US3555047A - 3 - lower alkyl or alkoxy - 6 - hydroxy flavans and ester derivatives thereof - Google Patents

3 - lower alkyl or alkoxy - 6 - hydroxy flavans and ester derivatives thereof Download PDF

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US3555047A
US3555047A US587667A US3555047DA US3555047A US 3555047 A US3555047 A US 3555047A US 587667 A US587667 A US 587667A US 3555047D A US3555047D A US 3555047DA US 3555047 A US3555047 A US 3555047A
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hydroxy
acid
cis
flavane
compounds
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Klaus Irmscher
Josef Kramer
Herbert Halpaap
Karl-Otto Freisberg
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Merck KGaA
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E Merck AG
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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
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
    • 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
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2

Definitions

  • R represents alkyl or alkoxy of 1-6 carbon atoms
  • R represents hydrogen, alkyl of 1-6 carbon atoms, or an ester, the acyl portion being up to carbon atoms.
  • This invention relates to 3,6-disubstituted flavane derivatives.
  • drugs which can lower the cholesterol level in mammals for example, 22,25-diaza-cholesterol, triparanol, and dehydro-epiandrosterone-3-diethylamino ethyl ether.
  • Such drugs effect a nonphysiological accumulation of desmosterol or 7-dehydrocholesterol in the sterols of the serum or of the liver.
  • agents capable of lowering the cholesterol level in mammals which do not exhibit the undesired side eifects.
  • an object of this invention is to provide cholesterol-level-lowering drugs which do not effect a nonphysiological accumulation of desmosterol or 7-dehydrocholesterol in the sterols of the serum or of the liver.
  • Another object is to provide novel and unobvious chemical compounds which are useful as intermediates for the production of further drugs.
  • An additional object is to provide chemical compounds exhibiting sex hormone activities, particularly female sex hormone activity.
  • Still another object is to provide pharmaceutical compositions based on the compounds of this invention.
  • R represents hydrogen, alkyl of l-6 carbon atoms, or
  • R and R" represent methyl, ethyl, or together with the N-atom, pyrrolidino, piperidino, or morpholino;
  • n 2 or 3
  • novel flavane derivatives possess valuable pharmacological properties. They are, therefore, suitable for the preparation of pharmaceutical compositions and are also of value as intermediates for the preparation of further drugs.
  • the novel flavane derivatives particularly exhibit a cholesterol-level-lowering activity, without, however, effecting a nonphysiological accumulation of desmosterol or 7-dehydrocholesterol in the sterols of the serum or of the liver.
  • Hal represents Cl, Br, or I
  • R and R have the above-indicated meanings
  • R 0 can be a phenolic hydroxy group in protected form
  • an esterified hydroxy group is saponified, or a free hydroxy group is alkylated or acylated by treatment with alkylating or acylating agents.
  • the wavy line in Formula I means that the residue R, can be in the cis-, as well as in the trans-position with respect to the phenyl group.
  • the residue R can be in the cis-, as well as in the trans-position with respect to the phenyl group.
  • Alkyl groups in the residues R and R are, for example: methyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl, n-amyl, isoamyl, n-hexyl, and isohexyl.
  • the residue R can represent, for example, one of the following alkoxy groups: methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.-butoxy, tert.butoxy, amyloxy, isoamyloxy, n-hexyloxy, and isohexyloxy, as well as isobutoxy.
  • Preferred dialkylaminoalkyl groups in the residue R are: Z-dimethylaminoethyl, 2-diethylaminoethyl, 3-dimethylaminopropyl, 3-diethylaminopropyl, 2-pyrrolidinoethyl, Z-piperidinoethyl, 2-morpholinoethyl, 3-pyrrolidinopropyl, S-piperidinopropyl, and 3-morpholinopropyl.
  • Esters of such phenolic derivatives are particularly the lower acylates wherein the acyl group contains 1-6 carbon atoms.
  • typical esters are the formates, acetates, propionates, butyrates, isobutyrates, valerates, isovalerates, trimethylacetates, caproates, isocaproates; furthermore, for example, the nicotinates, isonicotinates, diethylaminoacetates, and the acid addition salts thereof, particularly the hydrochlorides.
  • the sulfuric acid and phosphoric acid esters and the physiologically compatible metal salts thereof particularly the alkali metal salts (for example, sodium) and ammonium salts, since these represent water-soluble derivatives of the compounds of Formula I, which derivatives are thus particularly useful for therapeutic applications.
  • alkali metal salts for example, sodium
  • ammonium salts since these represent water-soluble derivatives of the compounds of Formula I, which derivatives are thus particularly useful for therapeutic applications.
  • ester is to include, within the scope of the present invention, the acid addition salts of basic substituted esters and the metal and ammonium salts of acid esters.
  • the compounds of Formula II comprise flavylium salts, A or A -fiavenes, flavanones, flavanols, or flavones, which can be substituted as stated above.
  • the flavylium salts of Formula II can contain anions of any desired strong acids.
  • the flavylium salts can be present, for example, in the form of the chlorides, bromides, iodides, perchlorates, tetrachloroferrates (III), or hydrogen sulfates.
  • Suitable catalysts are, for example, noble metal, nickel, and cobalt catalysts, as well as copper chromium oxide.
  • the noble metal catalysts can be used in the form of supported catalysts, such as, for example, palladium on charcoal, calcium carbonate, or strontium carbonate; as oxide catalysts, such as, for example, platinum oxide; or as finely divided metallic catalysts.
  • Nickel and cobalt catalysts are suitably employed as Raney metals; however, nickel is also used in the form of a supported catalyst with kieselguhr or pumice as the support.
  • the hydrogenation can be conducted at room temperature and normal pressure, or also at elevated temperature and/or elevated pressure.
  • the reaction is conducted at pressures between 1 and 100 atmospheres and at temperatures between and +l50 C.
  • a solvent is present during this reaction, such as methanol, ethanol, isopropanol, tert.-butanol, ethyl acetate, dioxane, glacial acetic acid, tetrahydrofuran, or water.
  • a mineral acid for example, hydrochloric or sulfuric acid.
  • a compound of Formula II having a basic nitrogen atom is used for the hydrogenation reaction, it is possible to employ the free base, or also a salt of this base.
  • flavanones can be converted into fiavanes of Formula I by using diborane; for example, the flavanone is dissolved for this purpose in diethylene glycol dimethyl ether, diborane is introduced under cooling, and the reaction mixture is allowed to stand overnight at room temperature.
  • flavanones can be converted into the thioketals thereof, preferably the ethylene thioketals, which are then split reductively, usually by reaction with Raney metals.
  • the flavylium salts can be produced by condensing a 2,S-dihydroxybenzaldehyde which is, if desired, etherified or esterified in the 5-position, with a ketone of the formula R CH COC H the A -fiavenes can be prepared by reducing the corresponding flavylium salts with lithium aluminum hydride; the flavanones can be produced by condensation of a 2,5 dihydroxyphenyl alkyl ketone which is, if desired, etherified or esterified in the 5-position, with benzaldehyde.
  • the flavanols are obtainable by reducing the corresponding flavanones, the flavones from the corresponding flavanones by dehydrogenation with selenium dioxide, or by oxidation with hydrogen peroxide in an alkaline solution, and the A -flavenols by reducing the corresponding flavones with lithium aluminum hydride.
  • Suitable starting compounds of Formula II are, for example, the 3-methyl, 3-ethyl, 3-n-propyl, 3-isopropyl, 3- n-butyl, 3-isobutyl, 3-n-amyl, 3-isoamyl, 3-n-hexyl, 3-isohexyl, 3-methoxy, 3-ethoxy, 3-n-propoxy, 3-isopropoxy, 3- u-butoxy, 3-isobut0xy, B-n-amyloxy, 3-isoamyloxy, 3-nhexyloxy, and 3-isohexyloxy derivatives of 6-hydroxyflavylium chloride, 6 hydroxy 2 fiavene, 6-hydroxy- 3 fiavene, 6 hydroxy fiavanone, 6-hyd-roxy-flavone, 4,6 dihydroxy 2 flavene, and 4,6-dihydroxy-flavane, as well as the 6-esters and 6 ethers thereof, derived from these compounds and corresponding to the meaning of the substitu
  • alkalis are employed in this connection, such as sodium or potassium hydroxide, sodium or potassium amide, sodium hydride, basic-reacting salts, such as sodium or potassium acetate, sodium or potassium carbonate, and organic bases, such as piperidine, pyridine, benzyl trimethylammonium hydroxide.
  • Buffered solutions can also be used, for example those of citric acid and disodium phosphate, or of sodium dihydrogen phosphate and borax, or of boric acid, sodium hydroxide, and potassium chloride.
  • the preferred acidic catalysts there are included mineral acids, such as hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, and polyphosphoric acid; organic sulfonic acids, such as p-toluenesulfonic acid or camphorsulfonic acid; and complexes of organic acids with inorganic acids, such as aluminum chloride, zinc chloride, or tin tetrachloride.
  • mineral acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, and polyphosphoric acid
  • organic sulfonic acids such as p-toluenesulfonic acid or camphorsulfonic acid
  • complexes of organic acids with inorganic acids such as aluminum chloride, zinc chloride, or tin tetrachloride.
  • the cyclization can be conducted in the presence of an additional inert solvent, such as methanol, ethanol, dioxane, tetrahydrofuran, ethyl acetate, glacial acetic acid, tetralin, benzene, toluene, and, if desired, also in mixtures of these solvents with one another or with water. It is likewise possible to employ an excess of the cyclization agent as the solvent.
  • the cyclization is carried out at room temperature and can be accelerated by heating, preferably to the boiling point of the solvent employed.
  • the reaction time is several minutes to several days.
  • the starting compounds of Formula III can be produced by condensing a hydroquinone derivative which is, if desired, etherified or esterified with a compound of the formula X -CH WC H It is possible to conduct the reaction in such a manner that the compound of Formula III does not have to be isolated. Furthermore, it is possible to react a compound of the formula OII R20 CH2CHR MgHal whose phenolic hydroxy group(s) can also be present in protected form, with benzaldehyde, in order to obtain the compound of Formula 111; or a chalcone of the formula can be reduced to a compound of Formula III by treatment with a reducing agent, such as sodium amalgam, or
  • the preferred starting compounds of Formula III are the following substances:
  • the cyclization of the compounds of Formula IV is conducted generally according to the same methods as the cyclization of the compounds of Formula III. It is not necessary to isolate the compounds of Formula IV which are used as the starting compounds. Rather, these compounds can also be produced in situ. This can be done by reacting a hydroquinone derivative which is, if desired, etherfied or esterified with a halogen compound of the formula X CH -CHR CHHalC H under the conditions set forth above for the cyclization of the compounds of Formula III. When operating under mild alkaline conditions, for example, by treatment with an alkali alcoholate, it is possible to isolate the compounds of Formula IV.
  • Suitable protective groups are ether groups, such as benzyl ether or methyl ether.
  • the splitting off of such ethers is conducted, for example, by employing hydrobromic acid as the cyclization agent, under conventional conditions for cleaving phenol ethers.
  • a compound of Formula I it is furthermore possible, in a compound of Formula I, to hydrolyze an esterified hydroxy group by treatment With basic or acidic agents.
  • Preferred bases are aqueous, aqueous-alcoholic, or alcoholic sodium or potassium hydroxide.
  • Preferred acids are hydrochloric acid and sulfuric acid.
  • a free hydroxy group can be alkylated or acylated to yield compounds of Formula I.
  • Alkylation can be conducted, for example, by reaction with the corresponding alkyl halogenides, sulfates, or lower alkyl esters in the presence of alkali, such as sodium or potassium hydroxide or carbonate, a conventional inert solvent being optionally present in this reaction.
  • alkali such as sodium or potassium hydroxide or carbonate
  • the starting compounds can be reacted with methyl iodide, dimethyl sulfate, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, and isoamyl halogenides, Z-dimethylaminoethyl, 2-diethylaminoethyl, Z-methylethylamino)-ethyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 2- morpholinoethyl, 3-dimethylaminopropyl, 3-diethylaminopropyl, 3-pyrrolidinopropyl, 3-piperidinopropyl, or 3-morpholinopropyl halogenides, or also with the corresponding alcohols.
  • Suitable halogenides are the chlorides, bromides, and iodides.
  • the etherification reactions are conducted, for example, in accordance with the methods of a Williamson synthesis, the starting compounds being the corresponding alkali phenolates.
  • acidic catalysts such as sulfuric acid, phosphoric acid, or ptoluenesulfonic acid.
  • the hydroxy groups can also be acylated, for example, by heating with an anhydride or halogenide of acetic, propionic, butyric, isobutyric, valeric, isovaleric, caproic, nicotinic, r isonicotinic acid, preferably in the presence of a base, such as pyridine, or an alkali salt of the corresponding acid, or also a small quantity of a mineral acid, such as sulfuric acid or hydrochloric acid.
  • a base such as pyridine
  • an alkali salt of the corresponding acid or also a small quantity of a mineral acid, such as sulfuric acid or hydrochloric acid.
  • organic and inorganic acids can be employed, such as, for example, aliphatic, alicyclic, araliphatic, aromatic, or heterocyclic, monoor polybasic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, pivalic acid, d iethylacetic acid, oxalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, aminocarboxylic acids, sulfamic acid, benzoic acid, salicylic acid, phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, isonicotinic acid, methane-sulfonic acid, naphthalene-monoand
  • a conversion of basic fiavanes of Formula I into the physiologically compatible quaternary ammonium derivatives thereof is accomplished by treatment with alkylating agents having 18 carbon atoms, such as methyl iodide, dimethyl sulfate, ethyl bromide, and ethyl iodide.
  • preferred subgeneric groups of compounds are the following, as well as, if desired, the esters, acid addition salts, and quaternary ammonium derivatives thereof:
  • Carrier substances can be such organic or inorganic compounds suitable for parenteral, enteral, or topical application and which do not react with the novel compounds, such as, for example, water, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, Vaseline, cholesterol, etc.
  • novel compounds such as, for example, water, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, Vaseline, cholesterol, etc.
  • parenteral application particularly oily or aqueous solutions, as well as suspensions, emulsions, or implants are employed.
  • tablets or dragees which are also characterized by the presence of a carbohydrate carrier or binder.
  • a syrup or the like can also be used wherein a sweetened vehicle is employed.
  • salves or creams which can, if desired, be sterilized or mixed with auxiliary substances, such as preservatives, stabilizers, or wetting agents, or salts for influencing the osmotic pressure, or with buffer substances.
  • auxiliary substances such as preservatives, stabilizers, or wetting agents, or salts for influencing the osmotic pressure, or with buffer substances.
  • novel flavane derivatives are preferably administered in dosages of 1-500 mg. per dosage unit.
  • the carrier is usually present in an amount of 1 to 5,000 mg.
  • EXAMPLE 1 (a) 10.8 g. 3-methyl-6-hydroxy-fiavylium chloride are catalytic-hydrogenated in 300 ml. methanol in the presence of platinum (produced by the hydrogenation of 1 g. platinum dioxide). After 37 minutes, 1.955 1. hydrogen has been absorbed. The hydrogenation is terminated. The suspension is mixed with 10 ml. pyridine, the platinum is filtered off, and the filtrate is concentrated to dryness under subatmospheric pressure; there is obtained crude 2,3- cis-3-methyl-6-hydroxy-flavane.
  • EXAMPLE 2 2 g. 3-methoxy-6-hydroxy-2-fiavene is hydrogenated in ml. ethanol in the presence of 500 mg. Raney nickel.
  • EXAMPLE 4 A solution of 1.5 g. 3-methoxy-6-isoamyloxy-flavanone in 2 ml. ethanedithiol and 2 ml. boron trifluoride etherate is allowed to stand at room temperature for 15 minutes and then, after the addition of 20 ml. chloroform, is allowed to stand overnight. The reaction mixture is diluted with 200 ml. chloroform, washed with water and sodium chloride solution, and dried over sodium sulfate. The residue obtained after the chloroform has been removed is dissolved in 300 ml. absolute ethanol and refluxed with activated Raney nickel for 10 hours. After the catalyst has been filtered olf, the solution is concentrated to 20 ml. Thereby, 2,3-trans-3 methoxy-6-isoamyloxy flavane is obtained.
  • EXAMPLE 5 2.4 g. 2,3-trans-3-methyl-4,6-dihydroxy-flavane are dissolved in 100 ml. dioxane, mixed with 1.2 g. palladium chloride, and hydrogenated at room temperature. After the stoichiometric quantity of hydrogen has been absorbed, the hydrogenation is terminated, the catalyst is filtered olf, the dioxane solution is concentrated under reduced pressure, diluted with water, and again concentrated for removing the residual dioxane. The crude product is recrystallized from ethanol, there being obtained 2,3- trans-3-methyl-6-hydroxy-flavane.
  • EXAMPLE 6 4 g. hydroquinone, 8 g. 1-phenyl-2-methyl-3-bromopropene, and 5 g. freshly melted zinc chloride are boiled under reflux in 55 ml. absolute benzene for 6 hours. Then, the reaction mixture is allowed to cool; the organic phase is washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The crude product is chromatograph on 20 g. aluminum oxide, there being obtained 2,3-trans-3-methyl-6-hydroxy flavane.
  • EXAMPLE 7 2 g. 1 phenyl 2 methyl-3-(2'-hydroxy-5'-methoxyphenyl)-propanol are heated to the boiling point, under reflux, in 10 ml. 2% methanolic hydrochloric acid for 4 hours. Thereafter, the reaction solution is concentrated under reduced pressure, there being obtained 2,3-trans- 3-methyl-6-methoxy-flavane.
  • EXAMPLE 8 2 g. l-phenyl-2-methyl-3-(2,5'-dimethoxyphenyl)-propanol are boiled under reflux in a 5% solution of hydrogen bromide in 50 ml. glacial acetic acid for 2 hours. Then, the mixture is poured into water, extracted with chloro form, the extract is washed With water, dried over sodium sulfate, and evaporated to dryness, there being obtained 2,3-trans-3-methyl-6-hydroxy-flavane.
  • EXAMPLE 9 2 g. l-phenyl-2-methyl-3-(2-hydroxy-5'-methoxyphenyl)-propy1 chloride are dissolved cold in 200 ml. 5% solution of caustic soda and subsequently heated on a steam bath. There are obtained 2,3-cisand 2,3-trans-3- methyl-6-methoxy-flavane, which can be separated from each other by chromatographing on silica gel.
  • EXAMPLE 1O 3 g. 3-phenyl-3-p-anisyloxy-Z-methyl-propyl chloride and 0.3 g. tin tetrachloride are heated in a tubular bomb for 6 hours to 200 C. After cooling, the reaction mixture is Worked up with ether and aqueous hydrochloric acid; the ether phase is washed with soda solution, dried over sodium sulfate, the solvent is Withdrawn under reduced pressure, and the crude product is recrystallized from methanol, there being obtained 2,3-trans-3-methy1-6-methoxyflavane.
  • EXAMPLE 11 3 g. 3-phenyl-3-p-anisyloxy-2-methyl-propanol are heated with 0.3 g. zinc chloride in a tubular bomb for 30 minutes to 200 C.; after cooling, the reaction mixture is worked up as described in Example 10; 2,3-trans-3-methyl- 6-methoxy-flavane is obtained.
  • EXAMPLE 12 (a) 5 g. 2,3-cis-3-methoxy-6-hydroxy-flavane and 20 g. 3-dimethylaminopropyl chloride are boiled with 5.7 g. anhydrous potassium carbonate in ml. absolute acetone for 20 hours, under stirring. The reaction mixture is concentrated, water and ether are added, the layers are separated, dried over potassium hydroxide, concentrated by evaporation, and chromatographed on aluminum oxide. With the aid of chloroform, 2,3-cis-3-methoxy-6-(3-dimethylaminopropoxy)-flavane is eluted.
  • the corresponding hydrobromide can be produced when employing hydrogen bromide.
  • the pyridine layer is separated, washed twice with a small amount of ether, taken up in methanol, concentrated, and the residue is mixed with ethanol, insoluble components are removed by suction, and the solution is filtered over basic aluminum oxide. From the concentrated filtrate, there crystallizes the sodium salt of 2,3-cis-3-methoxy-6-hydroxyfiavane-6-sulfuric acid ester. After recrystallization from methanol/ethanol, this compound melts at 192-195 C.
  • 6- (Z-dimethylaminoethyl -ethers, 6- Z-diethylaminoethyl -ethers, 6- (2-pyrrolidinoethyl -ethers,
  • EXAMPLE l6TABLETS corn starch and tragacanth Its weight is about 120 mg.
  • EXAMPLE 18-SOLUTION FOR INJECTION Ampoules containing 2 mg. 2,3 cis 3 methoxy-6- hydroxy-fiavane in 1 ml. of sesame oil are prepared and sealed in the conventional manner.
  • a dosage unit (5 ml.) contains 10 mg. of active substance.
  • a member selected from the group consisting of a 3,6-disubstituted flavane derivative of Formula I /O can mo R1 wherein R represents methyl, ethyl, propyl, amyl, methoxy or ethoxy; R represents hydrogen;
  • a member as defined by claim 1 wherein member is 2,3-cis-3-ethyl-6-hydroXy-flavane.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US587667A 1965-10-20 1966-10-19 3 - lower alkyl or alkoxy - 6 - hydroxy flavans and ester derivatives thereof Expired - Lifetime US3555047A (en)

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BE (1) BE688588A (enrdf_load_stackoverflow)
CH (1) CH487141A (enrdf_load_stackoverflow)
DE (1) DE1518038C3 (enrdf_load_stackoverflow)
DK (1) DK116739B (enrdf_load_stackoverflow)
ES (1) ES332458A1 (enrdf_load_stackoverflow)
FR (1) FR7297M (enrdf_load_stackoverflow)
GB (1) GB1087539A (enrdf_load_stackoverflow)
IL (1) IL26629A (enrdf_load_stackoverflow)
NL (1) NL6614645A (enrdf_load_stackoverflow)
SE (1) SE353536B (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4146539A (en) * 1974-07-30 1979-03-27 Beecham Group Limited Anorexic chromans
WO2003074044A1 (en) * 2002-03-01 2003-09-12 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3069830D1 (en) * 1979-09-13 1985-01-31 Wellcome Found Benzopyran compounds, useful as chemotherapeutic agents
US5446061A (en) * 1993-11-05 1995-08-29 Eli Lilly And Company Methods for lowering serum cholesterol

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4146539A (en) * 1974-07-30 1979-03-27 Beecham Group Limited Anorexic chromans
WO2003074044A1 (en) * 2002-03-01 2003-09-12 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists

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BE688588A (enrdf_load_stackoverflow) 1967-04-20
GB1087539A (en) 1967-10-18
DE1518038C3 (de) 1975-01-23
FR7297M (enrdf_load_stackoverflow) 1969-11-12
ES332458A1 (es) 1967-11-01
CH487141A (de) 1970-03-15
DE1518038B2 (de) 1974-06-06
DE1518038A1 (de) 1969-06-26
SE353536B (enrdf_load_stackoverflow) 1973-02-05
NL6614645A (enrdf_load_stackoverflow) 1967-04-21
IL26629A (en) 1970-08-19
DK116739B (da) 1970-02-09

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