Patent GB-1062572-A (GB)
Title: Morphanthridine derivatives,uses therefor and processes of preparing the same
Inventor: DRUKKER ALEXANDER EMANUEL
IPC: C07D403/04
Filed: 1963-10-29
Abstract: The invention comprises: (I) compounds of Formulae 1 and 2 -<FORM:1062572/C2/1> <FORM:1062572/C2/2> and non-toxic, physiologically acceptable acid addition salts and quaternary ammonium salts thereof, where A and A1 are hydrogen, halogen, alkoxy, alkyl, alkylthio, or trifluoromethyl; B is hydroxy, or -OCOR6 where R6 is lower alkyl, R and R1 are hydrogen, alkyl, alkenyl, alkynyl, phenylalkyl, p-chlorobenzyl, diphenylmethyl, trityl, naphthylmethyl, or phenylalkenyl, and CN is a 3- or 4-piperidyl, 3-pyrrolidyl or 3- or 4-homopiperidyl group, and the preparation thereof (1) by reacting a compound of formula <FORM:1062572/C2/3> with a compound of formula <FORM:1062572/C2/4> to produce a compound of formula 2 in which B is a hydroxy group, and dehydrating this compound to give a compound of Formula 1, in which M is an alkali metal, and R and R1 represent alkyl, alkenyl, alkynyl, phenylalkyl, p-chlorobenzyl, diphenylmethyl, trityl, naphthylmethyl or phenylalkenyl; (2) by reacting a compound of Formula 5 <FORM:1062572/C2/5> with a compound of formula <FORM:1062572/C2/6> to produce a compound of Formula 6 <FORM:1062572/C2/7> and dehydrating this compound to produce a compound of Formula 1, where R and R1 are as defined under (1) above, and Z is lithium or X-Mgwhere X is chlorine, bromine or iodine; (II) compounds of Formula 6 and non-toxic, physiological acceptable acid addition salts and lower alkyl quaternary ammonium salts thereof, (III) compounds of Formula 3 <FORM:1062572/C2/8> and non-toxic physiologically acceptable acid addition salts and lower alkyl quaternary ammonium salts thereof, where R2 is hydrogen, alkyl, alkenyl, alkynyl, phenylalkyl, p-chlorobenzyl, or phenylalkenyl, and Am is either pyridinyl, piperidinyl, pyrrolidinyl, homopiperidinyl or quinuclidinyl, of which the piperidine, pyrrolidine and homopiperidine rings may be R-substituted on the nitrogen atom, or an -NR3R4 group where R3 and R4 are hydrogen alkyl, alkenyl, phenyl, phenylalkyl, diphenylmethyl, trityl, naphthylmethyl, cycloalkyl, or cycloalkyl-alkyl, or a group in which-NR3R4 represents a morpholino, pyrrolidino, piperidino, homopiperidino, piperazino, 1,2,3,4-tetrahydroquinolino, 1,2,3,4-tetrahydroisoquinolino, N-alkylpiperazino, N-(aryl-alkyl)-piperazino or N-(hydroxyalkyl)-piperazino, and Y is a chemical bond, or, when Am is a -NR3R4 group, an alkylene radical, and the preparation thereof (1) by reacting a compound of Formula 4 above with a compound of formula O=C(R2)-Y-Am, to produce a compound of Formula 7 <FORM:1062572/C2/9> and dehydrating this compound to produce a compound of Formula 3 wherein R2, Y and Am are as defined above except that the cyclic amino groups represented by Am have N-substituents and R3 and R4 are not hydrogen, and R is defined under (I)(1) above; (2) by reacting a compound of Formula 5 above with a compound of formula Z-CH(R2)-Y-Am to produce a compound of Formula 8 <FORM:1062572/C2/100> and dehydrating this compound to produce a compound of Formula 3, wherein Z is as defined under (I)(2) above, and R, R2, Y and Am are as defined in (III)(1) above; (IV) compounds of Formula 8, and the non-toxic physilogically acceptable acid addition salts and lower alkyl quaternary ammonium salts thereof; (V) compounds of Formula 7, and the lower alkyl esters thereof, and the non-toxic physiologically acceptable acid addition salts and lower alkyl quaternary ammonium salts thereof; and (VI) compounds of Formula 9 <FORM:1062572/C2/111> and non-toxic, acid-addition salts and lower alkyl quaternary ammonium salts thereof, wherein R is as defined under (I) above except that it is not a benzyl group, and R3 is an alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl, phenyl, phenylalkyl (except benzyl), diphenylmethyl, trityl or naphthylmethyl group, and R5 is an alkoxy, alkylthio, phenoxy or phenylthio group. These compounds of Formula 9 may be prepared by reacting the compounds of Formula 3 wherein Am is -NR3R4 and R4 is benzyl with a chloroformic or chlorothioformic acid ester.  They may then be hydrolysed to produce the corresponding compounds in which R4 is hydrogen.  The compounds of the invention containing free hydroxy groups can be converted to esters by conventional methods. The free hydroxy containing compounds or esters thereof having a cleavable or removable substituent on one or both of the nitrogens, e.g. a trityl group, can be subjected to conditions such as reductive or hydrolytic cleavage to remove such groups. Therapeutic compositions, which have anti-cholinergic, analgetic, antispasmodic, anti-depressant and tranquillizing activity, and which may be administered orally or parenterally, contain as active ingredients compounds of Formulae 1, 2, 6, 3, 8, 7 and 9 above.  The compounds may also be used to purify penicillin, with which they form salts.