USRE30739E - Anorexic chromans - Google Patents

Anorexic chromans Download PDF

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USRE30739E
USRE30739E US06/038,737 US3873779A USRE30739E US RE30739 E USRE30739 E US RE30739E US 3873779 A US3873779 A US 3873779A US RE30739 E USRE30739 E US RE30739E
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dimethyl
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ether
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chroman
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Derek V. Gardner
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Beecham Group PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • British Pat. No. 1,357,633 describes inter alia compounds of the formula (I): ##STR2## and salts thereof wherein A 1 is an alkylene group 2-4 carbon atoms; A 2 is a hydrogen atom or a C 1-4 alkyl group and A 3 is a hydrogen atom or a C 1-4 alkyl group. These compounds were described as possessing activity on the central nervous system. However it is now believed that the compounds of the formula (I) are not sufficiently potent as use as anti-depressants. There has now been discovered a group of compounds which have more potent mood modifying activity than the compounds of the formula (I) and which at higher doses have the additional utility of suppressing appetite.
  • the present invention provides compounds of the formula (II): ##STR3## and salts thereof wherein X is an alkylene group of 2-4 carbon atoms; R 1 is a hydrogen atom or a C 1-6 alkyl group; R 2 is a hydrogen atom, a C 1-6 alkyl or benzyl group or R 2 is linked to R 1 so that the NR 1 R 2 is a 5-, 6- or 7-membered saturated ring; R 3 is an aryl group; R 4 is a hydrogen atom or a C 1-4 alkyl group; and R 5 is a hydrogen atom or a C 1-4 alkyl group.
  • ⁇ aryl ⁇ means a phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolidyl, substituted phenyl or substituted naphthyl group.
  • ⁇ substituted phenyl group ⁇ means a phenyl group substituted by one or two groups selected from fluorine, chlorine or bromine atoms or methoxyl, benzyloxyl, trifluoromethyl, methyl,, nitro, acetoxyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, hydroxyl, methoxycarbonyl, ethoxycarbonyl, carboxamido, sulphonamido, nitrile, carboxy, trifluoromethoxyl, trifluoromethylthio, methylsulphonyl, trifluoromethylsulphonyl or methylthio group.
  • ⁇ substituted naphthyl group ⁇ means a naphthyl group substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxyl, trifluoromethyl, benzyloxy, hydroxyl, or methylthio group.
  • ⁇ alkylene ⁇ means a straight or branched divalent alkyl group which produces a bridge of two or three carbon atoms between the O and N atoms.
  • Suitable groups R 1 include the hydrogen atom and the methyl, ethyl, propyl and butyl groups.
  • Suitable groups R 2 include the hydrogen atom and the methyl, ethyl and benzyl groups.
  • Suitable cyclic groups NR 1 R 2 include pyrrolidino, piperidino, piperazinyl, N-methylpiperazinyl, morpholino and like groups.
  • Particularly suitable groups NR 1 R 2 include the NHCH 3 and N(CH 3 ) 2 groups, the N(CH 3 ) 2 group being preferred.
  • R 4 and R 5 are both methyl groups.
  • Suitable groups X include the --CH 2 .CH 2 --, --CH 2 .CH 2 .CH 2 --, --CH 2 .CH(CH 3 ).CH 2 -- and --CH 2 .CH(CH 3 )-- groups. Most suitably X is a --CH 2 .CH 2 -- group.
  • One particularly suitable sub-group of compounds of the formula (II) are those of the formula (III): ##STR4## and salts thereof wherein R 1 , R 2 and R 3 are as defined in relation to formula (II).
  • NR 1 R 2 is suitably a methylamino or dimethylamino group, the dimethylamino group being preferred.
  • R 1 and R 2 are as defined in relation to formula (II);
  • R 7 is selected from a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl, methyl, methoxyl, nitro, cyano, hydroxyl, amino, dimethylamino, carboxamido, trifluoromethyloxy, trifluoromethylthio or sulphonamido group; and
  • R 8 is a hydrogen, fluorine or chlorine atom or a trifluoromethyl, methoxyl, methyl or nitro group.
  • R 7 is most suitably a hydrogen, fluorine or chlorine atom or a methyl, methoxyl or trifluoromethyl group.
  • R 8 is most suitably a hydrogen, fluorine or chlorine atom and is preferably a hydrogen atom.
  • R 1 is a hydrogen atom or a methyl or ethyl group and R 2 is a methyl or ethyl group.
  • R 1 and R 2 are both methyl groups.
  • a further particularly suitable group of compounds of the formula (II) are those of the formula (V): ##STR6## and salts thereof wherein suitable and preferred groups R 7 and R 8 are as defined in relation to formula (IV).
  • R 9 is a hydrogen, fluorine, chlorine or bromine atom or a methyl, methoxyl or trifluoromethyl group
  • R 10 is a hydrogen atom or a methyl or ethyl group
  • R 11 is a methyl or ethyl group or is joined to R 10 so that NR 10 R 11 is a piperidino, pyrrolidino or morpholino group.
  • R 11 is not joined to R 10 .
  • NR 10 R 11 is a methylamino group. In certain preferred compounds of the formula (VI) NR 10 R 11 is a dimethylamino group.
  • Particularly favoured compounds of the formula (VI) include those wherein R 9 is a meta- or para-trifluoromethyl group.
  • a further particularly suitable group of compounds of this invention are those of the formula (VII): ##STR8## and salts thereof wherein R 10 and R 11 are as defined in relation to formula (VI) and R 12 is a naphthyl or substituted naphthyl group.
  • NR 10 R 11 is a methylamino group. In certain preferred compounds of the formula (VII) NR 10 R 11 is a dimethylamino group.
  • R 12 is naphthyl and preferably a 2-naphthyl group.
  • the compounds of this invention are nitrogenous bases they are able to form acid addition salts in conventional manner.
  • Normally and preferably such salts are those formed from pharmaceutically acceptable organic or inorganic acids such as citric, acetic, propionic, lactic, tartaric, mandelic, succinic, fumaric, oleic, glutamic, gluconic, methanesulfphonic, toluenesulphonic, sulphuric, phosphoric, hydrobromic, hydrochloric or the like acids.
  • the nature of the salting acid is relatively unimportant as long as it forms a stable and preferably crystalline pharmaceutically acceptable acid addition salts.
  • Certain compounds within this invention and their salts are able to form solvates such as hydrates, for example, monohydrates.
  • the compounds of this invention contain an assymetric carbon atom at the 4-position of the chroman system they can exist as two optical isomers or mixtures of such isomers, for example racemic mixtures.
  • compositions which comprise a compound of this invention as hereinbefore described together with a pharmaceutically acceptable carrier.
  • compositions of this invention are adapted for oral administration to humans although compositions adapted for parenteral administration are also envisaged.
  • the most suitable dosage forms are unit dosage forms such as tablets, capsules, sachets and the like which contain a predetermined quantity of active material.
  • Such unit dosage forms normally contain from 0.1 to 200 mg of active material and may be taken once a day or several times a day according to the dose desired. Generally a human adult will be administered from 1 to 600 mgs per day, for example, from 5 to 200 mgs.
  • composition of this invention is intended for the induction of anorexia
  • the composition will normally be in the form of a solid unit dosage form which contains from 1 mg to 200 mg of active ingredient, for example, 2 mg to 150 mg of active ingredient.
  • composition of this invention is intended for mood-modification such as anti-depressant effects, it is likely that it will be used as a solid unit dosage form which contains from 0.1 mg to 50 mg of active ingredient, for example, 1 mg to 25 mg of active ingredient.
  • this invention provides a method of suppressing appetite, which comprises administering an anorexically effective amount of a compound of this invention.
  • this invention provides a method of reducing depression, which comprises administering an anti-depressively effective amount of a compound of this invention.
  • the useful anorexic activity of compounds of this invention may be determined by the oral administration to hungry rats of the compound and measuring the reduction in their food intake.
  • the results given in Table I were obtained for racemic compounds of the formula (VIII): ##STR9##
  • the useful mood-modifying activity of the compounds of this invention may be determined by standard tests such as the Reserpine Prevention test which demonstrates the ability of the compound to prevent reserpine-induced hypothermia in mice.
  • the results given in Table II were obtained for racemic compound of the formula (IX): ##STR10##
  • the D- and L-isomers of the compounds of this invention do not necessarily have identical pharmaceutical activity.
  • (-)-2,2-dimethyl-7-dimethylaminoethoxy-4-(3-trifluoromethylphenyl)chroman is a more potent anorexiogenic agent and a more potent mood-modifying agent than the corresponding (+)-isomer.
  • those optical isomers of the compounds of the formula (II) which have the same stereochemistry at the 4-position of the chroman ring as (-)-2,2-dimethyl-7-dimethylaminoethoxy-4-(3-trifluoromethylphenyl)chroman are more suitable then the corresponding isomer which has the opposite stereochemistry at that point.
  • R 1 and R 2 are as defined in relation to formula (II).
  • Suitable solvents include hydrocarbons such as toluene or xylene, ethers such as dimethoxyethane or dimethoxypropane, ketones such as acetone, alcohols such as ethanol and other conventional solvents.
  • the anion of the compound of the formula (X) may be produced before the etherification reaction or may be produced in situ by reaction with a base such as NaH or the like.
  • reaction is substantially complete in a conveniently short time if an elevated temperature is used.
  • the reaction may be carried out at from about 0°-180° C., preferably in the region of 50°-120° C., for example, at about 70°-100° C.
  • Suitable groups Q 1 in the compound of the formula (XI) include conventional good leaving groups such as chlorine, bromine or iodine atoms or groups of the formula O.SO 2 R 1 or O.CO 2 R 1 where R 1 is an inert organic group such as a methyl, ethyl, phenyl, tolyl or like group.
  • R 1 is an inert organic group such as a methyl, ethyl, phenyl, tolyl or like group.
  • the group Q 2 in the compounds of formulae (XII) and (XIII) may also have these values.
  • reaction of a compound of the formula (X) with one of the formula (XII) may take place under similar conditions to those outlined for the reaction of the compound of the formula (X) with one of the formula (XI).
  • reaction of the compound of the formula (XIII) with an amine of the formula (XIV) will normally take place in an inert organic solvent such as a lower alkanol such as methanol, ethanol or the like or a halohydrocarbon such as methylene chloride or chloroform or the like.
  • an inert organic solvent such as a lower alkanol such as methanol, ethanol or the like or a halohydrocarbon such as methylene chloride or chloroform or the like.
  • Such reactions take place at non-extreme temperatures such as -20°-140° C., and more usually at conventional temperatures such as 0°-30° C., for example at ambient temperature.
  • the reduction of the compound of the formula (XV) is normally brought about by catalytic hydrogenation.
  • Such hydrogenation reactions will generally take place in organic solvents such as methanol, ethanol, methyl acetate, ethyl acetate or other conventional hydrogenation solvents using a low, ambient or elevated pressure of hydrogen. Generally from 1-5 atmospheres of hydrogen are used. Normally the reaction takes place at a non-extreme temperature such as 0°-100° C., for example 12°-80° C.
  • the catalyst used in these reactions will normally be a transition metal catalyst such as palladium. We have found 10-30% palladium on charcoal to be suitable.
  • the reduction of a compound of the formula (XVI) is normally effected using a complex hydride such a lithium aluminium hydride.
  • a complex hydride such as lithium aluminium hydride.
  • Such reactions are carried out in an inert solvent medium such as dry ether solvent, for example, in tetrahydrofuran, dioxane, diethylether or the like.
  • the reaction may be carried out at any non-extreme temperature, for example, 0°-120° C. and more suitably at an ambient or slightly elevated temperature, for example, at about 15°-80° C.
  • Such groups include the benzyl, benzhydride, trityl, methoxybenzyl, halobenzyl, dimethoxybenzhydride or other equivalent group.
  • the removal of this group is effected by catalytic hydrogenation, for example, using low, medium or high pressures of hydrogen over a transition metal catalyst.
  • a transition metal catalyst We have found 1-5 atmospheres of hydrogen to be suitable for use in conjunction with a palladium on charcoal catalyst.
  • the reaction is carried out at a non-extreme temperature such as 0°-100° C., for example, 12°-80° C.; in a conventional solvent such as methanol, ethanol, methyl acetate, ethyl acetate or the like.
  • the compounds of the formula (II) wherein R 1 and/or R 2 are alkyl groups may be prepared by conventional methods of alkylation from corresponding compounds. Reaction with compounds R 1 Q 1 or R 2 Q 1 under conventional conditions may be employed but in general are not preferred because they tend to lend to unacceptable side reactions. Particularly suitable methods of alkylation include reductive alkylation using an aldehyde in the presence of a reducing agent.
  • compounds of the formula (II) wherein R 1 and/or R 2 are methyl groups may be prepared by reaction with formaldehyde in the presence of formic acid or by reaction with formaldehyde in the presence of a reducing agent such as hydrogen and a transition metal catalyst.
  • Such reactions normally take place at a non-extreme temperature such as -10°-120° C., for example, 10°-60° C. and preferably at ambient temperature. Such reaction frequently takes place in a conventional organic solvent.
  • Dehydration of the compounds of the formula (XVII) may be brought about by treatment with an acid catalyst and/or by heating. Generally the reaction takes place in a solvent which is frequently a hydrocarbon solvent.
  • Suitable acid catalysts include mineral acids or stronger organic acids such as toluenesulphonic acid. If the dehydration is promoted by heating it is frequently sufficient to warm the reaction medium to 25°-100° C.
  • Demethylation of such a compound may be brought about by the action of a strong acid such as a hydroiodic acid or hydrobromic acid and debenzylation may be brought about by catalytic hydrogenation in conventional manner.
  • Such hydrogenation reactions may be carried out in ethanol at ambient temperature using hydrogen at atmospheric pressure and a 10% palladium on charcoal catalyst.
  • the compounds of the formula (XIX) may be prepared by the reaction of a compound of the formula (XX): ##STR18## wherein R 4 , R 5 and R 21 are as defined in relation to formula (XIX) and a metal derivative of the formula R 3 M where M is Li, Na, MgI, MgBr or MgCl in conventional manner.
  • the compounds of the formula (XV) may be prepared by the reaction in a conventional manner of the corresponding compound of the formula (XXI): ##STR19## wherein R 1 , R 2 , R 4 , R 5 and X are as defined in relation to formula (II) with a compound of the formula R 3 M where M is Li, Na, MgI, MgBr or MgCl, followed by dehydration.
  • the initial step of such reaction takes place in aprotic media, for example, in an ether solvent such as diethylether, tetrahydrofuran, dimethoxyethane or the like.
  • aprotic media for example, in an ether solvent such as diethylether, tetrahydrofuran, dimethoxyethane or the like.
  • the dehydration stage may conveniently be carried out using an aqueous or alkanolic solution of an acid in conventional manner.
  • the compound of the formula (XXI) may be prepared from the corresponding compound of the formula (XXII): ##STR20## by conventional methods of ether formation such as by reaction of the sodium salt with a compound such as Cl--X--NR 1 R 2 at ambient temperature in an alkanolic or similar solvent.
  • Compounds of the formula (XVII) may be prepared by the reaction of CH 3 Li, CH 3 MgBr, CH 3 MgI, CH 3 MgCl or the chemical equivalent on a compound of the formula (XXIII): ##STR21## wherein R 1 , R 2 , R 3 and X are as defined in relation to formula (II).
  • Such reactions occur under conventional conditions for Grignard reactions, for example, in an ether solution in the absence of water.
  • the resulting diol frequently dehydrates spontaneously during work up to yield a chroman of the formula (II), especially if heat or acid is involved in the work up.
  • Compounds of the formula (II) wherein XNR 1 R 2 is a CH 2 CH 2 NH 2 group may also be prepared by a further process of the invention which comprises the reduction of a corresponding compound wherein the XNR 1 R 2 group is a CH 2 CN group which compound in turn may be prepared from, for example, a sodium salt of a compound of the formula (X) and compound such as BrCH 2 CN.
  • the elements of carbon dioxide may be generally removed from the compound of the formula (XXV) by heating to about 200° C. optionally in the presence of a high boiling inert solvent.
  • the carbonate of the formula (XXV) may be obtained by resolution of the corresponding racemate. Such resolution may be brought about by fractional crystallisation from solvents such as ethanol and ethanol/diethyl ether mixtures.
  • the racematic carbonate may be prepared by the acylation of a compound of the formula (X) with (-)-menthyloxycarbonylchloride in ether solution in the presence of a tertiary base such as pyridine.
  • the aqueous layer was extracted with ether and the extract used to dissolve the residue from the toluene evaporation.
  • the organic layer was extracted with 5 N hydrochloric acid (45, 35 and 20 ml respectively), the combined acid extract was basified and extracted into ether. After being dried the ether was removed in vacuo to give a yellow oil (6.2 g) which was chromatographed on alumina in 8% ether-- 92% petroleum ether (b.p. 60°-80°) to give the title compound (4.71 g, 51%) as a colourless oil.
  • the hydrochloric salt had m.p. 178.5°-181.5° C.
  • N-benzylmethylaminoethyl chloride hydrochloride (1.37 g) was added to 2,2-dimethyl-4-(3-trifluoromethylphenyl)chroman-7-ol (2.0 g), potassium carbonate (5.16 g) and potassium iodide(1.03 g) in methyl ethyl ketone (50 ml). The mixture was refluxed for 2 days and left to stand at ambient temperature for a further 3 days. The mixture was filtered and the solvent evaporated under reduced pressure. The resulting crude oil was taken up in water, and extracted into ether. The ether was dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to yield an oil. This oil was dissolved in dry ether and passage of dry hydrogen chloride through the solution yielded the title compound (1.0 g) as a non-crystalline foam which analysed as the monohydrate.
  • Dimethylaminoethylchloride hydrochloride (1.5 g) was added to 2,2-dimethyl-4-(4-trifluoromethylphenylchroman-7-ol (1.0 g), potassium carbonate (4.0 g) and potassium iodide (1.5 g) in acetone (50 ml) and the mixture refluxed for 2 days. The mixture was filtered and the acetone was evaporated under reduced pressure. The resulting crude oil was chromatographed on alumina. Elution with ether:petrol (1:1) gave a clear oil which afer dissolution in dry ether and passage of dry hydrogen chloride through the solution yielded the required chroman as the hydrochloride salt (0.35 g), m.p. 200°-203° C.
  • 2,2-Dimethyl-7-(2-hydroxyethoxy)-4-(-4-trifluoromethylphenyl) chroman tosylate (0.65 g) was dissolved in a solution of dimethylamine (excess) containing a trace of sodium iodide and the mixture was heated in an autoclave at 120° C. for 4 hours and allowed to cool to room temperature overnight. The solvents were then removed under reduced pressure. The resulting dark oily solid was washed with dilute sodium bicarbonate and taken up into ether. The ether solution was dried (MgSO 4 ) and the solvent evaporated under reduced pressure to yield an oil. The oil was redissolved in dry ether and the passage of dry halogen chloride through the solution yielded the title compound.
  • the title compound may be prepared by the method of R. N. Icke, V. B. Wisegarber and G. A. Alles, Organic Synthesis, Collected Volume 3, page 723 from 2,2-dimethyl-7-methylaminoethoxy-4-(4-trifluoromethylphenyl) chroman or from 2,2-dimethyl-7-aminoethoxy-4-(4-trifluoromethylphenyl)chroman.
  • the corresponding 4-(3-trifluoromethylphenyl) compound may be prepared in an analogous manner.
  • Formaldehyde (30 ml of a 35% aqueous solution) was added to 7-aminoethoxy-2,2-dimethyl-4-(3-trifluoromethylphenyl) chroman (1 g) in ethanol (30 ml) and the mixture was hydrogenated over 10% palladium of charcoal (0.1 g) at 4 atmospheres.
  • the catalyst was removed by filtration and the filtrate evaporated under reduced pressure to give an oil which was taken up in water and extracted with ether. The ethereal extracts were evaporated to give an oil which contained the title compound.
  • the above reactions may also be carried out using starting compounds in which the N-benzyl group is replaced by a N-(4-methoxybenzyl) or N-(4-chlorobenzyl) group.
  • (+)-2,2-Dimethyl-4-(3-trifluoromethylphenyl)chroman-7-ol (3.8 g) potassium carbonate (10 g) and dimethylaminoethyl chloride hydrochloride (4 g) refluxed in dry acetone (200 ml) for 16 hours, the solid filtered off and the acetone evaporated, giving a clear brown oil (3.6 g).
  • the acid layer was neutralised (K 2 CO 3 ) and extracted with ether (2 ⁇ 100 ml).
  • a mixed melting point yielded a temperature range of 175°-195° C.
  • Authentic unresolved material has a melting point of 180°-195° C.
  • the n.m.r. spectra were identical with unresolved material.
  • 2,2-Dimethyl-7-(2-methylaminoethoxy)-4-(2-naphthyl)chroman and 7-(2-diethylaminoethoxy)-2,2-dimethyl-4-(2-naphthyl)chroman were prepared from 7-[2-(N-benzyl-N-methylamino)ethoxy]-2,2-dimethyl-4-(2-naphthyl)-2H-chromene and 7-(2-diethylaminoethoxy)-2,2-dimethyl-4-(2-naphthyl)-2H-chromene respectively in a similar manner as colourless oils.
  • n-Butyl-lithium (142 ml of a 2.4 M solution) was added under dry nitrogen to a solution of 4-bromobenzotrifluoride (76.5 g) in dry ether at -50° C. The mixture was left to stir for 2 hours. 7-Benzyloxy-2,2dimethylchroman-4-one (64 g) in dry ether was added dropwise. Water was added and the ether layer washed with 5N.HCl (2 ⁇ 100 ml), and dried (MgSO 4 ). Removal of the solvent under reduced pressure gave an oil (84 g) which was chromatographed on alumina. Elution with petrolether (1:1) gave the title compound (52 g).
  • n-Butyl-lithium 28.6 ml of a 2.4 M solution was added dropwise under dry nitrogen to a solution of dibromobenzene (13.5 g) in dry ether at -30° C.
  • 2,2-dimethyl-7-dimethylaminoethyloxychroman-4-one (10.0 g) in dry ether was added dropwise and the solution was allowed to stir for 2 hours and then left to stand for 16 hours.
  • Water 50 ml was added and the mixture was extracted with 5 N.HCl (3 ⁇ 100 ml). The acid layers were basified, the basic solution extracted with ether and the ether layers dried (MgSO 4 ).
  • n-Butyl-lithium (56 ml of a 2 N solution) was added under dry nitrogen to a solution of furan (10 ml) in dry ether (15 ml) at room temperature and the solution was refluxed for 1 hour.
  • 2,2-Dimethyl-7-dimethylaminoethyl oxychroman-4-one (10.0 g) in dry ether (40 ml) was added dropwise and the solution was refluxed for 1 hour.
  • Water (50 ml) was added and the mixture extracted with 2 N.HCl (3 ⁇ 100 ml). The acid layers were basified and the basic solution extracted with ether and the organic layers dried (MgSO 4 ).
  • Methyl-lithium 150 ml of a 2 N solution was added under dry N 2 to a solution of 7-hydroxy-4-(2-thienyl)dihydrocoumarin (14.8 g) in dry ether (120 ml) and the mixture allowed to stand for 3 days. Water (500 ml) was added and the ether layer discarded. The aqueous layer was acidified, extracted with ether and the combined ether layers dried (MgSO 4 ). Removal of the solvent under reduced pressure gave a black oil which was then dissolved in dry benzene (100 ml) containing a trace of p-toluene sulphonic acid. The mixture was heated under reflux for 3 hours in a Dean & Stark apparatus. Removal of the solvent under reduced pressure and chromatography on silica gave the required phenol (7 g).
  • N-Benzylmethylaminoethylchloride hydrochloride 14.98 g was added to a mixture of potassium carbonate (86.28 g), potassium iodide (17.28 g) and 2,2-dimethylchroman-4-one-7-ol (20 g) and the reaction mixture refluxed in acetone for two days. Filtration and removal of the solvent under reduced pressure gave an oil which was taken up in ether and washed with 1 M sodium hydroxide and then with water. The ether layer was dried (MgSO 4 ) and evaporated under reduced pressure to give the title compound as an oil (19.9 g).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Pyrane Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US06/038,737 1974-07-30 1979-05-14 Anorexic chromans Expired - Lifetime USRE30739E (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB33549/74 1974-07-30
GB33549/74A GB1486001A (en) 1974-07-30 1974-07-30 7-aminoalkoxy substituted benzopyrans benzo thiopyrans and naphthalenes

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US59969475A Continuation-In-Part 1975-05-03 1975-07-28
US05/652,041 Reissue US4080335A (en) 1974-07-30 1976-01-26 Anorexic chromans

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US (1) USRE30739E (de)
JP (1) JPS51125055A (de)
AR (1) AR210500A1 (de)
AT (1) AT345283B (de)
AU (1) AU500006B2 (de)
BE (1) BE831939A (de)
CA (1) CA1077478A (de)
CH (3) CH622789A5 (de)
DE (1) DE2533885A1 (de)
DK (1) DK344175A (de)
ES (1) ES439856A1 (de)
FR (2) FR2280368A1 (de)
GB (1) GB1486001A (de)
IE (1) IE41273B1 (de)
IL (1) IL47826A (de)
SE (1) SE420490B (de)
ZA (1) ZA754821B (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5043352A (en) * 1988-11-23 1991-08-27 Sanofi Chroman derivatives for the treatment of depressive states
US5166367A (en) * 1991-06-21 1992-11-24 American Home Products Corporation Antipsychotic benzodioxan derivatives

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2408600A1 (fr) * 1977-10-11 1979-06-08 Beecham Group Ltd Derives des chromanes et leur application therapeutique
JPS5832847A (ja) * 1981-08-20 1983-02-25 Mitsubishi Chem Ind Ltd （３−アミノプロポキシ）ビベンジル類
GB2271566A (en) * 1992-10-14 1994-04-20 Merck & Co Inc HIV integrase inhibitors
US6017768A (en) * 1994-05-06 2000-01-25 Pharmacopeia, Inc. Combinatorial dihydrobenzopyran library
CA2190708A1 (en) * 1995-12-08 1997-06-09 Johannes Aebi Aminoalkyl substituted benzo-heterocyclic compounds
EP2725026B1 (de) * 2012-10-29 2017-09-06 Symrise AG Heterozyklische neoflavonoide mit geschmacksmaskierenden eigenschaften

Citations (1)

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Publication number Priority date Publication date Assignee Title
GB1357633A (en) * 1971-03-02 1974-06-26 Beecham Group Ltd Chromanone basic ether derivatives

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
US3476767A (en) * 1965-10-11 1969-11-04 Ciba Geigy Corp 1,2-diaryl - 6 - tertiary amino lower-alkoxy-3,4-dihydro naphthalenes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1357633A (en) * 1971-03-02 1974-06-26 Beecham Group Ltd Chromanone basic ether derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5043352A (en) * 1988-11-23 1991-08-27 Sanofi Chroman derivatives for the treatment of depressive states
US5166367A (en) * 1991-06-21 1992-11-24 American Home Products Corporation Antipsychotic benzodioxan derivatives

Also Published As

Publication number Publication date
CH622789A5 (en) 1981-04-30
CH624111A5 (en) 1981-07-15
JPS51125055A (en) 1976-11-01
CA1077478A (en) 1980-05-13
ES439856A1 (es) 1977-06-16
BE831939A (fr) 1976-01-30
ATA582775A (de) 1978-01-15
IL47826A (en) 1979-05-31
AU8353675A (en) 1977-02-03
IE41273L (en) 1976-01-30
DK344175A (da) 1976-01-31
DE2533885A1 (de) 1976-02-19
ZA754821B (en) 1976-07-28
IE41273B1 (en) 1979-11-21
FR2313025A1 (fr) 1976-12-31
IL47826A0 (en) 1975-10-15
SE420490B (sv) 1981-10-12
AR210500A1 (es) 1977-08-15
SE7508414L (sv) 1976-02-02
FR2313025B1 (de) 1979-10-05
CH624110A5 (en) 1981-07-15
FR2280368B1 (de) 1979-08-10
FR2280368A1 (fr) 1976-02-27
GB1486001A (en) 1977-09-14
AT345283B (de) 1978-09-11
AU500006B2 (en) 1979-05-10

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