Patent GB-1446953-A (GB)
Title: Substituted indanyloxy and indanylthio alkanoic acids and their derivatives
IPC: C07C59/70
Filed: 1973-10-08
Abstract: 1446953 Substituted indanyloxy and indanylthioalkanoic acids and their derivatives MERCK & CO Inc 8 Oct 1973 [13 Oct 1972] 46936/73 Heading C2C The invention comprises novel compounds of the Formulae I and II in which A is an oxygen or sulphur atom; R is a C 1-5  alkyl radical or a cycloalkyl radical, optionally substituted by C 1-5  alkyl; R<SP>1</SP> is a C 1-5  alkyl, C 3-5  alkenyl, C 3-5  haloalkenyl, C 3-5  alkynyl, phenyl-(C 1-3  alkyl), phenyl-(C 2-6  alkenyl), C 1-5  hydroxyalkyl, (C 1-5  alkoxy)-(C 1-5  alkyl), C 1-5  oxo alkyl, C 3-6  hydroxy cycloalkyl, C 4-7  cycloalkyl alkyl or cycloalkoxyalkyl; R and R<SP>1</SP> may be joined together with the carbon atom to which they are attached to form a C 3-7  cycloalkyl radical optionally having hydroxy or C 1-4  alkyl substitution; R<SP>2</SP> is hydrogen, halogen, C 1-5  alkyl, aryl or aryl having C 1-5  alkyl or halo substitution; R<SP>2</SP>' is hydrogen, C 1-5  alkyl, aryl or aryl having C 1-5  alkyl or halo substitution; R n  is hydrogen or methyl; X<SP>1</SP> is hydrogen, methyl or halogen and X<SP>2</SP> is methyl or halogen or X<SP>1</SP> and X<SP>2</SP> are joined to form a bivalent hydrocarbon chain containing 3 or 4 carbon atoms; and Y is alkylene or haloalkylene containing a maximum of 4 carbon atoms, not more than 3 of which are in the chain joining A to the COOH group; with the provisos that in Formula I(a) if R<SP>1</SP> is cycloalkoxyalkyl other than cycloalkoxymethyl, Y must be methylene and A oxygen; (b) if R<SP>1</SP> is cycloalkoxymethyl, Y must be methylene and unless A is oxygen, R<SP>2</SP> must be hydrogen or halogen; (c) if Y is haloalkylene containing 2 carbon atoms in the said chain, R<SP>2</SP> must be halogen, R n  hydrogen and R<SP>1</SP> other than cycloalkoxyalkyl, and (d) if R<SP>2</SP> is halogen and R n  is methyl, Y must be methylene and A oxygen; and the non-toxic pharmacologically acceptable salt, amide, anhydride and ester derivatives thereof. The compounds of the Formulae I and II may be prepared as follows: (a) for compounds of the formula in which R<SP>1</SP>' is C 1-5  alkyl, C 3-5  alkenyl, C 3-5  haloalkenyl, C 1-5  alkynyl, phenyl-C 1-3 -alkyl, phenyl- C 2-6 -alkenyl, C 1-5  hydroxyalkyl, C 1-5  alkoxy, C 1-5  alkyl, C 1-5  oxoalkyl, C 3-6  hydroxycycloalkyl or C 4-7  cycloalkylalkyl; or R and R<SP>11</SP> are joined to form, together with the carbon atom to which they are attached, a cycloalkyl radical containing 3 to 7 nuclear carbon atoms which may be unsubstituted or have hydroxy or C 1-4  alkyl substitution; R<SP>2</SP>' is hydrogen, C 1-5  alkyl, aryl or substituted aryl having C 1-5  alkyl or halosubstitution ; and Y<SP>1</SP> is alkylene or haloalkylene containing 1 or 3 linear carbon atoms and a maximum of 4 carbon atoms, treating a compound XXII with a reagent ZY<SP>1</SP>-CO-OR<SP>5</SP> in which Z is chlorine, bromine or iodine and R<SP>5</SP> is hydrogen or C 1-5  alkyl, in the presence of a base and, when R<SP>5</SP> is C 1-5  alkyl, hydrolysing the resulting ester to produce the desired compound; (b) for preparing a compound in which each R<SP>5</SP>" is a hydrogen atom or an alkyl radical; the four R<SP>5</SP>"s together containing 0, 1 or 2 carbon atoms, treating a compound XXII with a compound in the presence of a base, followed by acidification, (c) for preparing a compound heating a compound in the presence of a strong acid; (d) for preparing a compound treating a compound with a halogenating agent; (e) for preparing a compound in which R<SP>7</SP> is hydrogen or C 1-4  alkyl, treating a compound with an alkali metal base, followed by treatment with an agent capable of inserting a methylene group; (f) for a compound treating a compound with a formaldehyde in the presence of base, followed by acidification; (g) for a compound in which R<SP>*</SP> is C 1-5  alkyl or cycloalkyl, treating a compound with an alkylating or cycloalkylating agent in the presence of a base, followed by hydrolysis, (h) for a compound in which R<SP>1</SP>"' is C 3-6  hydroxycycloalkyl, adding a compound in which m is 2 to 5, to a sterile, hydroxylated production medium and incubating the medium, (i) for a compound II, treating a compound with haloacetonitrile in the presence of base followed by treating the nitrile intermediate with sodium azide and ammonium chloride or (j) optionally modifying substituent groups on the compounds I. The invention also comprises novel compounds of the Formula XX in which R<SP>10</SP> is C 1-5  alkyl, C 3-5  alkenyl, C 3-5  haloalkenyl, C 3-5  alkynyl, phenyl-(C 1-3  alkyl), phenyl-(C 6-2  alkenyl), C 1-5  hydroxyalkyl, C 1-5  oxoalkyl, C 3-6  hydroxycycloalkyl or C 4-7  cycloalkyl-alkyl, or R and R<SP>10</SP> are joined to form, together with the carbon atom to which they are attached, a C 4-7  cycloalkyl radical; and R<SP>5</SP> is hydrogen or C 1-5  alkyl, which may be prepared by (1) dealkylation an ether group at R<SP>5</SP>A-; (2) modifying or introducing substituent groups on the compounds XX; (3) alkylating a free hydroxy group at R<SP>5</SP>A or (4) cyclization of appropriately substituted 4- (2-methylene acetyl) anisoles to the corresponding 5-methoxy-1- indanones followed by (2). The intermediate substituted 4-(2-methylene acetyl)-anisoles are prepared by Friedel Craft acylation of an anisole to produce a 4-acyl anisole followed by formation of the methylene group either directly or by halogenation followed by dehydrohalogenation. Alternatively 2,3- dichloro-4-(2-benzylidenebutyryl)-anisole is prepared by methylating 2<SP>1</SP>,3<SP>1</SP>-dichloro-4<SP>1</SP>-hydroxybutyrophenone and reacting the product with benzaldehyde in the presence of base. Pharmaceutical compositions of the compounds I, II and XX with the usual excipients exhibit diuretic and uricosuric activity when administered orally or parenterally. The compounds I and II also exhibit saluretic activity.