Preparation of pyrrolopyridine containing spiro compounds as CGRP receptor antagonists.

Abstract

The present invention is directed to compds. I [A1 = O, S(O)0-2, C(O), etc.; A2 = (un)substituted CH2, C(O); A3 = (un)substituted CH2, NH; A4 = a bond, C(O), (un)substituted CH2, NH; A5, A7 = a bond, O, S(O)0-2, etc.; A6, A8 = O, S(O)0-2, C(O), etc.; E1-E3 = N, N(O), (un)substituted CH; G1 = a bond, C(O), (un)substituted CH2, etc.; G2 = a bond, C(O), O, etc.; G3-G4 = O, S(O)0-2, C≡C, etc.; Q = C(O), SO2, SO, (un)substituted CH2; R6, R7 = H, (un)substituted alkyl, cycloalkyl, etc.; or R6 and R7 and the carbon atoms to which they attached join to form a ring selected from cyclopentyl, cyclohexyl, cycloheptyl, etc.; R8 = H, alkyl, haloalkyl, etc.; J = C(O), (un)substituted NH, CH2, CH; Y = N, C(O), (un)substituted NH, CH, CH2] which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. E.g., a multi-step synthesis of (1E),(8R)-II, starting from 3,5-difluoroacetophenone, was given. Representative compds. I (including II) were tested and had activity in the recombinant receptor binding assay, generally with a Ki value of <50 μM. The invention is also directed to pharmaceutical compns. comprising compds. I and the use of these compds. and compns. in the prevention or treatment of such diseases in which CGRP is involved. [on SciFinder(R)]