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, 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, (1-6C)alkoxy, (1-4C)alkylenedioxy, trifluoromethyl, cyano, nitro, hydroxy, (2-6C)alkanoyloxy, (1-6C)alkylthio, (1-6C)alkanesulphonyl, (1-6C)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 (1-4C)alkyl substituents; Rc is hydroxy, (1-6C)alkanesulphonamido; n is the integer 1 or 2; A is ethylene or vinylene; Y is polymethylene of 2 to 5 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)alkanoylanino, 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, isoproplidenedioxy, trifluoromethyl, 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 wherein Ra and Rb are, independently, hydrogen, 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 OCH 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 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 claim 1 wherein Rc is hydroxy, methoxy, ethoxy, methanesulphonamido or ethanesulphonamido.

Claim 7

A 7-(4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid derivative of the formula Ia ##STR3## 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, (1-4C)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)alkansulphonamido; and benzene ring B optionally bears a single substituent located at the 2-position selected from halogeno, (1-4C)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-1,3-dioxan-cis-5-yl)heptenoic acid derivative of the formula Ia ##STR3## 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, (1-4C)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)alkansulphonamido; and benzene ring B optionally bears a single substituent located at the 2-position selected from halogeno, (1-4C)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, isoproply, hexyl, octyl, phenyl, (optionally bearing 1 or 2 fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl, hydroxy, cyano, methylthio or acetamido), phenyl bearing methylenedixoy or methyleneoxymethylene (--CH 2 OCH 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-methoxpyhenyl, 2-hydroxphyenyl, 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 ##STR4## 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, (1-4C) alkyl, (1-4C)alkoxy, trifluoromethyl, hydroxy, cyano, (1-4C)alkylthio or (1-4C)alkanoylamino substituents, or a methylenedioxy or methylene neoxymethylene substituent, and Rb is hydrogen; benzene ring B is unsubstituted or is 2-halogeno-, 2-(1-4C)alkyl-, 2-(1-4C)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 1-methylethanesulphonamido derivative thereof.

Claim 11

A 5(Z)-7-(4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid of the formula Ib ##STR4## 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, (1-4C) alkyl, (1-4C)alkoxy, trifluoromethyl, hydroxy, cyano, (1-4C)alkylthio or (1-4C)alkanoylamino substituents, or a methylenedioxy or methylene neoxymethylene substituent, and Rb is hydrogen; benzene ring B is unsubstituted or is 2-halogeno-, 2-(1-4C)alkyl-, 2-(1-4C)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 1-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, trifuoromethyl, 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-methoxy, or 2-hydroxy substituent.

Claim 13

A 5(Z)-7-(4-phenyl-1,3-dioxan-cis-5-yl) heptenoic acid of the formula Ib ##STR5## wherein Ra, Rb and benzene ring B are selected from the following combinations: ______________________________________ No. Ra Rb Benzene Ring B ______________________________________ 1 methyl methyl 3-fluorophenyl 2 methyl methyl 3-chlorophenyl 3 methyl methyl 2-methoxyphenyl 4 methyl methyl 2-methylphenyl 5 methyl H phenyl 6 trifluoromethyl H phenyl 7 isopropyl H phenyl 8 ethyl ethyl phenyl 9 ethyl ethyl 2-fluorophenyl 10 2-chlorophenyl H phenyl 11 2-methylphenyl H phenyl 12 2-ethylphenyl H phenyl 13 2-fluorophenyl H phenyl 14 2-chlorophenyl H phenyl 15 2-methylthiophenyl H phenyl 16 4-fluorophenyl H phenyl 17 4-chlorophenyl H phenyl 18 4-methoxyphenyl H phenyl 19 3,4-methylene H phenyl dioxyphenyl 20 3,4-(methylene- H phenyl oxymethylene)- phenyl 21 methyl methyl 2-hydroxyphenyl ______________________________________ (wherein H stands for hydrogen); and from the following combinations; ______________________________________ No Ra + Rb Benzene Ring B ______________________________________ 22 pentamethylene phenyl 23 hexamethylene phenyl 24 (3-methyl)pentamethylene phenyl ______________________________________ 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 ##STR5## wherein Ra, Rb and benzene ring B are selected from the following combinations: ______________________________________ No. Ra Rb Benzene Ring B ______________________________________ 1 methyl methyl 3-fluorophenyl 2 methyl methyl 3-chlorophenyl 3 methyl methyl 2-methoxyphenyl 4 methyl methyl 2-methylphenyl 5 methyl H phenyl 6 trifluoromethyl H phenyl 7 isopropyl H phenyl 8 ethyl ethyl phenyl 9 ethyl ethyl 2-fluorophenyl 10 2-chlorophenyl H phenyl 11 2-methylphenyl H phenyl 12 2-ethylphenyl H phenyl 13 2-fluorophenyl H phenyl 14 2-chlorophenyl H phenyl 15 2-methylthiophenyl H phenyl 16 4-fluorophenyl H phenyl 17 4-chlorophenyl H phenyl 18 4-methoxyphenyl H phenyl 19 3,4-methylene H phenyl dioxyphenyl 20 3,4-(methylene- H phenyl oxymethylene)- phenyl 21 methyl methyl 2-hydroxyphenyl ______________________________________ (wherein H stands for hydrogen); and from the following combinations; ______________________________________ No Ra + Rb Benzene Ring B ______________________________________ 22 pentamethylene phenyl 23 hexamethylene phenyl 24 (3-methyl)pentamethylene phenyl ______________________________________ or a salt thereof with a base affording a physiologically acceptable cation.

Claim 15

A salt as claimed in claim 1 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-1,3-dioxan-cis-5-yl)heptenoic acid.

Claim 17

A method for antagonising one or more of the actions of thromboxane A 2 in a warm-blooded animal requiring such treatment which comprises administering to said animal a thromboxane A 2 antagonistically effective amount of a compound of formula I as defined in claim 1, when Rc is hydroxy, a salt of said compound with a base affording a physiologically acceptable cation.

Claim 18

A pharmaceutical composition for use in antagonising one or more of the actions thromboxane A 2 in a warm-blooded animal requiring such treatment which comprises an antagonistically effective amount of a compound of formula I, or a salt thereof, as claimed in claim 1 together with a pharmaceutically acceptable diluent or carrier.