Piperidinone carboxamide azaindane CGRP receptor antagonists
The present invention is directed to piperidinone carboxamide azaindane 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 method of treating migraine in a mammalian patient in need of such treatment which method comprises administering to the patient a therapeutically effective amount comprising a combination of a first compound of Formula (I); and,
a second compound selected from the group consisting of a beta-adrenergic antagonist, a MAO inhibitor, a calcium channel blocker, a neuroleptic, an anticonvulsant, an angiotensin I antagonist, an angiotensin II antagonist, an angiotensin converting enzyme inhibitor, and a botulinum toxin;
wherein Formula (I) is:
or a pharmaceutically acceptable salt thereof, wherein:
X is (CR 8 )═, wherein R 8 is hydrogen, F or CN:
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 or more substituents as allowed by valence independently selected from the group consisting of F and hydroxy;
R 2 is selected from hydrogen and methyl; and wherein:
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 with the proviso that 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 with the proviso that
if R 4 is methyl or Cl then R 7 cannot be methyl or Cl.
2. The method of claim 1 , wherein the first compound is:
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the first compound is:
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the second compound is a beta-adrenergic antagonist selected from the group consisting of timolol, propanolol, atenolol, metoprolol and nadolol.
5. The method of claim 1 , wherein the second compound is a MAO inhibitor selected from the group consisting of phenelzine, rasagiline, selegiline, isocarboxazid, and tranylcypromine.
6. The method of claim 1 , wherein the second compound is a calcium channel blocker selected from the group consisting of example flunarizine, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, verapamil, nifedipine, and prochlorperazine.
7. The method of claim 1 , wherein the second compound is a neuroleptic selected from the group consisting of olanzapine, droperidol, prochlorperazine, chlorpromazine and quetiapine.
8. The method of claim 1 , wherein the second compound is an anticonvulsant selected from the group consisting of topiramate, zonisamide, tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine, gabapentin, pregabalin and divalproex sodium.
9. The method of claim 1 , wherein the second compound is an angiotensin II antagonist selected from the group consisting of losartan, irbesartin, valsartan, eprosartan, telmisartan, olmesartan, medoxomil, candesartan and candesartan cilexetil.
10. The method of claim 1 , wherein the second compound is an angiotensin I antagonist.
11. The method of claim 1 , wherein the second compound is an angiotensin converting enzyme inhibitor selected from the group consisting of lisinopril, enalapril, captopril, benazepril, quinapril, perindopril, ramipril and trandolapril.
12. The method of claim 1 , wherein the second compound is a botulinum toxin A or botulinum toxin B.
13. The method of claim 1 , wherein the first compound is:
and the second compound is botulinum toxin A.
14. The method of claim 1 , wherein the first compound is:
and the second compound is botulinum toxin B.
15. The method of claim 1 , wherein the first compound is:
and the second compound is botulinum toxin A.
16. The method of claim 1 , wherein the first compound is:
and the second compound is botulinum toxin B.
17. The method of claim 1 , wherein the combination may be administered separately or in conjunction.
18. The method of claim 1 , wherein the administration of the first compound may be prior to, concurrent to, or subsequent to the administration of the second compound.
19. The method of claim 1 , wherein the administration of the first compound and second compound is via the same or different routes of administration.