Patent GB-1115049-A (GB)
Title: O-(indolyl)-glycolic acids and their derivatives
IPC: C07D209/36
Filed: 1965-12-29
Abstract: Novel compounds of the Formula (I) <FORM:1115049/C2/1> <FORM:1115049/C2/2> <FORM:1115049/C2/3> <FORM:1115049/C2/4> <FORM:1115049/C2/5> (wherein A is a substituted or unsubstituted aromatic or heteroacromatic carboxylic acyl radical of one or two fused rings; R1 is H or a substituted or unsubstituted C1- 8 hydrocarbon radical; R2 is H, phenyl or C1- 5 alkyl; R3\t is H, halogen, CF3, NO2, C1- 5 alkyl, or C1- 5 alkoxy; R4 is H, halogen, OH, C1- 5 alkyl, aryl, haloalkyl, C1- 5 alkoxy, aryloxy, aralkoxy, alkenyloxy, cycloalkoxy, amino, dialkylamino C1- 5 alkyl, C1- 5 alkylamino, di(C1- 5 alkyl)amino, arylamino, alkarylamino, C2- 6 acylamino, bis(b -hydroxyethyl) amino, cyano, 1-azacyclopropyl, 1-pyrrolidino, nitro, mercapto, piperazinyl, 4-methylpiperazinyl, morpholinyl, C1- 5 alkylthio or aralkylthio; and M is OH, C1- 5 alkoxy, C2- 5 alkenyloxy, C2- 5 alkynyloxy, cycloalkoxy, aryloxy or C2- 5 alkynyloxy which may be substituted, or is tetrahydrofurfuryloxy, N-ethyl-3-piperidyloxy or 3-quinuclidinyloxy) and salts and anhydrides of the free acids are prepared (1) by reacting a compound of the Formula (II) (wherein R5 is H or C1- 5 alkyl) with an appropriate a -halo acid or ester thereof to give a compound of the Formula (III) (wherein R6 is H or C1- 5 alkyl; and R7 is H, C1- 5 alkyl or phenyl), acylating this to give a compound of the Formula (IV) (wherein R8 is C1- 5 alkyl), cyclizing this to give a compound of the Formula (V), or a corresponding O-acylate, hydrolysing this to remove the ester and acyl groups, and then esterifying with t-butanol to give a compound of the Formula (VI), reacting this with an ester of an appropriate a -halo-acid to give a compound of the Formula (VII) (wherein R10 is H, C1- 5 alkyl or phenyl and R9 has the appropriate esterifying values of M) and then N-acylating and removing the 2-substituent by heating in either order (if R9 is t-butyl, the product is the free acid); or (2) by reacting an indoline compound of the Formula (VIII) (prepared by N-acylation of the corresponding N-unsubstituted indoline, which in turn is prepared by reduction of the corresponding indole) with an appropriate a -haloester halCH(R10)-COOR9 to give an indoline 3-OCH(R10)COOR9 product from which the required indole product is obtained by dehydrogenation; or (3) reacting a compound of the Formula (IX) (wherein X is a halogen, these compounds being prepared by halogenation of the corresponding C-unhalogenated compounds) with the compound halCH(R10)COOR9 to give a compound of the Formula (X) and cyclizing and N-acylating this. In the products, benzyl esters may be hydrogenolysed to the free acids, which may be reesterified. Salts and anhydrides are prepared by conventional procedures. Substituents in the benzene ring may be interconverted, e.g. nitro to amino to mono- or di-alkyl-amino or cyclic amino or to acylamino (the preparation of morpholino and 1-piperazinyl compounds proceeds via the N-bis(hydroxyethyl) intermediates).  p - Nitrophenyl 1 - methylpyrrole - 2 - carboxylate, used as an acylating agent, is prepared from p-nitrophenol and the appropriate free acid.  The indole derivatives of the invention, which are stated to have anti-inflammatory and anti-pyretic activity, may be made up into pharmaceutical compositions with suitable carriers.