# US 5,703,113 A · Benzopyran derivatives > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,703,113 A - Document ID: US5703113A - Status: Granted - Kind: A - Application number: 08/481,440 - Filed: 1995-11-08 - Granted: 1997-12-30 - Earliest claimed: 1992-12-19 - Assignees: Alkaloida Vegyeszeti Gyar - Inventors: Tibor Eszenyi; Peter Sebok; Laszlo Frank; Gyula Papp; Tibor Timar; Tamas Bartik - Web page: https://patentgrep.com/patent/US5703113A ## CPC - C07D 405/04: directly linked by a ring-member-to-ring-member bond - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 9/12: Antihypertensives - A61P 11/00: Drugs for disorders of the respiratory system - A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers - A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives - A61P 25/00: Drugs for disorders of the nervous system - C07D 311/22: with oxygen or sulfur atoms directly attached in position 4 - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The invention relates to benzopyran compounds of formula (I) possessing pharmacological activity, as well as to pharmaceutical compositions containing the compounds of formula (I) and processes for the preparation thereof. ##STR1## ## Claims ### Claim 1 A compound of the Formula (I) ##STR13## wherein R.sub.1 is C.sub.1 to C.sub.6 alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy, aralkoxy, hydroxy, nitro, cyano, formyl, C.sub.1 to C.sub.6 acyl, cyano-C.sub.1 -C.sub.6 alkyl or halo; R.sub.2 is C.sub.1 to C.sub.6 alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy, aralkoxy or hydroxy; or R.sub.1 and R.sub.2 together are alkylenedioxy; and R.sub.3 and R.sub.4 are each C.sub.1 to C.sub.6 alkyl. ### Claim 2 A compound of the Formula ##STR14## wherein R.sub.1 is nitro, cyano or cyano-C.sub.1 -C.sub.6 alkyl; R.sub.2 is C.sub.1 to C.sub.4 alkoxy; and R.sub.3 and R.sub.4 are each C.sub.1 to C.sub.4 alkyl. ### Claim 3 (depends on 1) A compound of the Formula (I) defined in claim 1 and selected from the group consisting of: (+/-)-6,7-dimethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl) -2H-benzo(b)pyran-3-ol; (+/-)-6-bromo-7-methoxy-3,4-dihydro -2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol; (+/-)-6-chloro-7-methoxy-3,4-dihydro -2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol; (+/-)-6-nitro-7-methoxy-3,4-dihydro -2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol; and (+/-)-6-cyano-7-methoxy-3,4-dihydro -2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol. ### Claim 4 (depends on 1) An anti-hypertensive pharmaceutical composition which comprises a therapeutically effective amount of a compound of the Formula (I) defined in claim 1 in combination with a pharmaceutically acceptable inert carrier. ### Claim 5 (depends on 1) A method of treating hypertension in a mammalian subject which comprises the step of administering to said mammalian subject to be treated, a therapeutically effective amount of the compound of the Formula (I) defined in claim 1. ### Claim 6 A process for the preparation of a compound of the Formula (I) ##STR15## wherein R.sub.1 is C.sub.1 to C.sub.6 alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy, aralkoxy, hydroxy, nitro, cyano, formyl, C.sub.1 to C.sub.6 acyl, cyano-C.sub.1 -C.sub.6 alkyl or halo; R.sub.2 is C.sub.1 to C.sub.6 alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy, aralkoxy or hydroxy; or R.sub.1 and R.sub.2 together are alkylenedioxy; and R.sub.3 and R.sub.4 are each C.sub.1 to C.sub.6 alkyl, which comprises the steps of: (a) reducing a compound of the Formula (XVIII) ##STR16## with a metal hydride to yield a compound of the Formula (XIX) ##STR17## (b) dehydrating the compound of the Formula (XIX) by boiling said compound in a water immiscible solvent forming therewith an azeotropic mixture in the presence of a catalytically effective amount of p-toluene sulfonic acid to obtain a compound of the Formula (V) ##STR18## (c) converting the compound of the Formula (V) with N-bromo-succinimide to a compound of the Formula (VII) ##STR19## and (d) reacting the compound of the Formula (VII) with 2-pyrrolidone in the presence of an alkali metal alcoholate to obtain the compound of the Formula (I). ### Claim 7 (depends on 6) The process for preparing a compound of the Formula (I) defined in claim 6 wherein R.sub.2 is hydroxy further comprising the step of catalytically hydrogenating under pressure a compound of the Formula (I) where R.sub.2 is aralkoxy. ### Claim 8 (depends on 6) The process for preparing a compound of the Formula (I) defined in claim 6 wherein R.sub.2 is alkenyloxy or alkynyloxy further comprising the step of reacting a compound of the Formula (I) where R.sub.2 is hydroxy with an alkenyl or alkynyl halogenide in the presence of an acid binding agent and a catalytic amount of potassium iodide. ### Claim 9 (depends on 6) The process for preparing a compound of the Formula (I) defined in claim 6 wherein according to step (a) the metal hydride is sodium borohydride. ### Claim 10 (depends on 6) The process for preparing a compound of the Formula (I) defined in claim 6 wherein according to step (d) the alkali metal alcoholate is potassium tert-butoxide. ### Claim 11 (depends on 7) The process for preparing a compound of the Formula (I) defined in claim 7 wherein R.sub.2 is hydroxy in that the catalyst is palladium-on-charcoal. ### Claim 12 (depends on 8) The process for preparing a compound of the Formula (I) defined in claim 8 wherein R.sub.2 is alkenyloxy or alkynyloxy in that the acid binding agent is potassium carbonate. ### Claim 13 A process for preparing a compound of the Formula (X) ##STR20## wherein R.sub.2 is C.sub.1 to C.sub.4 alkoxy; and R.sub.3 and R.sub.4 are each C.sub.1 to C.sub.4 alkyl, which comprises the step of nitrating a compound of the Formula (IX) ##STR21## with copper(II)nitrate in a carboxylic anhydride. ### Claim 14 A process for the preparation of a compound of the Formula (XII) ##STR22## wherein R.sub.2 is C.sub.1 to C.sub.4 alkoxy; and R.sub.3 and R.sub.4 are each C.sub.1 to C.sub.4 alkyl, which comprises the steps of (a) reacting a compound of the Formula (IX) ##STR23## in a mixture of phosphorous trichloride oxide and dimethyl formamide to obtain a compound of the Formula (XI) ##STR24## (b) dissolving the compound of the Formula (XI) in a carboxylic acid; and (c) boiling the dissolved compound of the Formula (XI) in the carboxylic acid in the presence of hydroxylamine hydrochloride and an alkali metal formiate. ### Claim 15 A process for preparing a compound of the Formula (XV) ##STR25## wherein R.sub.2 is C.sub.1 to C.sub.4 alkoxy; and R.sub.3 and R.sub.4 are each C.sub.1 to C.sub.4 alkyl, which comprises the step of: (a) condensing a compound of the Formula (XI) ##STR26## with acetonitrile in the presence of an alkali metal alcoholate to obtain a compound of the Formula (XIII) ##STR27## (b) reacting the compound of the Formula (XIII) with a mineral acid to yield a compound of the Formula (XIV) ##STR28## and; (c) hydrogenating the compound of the Formula (XIV) in the presence of a catalyst under pressure. ### Claim 16 A process for preparing a compound of the Formula (XVIII) ##STR29## wherein R.sub.1 is hydrogen; R.sub.2 is hydroxy; and R.sub.3 and R.sub.4 are each C.sub.2 to C.sub.6 alkyl, which comprises reacting the compound of the Formula (XVI) ##STR30## with a compound of the Formula (XVII) ##STR31## in which R.sub.3 and R.sub.4 are each C.sub.2 to C.sub.6 alkyl. ### Claim 17 (depends on 1) The compound of the Formula (I) defined in claim 1 wherein R1 is cyano-C.sub.1 to C.sub.6 alkyl.