 , wherein in the compound of Formula Ia, each of Z 1 and Z 2 is hydrogen.
16. The method of claim 10 , wherein in the compound of Formula Ia, each of Z 1 and Z 2 is deuterium.
17. The method of claim 10 , wherein the compound of Formula Ia is selected from any one of the compounds set forth in the table below:
Cmpd #
Y 1a = Y 1b
Y 2a = Y 2b
Z 1 = Z 2
X 1 = X 2
R
100
D
D
D
H
CH 3
101
D
D
D
H
CD 3
102
D
D
D
D
CH 3
103
D
D
D
D
CD 3
108
H
H
D
H
CH 3
109
H
H
D
H
CD 3
110
H
H
D
D
CH 3
111
H
H
D
D
CD 3
112
D
D
H
H
CH 3
113
D
D
H
H
CD 3
114
D
D
H
D
CH 3
115
D
D
H
D
CD 3
120
H
H
H
H
CD 3
121
H
H
H
D
CH 3
122
H
H
H
D
CD 3
or a pharmaceutically acceptable salt thereof.
18. The method of claim 10 , comprising the additional step of co-administering methotrexate to the subject.