Benzopyran, benzothiapyran and quinoline compounds and pharmaceutical compositions containing them

Claim 2

A compound of formula I, in which X is -0-, -S- or -NR 3 -, R 3 is hydrogen or alkyl C 1 to 6, A is -COOH or 5-(lH-tetrazolyl), and B is hydrogen, or A and B together form a chain -N= N - NH -, R 1 is hydrogen or hydroxy, R 2 is hydroxy or esterified hydroxy, R 6 is hydrogen or alkyl C 1 to 3, R 7 is hydrogen or methyl, and R 8 is alkyl C 1 to 4 optionally substituted by phenyl, provided that when B is hydrogen, A is -COOH, X is -0-, R 1 is hydrogen, R 2 is hydroxy, R 6 and R 7 are both hydrogen then R 8 is not propyl, and pharmaceutically acceptable derivatives thereof.

Claim 3

A compound according to Claim 1, wherein B is hydrogen and A is -COOH.

Claim 4

A compound according to Claim 1 or 2, wherein X is -S- or -0-.

Claim 5

A compound according to any one of the preceding claims, wherein R 1 is hydrogen.

Claim 6

A compound according to any one of the preceding claims, wherein R 2 is hydroxy esterified by a C 1 to 7 hindered monocarboxylic acid, with an aryl C7 to 12 acid, or with a C3 to 7 dibasic acid.

Claim 7

A compound according to Claim 5, wherein R 2 is hydroxy esterified by benzoic acid.

Claim 8

A compound according to any one of the preceding claims, wherein R 6 is hydrogen, ethyl or propyl, R 7 is hydrogen and R 8 is ethyl, propyl, butyl or benzyl.

Claim 9

5-[5-(2-Hydroxypropoxy)-4-oxo-8-propyl-4H-l-benzopyran-2-yl]lH-tetrazole, l-Ethyl-l,4-dihydro-5-(2-hydroxypropoxy)-4-oxo-8-propylquinoline-2-carboxylic acid, l,4-Dihydro-5-(2-hydroxypropoxy)-4-oxo-8 - propylquinoline-2-carboxylic acid, 5-(2-Hydroxypropoxy)-4-oxo-6,8-dipropyl-4H-1-benzopyran -2-carboxylic acid, 5-(2-Hydroxypropoxy)-7-methyl-4-oxo-8-propyl-4H-l-benzopyran-2-carboxylic acid, 6,8-Diethyl-5-(2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid, 5-(2,3-Dihydroxy-n-propoxy)-4-oxo-8-n-propyl-4H-1-benzopyran-2-carboxylic acid, 5-(2- H ydroxypropoxy)-4-oxo-8-phenylmethyl-4H-1-benzopyran-2-carboxylic acid, 5-(2-Benzoyloxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, Butanedioic acid, mono(2-ethoxycarbonyl-4-oxo-8-propyl-4H-1-benzopyran-5-yloxy)prop-2-yl ester 5-(2- H ydroxypropoxy)-4-oxo-8-propyl-4H-1-thiabenzopyran -2-carboxylic acid, 8-(1,1-Dimethylethyl)-5-(2-hydroxypropoxy)-4-oxo-4H[l]benzopyran-2-carboxylic acid 8-(2-Hydroxypropoxy)-9-oxo-5-propyl-1H,9H-benzopyrano [2,3-d]-v-triazole,- or the sodium salt of any one thereof.

Claim 10

5-[5-(2-Hydroxypropoxy)-4-oxo-8-propyl-4H-l-benzopyran-2-yl]lH-tetrazole, l-Ethyl-l,4-dihydro-5-(2-hydroxypropoxy)-4-oxo-8-propylquinoline-2-carboxylic acid, l,4-Dihydro-5-(2-hydroxypropoxy)-4-oxo-8 - propylquinoline-2-carboxylic acid, 5-(2-Hydroxypropoxy)-4-oxo-6,8-dipropyl-4H-1-benzopyran -2-carboxylic acid, 5-(2-Hydroxypropoxy)-7-methyl-4-oxo-8-propyl-4H-l-benzopyran-2-carboxylic acid, 6,8-Diethyl-5-(2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid, 5-(2,3-Dihydroxy-n-propoxy)-4-oxo-8-n-propyl-4H-1-benzopyran-2-carboxylic acid, 5-(2- H ydroxypropoxy)-4-oxo-8-phenylmethyl-4H-1-benzopyran-2-carboxylic acid, 5-(2-Benzoyloxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, Butanedioic acid, mono(2-ethoxycarbonyl-4-oxo-8-propyl-4H-1-benzopyran-5-yloxy)prop-2-yl ester 5-(2- H ydroxypropoxy)-4-oxo-8-propyl-4H-1-thiabenzopyran -2-carboxylic acid, 8-(1,1-Dimethylethyl)-5-(2-hydroxypropoxy)-4-oxo-4H[l]benzopyran-2-carboxylic acid 8-(2-Hydroxypropoxy)-9-oxo-5-propyl-1H,9H-benzopyrano [2,3-d]-v-triazole,- or the sodium salt of any one thereof.

Claim 11

A pharmaceutical composition conprising a compound according to any one of the preceding claims and a pharmaceutically acceptable adjuvant, diluent or carrier.

Claim 12

A process for the production of a compound of formula I, or a pharmaceutically acceptable derivative thereof, which comprises a) producing a compound of formula I in which A and B together form a chain -N= N - NH - by removing a protecting group L from a compound of formula III, in which X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, and L is a protecting group, b) producing a compound of formula I in which B is hydrogen and A is 5-(lH-tetrazolyl), by reacting a compound of formula IV, in which X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, with an azide, in solvent which is inert under the reaction conditions, c) producing a compound of formula I in which R 1 or R 2 is hydroxy by selectively reducing a compound of formula V, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, and R 5 represents a group -CH 2 CZCHZ, where one Z represents carbonyl oxygen and the other represents H 2 , with a suitable selective carbonyl reducing agent, d) producing a compound of formula I in which B is hydrogen and A is -COOH by hydrolysing a compound of formula VI, in which D represents a group hydrolyseable to -COOH, and X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, e) producing a compound of formula I in which B is hydrogen and A is -COOH by cyclising a compound of formula VII, in which R l , R 2 , R 6 , R 7 and R 8 are as defined above, A 1 and A 2 represent the pairs of groups i) -COCH 2 COCOR" and -OM, or ii) -H and -X-C(COR")= CH -COR" X is as defined above, R" represents -OM, or a group which is hydrolysable thereto, and M represents hydrogen or a cation, and if necessary or desired hydrolysing the group -COR", to a group -COOM, f) reacting a compound of formula VIII, or a salt, ester or amide thereof, in which X , A, B , R6 , R7 and R8 are as defined 6above, with propylene oxide or a compound of formula IX, in which G is a good leaving group, g) producing a compound of formula I in which R 1 and R 2 are both hydroxy by i) hydrolysing a compound of formula X, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, or ii) subjecting a compound of formula XI, in which X, A, B, R 6 , R 7 and R 8 are as defined above, or a salt, ester or amide thereof, to mammalian metabolism, or iii) reaction of a compound of formula XII, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, with osmium tetroxide, and hydrolysis of the resulting complex, or h) producing a compound of formula I in which R 2 is esterified hydroxy, by reaction of a corresponding compound of formula I, or a salt, carboxylic ester or amide thereof, in which R 2 is hydroxy with an appropriate acid, or a derivative thereof, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable derivative thereof, or vice versa.

Claim 13

A process for the production of a compound of formula I, or a pharmaceutically acceptable derivative thereof, which comprises a) producing a compound of formula I in which A and B together form a chain -N= N - NH - by removing a protecting group L from a compound of formula III, in which X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, and L is a protecting group, b) producing a compound of formula I in which B is hydrogen and A is 5-(lH-tetrazolyl), by reacting a compound of formula IV, in which X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, with an azide, in solvent which is inert under the reaction conditions, c) producing a compound of formula I in which R 1 or R 2 is hydroxy by selectively reducing a compound of formula V, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, and R 5 represents a group -CH 2 CZCHZ, where one Z represents carbonyl oxygen and the other represents H 2 , with a suitable selective carbonyl reducing agent, d) producing a compound of formula I in which B is hydrogen and A is -COOH by hydrolysing a compound of formula VI, in which D represents a group hydrolyseable to -COOH, and X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, e) producing a compound of formula I in which B is hydrogen and A is -COOH by cyclising a compound of formula VII, in which R l , R 2 , R 6 , R 7 and R 8 are as defined above, A 1 and A 2 represent the pairs of groups i) -COCH 2 COCOR" and -OM, or ii) -H and -X-C(COR")= CH -COR" X is as defined above, R" represents -OM, or a group which is hydrolysable thereto, and M represents hydrogen or a cation, and if necessary or desired hydrolysing the group -COR", to a group -COOM, f) reacting a compound of formula VIII, or a salt, ester or amide thereof, in which X , A, B , R6 , R7 and R8 are as defined 6above, with propylene oxide or a compound of formula IX, in which G is a good leaving group, g) producing a compound of formula I in which R 1 and R 2 are both hydroxy by i) hydrolysing a compound of formula X, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, or ii) subjecting a compound of formula XI, in which X, A, B, R 6 , R 7 and R 8 are as defined above, or a salt, ester or amide thereof, to mammalian metabolism, or iii) reaction of a compound of formula XII, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, with osmium tetroxide, and hydrolysis of the resulting complex, or h) producing a compound of formula I in which R 2 is esterified hydroxy, by reaction of a corresponding compound of formula I, or a salt, carboxylic ester or amide thereof, in which R 2 is hydroxy with an appropriate acid, or a derivative thereof, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable derivative thereof, or vice versa.

Claim 14

A compound according to any one of Claims 1 to 9 for use as a pharmaceutical.

Claim 15

A process for the production of a compound of formula I,

Claim 16

A process for the production of a compound of formula I,

Claim 17

in which X is -O-, -S- or -NR3-, R 3 is hydrogen or alkyl C 1 to 6, A is -COOH or 5-(lH-tetrazolyl), and B is hydrogen, or A and B together form a chain -N= N - NH -, R 1 is hydrogen or hydroxy, R 2 is hydroxy or esterified hydroxy, R 6 is hydrogen or alkyl C 1 to 3, R 7 is hydrogen or methyl, and R 8 is alkyl C 1 to 4 optionally substituted by phenyl, provided that when-B is hydrogen, A is -COOH, X is -O-, R 1 is hydrogen, R 2 is hydroxy, R 6 and R 7 are both hydrogen then R 8 is not propyl, or a pharmaceutically acceptable derivative thereof, which comprises a) producing a compound of formula I in which A and B together form a chain -N=N-NH- by removing a protecting group L from a compound of formula III, in which X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, and L is a protecting group, b) producing a compound of formula I in which B is hydrogen and A is 5-(lH-tetrazolyl), by reacting a compound of formula IV, in which X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, with an azide, in solvent which is inert under the reaction conditions, c) producing a compound of formula I in which R 1 or R 2 is hydroxy by selectively reducing a compound of formula V, or a salt, ester or amide thereof, in which x, A, B, R 6 , R 7 and R 8 are as defined above, and R 5 represents a group -CH 2 CZCHZ, where one Z represents carbonyl oxygen and the other represents H 2 , with a suitable selective carbonyl reducing agent, d) producing a compound of formula I in which B is hydrogen and A is -COOH by hydrolysing a compound of formula VI, in which D represents a group hydrolyseable to -COOH, and X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, e) producing a compound of formula I in which B is hydrogen and A is -COOH by cyclising a compound of formula VII, in which R l , R 2 , R 6 , R 7 and R 8 are as defined above, A 1 and A 2 represent the pairs of groups i) -COCH 2 COCOR" and -OM, or ii) -H and -X-C(COR")= CH -COR" X is as defined above, R" represents -OM, or a group which is hydrolysable thereto, and M represents hydrogen or a cation, and if necessary or desired hydrolysing the group -COR", to a group -COOM, f) reacting a compound of formula VIII, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, with propylene oxide or a compound of formula IX, in which G is a good leaving group, g) producing a compound of formula I in which R 1 and R 2 are both hydroxy by i) hydrolysing a compound of formula X, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, or ii) subjecting a compound of formula XI, in which X, A, B, R 6 , R 7 and R 8 are as defined above, or a salt, ester or amide thereof, to mammalian metabolism, or iii) reaction of a compound of formula XII, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, with osmium tetroxide, and hydrolysis of the resulting complex, or h) producing a compound of formula I in which R 2 is esterified hydroxy, by reaction of a corresponding compound of formula I, or a salt, carboxylic ester or amide thereof, in which R 2 is hydroxy with an appropriate acid, or a derivative thereof, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable derivative thereof, or vice versa.

Claim 18

in which X is -O-, -S- or -NR3-, R 3 is hydrogen or alkyl C 1 to 6, A is -COOH or 5-(lH-tetrazolyl), and B is hydrogen, or A and B together form a chain -N= N - NH -, R 1 is hydrogen or hydroxy, R 2 is hydroxy or esterified hydroxy, R 6 is hydrogen or alkyl C 1 to 3, R 7 is hydrogen or methyl, and R 8 is alkyl C 1 to 4 optionally substituted by phenyl, provided that when-B is hydrogen, A is -COOH, X is -O-, R 1 is hydrogen, R 2 is hydroxy, R 6 and R 7 are both hydrogen then R 8 is not propyl, or a pharmaceutically acceptable derivative thereof, which comprises a) producing a compound of formula I in which A and B together form a chain -N=N-NH- by removing a protecting group L from a compound of formula III, in which X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, and L is a protecting group, b) producing a compound of formula I in which B is hydrogen and A is 5-(lH-tetrazolyl), by reacting a compound of formula IV, in which X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, with an azide, in solvent which is inert under the reaction conditions, c) producing a compound of formula I in which R 1 or R 2 is hydroxy by selectively reducing a compound of formula V, or a salt, ester or amide thereof, in which x, A, B, R 6 , R 7 and R 8 are as defined above, and R 5 represents a group -CH 2 CZCHZ, where one Z represents carbonyl oxygen and the other represents H 2 , with a suitable selective carbonyl reducing agent, d) producing a compound of formula I in which B is hydrogen and A is -COOH by hydrolysing a compound of formula VI, in which D represents a group hydrolyseable to -COOH, and X, R 1 , R 2 , R 6 , R 7 and R 8 are as defined above, e) producing a compound of formula I in which B is hydrogen and A is -COOH by cyclising a compound of formula VII, in which R l , R 2 , R 6 , R 7 and R 8 are as defined above, A 1 and A 2 represent the pairs of groups i) -COCH 2 COCOR" and -OM, or ii) -H and -X-C(COR")= CH -COR" X is as defined above, R" represents -OM, or a group which is hydrolysable thereto, and M represents hydrogen or a cation, and if necessary or desired hydrolysing the group -COR", to a group -COOM, f) reacting a compound of formula VIII, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, with propylene oxide or a compound of formula IX, in which G is a good leaving group, g) producing a compound of formula I in which R 1 and R 2 are both hydroxy by i) hydrolysing a compound of formula X, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, or ii) subjecting a compound of formula XI, in which X, A, B, R 6 , R 7 and R 8 are as defined above, or a salt, ester or amide thereof, to mammalian metabolism, or iii) reaction of a compound of formula XII, or a salt, ester or amide thereof, in which X, A, B, R 6 , R 7 and R 8 are as defined above, with osmium tetroxide, and hydrolysis of the resulting complex, or h) producing a compound of formula I in which R 2 is esterified hydroxy, by reaction of a corresponding compound of formula I, or a salt, carboxylic ester or amide thereof, in which R 2 is hydroxy with an appropriate acid, or a derivative thereof, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable derivative thereof, or vice versa.

Claim 19

A process according to Claim 1, wherein B is hydrogen and A is -COOH.

Claim 20

A process according to Claim 1 or 2, wherein X is -S-or -O-.

Claim 21

A process according to any one of the preceding claims, wherein R1 is hydrogen.

Claim 22

A process according to any one of the preceding claims, wherein R 2 is hydroxy esterified by a C 1 to 7 hindered monocarboxylic acid, with an aryl C7 to 12 acid, or with a C3 to 7 dibasic acid.

Claim 23

A process according to Claim 5, wherein R 2 is hydroxy esterified by benzoic acid.

Claim 24

A process according to any one of the preceding claims, wherein R 6 is hydrogen, ethyl or propyl, R 7 is hydrogen and R 8 is ethyl, propyl, butyl or benzyl.

Claim 25

A process according to Claim 1, wherein the compound of formula I is 5-[5-(2-Hydroxypropoxy)-4-oxo-8-propyl-4H-l-benzopyran-2-yl]lH-tetrazole, 1-Ethyl-1,4-dihydro-5-(2-hydroxypropoxy)-4-oxo-8-propylquinoline-2-carboxylic acid, l,4-Dihydro-5-(2-hydroxypropoxy)-4-oxo-8-propylquinoline-2-carboxylic acid, 5-(2-Hydroxypropoxy)-4-oxo-6,8-dipropyl-4H-l-benzopyran -2-carboxylic acid, 5-(2-Hydroxypropoxy)-7-methyl-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, 6,8-Diethyl-5-(2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid, 5-(2,3-Dihydroxy-n-propoxy)-4-oxo-8-n-propyl-4H-1-benzopyran-2-carboxylic acid, 5-(2-Hydroxypropoxy)-4-oxo-8-phenylmethyl-4H-1-benzopyran-2-carboxylic acid, 5-(2-Benzoyloxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, Butanedioic acid, mono(2-ethoxycarbonyl-4-oxo-8-propyl-4H-1-benzopyran-5-yloxy)prop-2-yl ester 5-(2-Hydroxypropoxy)-4-oxo-8-propyl-4H-1-thiabenzopyran -2-carboxyli-c acid. 8-(1,1-Dimethylethyl)-5-(2-hydroxypropoxy)-4-oxo-4H[l]benzopyran-2-carboxylic acid 8-(2-Hydroxypropoxy)-9-oxo-5-propyl-lH,9H-benzopyrano [2,3-d]-v-triazole, or the sodium salt of any one thereof.