Active benzopyran compounds

Claim 2

A compound of formula (I): wherein: either one of R 1 and R 2 is hydrogen and the other is selected from the class of C 1-6 alkylcarbonyl, C l-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy, C l - 6 alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C 1-6 alkylsulphinyl, C l - 6 alkylsulphonyl, C l-6 alkoxysulphinyl, C 1-6 alkoxysulphonyl, C 1-6 alkylcarbonylamino, C l - 6 alkoxycarbonylamino, C l - 6 alkyl-thiocarbonyl, C l-6 alkoxy-thiocarbonyl, C 1-6 alkyl-thiocarbonyloxy, 1-mercapto C 2-7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C 1-6 alkyl groups, or C 1-6 alkylsulphinylamino, C 1-6 alkylsulphonylamino, C l - 6 alkoxysulphinylamino or C 1-6 alkoxysulphonylamino, or ethylenyl terminally substituted by Cl - 6 alkylcarbonyl, nitro or cyano, or -C(C l - 6 alkyl)NOH or -C(C 1-6 alkyl)NNH 2 , or one of R 1 and R 2 is nitro, cyano or C l-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C 1-6 alkyl or by C 2-7 alkanoyl; one of R 3 and R 4 is hydrogen or C l - 4 alkyl and the otner is C 1-4 alkyl or R 3 and R 4 together are C 2-5 polymethylene; either R5 is hydrogen, hydroxy, C 1-6 alkoxy or C l - 7 acyloxy and R 6 is hydrogen or R 5 and R 6 together are a bond; n is 0 or 1; and X is CH 2 or NR 7 wherein R 7 is hydrogen or C l - 6 alkyl; the nitrogen-containing group in the 4-position being trans to the R5 group when R5 is hydroxy, C 1-6 alkoxy or C l - 7 acyloxy; or a pharmaceutically acceptable salt or solvate thereof.

Claim 3

A compound according to claim 1 wherein X is CH 2 and n is O.

Claim 4

A compound according to claim 1 or 2 wherein one of R 1 and R 2 is hydrogen and the other is selected from the class of C l - 6 alkylcarbonyl, C l - 6 alkoxycarbonyl, nitro or cyano.

Claim 5

A compound according to claim 3 wherein R 1 is acetyl, nitro or cyano and R 2 is hydrogen.

Claim 6

A compound according to any one of claims 1 to 4 wherein R 3 and R 4 are both methyl groups.

Claim 7

A compound according to any one of claims 1 to 5 wherein R 5 is hydroxy and R 6 is hydrogen.

Claim 8

A compound according to any one of claims 1 to 6 wherein n is 0 and X is CH 2 .

Claim 9

A compound according to any one of claims 1 to 6 wherein n is 0 or 1 and X is NR 7 wherein R 7 is as defined in claim 1.

Claim 10

A compound according to claim 8 wherein R 7 is methyl.

Claim 11

Trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-4-dioxo-1-imidazolidinyl)-2H-benzo[b]pyran-3-ol, trans-6-cyano-3,4-dihydro-4-N-(2,4-dioxo-l-pyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol, trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2,5-dioxo-l-piperazinyl)-2H-benzo[b]pyran-3-ol or 6-cyano-2, 2-dimethyl-4-(3-methyl-2-4-dioxo-l-imidazolidinyl)-2H-benzo[b]pyran.

Claim 12

Trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-4-dioxo-1-imidazolidinyl)-2H-benzo[b]pyran-3-ol, trans-6-cyano-3,4-dihydro-4-N-(2,4-dioxo-l-pyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol, trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2,5-dioxo-l-piperazinyl)-2H-benzo[b]pyran-3-ol or 6-cyano-2, 2-dimethyl-4-(3-methyl-2-4-dioxo-l-imidazolidinyl)-2H-benzo[b]pyran.

Claim 13

A process for the preparation of a compound according to any one of claims 1 to 10, which comprises the reaction of a compound of formula (II): wherein R 8 is a protecting group; R 1 ' is R 1 as defined in claim 1 or a group or atom convertible thereto, R 2 ' is R 2 as defined in claim 1 or a group or atom convertible thereto, and R 3 , R 4 , R 5 , and R 6 are as defined in claim 1 with i) when n is O and X is NR 7 , a compound of formula (III): wherein R 7 is as defined in claim 1; ii) when n is O or 1 and X is CH 2 , a compound of formula (IV) wherein Rg is a protecting group and Q 1 is a leaving group, followed by treatment with base; iii) when n is 1 and X is NR 7 , a compound of formula (V): wherein Q 2 is a leaving group R 10 is a protecting group, followed by removal of R 10 ; in the case where R 1 is a group or atom convertible into R l , converting the group or atom into R 1 ; in the case where R 2 ' is a group or atom convertible into R 2 , converting the group or atom into R 2 ; optionally converting R 1 or R 2 in the resulting compound of formula (I) into another R 1 or R 2 ; optionally converting the resulting compound of formula (I), wherein R 5 is hydroxy and R 6 is hydrogen, into another compound of formula (I) wherein R 5 is C l - 6 alkoxy or C l-7 acyloxy and R 6 is hydrogen, or optionally dehydrating the'resulting compound of formula (I), wherein R 5 is hydroxy and R 6 is hydrogen, so as to obtain the corresponding compound of formula (I), wherein R 5 and R 6 together are a bond, and optionally reducing the resulting compound of formula (I), wherein R 5 and R 6 together are a bond, so as to obtain the corresponding compound of formula (I) wherein R 5 and R 6 are both hydrogen; and optionally forming a pharmaceutically acceptable salt or solvate.

Claim 14

A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Claim 15

A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for use as a active therapeutic substance.

Claim 16

A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for use in the treatment of hypertension.

Claim 17

A compound of formula (II) as defined in claim 11 or a pharmaceutically acceptable salt thereof.

Claim 18

Trans-6-cyano-3, 4-dihydro-2, 2-dimethyl-4-(N-carbethoxymethyleneamino)-2H-benzo[b]pyran-3-01.

Claim 19

Trans-6-cyano-3, 4-dihydro-2, 2-dimethyl-4-(N-carbethoxymethyleneamino)-2H-benzo[b]pyran-3-01.

Claim 20

A process for the preparation of a compound of formula (I): wherein: either one of R 1 and R 2 is hydrogen and the other is selected from the class of C 1-6 alkylcarbonyl, C l-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C 1-6 , alkylsulphinyl, C 1-6 alkylsulphonyl, C 1-6 alkoxysulphinyl, C l - 6 alkoxysulphonyl, C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, C 1-6 alkyl-thiocarbonyl, C l - 6 alkoxy-thiocarbonyl, C 1-6 alkyl-thiocarbonyloxy, 1-mercapto C 2 - 7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C 1-6 alkyl groups, or C 1-6 alkylsulphinylamino, C 1-6 alkylsulphonylamino, C 1-6 alkoxysulphinylamino or C 1-6 alkoxysulphonylamino, or ethylenyl terminally substituted by C 1-6 alkylcarbonyl, nitro or cyano, or -C(C 1-6 alkyl)NOH or -C(C 1-6 alkyl)NNH 2 , or one of R 1 and R 2 is nitro, cyano or C 1-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C 1-6 alkyl or by C 2-7 alkanoyl; one of R 3 and R 4 is hydrogen or C l - 4 alkyl and the other is C 1-4 alkyl or R 3 and R 4 together are C 2-5 polymethylene; either R 5 is hydrogen, hydroxy, C l - 6 alkoxy or C 1-7 acyloxy and R 6 is hydrogen or R 5 and R 6 together are a bond; n is 0 or 1; and X is CH 2 or NR 7 wherein R 7 is hydrogen or C 1-6 alkyl; the nitrogen-containing group in the 4-position being trans to the R5 group when R 5 is hydroxy, C l - 6 alkoxy or C 1-7 acyloxy; or a pharmaceutically acceptable salt or solvate thereof which comprises the reaction of a compound of formula (II): wherein R 8 is a protecti.ng group; R 1 ' is R 1 or a group or atom convertible thereto, R 2 ' is R 2 or a group or atom convertible thereto, and R 3 , R 4 , R 5 , and R 6 are as defined with i) when n is O and X is NR 7 , a compound of formula (III): wherein R 7 is as defined in claim 1; ii) when n is O or 1 and X is CH 2 , a compound of formula (IV) wherein Rg is a protecting group and Q l is a leaving group, followed by treatment with base; iii) when n is 1 and X is NR 7 , a compound of formula (V): wherein Q 2 is a leaving group R 10 is a protecting group, followed by removal of R 10 ; in the case where R 1 is a group or atom convertible into R l , converting the group or atom into R 1 ; in the case where R 2 ' is a group or atom convertible into R 2 , converting the group or atom into R 2 ; optionally converting R 1 or R 2 in the resulting compound of formula (I) into another R 1 or R 2 ; optionally converting the resulting compound of formula (I), wherein R 5 is hydroxy and R 6 is hydrogen, into another compound of formula (I) wherein R 5 is C l - 6 alkoxy or C 1-7 acyloxy and R 6 is hydrogen, or optionally dehydrating the resulting compound of formula (I), wherein R 5 is hydroxy and R 6 is hydrogen, so as to obtain the corresponding compound of formula (I), wherein R 5 and R 6 together are a bond, and optionally reducing the resulting compound of formula (I), wherein R 5 and R 6 together are a bond, so as to obtain the corresponding compound of formula (I) wherein R 5 and R 6 are both hydrogen; and optionally forming a pharmaceutically acceptable salt or solvate.

Claim 21

A process according to claim 1 wherein X is CH 2 and n is O.

Claim 22

A process according to claim 1 or 2 wherein one of R l and R 2 is hydrogen and the other is selected from the class of C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, nitro or cyano.

Claim 23

A process according to claim 3 wherein R l is acetyl, nitro or cyano and R 2 is hydrogen.

Claim 24

A process according to any one of claims 1 to 4 wherein R 3 and R 4 are both methyl groups.

Claim 25

A process according to any one of claims 1 to 5 wherein R 5 is hydroxy and R 6 is hydrogen.

Claim 26

A process according to any one of claims 1 to 6 wherein n is 0 and X is CH 2 .

Claim 27

A process according to any one of claims 1 to 6 wherein n is 0 or 1 and X is NR 7 wherein R 7 is as defined in claim 1.

Claim 28

A process according to claim 8 wherein R 7 is methyl.

Claim 29

A process according to claim 1 for the preparation of trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-4-dioxo-l-imidazolidinyl)-2H-benzo[b]pyran-3-ol, trans-6-cyano-3,4-dihydro-4-N-(2,4-dioxo-l-pyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol, trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2,5-dioxo-1-piperazinyl)-2H-benzo[b]pyran-3-ol or 6-cyano-2,2-dimethyl-4-(3-methyl-2-4-dioxo-l-imidazolidinyl)-2H-benzo[b]pyran