EP0107423B1 — Novel chromans and chromenes

Claim 1

Independent Claim 358 words

A compound of formula (I): wherein: either one of R, and R 2 is hydrogen and the other is selected from the class of C 1-6 alkylcarbonyl, C 1-6 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 1-6 alkoxysulphonyl; C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, C 1-6 alkyl-thiocarbonyl, C 1-6 alkoxy-thiocarbonyl, C 1-6 alkyl-thiocarbonyloxy, C 1-6 alkyl-thiolmethyl, 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 ethenyl 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 -, alkanoyl; one of R 3 and R 4 is hydrogen or C 1-4 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 1-6 alkoxy or C 1-8 acyloxy and R 6 is hydrogen or R 5 and R 6 together are a bond; Q is 0 or S; m is an integer from 0 to 2 and n is an integer from 0 to 2 such that m + n is 1 or 2; X is O or S, or N-R 7 being hydrogen, C 1-9 alkyl, C 2-7 alkanoyl, phenyl C 1-4 alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl or naphthyl ring by one or two C l - 6 alkyl, C 1-6 alkoxy or halogen; mono- or bi-cyclicheteroarylcarbonyl; the lactam or thiolactam group being trans to the R 5 group when R 5 and R 6 are not a bond; or, when one or the other of R 1 and R 2 is an amino or an amino-containing group, or when X is NR 7 and R 7 is hydrogen, a pharmaceutically acceptable salt or solvate thereof.

Claim 2

Dependent Claim 358 words

A compound of formula (I): wherein: either one of R, and R 2 is hydrogen and the other is selected from the class of C 1-6 alkylcarbonyl, C 1-6 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 1-6 alkoxysulphonyl; C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, C 1-6 alkyl-thiocarbonyl, C 1-6 alkoxy-thiocarbonyl, C 1-6 alkyl-thiocarbonyloxy, C 1-6 alkyl-thiolmethyl, 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 ethenyl 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 -, alkanoyl; one of R 3 and R 4 is hydrogen or C 1-4 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 1-6 alkoxy or C 1-8 acyloxy and R 6 is hydrogen or R 5 and R 6 together are a bond; Q is 0 or S; m is an integer from 0 to 2 and n is an integer from 0 to 2 such that m + n is 1 or 2; X is O or S, or N-R 7 being hydrogen, C 1-9 alkyl, C 2-7 alkanoyl, phenyl C 1-4 alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl or naphthyl ring by one or two C l - 6 alkyl, C 1-6 alkoxy or halogen; mono- or bi-cyclicheteroarylcarbonyl; the lactam or thiolactam group being trans to the R 5 group when R 5 and R 6 are not a bond; or, when one or the other of R 1 and R 2 is an amino or an amino-containing group, or when X is NR 7 and R 7 is hydrogen, a pharmaceutically acceptable salt or solvate thereof.

Claim 3

Dependent Claim 88 words

A compound according to claim 1 of formula (II): wherein m, X and Q are as defined in claim 1, one of R 2 1 and R 2 1 is hydrogen and the other is selected from the class of C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkylhydroxymethyl, nitro or cyano and n is 1 or 2; the lactam group orthiolactam group being trans to the hydroxy group, or, when X is NR 7 and R 7 is hydrogen, a pharmaceutically acceptable salt thereof.

Claim 4

Dependent Claim 14 words

A compound according to claim 1 or 2 wherein X is 0 or S.

Claim 5

Dependent Claim 22 words

A compound according to claim 1 or 2 wherein X is NR 7 wherein R 7 is as defined in claim 1.

Claim 6

Dependent Claim 13 words

A compound according to claim 4 wherein m and n are both 1.

Claim 7

Dependent Claim 37 words

A compound according to any one of claims 1 to 5 wherein one R 1 (or R 1 1 ) and R 2 (or R 2 1 ) is hydrogen and the other is nitro or cyano.

Claim 8

Dependent Claim 12 words

6-cyano-2,2-dimethyl-3,4-dihydro-trans-4-(2-oxo-3-oxazolidin-1-yl)-2H-benzo[b]pyran-3-ol); 6-cyano-2,2-dimethyl-3,4-dihydro-trans-4-(2-oxomorpholin-1-yl)-2H-benzo[b]pyran-3-ol; 6-cyano-2,2-dimethyl-3,4-dihydro-trans-4-(2-oxo-3-thiazolidin-1-yl)-2H-benzo[b]-pyran-3-ol; 6-cyano-2,2-dimethyl-3,4-dihydro-trans-4-(2-oxothio morpholin-1-yl)-2H-benzo[b]-pyran-3-ol; 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(N-4-methylpiperazin-1-one)-2H-benzo[b]-pyran-3-ol; trans-4-(N-acetylpiperazine-2-one)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol; 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(1-piperazine-2-one)-2H-benzo[b]pyran-3-ol; trans-4-(N-benzyl-2-oxopiperazinyl)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol; trans-4-(N-benzoyl-2-oxopiperazinyl)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol; 6-cyano-2,2-dimethyl-4-(2-ketothiazolidinyl)-2H-benzo[b]pyran; 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(4-furoyl)-2-oxopiperazinyl)-2H-benzo[b]-pyran-3-ol;

Claim 9

Dependent Claim 12 words

6-cyano-2,2-dimethyl-3,4-dihydro-trans-4-(2-oxo-3-oxazolidin-1-yl)-2H-benzo[b]pyran-3-ol); 6-cyano-2,2-dimethyl-3,4-dihydro-trans-4-(2-oxomorpholin-1-yl)-2H-benzo[b]pyran-3-ol; 6-cyano-2,2-dimethyl-3,4-dihydro-trans-4-(2-oxo-3-thiazolidin-1-yl)-2H-benzo[b]-pyran-3-ol; 6-cyano-2,2-dimethyl-3,4-dihydro-trans-4-(2-oxothio morpholin-1-yl)-2H-benzo[b]-pyran-3-ol; 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(N-4-methylpiperazin-1-one)-2H-benzo[b]-pyran-3-ol; trans-4-(N-acetylpiperazine-2-one)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol; 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(1-piperazine-2-one)-2H-benzo[b]pyran-3-ol; trans-4-(N-benzyl-2-oxopiperazinyl)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol; trans-4-(N-benzoyl-2-oxopiperazinyl)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol; 6-cyano-2,2-dimethyl-4-(2-ketothiazolidinyl)-2H-benzo[b]pyran; 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(4-furoyl)-2-oxopiperazinyl)-2H-benzo[b]-pyran-3-ol;

Claim 10

Dependent Claim 6 words

6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(N-3-methyl-tetrahydro-2-pyrimidone)-2H-benzo[b]-pyran-3-ol; 6-cyano-2,2-dimethyl-4-(N-3-methyltetrahydro-2-pyrimidone)-2H-benzo[b]-pyran; 6-acetyl-3,4-dihydro-2,2-dimethyl-trans-4-(N-4-fluorobenzoyl-2-oxopiperazinyl)-2H-benzo[b]-pyran-3-ol; or trans-4-(n-butlypiperazin-2-one)-6-cyano-3,4-dihydro-2,2-dimethyl-:2H-benzo[b]pyran-3-ol. 86-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(1-piperazine-2-one)-2H-benzo[b]pyran-3-ol.

Claim 11

Dependent Claim 6 words

6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(N-3-methyl-tetrahydro-2-pyrimidone)-2H-benzo[b]-pyran-3-ol; 6-cyano-2,2-dimethyl-4-(N-3-methyltetrahydro-2-pyrimidone)-2H-benzo[b]-pyran; 6-acetyl-3,4-dihydro-2,2-dimethyl-trans-4-(N-4-fluorobenzoyl-2-oxopiperazinyl)-2H-benzo[b]-pyran-3-ol; or trans-4-(n-butlypiperazin-2-one)-6-cyano-3,4-dihydro-2,2-dimethyl-:2H-benzo[b]pyran-3-ol. 86-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(1-piperazine-2-one)-2H-benzo[b]pyran-3-ol.

Claim 12

Dependent Claim 319 words

A process for the preparation of a compound according to any one of claims 1 to 8 which process comprises the reaction of a compound of formula (III): wherein R 1 ' and R 2 ' are R 1 andr R 2 , as defined hereinbefore, or a group or atom convertible thereto, and R 3 and R 4 are as defined hereinbefore, with an anion of formula (IV): wherein m, n and X are as hereinbefore defined; in the case where R 1 ' or R 2 ' is a group or atom convertible into R 1 or R 2 , converting the group or atom into R 1 or R 2 ; optionally converting R 1 or R 2 in the resulting compound of formula (I) into another R 1 , or optionally alkylating or acytating, the resulting compound of formula (I), wherein R 5 is hydroxy, to give another compound of formula (I), wherein R 5 is C 1-6 alkoxy or C 1-8 acyloxy, optionally dehydrating the resulting compound of formula (I), wherein R 5 and R 6 are hydroxy and hydrogen respectively to give another compound of formula (I), wherein R s and R 6 together are a bond; reducing a compound of formula (I) wherein R 5 and R 6 together are a bond to give a compound wherein R 5 and R 6 are both hydrogen, optionally thiating the carbonyl group in the lactam ring of the resulting compound of formula (I) to give another compound of formula (I), wherein Q is sulphur; in the case where X is NR 7 , optionally converting R 7 into another R 7 ; and, when one or the other of R 1 and R 2 in the resulting compound of formula (I) is amino or an amino-containing group, or when X is NR 7 and R 7 is hydrogen, optionally forming a pharmaceutically acceptable salt.

Claim 13

Dependent Claim 26 words

A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Claim 14

Dependent Claim 24 words

A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.

Claim 15

Dependent Claim 23 words

A compound according to anyone of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use in the treatment of hypertension.

Novel chromans and chromenes

Abstract

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