Phenoxy- and thiophenoxy compounds, methods for their preparation and pharmaceutical formulations containing them

Claim 2

Compounds of formula I, in which R is a group of formula II, R 1 , R 2 and R 3 , which may be the same or different each represent hydrogen, alkyl, alkenyl, alkenyloxy, halogen, alkoxy, alkanoyl or hydroxy, one or more of R 4 , R 5 and R represents alkyl, alkanoyl, alkenyl, -COOH or -ACOOH where A represents Y, OY or SY and Y represents a -CH=CH-, methylene, ethylene or 1,3-propylene chain, and the remainder of R 4 , R 5 and R 6 represent hydrogen, X represents a hydrocarbon chain having from 2 to 7 carbon atoms optionally substituted by hydroxy, E represents -S-, -O- or -CH 2 -, and G represents -S- or -0-, provided that a) when R 1 and R 2 are hydrogen R 3 does not represent chlorine, isopropyl or t-butyl and is not para to E, or b) when E and G are both -0-, either i) the R group is not of formula III, in which R 7 is hydrogen or alkyl, R 8 is alkanoyl, and R 9 is alkyl or alkenyl, when only one of R 4 , R 5 and R represent a group -COOH, -Y-COOH or -OYCOOH, or when one of R 4 , R 5 and R represent a group -COOH, -Y-COOH or -OYCOOH and another of R 4 , R 5 and R 6 represents -COOH, or ii) two or more of R 4 , R 5 and R 6 represent -ACOOH, or iii) at least one or R 4 , R and R 6 represents a group -SYCOOH, or iv) none of R 4 , R 5 and R 6 represents a group selected from -COOH and -ACOOH, c) when one of R 4 , R 5 and R 6 represents -COOH, -CH 2 COOH, -(CH 2 ) 2 COOH or -(CH 2 ) 3 COOH para to G , another of R 4 , R 5 and R 6 is hydrogen or alkyl, the third of R 4 , R 5 and R 6 is hydrogen, R 1 and R 2 are selected from hydrogen, alkyl, alkoxy and halogen, and R 3 is other than hydrogen, then X carries a hydroxy substituent, or d) when R 4 represents -OCH 2 COOH, R 5 and R 6 are both hydrogen, R 1 is hydrogen and R 2 and R 3 are selected from alkyl, alkoxy and halogen, then X carries a hydroxy substituent, and pharmaceutically acceptable derivatives of those compounds containing an acidic function.

Claim 3

A compound according to Claim 1, wherein each of R 1 to R 6 when they contain carbon, contain less than 7 carbon atoms.

Claim 4

A compound according to Claim 1 or 2, wherein one of R 4 , R 5 and R 6 is - COOH or -ACOOH para to the group G.

Claim 5

A compound according to any one of the preceding claims, wherein X represents trimethylene or 2-hydroxytrimethylene.

Claim 6

A compound according to any one of the preceding claims, wherein E and G are both oxygen or one is oxygen and the other is sulphur.

Claim 7

A compound according to any one of the preceding claims, wherein E and G are both oxygen, one or more of R 1 , R 2 and R represent alkyl, alkenyl, alkoxy, alkanoyl or hydroxy and the remainder each represent hydrogen, and X , R 4 , R and R are as defined in Claim 1 save that Y does not represent -CH=CH-.

Claim 8

A compound according to any one of the preceding claims, wherein E and G are both oxygen, R 1 represents alkanoyl C 2 to 4, R 3 is -OH, R 4 is ortho to G , R 2 and R 4 , which may be the same or different, each represent alkyl C 1 to 4, R 5 is hydrogen and R 6 represents carboxy, -YCOOH or -OYCOOH in which Y does not represent -CH=CH-.

Claim 9

A compound of formula Ia, in which M is hydrogen or -OH, A a is -SCH 2 COOH, -CH=CHCOOH or -CH 2 CH 2 COOH, and E a is -0- when A a is -SCH 2 COOH or -S- when A a is -CH=CHCOOH or -CH 2 CH 2 COOH, or a pharmaceutically acceptable salt thereof.

Claim 10

A compound of formula Ia, in which M is hydrogen or -OH, A a is -SCH 2 COOH, -CH=CHCOOH or -CH 2 CH 2 COOH, and E a is -0- when A a is -SCH 2 COOH or -S- when A a is -CH=CHCOOH or -CH 2 CH 2 COOH, or a pharmaceutically acceptable salt thereof.

Claim 11

Trans-3-(4-[3-(2-allyl-4-acetylphenoxy)propyloxy] phenyl)propenoic acid, 3-[4-(3-[2-Acetyl-3-hydroxyphenoxy]propyloxy)phenyl] propanoic acid, (4-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy] phenylthio)acetic acid, (4-[3-(4-acetyl-3-hydroxy-2-propyl- phenoxy-2-hydroxypropoxy]phenylthio)acetic acid, Trans-3-(4-[3-(2-acetyl-3-allyloxyphenoxy)propyloxy] phenyl)propenoic acid, trans-3-(4-(3-[2-acetyl-4-allyl-3-hydroxyphenoxy) propyloxy]phenyl)propenoic acid, Trans-3-(4-(3-[2-propylphenoxy]propyloxy)phenyl] propenoic acid, Trans-3-(4-(3-[2-acetyl-3-hydroxyphenoxy]propyloxy) phenyl)propenoic acid, Trans 3-(4-(3-[4-acetyl-3-hydroxy-2-propylphenylthio] propyloxy)phenyl)propenoic acid, Trans 3-[4-(3-[3-acetyl-4-hydroxy-5-propylphenoxy] propyloxy)phenyl]propenoic acid, 3-(4-(3-[4-Acetyl-3-hydroxy-2-propylphenythio] propyloxy)phenyl)propanoic acid, 3-[4-(5-(2-Acetyl-3-hydroxyphenoxy)pentyloxy)-3, 5-diallylphenyljpropanoic acid, (4-[3-(4-Acetyl-6-bromo-3-hydroxy-2-propylphenoxy) propoxy]phenylthio)acetic acid, 6-Acetyl-3-(5-phenylpentylthio)-2-propylphenoxy acetic acid, or the sodium salt of any one thereof.

Claim 12

Trans-3-(4-[3-(2-allyl-4-acetylphenoxy)propyloxy] phenyl)propenoic acid, 3-[4-(3-[2-Acetyl-3-hydroxyphenoxy]propyloxy)phenyl] propanoic acid, (4-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy] phenylthio)acetic acid, (4-[3-(4-acetyl-3-hydroxy-2-propyl- phenoxy-2-hydroxypropoxy]phenylthio)acetic acid, Trans-3-(4-[3-(2-acetyl-3-allyloxyphenoxy)propyloxy] phenyl)propenoic acid, trans-3-(4-(3-[2-acetyl-4-allyl-3-hydroxyphenoxy) propyloxy]phenyl)propenoic acid, Trans-3-(4-(3-[2-propylphenoxy]propyloxy)phenyl] propenoic acid, Trans-3-(4-(3-[2-acetyl-3-hydroxyphenoxy]propyloxy) phenyl)propenoic acid, Trans 3-(4-(3-[4-acetyl-3-hydroxy-2-propylphenylthio] propyloxy)phenyl)propenoic acid, Trans 3-[4-(3-[3-acetyl-4-hydroxy-5-propylphenoxy] propyloxy)phenyl]propenoic acid, 3-(4-(3-[4-Acetyl-3-hydroxy-2-propylphenythio] propyloxy)phenyl)propanoic acid, 3-[4-(5-(2-Acetyl-3-hydroxyphenoxy)pentyloxy)-3, 5-diallylphenyljpropanoic acid, (4-[3-(4-Acetyl-6-bromo-3-hydroxy-2-propylphenoxy) propoxy]phenylthio)acetic acid, 6-Acetyl-3-(5-phenylpentylthio)-2-propylphenoxy acetic acid, or the sodium salt of any one thereof.

Claim 13

A pharmaceutical formulation comprising a compound according to any one of the preceding claims in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Claim 14

A process for the production of a compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable derivative thereof, which comprises (a) producing a compound of formula I in which one or more of R 4 , R 5 and R represents -COOH or -ACOOH, by selective hydrolysis of a compound of formula IV, in which R, E, X and G are as defined above, one or more of D 4 , D 5 and D 6 represent a group hydrolysable to -COOH, or to'-ACOOH, and the remainder of D 4 , D 5 and D 6 represent groups R 4 , R 5 and R as defined above, (b) reacting a compound of formula REZ with a compound of formula V or an ester thereof, in which R , E , G , R 4 , R 5 and R 6 are as defined above, and L and Z represent the pair of groups (i) hydrogen or a reactive metal, and (ii) a hydrocarbon chain having from 2 to 7 carbon atoms and carrying an anion forming group or an epoxide group, (c) producing a compound of formula I in which one or more of R 1 to R 6 represent an alkyl group containing at least 2 carbon atoms and/or A represents an ethylene chain, by hydrogenation of a compound of formula I wherein one or more of R 1 to R 6 represents an alkenyl or alkanoyl group, and/or A represents -CH=CH-, (d) producing a compound of formula I in which one or more of R 4 , R 5 and R represent -ACOOH where A represents a group OY or SY, by reacting a corresponding compound of formula I in which either an adjacent pair of R 1 , R 2 and R represent -OH and an alkanoyl group, or none of R 1 , R 2 and R represents a non-hydrogen-bonded hydroxyl group and one of R 4 , R and R 6 represents an -OH or -SH group, with an appropriate haloalkanoic acid derivative in the presence of a suitable base, e) production of a compound of formula I in which at least one of R 1 , R 2 and R 3 represents alkenyloxy or alkoxy, by alkenylating or alkylating a corresponding compound of formula I in which at least one of R 1 , R 2 and R 3 represents hydroxy, f) production of a compound of formula I, or an ester thereof, in which at least one of R 1 , R 2 and R 3 represents -OH and another of R 1 , R 2 and R 3 represents an allyl group or an allyl group substituted by alkyl in the position adjacent to the benzene ring, by subjecting to an elevated temperature a corresponding compound of formula I, or an ester therefore, in which at least one of R 1 , R 2 and R 3 represents hydrogen and another of R 1 , R 2 and R 3 represents an allyloxy group or an alkyl substituterd allyloxy group, or g) converting an acid of formula I to a pharmaceutically acceptable derivative thereof or vice versa.