1,3-Dioxan-5-ylalkenoic acids

Claim 2

A 4-phenyl-1,3-dioxan-cis-5-ylalkenoic acid derivative of the formula I wherein Ra and Rb are independently hydrogen, (2-6C)alkenyl, (1-8C)alkyl optionally bearing up to three halogeno substituents, pentafluorophenyl, aryl or aryl(1-4C)alkyl, the latter two of which may optionally bear up to three substituents selected from halogeno, (1-6C)alkyl, (1-6C)alkoxy, (l-6C)alkoxy, (1-4C)alkenedioxy, trifluoromethyl, cyano, nitro, hydroxy,(2-6C)alkanoyloxy, (1-6C)alkylthio, (1-6C)alkanesulphonyl, (l-6C)alkanoylamino, and oxapolymethylene of 2 to 4 carbon atoms, provided that when both Ra and Rb are alkyl or alkenyl, the total number of carbon atoms in Ra and Rb taken together is 8 or less; or Ra and Rb together form polymethylene of 2 to 7 carbon atoms, optionally bearing one or two (l-4C)alkyl substituents; Rc is hydroxy, (l-6C)alkoxy or (1-6C)alkanesulphonamido ; n is the integer 1 or 2; A is ethylene or vinylene; Y is polymethylene of 2to 5 carbon atoms optionally bearing (1-4C)alkyl as a substituent; benzene ring B optionally bears one or two substituents selected from halogeno, (1-6C)alkyl, (1-6C)alkoxy, hydroxy,(2-6C)alkanoyloxy, (1-6C)alkanoylamino, trifluoromethyl and nitro; and the substituents at positions 4 and 5 of the dioxane ring have cis-relative stereochemistry; or for those compounds wherein Rc is hydroxy, a salt thereof with a base affording a physiologically acceptable cation.

Claim 3

A compound as claimed in claim 1 wherein Ra and Rb are, independently, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, allyl, 2-methylallyl, chloromethyl, trifluoromethyl or 2,2,2-trifluoroethyl, pentafluorophenyl, 1-naphthyl, 2-napthyl, benzyl, 1-phenylethyl, 2-phenylethyl or phenyl, the latter six of which may optionally bear up to three substituents selected from: fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methylenedioxy, ethylenedioxy, isopropylidenedioxy, trifluorometyl, cyano, nitro, methylthio, ethylthio, methanesulphonyl, ethanesulphonyl, formamido, acetamido, propionamido, hydroxy, acetoxy, propionyloxy, methyleneoxymethylene and ethyleneoxymethylene; provided that when both Ra and Rb are alkyl or alkenyl, the total number of carbon atoms in Ra and Rb taken together is 8 or less; or Ra and Rb together constitute ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene, any of which may bear an optional methyl substituent; Rc is hydroxy, methoxy, ethoxy, methanesulphonamido, ethanesulphonamido or 1-methylethanesulphonamido; n is the integer 1 or 2; A is ethylene or vinylene; Y is ethylene, trimethylene or tetramethylene, any of which may optionally bear a methyl substituent; and benzene ring B optionally bears one or two substituents selected from fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, hydroxy, acetoxy, propionyloxy, formamido, acetamido, propionamido, trifluoromethyl and nitro.

Claim 4

A compound as claimed in claim 1 or 2 wherein Ra and Rb are, independently, hyrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, octyl, vinyl, allyl, 2-methylallyl, trifluoromethyl, chloromethyl, 2-chloroethyl, phenyl optionally bearing a fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl, methylthio, methanesulphonyl, nitro, hydroxy, cyano, acetamido, methylenedioxy or a methyleneoxymethylene (-CH 2 0CH 2 ) substituent , dichlorophenyl, dimethylphenyl, pentafluorophenyl, 1-naphthyl, 2-naphthyl or benzyl: or together form trimethylene, pentamethylene or hexamethylene, optionally bearing a methyl substituent; provided that when both Ra and Rb are alkyl or alkenyl the total number of carbon atoms in Ra and Rb taken together is 8 or less; and benzene ring B is phenyl, 2-methylphenyl, 2-ethylphenyl, 2-isopropylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-methylphenyl or 2,6-difluorophenyl.

Claim 5

A compound as claimed in claim 1, 2 or 3 wherein benzene ring B is unsubstituted: ortho-substituted by fluoro, chloro, methyl, hydroxy, methoxy, ethyl or isopropyl, or meta-substituted by fluoro or chloro.

Claim 6

A compound as claimed in any one of claims 1-4 wherein Rc is hydroxy, methoxy, ethoxy, methanesulphonamido or ethanesulphonamido.

Claim 7

A 7-(4-phenyl-l,3-dioxan-cis-5-yl)heptenoic acid derivative of the formula Ia wherein Ra and Rb are:- (i) independently hydrogen or (1-4C)alkyl, optionally bearing 1 to 3 halogeno substituents; (ii) one of the two is hydrogen or (1-4C)alkyl, and the other is phenyl, naphthyl or phenyl-(1-4C)alkyl, optionally bearing 1 or 2 substituents selected from halogeno, (l-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylenedioxy, trifluoromethyl, cyano, nitro, hydroxy, (2-4C)alkanoyloxy, (1-4C)alkylthio, (1-4C)alkanesulphonyl, (1-4C)alkanoylamino and oxapolymethylene of 2 to 4 carbon atoms, or pentafluorophenyl ; (iii) one of the two is hydrogen and the other is (5-8C)alkyl or (2-6C)alkenyl; or (iv) both together form polymethylene of 2 to 7 carbon atoms optionally bearing a (1-4C)alkyl substituent; Rc is hydroxy, (1-4C)alkoxy or (1-4C)alkanesulphonamido; and benzene ring B optionally bears a single substituent located at the 2-position selected from halogeno, (l-4C)alkyl, (1-4C)alkoxy, hydroxy, (2-4C)alkanoyloxy, (1-4C)alkanoylamino and trifluoromethyl, or bears a 3-halogeno substituent; and the substituents at positions 4 and 5 of the dioxane ring have cis-relative stereochemistry; or for those compounds wherein Rc is hydroxy, a salt thereof with a base affording a physiologically acceptable cation.

Claim 8

A 7-(4-phenyl-l,3-dioxan-cis-5-yl)heptenoic acid derivative of the formula Ia wherein Ra and Rb are:- (i) independently hydrogen or (1-4C)alkyl, optionally bearing 1 to 3 halogeno substituents; (ii) one of the two is hydrogen or (1-4C)alkyl, and the other is phenyl, naphthyl or phenyl-(1-4C)alkyl, optionally bearing 1 or 2 substituents selected from halogeno, (l-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylenedioxy, trifluoromethyl, cyano, nitro, hydroxy, (2-4C)alkanoyloxy, (1-4C)alkylthio, (1-4C)alkanesulphonyl, (1-4C)alkanoylamino and oxapolymethylene of 2 to 4 carbon atoms, or pentafluorophenyl ; (iii) one of the two is hydrogen and the other is (5-8C)alkyl or (2-6C)alkenyl; or (iv) both together form polymethylene of 2 to 7 carbon atoms optionally bearing a (1-4C)alkyl substituent; Rc is hydroxy, (1-4C)alkoxy or (1-4C)alkanesulphonamido; and benzene ring B optionally bears a single substituent located at the 2-position selected from halogeno, (l-4C)alkyl, (1-4C)alkoxy, hydroxy, (2-4C)alkanoyloxy, (1-4C)alkanoylamino and trifluoromethyl, or bears a 3-halogeno substituent; and the substituents at positions 4 and 5 of the dioxane ring have cis-relative stereochemistry; or for those compounds wherein Rc is hydroxy, a salt thereof with a base affording a physiologically acceptable cation.

Claim 9

A compound as claimed in claim 6 wherein :- (i) Ra and Rb are both hydrogen, methyl, ethyl, propyl, butyl or trifluoromethyl; (ii) one of Ra is hydrogen and the other is trifluoromethyl, chloromethyl, benzyl, isopropyl, hexyl, octyl, phenyl (optionally bearing 1 or 2 fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl, hydroxy, cyano, methylthio or acetamido), phenyl bearing methylenedioxy or methyleneoxymethylene (-CH 2 0CH 2 ), pentafluorophenyl, 1-naphthyl or 2-naphthyl; or (iii) Ra and Rb together form trimethylene, tetramethylene, pentamethylene, hexamethylene or a group of the formula: -CH 2 CH 2 .CHCH 3 .CH 2 CH 2 -; and benzene ring B is phenyl; 2-fluorophenyl, 2-chlorophenyl 2-bromophenyl, 2-methylphenyl, 2-ethylphenyl, 2-isopropylphenyl, 2-methoxyphenyl, 2-hydroxyphenyl, 3-fluorophenyl or 3-chlorophenyl; and Rc is hydroxy, methanesulphonamido or ethanesulphonamido.

Claim 10

A 5(Z)-7-(4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid of the formula Ib wherein:- (i) Ra and Rb are both hydrogen, methyl, ethyl, propyl, butyl, or trifluoromethyl. (ii) Ra and Rb together form trimethylene, tetramethylene, pentamethylene, hexamethylene or a group of the formula: -CH 2 CH 2 .CHCH 3 .CH 2 CH 2 -; or (iii) Ra is (3-8C)alkyl, trifluoromethyl, chloromethyl, 2-chloroethyl, pentafluorophenyl, or phenyl, benzyl or naphthyl, the last three of which may optionally bear 1 or 2 halogeno, (l-4C)alkyl, (1-4C)alkoxy, trifluoromethyl, hydroxy, cyano, (1-4C)alkylthio or (1-4C)alkanoylamino substituents, or a methylenedioxy or methyleneoxymethylene substituent, and Rb is hydrogen; benzene ring B is unsubstituted or is 2- halogeno-, 2-(1-4C)alkyl-, 2-(l-4C)alkoxy-, 2-hydroxy-or 3-halogeno-phenyl; Ra and the substituents at the 4 and 5- positions of the dioxane ring have cis-relative stereochemistry; and the carbon atoms adjacent to the vinylene group have the indicated cis-relative stereochemistry; or a salt thereof with a base affording a physiologically acceptable cation; or a methyl or ethyl ester thereof; or a methanesulphonamido, ethanesulphonamido or l-methylethanesulphonamido derivative thereof.

Claim 11

A 5(Z)-7-(4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid of the formula Ib wherein:- (i) Ra and Rb are both hydrogen, methyl, ethyl, propyl, butyl, or trifluoromethyl. (ii) Ra and Rb together form trimethylene, tetramethylene, pentamethylene, hexamethylene or a group of the formula: -CH 2 CH 2 .CHCH 3 .CH 2 CH 2 -; or (iii) Ra is (3-8C)alkyl, trifluoromethyl, chloromethyl, 2-chloroethyl, pentafluorophenyl, or phenyl, benzyl or naphthyl, the last three of which may optionally bear 1 or 2 halogeno, (l-4C)alkyl, (1-4C)alkoxy, trifluoromethyl, hydroxy, cyano, (1-4C)alkylthio or (1-4C)alkanoylamino substituents, or a methylenedioxy or methyleneoxymethylene substituent, and Rb is hydrogen; benzene ring B is unsubstituted or is 2- halogeno-, 2-(1-4C)alkyl-, 2-(l-4C)alkoxy-, 2-hydroxy-or 3-halogeno-phenyl; Ra and the substituents at the 4 and 5- positions of the dioxane ring have cis-relative stereochemistry; and the carbon atoms adjacent to the vinylene group have the indicated cis-relative stereochemistry; or a salt thereof with a base affording a physiologically acceptable cation; or a methyl or ethyl ester thereof; or a methanesulphonamido, ethanesulphonamido or l-methylethanesulphonamido derivative thereof.

Claim 12

A compound as claimed in claim 8 wherein Ra and Rb have the meanings defined in (i) and (ii) of claim 8; or Ra is isopropyl, butyl, hexyl, octyl, trifluoromethyl, chloromethyl, 2-chloroethyl, pentafluorophenyl, benzyl, naphthyl or phenyl (optionally bearing 1 or 2 fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl, hydroxy, cyano, methylthio or acetamido substituents, or bearing a methylenedioxy or methyleneoxymethylene substituent), and Rb is hydrogen; and benzene ring B is unsubstituted or bears a 2-fluoro, 2-chloro, 2-bromo, 3-fluoro, 3-chloro, 2-methyl, 2-ethyl, 2-isopropyl, 2-methoxyt, or 2-hydroxy substituent.

Claim 13

A 5(Z)-7-(4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid of the formula Ib wherein Ra, Rb and benzene ring B are selected from the following combinations:- (wherein H stands for hydrogen); and from the following combinations;- or a salt thereof with a base affording a physiologically acceptable cation.

Claim 14

A 5(Z)-7-(4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid of the formula Ib wherein Ra, Rb and benzene ring B are selected from the following combinations:- (wherein H stands for hydrogen); and from the following combinations;- or a salt thereof with a base affording a physiologically acceptable cation.

Claim 15

A salt as claimed in any one preceding claim which is an alkali metal, alkaline earth metal, aluminium or ammonium salt, or a salt with an organic amine or quaternary base, forming a physiologically acceptable cation.

Claim 16

A methanesulphonamido derivative of an acid as claimed in claim 10 or of 5(Z)-7-(2,2-dimethyl-4-phenyl- l,3-dioxan-cis-5-yl)heptenoic acid.

Claim 17

A 5-allyl-5-phenyl-1,3-dioxane derivative of the formula VII wherein Ra, Rb and benzene ring B have any of the meanings defined in claims 1-10, and the substituents at positions 4 and 5 of the dioxane ring have cis-relative stereochemistry.

Claim 18

A (4-phenyl-l,3-dioxan-cis-5-yl)acetaldehyde derivative of the formula II wherein n is the integer 1, and Ra, Rb and benzene ring B have any of the meanings defined in claims 1-10, and the substituents at positions 4 and 5 of the dioxane ring have cis-relative stereochemistry.

Claim 19

A pharmaceutical composition which comprises a compound of formula I, or a salt thereof, as claimed in any one of claims 1-12, together with a pharmaceutically acceptable diluent or carrier.

Claim 20

A process for the manufacture of a compound of the formula I, or a salt thereof, as claimed in claim 1, wherein Ra, Rb, Rc, benzene ring B, n, A and Y have any of the meanings defined in claims 1-10; characterised by:- (a) for a compound wherein Rc is hydroxy and A is vinylene, reacting an aldehyde of the formula II with a Wittig reagent of the formula:- wherein Rd is (1-6C)alkyl or aryl and M is an alkali metal cation; (b) reacting an erythro-diol derivative of the formula XIII wherein one of Qa and Qb is hydrogen and the other is hydrogen, alkanesulphonyl, arenesulphonyl or a group of the formula -CRR 1. OH wherein R and R 1 are the same or different alkyl, with a carbonyl compound of the formula RaRb.CO, or an acetal, hemiacetal or hydrate thereof; (c) for a compound of formula I wherein Rc is hydroxy, oxidising an alcohol of the formula XVI; (d) for a compound of formula I wherein Rc is hydroxy, hydrolysing a compound of the formula XVII wherein W is alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, cyano or carbamoyl; (e) for a compound of formula I wherein Ra, Rb or benzene ring B bears a hydroxy substituent, deprotecting a corresponding derivative of said compound wherein the hydroxy substituent is protected by a trimethylsilyl, (1-6C)alkyl or acyl protecting group; (f) for a compound of formula I wherein Ra and Rb are both hydrogen, reacting an erythro-diol of the formula XIII wherein Qa and Qb are both hydrogen, with methylene bromide in the presence of a base; whereafter: when a compound of formula I wherein Rc is (1-6C)alkoxy is required, the corresponding acid of formula I wherein Ra is hydroxy, or a reactive derivative thereof, is esterified using a conventional procedure; when a compound of formula I wherein Rc is (1-6C)alkanesulphonamido is required, the corresponding acid of formula I wherein Rc is hydroxy is reacted with the appropriate (1-6C)alkanesulphonamide in the presence of a dehydrating agent, or a reactive derivative of said acid of formula I is reacted with the appropriate (1-6C)alkanesulphonamide or an alkali metal salt thereof; when a compound of formula I wherein A is ethylene is required, the corresponding compound of formula I wherein A ix vinylene is hydrogenated in the presence of a catalyst; when a salt of a compound of formula I wherein Rc is hydroxy is required, said compound is reacted with the appropriate base affording a physiologically acceptable cation; and when an optically active form of a compound of formula I is required, either one of the aforesaid procedures is carried out using an optically active starting material, or a racemic form of a compound of formula I wherein Rc is hydroxy is reacted with an optically active form of a suitable organic base, followed by separation of the diastereoisomeric mixture of salts thus obtained, and liberation of the required optically active form of said compound of formula I by treatment with acid followed, when Rc is other than hydroxy, by esterification or amidifiction as aforesaid.