Patent GB-1456214-A (GB)
Title: Substitution derivatives of naphthyloxy benzcyclopentanyloxy- and benzcycloheptanyloxy acetic acids and related compounds
IPC: C07D331/02
Filed: 1973-11-10
Abstract: 1456214 Naphthyloxy-, benzcyclopentanyloxy and benzcycloheptanyloxy acetic acids and related compounds E R SQUIBB & SONS Inc 10 Nov 1973 [10 Nov 1972] 51027/73 Heading C2C Novel compounds of the Formula I wherein R<SP>1</SP> is hydrogen, alkyl, monocyclic cycloalkyl, optionally substituted monocyclic carbooyclic aryl or aralkyl; R<SP>2</SP> is hydrogen, alkyl or aralkyl; R<SP>3</SP> is alkyl, aralkyl, carboxy, monocyclic cycloalkyl, alkenyl, halogen acyl, amino, mono or dialkyl amino, acylamino, nitro, dihydroxyalkyl or R<SP>6</SP>O(CH 2 ) n2 - where R<SP>6</SP> is hydrogen, alkyl or aralkyl, n is 0, 1 or 2, n<SP>1</SP> is 0, 1 or 2 and n<SP>2</SP> is 0 to 10 except that when R 6  is hydrogen n<SP>2</SP> cannot be 0, R<SP>4</SP> and R<SP>5</SP> are the same or different and are hydrogen, alkyl, monocyclic cycloalkyl, optionally substituted monocyclic carbocyclic aryl or aralkyl; and where Z<SP>2</SP> is not present, Z and Z<SP>1</SP> are the same or different and are R<SP>7</SP>X and R<SP>8</SP>Y respectively or formyl, cyano, azido, or -NR<SP>10</SP>R<SP>11</SP>, where X and Y are (CH 2 ) n <SP>3</SP> (n<SP>3</SP> = 1 to 8), O, S, NH, NR<SP>9</SP> where R<SP>9</SP> is H, alkyl, aralkyl or acyl and R<SP>10</SP> and R<SP>11</SP> are the same or different and are hydrogen alkyl, alkenyl, hydroxyalkyl, phenylalkyl or R<SP>10</SP> and R<SP>11</SP> together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring optionally containing a further heteroatom selected from oxygen sulphur or nitrogen, optionally substituted and containing less than 21 atoms other than hydrogen atoms and R<SP>7</SP> and R<SP>8</SP> are the same or different and are H, alkyl, aryl, acyl, alkoxy, hydroxy, NR<SP>10</SP>R<SP>11</SP>, alkynyl or alkenyl and where Z<SP>2</SP> is present, the group Z - - - Z<SP>2</SP> - - - Z<SP>1</SP> is the group -Z<SP>4</SP>-Z<SP>2</SP>-Z<SP>3</SP> which together with two carbon atoms of the cycloalkyl ring form a 5- or 6-membered ring, Z<SP>3</SP> and Z<SP>4</SP> are the same or different and are CH 2 , = N-, O, S, NR<SP>14</SP>, OCH 2 , SCH 2  or CH 2 NR<SP>4</SP> where R<SP>14</SP> is H, alkyl or aryl, Z<SP>2</SP> is CO, CS, C = NR<SP>14</SP>, CH 2 CO, COCO or CR<SP>12</SP>R<SP>13</SP> where R<SP>12</SP> and R<SP>13</SP> are H, alkyl, cycloalkyl, aryl, haloalkyl or unsubstituted, mono or dialkyl-amino or aminoalkyl or Z<SP>3</SP>-Z<SP>2</SP>-Z<SP>4</SP> together for -O-C(R<SP>12</SP>) = N- or -S-C(R<SP>22</SP>) = N- and stereo isomers and salts thereof may be prepared by reacting in the presence of a base a phenol of the Formula V with a haloester QCR<SP>4</SP>R<SP>5</SP>COOR<SP>1'</SP> where R<SP>1'</SP> is as R<SP>1</SP> above other than hydrogen and optionally hydrolysing the ester to the free acid or forming a group Z<SP>4</SP>-Z<SP>2</SP>-Z<SP>3</SP>, wherein alkyl groups containing one to eight carbon atoms, alkenyl and alkynyl groups have from three to eight carbon atoms and acyl is derived from hydrocarbon carboxylic acids containing up to 15 carbon atoms. Numerous phenols of the Formula V may be formed by introducing the grouping -Z-Z<SP>2</SP>- Z<SP>1</SP>- and/or interconverting -Z-Z<SP>2</SP>-Z<SP>1</SP>- groups by known methods preceded where necessary by protecting the phenolic hydroxy group and followed where necessary by removing the protecting group. 5,6- and 7,8-Dihydro-1-naphthol may be prepared by isomerization of 5,8-dihydro-1-naphthol. 2.5-Dihydroxyindane may be prepared by reducing 2-indanone to 2-indanol followed by aceticanhydride/nitric acid nitration to 4- and 5- nitro-2-acetoxyindane followed by reduction of the 5-nitro compound to 5-amino-2-hydroxindane followed by diazotization and decomposition of the diazo compound. 2-Piperidino-5-indanol may be prepared by diazotization of 5 - amino - 2 - piperidinoindane followed by decomposition of the diazo compound. Pharmaceutical compositions of the compound I with the usual excipients show hypocholesteremic activity when administered orally or parenterally and anti-inflammatory activity when administered orally or topically. The compounds I also inhibit the corrosivity of engine lubricants and have water softening properties.