Piperidinone carboxamide spirohydantoin CGRP receptor antagonists
View Patent ↗The present invention is directed to piperidinone carboxamide spirohydantoin derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of: C 1-4 alkyl, cyclopropylmethyl, cyclobutylmethyl and [1-(trifluoromethyl)cyclopropyl]methyl, each of which is optionally substituted with one to four substituents as allowed by valence independently selected from the group consisting of: F and hydroxy;
R 2 is hydrogen or methyl;
when R 2 is hydrogen then
R 3 is selected from hydrogen, F or Cl;
R 4 is selected from hydrogen, F or Cl;
R 5 is hydrogen;
R 6 is selected from hydrogen or F; and
R 7 is selected from hydrogen, F or Cl;
except that at least two of R 3 , R 4 , R 6 and R 7 must be F or Cl unless R 3 is F in which case R 4 , R 6 and R 7 may all be hydrogen; and if R 4 is Cl then R 7 cannot be Cl;
when R 2 is methyl then
R 3 is selected from hydrogen, methyl, F, Cl, or Br;
R 4 is selected from hydrogen, methyl, F or Cl;
R 5 is selected from hydrogen or F;
R 6 is selected from hydrogen or F; and
R 7 is selected from hydrogen, methyl, F or Cl;
except that if R 5 is F then at least three of R 3 , R 4 , R 6 and R 7 must be F; and if R 4 is methyl or Cl then R 7 cannot be methyl or Cl; and
R 8 is selected from the group consisting of: hydrogen, C 1-4 alkyl, cyclopropylmethyl, and cyclobutylmethyl, each of which is optionally substituted with one to three fluoro substituents as allowed by valence.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-4 alkyl, optionally substituted with one to four substituents as allowed by valence independently selected from the group consisting of F and hydroxy.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from: isopropyl, 2,2,2-trifluoroethyl and 2-methylpropyl.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is 2,2,2-trifluoroethyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein at least two of R 3 , R 4 , R 6 and R 7 are F or Cl, except that if R 4 is Cl then R 7 cannot be Cl.
7. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is F and R 4 , R 6 and R 7 are hydrogen.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 5 is F and at least three of R 3 , R 4 , R 6 and R 7 are F.
10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen and if R 4 is methyl or Cl then R 7 cannot be methyl or Cl.
11. The compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, methyl or F; R 4 is selected from hydrogen, methyl or F; R 5 is hydrogen; R 6 is selected from hydrogen or F; and R 7 is selected from hydrogen, methyl or F; except that if R 4 is methyl then R 7 cannot be methyl.
12. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen or F, R 4 is hydrogen or F, R 6 is hydrogen or F and R 7 is hydrogen or F.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is C 1-4 alkyl.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 8 is methyl.
15. The compound of claim 1 , which is selected from the following:
R 2
Ar
Me
2,3,5-trifluorophenyl
Me
2,3,6-trifluorophenyl
Me
2,3,5,6-tetrafluorophenyl
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
17. A method of treating headache in a mammalian patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , wherein the headache is migraine headache.