The invention encompasses a novel process for making piperidinone carboxamide indane and azainane derivatives, which are CGRP receptor antagonists useful for the treatment of migraine.

A compound of formula (1a), (1b) or (1c) wherein: n is 1 or 2; R.sup.N is H or Me; R.sup.1 is optionally one or more halo or methyl groups; R.sup.1 and R.sup.2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH.sub.2OH; R.sup.2c and R.sup.2d (if present) are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH.sub.2OH; R.sup.3a and R.sup.3b are independently selected from H and Me; R.sup.4a is selected from OH, —NH.sub.2, —C(═O)NH.sub.2, and —CH.sub.2OH; R.sup.4b is either H or Me; R.sup.5 is either H or Me; A is either (i) optionally substituted phenyl; (ii) optionally substituted naphthyl; or (iii) optionally substituted C.sub.5-12 heteroaryl.

##STR00001##

A compound of formula (1a), (1b) or (1c) wherein: n is 1 or 2; R.sup.N is H or Me; R.sup.1 is optionally one or more halo or methyl groups; R.sup.1 and R.sup.2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH.sub.2OH; R.sup.2c and R.sup.2d (if present) are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH.sub.2OH; R.sup.3a and R.sup.3b are independently selected from H and Me; R.sup.4a is selected from OH, —NH.sub.2, —C(═O)NH.sub.2, and —CH.sub.2OH; R.sup.4b is either H or Me; R.sup.5 is either H or Me; A is either (i) optionally substituted phenyl; (ii) optionally substituted naphthyl; or (iii) optionally substituted C.sub.5-12 heteroaryl.

##STR00001##

An object of this disclosure provides a novel method for producing a fluorovinyl amide compound and the like. The object is achieved by a method for producing a compound represented by formula (1):

##STR00001##

wherein
Rf is —F or fluoroalkyl,
R.sup.a1 is —H or an organic group, and
R.sup.a2 is —H or an organic group, or
(i) R.sup.a1 and R.sup.a2, (ii) R.sup.a1 and Rf, or (iii) Rf and R.sup.a2, may be linked to each other,
R.sup.b1 is —H or an organic group, and
R.sup.b2 is —H or an organic group, or
R.sup.b1 and R.sup.b2 may be linked together with their adjacent atoms to form a nitrogen-containing ring optionally having one or more substituents,
the method comprising
step A of reacting a compound represented by formula (2):

##STR00002##

wherein
R.sup.x is a leaving group,
with a compound represented by formula (3) or a salt thereof:

##STR00003##

in the presence of a transition metal catalyst.

An object of this disclosure provides a novel method for producing a fluorovinyl amide compound and the like. The object is achieved by a method for producing a compound represented by formula (1):

##STR00001##

wherein
Rf is —F or fluoroalkyl,
R.sup.a1 is —H or an organic group, and
R.sup.a2 is —H or an organic group, or
(i) R.sup.a1 and R.sup.a2, (ii) R.sup.a1 and Rf, or (iii) Rf and R.sup.a2, may be linked to each other,
R.sup.b1 is —H or an organic group, and
R.sup.b2 is —H or an organic group, or
R.sup.b1 and R.sup.b2 may be linked together with their adjacent atoms to form a nitrogen-containing ring optionally having one or more substituents,
the method comprising
step A of reacting a compound represented by formula (2):

##STR00002##

wherein
R.sup.x is a leaving group,
with a compound represented by formula (3) or a salt thereof:

##STR00003##

in the presence of a transition metal catalyst.

The N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n is 1 or 2; L represents a C.sub.1-3alkyl linker optionally substituted with one or two substituents selected from C.sub.1-4alkyl, C.sub.1-3alkyloxy-C.sub.1-4alkyl-, hydroxy-C.sub.1-4alkyl, hydroxy, C.sub.1-3alkyloxy- or phenyl-C.sub.1-4alkyl; M represents a direct bond or a C.sub.1-3alkyl linker optionally substituted with one or two substituents selected from hydroxy, C.sub.1-4alkyl or C.sub.1-4alkyloxy; R.sup.1 and R.sup.2 each independently represent hydrogen, halo, cyano, hydroxy, C.sub.1-4alkyl optionally substituted with halo, C.sub.1-4alkyloxy- optionally substituted with one or where possible two or three substituents selected from hydroxy, Ar.sup.1 and halo; or R.sup.1 and R.sup.2 taken together with the phenyl ring to which they are attached form naphtyl or 1,3-benzodioxolyl, wherein said naphtyl or 1,3-benzodioxolyl are optionally substituted with halo; R.sup.3 represents hydrogen, halo, C.sub.1-4alkyl, C.sub.1-4alkyloxy-, cyano or hydroxy; R.sup.4 represents hydrogen, halo, C.sub.1-4alkyl, C.sub.1-4alkyloxy-, cyano or hydroxy; R.sup.5 represents hydrogen, C.sub.1-4alkyl or Ar.sup.2—C.sub.1-4alkyl-; R.sup.6 represents hydrogen, halo, C.sub.1-4alkyl or C.sub.1-4alkyoxy-; Ar.sup.1 and Ar.sup.2 each independently represent phenyl or naphtyl wherein said phenyl and naphtyl are optionally substituted with C.sub.1-4alkyl, C.sub.1-4alkyloxy-, or phenyl-C.sub.1-4alkyl;
for use as a medicine. ##STR00001##

The N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n is 1 or 2; L represents a C.sub.1-3alkyl linker optionally substituted with one or two substituents selected from C.sub.1-4alkyl, C.sub.1-3alkyloxy-C.sub.1-4alkyl-, hydroxy-C.sub.1-4alkyl, hydroxy, C.sub.1-3alkyloxy- or phenyl-C.sub.1-4alkyl; M represents a direct bond or a C.sub.1-3alkyl linker optionally substituted with one or two substituents selected from hydroxy, C.sub.1-4alkyl or C.sub.1-4alkyloxy; R.sup.1 and R.sup.2 each independently represent hydrogen, halo, cyano, hydroxy, C.sub.1-4alkyl optionally substituted with halo, C.sub.1-4alkyloxy- optionally substituted with one or where possible two or three substituents selected from hydroxy, Ar.sup.1 and halo; or R.sup.1 and R.sup.2 taken together with the phenyl ring to which they are attached form naphtyl or 1,3-benzodioxolyl, wherein said naphtyl or 1,3-benzodioxolyl are optionally substituted with halo; R.sup.3 represents hydrogen, halo, C.sub.1-4alkyl, C.sub.1-4alkyloxy-, cyano or hydroxy; R.sup.4 represents hydrogen, halo, C.sub.1-4alkyl, C.sub.1-4alkyloxy-, cyano or hydroxy; R.sup.5 represents hydrogen, C.sub.1-4alkyl or Ar.sup.2—C.sub.1-4alkyl-; R.sup.6 represents hydrogen, halo, C.sub.1-4alkyl or C.sub.1-4alkyoxy-; Ar.sup.1 and Ar.sup.2 each independently represent phenyl or naphtyl wherein said phenyl and naphtyl are optionally substituted with C.sub.1-4alkyl, C.sub.1-4alkyloxy-, or phenyl-C.sub.1-4alkyl;
for use as a medicine. ##STR00001##

The present invention is directed to a compound represented by Structural Formula (A):

##STR00001##

or a pharmaceutically acceptable salt thereof. The variables for Structural Formula (A) are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula (A) and its therapeutic use.

The present invention is directed to a compound represented by Structural Formula (A):

##STR00001##

or a pharmaceutically acceptable salt thereof. The variables for Structural Formula (A) are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula (A) and its therapeutic use.

The present disclosure provides compositions and methods for selectively killing senescent cells, wherein the composition comprises piperlongumine (PL) or derivative thereof. The selective killing of senescent cells may delay aging and/or treat age-related disorders.