Benzopyrans, their production and pharmaceutical compositions containing them

Claim 2

A compound represented by the formula: wherein A represents a direct bond or -O-CH 2 , R 1 represents a C 3 - C 5 alkyl group, a hydroxy-(C 3 - C 5 ) alkyl group, a lower alkylamino-lower alkyl group, a nitrato-(C 3 - C 5 alkyl) group or a phenyl-(C 1 - C 5 ) alkyl group with the proviso that the phenyl may be substituted by a lower alkoxy group, R 2 represents hydrogen, halogen, OH, N0 2 , a carbamoyl group, a lower alkyl group, a lower alkoxy group, a lower alkyleneoxy group or an acetyl group, R 3 represents hydrogen or N0 2 , B represents a direct bond, a C l - C 7 alkylene group, a -0- lower alkylene group or a -CONH-lower alkylene group, and n represents 1 or 2; and acid addition salts thereof.

Claim 3

A compound according to claim 1 represented by the formula: wherein R' 1 represents a branched C 3 - C 5 alkyl group and B' represents a direct bond or a C 1 - C 5 alkylene group.

Claim 4

A compound according to claim 1 which is selected from 3,4-dihydro-8-[(2-hydroxy-3-isopropylamino) propoxy]-3-nitratomethyl-2H-benzopyran, 3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-3-nitrato-2H-l-benzopyran, 3,4-dihydro-8-[(2-hydroxy-3-isopropylamino) propoxy]6-methoxy-3-nitratomethyl-2H-1-benzopyran,6-bromo-3.4-dihydro-8-((1-hydroxy-2-isopropylamino)ethyl]-3-nitratomethyl-2H-1-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-isopropyl- amino-propoxy]-6-(2-nitratoethoxy)-2H-1-benzopyran,3,4-dihydro-6-[(2-hydroxy-3-isopropylamino)propoxy]2-[N-(2-nitratoethyl) carbamoyl]-2H-1-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-2-nitratomethyl-2H-l-benzopyran, 3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy-7-methoxy-2-nitratomethyl-2H-l-benzopyran,3,4-dihydro-5-carbamoyl-8-[(2-hydroxy-3-isopropylamino)propoxy]-2-nitratomethyl-2H-l-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-t-butylamino) propoxy]-3-nitratomethyl-2H-1-benzopyran,3,4-dihydro-8-[[(2-hydroxy-3-(l-ethylpropyl)amino]-propoxy]-3-nitratomethyl-2H-l-benzopyran,8-allyloxy-3,4-dihydro-7-[(2-hydroxy-3-isopropylamino)propoxy]-2-nitratomethyl-2H-1-benzopyran, 3,4-aihydro-8-[(2-hydroxy-3-(1-methyl-3-phenyl-propyl) amino]propoxy]-3-nitratomethyl-2H-l-benzopyran,3,4-dihydro-5-carbamoyl-8-[(2-hydroxy-3-isopropylamino)propoxy]-3- nitratomethyl-2H-1-benzopyran,3,4-dihydro-2,3-dinitrato- methyl-8-[(2-hydroxy-3-isopropylamino)propoxy]-2H-1-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-isopropylamino) propoxy]-4-nitratomethyl-2H-1-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-2-methyl-3-nitratomethyl-2H-1-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-3-(2-nitrato)ethyl-2H-1-benzopyran, 3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-4-methoxy-3-nitrato-2H-1-benzopyran,3,4-dihydro-5-[(2-hydroxy-3-isopropylamino)propoxy]-2-nitratomethyl-2H-l-benzopyran,3,4-dihydro-8-[[ 2-hydroxy-3-(l-phenylethyl) amino]-propoxy]-3-nitrato-2H-1-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-4-nitrato-5-or 7-nitro-2H-1-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-4-nitrato-6-nitro-2H-1-benzopyran, 3,4-dihydro-4-hydroxy-8-[(2-hydroxy-3-isopropylamino)-propoxy]-3-nitrato-2H-1-benzopyran,3,4-dihydro-8-[[(2-hydroxy-3-(2-diethylaminoethyl)-amino]propoxy]-3-nitrato-2H-1-benzopyran,3,4-dihydro-8-[[2-hydroxy-3-(2-(2-methoxyphenyl)-ethyl]amino]propoxy]-3-nitrato-2H-l-benzopyran, 2,3-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-3- nitratoheptyl-2H-1-benzopyran,2,3-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-3-nitratoethoxy-2H-1-benzopyran, 6-acetyl-3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)-propoxy]-3-nitratomethyl-2H-1-benzopyran,3,4-dihydro-8-[[1-hydroxy-2-(1-methyl-3-phenyl-propyl)amino]ethyl] nitratomethyl-2H-l-benzopyran,3,4-dihydro-5-[(2-hydroxy-3-isopropylamino)propoxy]-7-methoxy-2-nitratomethyl-2H-1-benzopyran,6-acetyl-3,4-dihydro-8-[(2-hydroxy-3-isopropyl- amino)propoxy]-3-nitrato-2H-l-benzopyran,6-acetyl-3,4-dihydro-8-[(2-hydroxy-3-t-butylamino)-propoxy]-3-nitrato-2H-l-benzopyran,8-acetyl-3,4-dihydro-5-[(2-hydroxy-3-isopropylamino)propoxy]-2-nitratomethyl-2H-1-benzopyran, 3,4-dihydro-3-hydroxy-8-[(2-hydroxy-3-isopropylamino) propoxy-6-(2-nitrato)ethoxy-2H-1-benzopyran,3,4-dihydro-8-[[2-hydroxy-3-(1,1-dimethyl-2-hydroxyethyl)amino]propoxy] -3-nitratomethyl-2H-1-benzopyran,3,4-dihydro-8-[[2-hydroxy-3-(l-methyl-3-hydroxypropyl)amino]propoxy]-3-nitratomethyl-2H-1-benzopyran,3.4-dihydro-6-[[2-hydroxy-3-(1-methyl-3-phenylpropyl)amino]propoxy]-2-[N-(2-nitratoethyl)carbamoyl]-2H-l-benzopyran,3,4-dihydro-5-[(2-hydroxy-3-isopropylamino)-propoxy]-2-[N-(2-nitratoethyl)carbamoyl]-2H-l-benzopyran, 3,4-dihydro-8-[(2-mydroxy-3-isopropylamino)propoxy]-2-[N-(2-nitratoethyl)carbamoyl]-2H-l-benzopyran,3,4-dihydro-7-[(2-hydroxy-3-isopropylamino)propoxy]-2-[N-(2-nitratoethyl)carbamoyl]-2H-1-benzopyran,3,4-dihydro-8-[(2-hydroxy -3-isopropylamino)propoxy]-7-methoxy-2-[N-(2-nitratoethyl) carbamoyl]-2H-1-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-5-methoxy-2-[N-(2-nitratoethyl) carbamoyl]-2H-1-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-2-[N-(3-nitratopropyl)carbamoyl]-2H-1-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-6-methoxy-2-[N-(2-nitratoethyl)carbamoyl]-2H-1-benzopyran, 8-allyloxy-3,4-dihydro-7-[(2-hydroxy-3-isopropylamino) propoxy]-2-[N-(2-nitratoethyl)carbamoyl]-2H-1-benzopyran, 3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-3-[N-(2-nitratoethyl)carbamoyl]-2H-l-benzopyran,3,4-dihydro-8-[(2-hydroxy-3-isopropylamino)propoxy]-4-[N-(2-nitratoethyl) carbamoyl]-2H-1-benzopyran,3,4-dihydro-8-[(3-t-butylamino-2-hydroxy)propoxy]-3-nitrato-2H-1-benzopyran,3,4-dihydro-8-[[2-hydroxy-3-(l-methyl-3-nitratopropyl)amino]propoxy]-3- nitratomethyl-2H-1-benzopyran, and 3,4-dihydro-8-[[2- nitrato-3-(l-methyl-3-nitratopropyl)amino]propoxy]-3- nitratomethyl-2H-1-benzopyran.

Claim 5

A pharmaceutical composition comprising, as. active ingredient, a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier or diluent.

Claim 6

A pharmaceutical composition according to claim 4 wherein the compound of formula (I) or its acid addition salt is present in an amount of from 0.01 to 99% by weight, based on the total weight of the pharmaceutical composition.

Claim 7

A process for producing a compound of the formula (I) as defined in claim 1 or an acid addition salt thereof, which process comprises subjecting a compound of the formula (II) wherein A, B, R 1 , R 2 , R 3 and n are as defined in claim 1, to a nitrate ester-forming reaction, and optionally converting the resulting compound of formula (I) to an acid addition salt thereof.

Claim 8

A process for producing a compound of the formula (I) as defined in claim 1 or an acid addition salt thereof which process comprises reacting a compound of the formula (VI) wherein Z represents halogen, and A, B, R 2 , R 3 and n are as defined in claim 1, with an amine of the formula NH 2 R 1 wherein R 1 is as defined in claim 1, and optionally converting the resulting compound of formula (I) to an acid addition salt thereof.

Claim 9

A process for producing a compound of the formula (I) as defined in claim 1 or an acid addition salt thereof, which process comprises reacting a compound of the formula (V) wherein Q represents a hydroxy group, a halogen group, a haloacetyl group, a tosyloxy group or a mesyloxy group, and B, R 2 and n are as defined in claim 1, with(i) an oxazolidene of the formula (IX) wherein R 1 is as defined in claim 1, and R 4 and R 5 , independently from each other, represent a hydrogen atom or a phenyl group, when Q is a halogen group, a tosyloxy group or a mesyloxy group, or (ii) an oxazolidine of the formula (X) wherein X represents a tosyloxy group, mesyloxy group or a halogen atom, and R 1 , R 4 and R 5 are as defined above, when Q is a hydroxyl group, or (iii) an amine of the formula wherein R 1 is as defined above, then reducing the thus-formed amino-acetyl compound, when Q is a haloacetyl group;and optionally converting the resulting compound of formula (I) to an acid addition salt thereof.

Claim 10

A process for producing a compound of the formula (I) as defined in claim 1 wherein B is a -CONH-lower alkylene group or an acid addition salt thereof, which process comprises reacting a compound of the formula (VII) wherein A, R 1 , R 21 R 3 and n are as defined in claim 1, with a compound of the formula (VIII) wherein m is a positive number of 1 to 4, and optionally converting the resulting compound of formula (I) to an acid addition salt thereof.