Alpha 1A-adrenoceptor antagonists
This invention relates to novel compounds that are dihydroindoles derivatives and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel dihydroindoles derivatives that are derivatives of silodosin. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering an α-1A-adrenoreceptor antagonist, such as silodosin.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each R is independently selected from hydrogen or deuterium; and
at least one R is deuterium;
each deuterium present at a site designated as a site of deuteration is present at an isotopic enrichment of at least 500; and
wherein (a) R 4a and R 4b are simultaneously deuterium (b) R 4a and R 5b are simultaneously deuterium and (c) R 6a and R 6b are simultaneously deuterium.
2. The compound of claim 1 , wherein each pair of R groups bound to a common carbon atom is the same, and is selected independently from any other pair of R groups.
3. The compound of claim 1 , wherein R 7a , R 7b , R 8a and R 8b are the same.
4. The compound of claim 3 , wherein R 7a , R 7b , R 7a and R 8b are simultaneously deuterium.
5. The compound of claim 1 , wherein R 1a , R 1b , R 2a , R 2b , R 3a , and R 3b are simultaneously deuterium.
6. The compound of claim 2 selected from any one of the compounds set forth in the table below:
each
each
each
each
each
each
each
each
Cmpd
R 1
R 2
R 3
R 4
R 5
R 6
R 7
R 8
100
D
D
D
D
D
D
D
D
108
D
D
D
D
D
D
H
H
110
H
H
H
D
D
D
H
H
or a pharmaceutically acceptable salt thereof.
7. A pyrogen-free composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and an acceptable carrier.
8. The composition according to claim 7 , wherein the composition is suitable for pharmaceutical use and said carrier is a pharmaceutically acceptable carrier.
9. The composition according to claim 8 , further comprising a second therapeutic agent selected from a 5-alpha reductase inhibitors, an HMG-CoA reductase inhibitor, an EGF-receptor antagonist and a beta-3-adrenoceptor antagonist.
10. The composition of claim 9 , wherein the second therapeutic agents is finasteride or dutasteride.
11. A method of increasing the activity of an alpha (1A)-adrenoceptor in a cell, comprising the step of contacting the cell with a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
12. A method of treating benign prostate hyperplasia (BPH) in a patient in need thereof comprising the step of administering to the patient a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
13. The method of claim 12 , comprising the additional step of co-administering to the patient in need thereof a second therapeutic agent selected from a 5-alpha reductase inhibitors, an HMG-CoA reductase inhibitor, an EGF-receptor antagonist and a beta-3-adrenoceptor antagonist.
14. The method of claim 13 , wherein the second therapeutic agents is finasteride or dutasteride.
15. The compound of claim 2 , wherein R 7a , R 7b , R 8a and R 8b are the same.
16. The compound of claim 15 , wherein R 7a , R 7b , R 8a and R 8b are simultaneously deuterium.
17. The compound of claim 2 , wherein R 1a , R 1b , R 2a , R 2b , R 3a , and R 3b are simultaneously deuterium.
18. The composition of claim 8 , wherein each pair of R groups bound to a common carbon atom is the same, and is selected independently from any other pair of R groups.
19. The composition of claim 8 , wherein R 7a , R 7b , R 8a and R 8b are the same.
20. The composition of claim 19 , wherein R 7a , R 7b , R 8a and R 8b are simultaneously deuterium.
21. The composition of claim 8 , wherein R 1a , R 1b , R 2a , R 2b , R 3a , and R 3b are simultaneously deuterium.
22. The composition of claim 18 wherein the compound is selected from any one of the compounds set forth in the table below:
each
each
each
each
each
each
each
each
Cmpd
R 1
R 2
R 3
R 4
R 5
R 6
R 7
R 8
100
D
D
D
D
D
D
D
D
108
D
D
D
D
D
D
H
H
110
H
H
H
D
D
D
H
H
or a pharmaceutically acceptable salt thereof.
23. The composition of claim 18 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
24. The method of claim 12 , wherein each pair of R groups bound to a common carbon atom is the same, and is selected independently from any other pair of R groups.
25. The method of claim 12 , wherein R 7a , R 7b , R 8a and R 8b are the same.
26. The method of claim 25 , wherein R 7a , R 7b , R 8a and R 8b are simultaneously deuterium.
27. The method of claim 12 , wherein R 1a , R 1b , R 2a , R 2b , R 3a , and R 3b are simultaneously deuterium.
28. The method of claim 24 wherein the compound is selected from any one of the compounds set forth in the table below:
each
each
each
each
each
each
each
each
Cmpd
R 1
R 2
R 3
R 4
R 5
R 6
R 7
R 8
100
D
D
D
D
D
D
D
D
108
D
D
D
D
D
D
H
H
110
H
H
H
D
D
D
H
H
or a pharmaceutically acceptable salt thereof.
29. The method of claim 24 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
30. The compound of any one of claims 1 , 2 , 3 - 6 or 15 - 17 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.