US3471520A - 4-aryl-isoflavanoids - Google Patents

4-aryl-isoflavanoids Download PDF

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US3471520A
US3471520A US517782A US3471520DA US3471520A US 3471520 A US3471520 A US 3471520A US 517782 A US517782 A US 517782A US 3471520D A US3471520D A US 3471520DA US 3471520 A US3471520 A US 3471520A
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ethyl
phenyl
methoxy
acid
methyl
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Klaus Irmscher
Josef Kramer
Hans-Gunther Kraft
Hartmut Kieser
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Merck KGaA
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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
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • R is H or alkyl of 1-3 carbon atoms
  • R and R each represents H, OH, alkoxy of 1-6 carbon atoms, acyloxy of 1-6 carbon atoms,
  • R and R each represents alkyl of 1-4 carbon atoms
  • Q represents OH or together with R a ring carbon-tocarbon double bond
  • R represents H or together with Q a ring carbon-to-carbon double bond
  • X and Y each represents H or F
  • Z represents OH, alkoxy of l-6 carbon atoms, --NH or an alkylated amino group wherein the alkyl portion is of 1-6 carbon atoms, and
  • n is an integer of 2 to 3, inclusive.
  • This invention generally relates to 4-aryl-isofiavanoids, and in particular to the use of such compounds in the field of gynecology.
  • An object of this invention is to provide novel and unobvious 4-aryl-isoflavanoids.
  • a still further object is to provide pharmaceutical compositions based on 4-aryl-isofiavanoids.
  • Still another object is to provide methods of administering 4-aryl-isoflavanoids to effect specific activities in mammals.
  • R represents H or alkyl of 1-3 carbon atoms
  • R and R being the same or dilferent, e'ach represents H, OH, alkoXy, or acyloxy, particularly alkanoyloxy of l-6 carbon atoms, and -OSO H, OPO H R and R being the same or different, each represents alkyl of respectively 1-4 carbon atoms, or R and R together with the N atom represent a 5- or 6-membered heterocyclic ring,
  • X and Y represent H or F
  • Z represents OH, alkoxy of 1-6 carbon atoms, NH or an alkylated amino group of 1-6 carbon atoms
  • n 2 or 3
  • physiologically compatible salts with acids or bases and the quaternary ammonium salts of these compounds.
  • the new isoflavanoids possess gonadotropininhibiting, contraceptive and/or ovulation-stimulating effects.
  • R is a protected OH group or R is reacted with an organometallic compound of Formula III R (III) wherein R is a protected OH group or R and M is Li or MgHal, wherein Hal is Cl, Br, or I;
  • Alkyl groups in the residue R can be methyl, ethyl, n-propyl, and isopropyl; alkoxy groups in the residues R R and Z can be, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, amyloxy, isoamyloxy, hexyloxy, isohexyloxy.
  • Acyloxy in the residues R or R can be, inter alia: formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, caproyloxy.
  • the group O(CH NH R preferably represents Z-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-dipropylaminoethoxy, 2 di-n-butylaminoethoxy, 2-pyrr0lidinoethoxy, 2- piperidinoethoxy, or also 2-morpholinoethoxy, or 2- (N-methylpiperazino)-ethoxy, furthermore 3 dimethylaminopropoxy, 3 diethylaminopropoxy, 3- piperidinopropoxy, or 3-morpholinopropoxy, as well as 3-pyrrolidinopropoxy.
  • Z can have, in addition to OH, alkoxy, and NH the following preferred meanings: methylamino, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino.
  • the residues R and R can also be OH groups present in protected form.
  • Protecting groups can be all those which can be split oif conventionally under hydrolyzing or hydrogenolyzing conditions.
  • preferred are benzyloxy, tetrahydropyranyloxy, and lower alkanoyloxy groups such as those mentioned above.
  • the 4-aryl-isofiavanoids of Formula I are obtainable by reacting isoflavanones of Formula II with organometallic compounds of Formula HI.
  • isoflavanones of Formula H the following are preferred:
  • Organometallic compounds of Formula III are preferably those derived from chlorobenzene, bromobenzene, iodobenzene, p-chloranisole, p-bromanisole, p-iodoanisole, p-chlorophenyl-(Z-diethylaminoethyl)-ether, p-bromophenyl-(Z-diethylaminoethyl)-ether, p-chlorophenyl-(Z- pyrrolidinoethyD-ether, p-bromophenyl-(2-pyrrolidinoethyl)ether, p-chlorophenylbenzyl-ether, p-bromophenylbenzyl-ether, p-iodophenylbenzyl-ether, pchlorophenyltetrahydropyranyl (2)-ether, p-bromophenyl-tetrahydropyranyl-(2)-
  • the reaction of an isofiavanone of Formula II with an organometallic compound of Formula III is conducted suitably in an inert solvent, such as ether, anisole, dibenzyl ether, dioxane, benzene, toluene, methylene chloride, or preferably tetrahydrofuran, or in mixtures of these solvents.
  • an inert solvent such as ether, anisole, dibenzyl ether, dioxane, benzene, toluene, methylene chloride, or preferably tetrahydrofuran, or in mixtures of these solvents.
  • a Lewis acid such as, for example, magnesium bromide
  • the ketone is added in a solution, or in solid form, to a solution of the organometallic compound in one of the above-mentioned solvents.
  • the reaction is in most cases exothermic; the reaction temperature ranges generally between 10 C. and +70 0., however is preferably room temperature.
  • the carbinols can be treated with dilute mineral acid, such as aqueous sulfuric acid, or aqueous hydrochloric acid, under warm conditions, or, for an extended period of time, under cold conditions.
  • water can be split off, for example treatment with formic acid, perchloric acid, p-toluenesulfonic acid, acetic acid, acetic anhydride, ptoluenesulfonic acid chloride, or with thionyl chloride, phosphorus oxychloride, methane sulfonic acid chloride, or methyl chlorosulfite in pyridine.
  • the dehydration step can be conducted in the presence of one of the customary inert solvents (for example, dioxane, tetrahydrofuran, methanol, or ether). It is also possible to do without an isolation of the carbinols.
  • the 4-aryl-3- isoflavenes of Formula IV are obtained directly if the working-up step of the Grignard reaction is conducted with dilute mineral acids under warm conditions.
  • the starting compounds of Formula II are obtainable by reacting desoxybenzoins of Formula V Ra OH with lower esters or orthoesters, preferably formic acid ethyl ester, orthoformic acid triethyl ester, or with a mixture of an alkali metal salt of a carboxylic acid and a corresponding carboxylic acid anhydride, for example, sodium acetate and acetic anhydride, or sodium propionate and propionic acid anhydride.
  • subsequently blocking of an OH-group in the 7-position can be conducted, preferably as the benzyl or tetrahydropyranyl ether, under the conditions of such ester condensation or blocking reactions known from the literature.
  • the desoxybenzoins of Formula V can be produced from phenols of Formula VI R OH and derivatives of phenylacetic acids of Formula VII HOOC-GHa- (VII) preferably the corersponding benzyl cyanides, in accordance with methods of the Friedel-Crafts or Hoesch Synthesis, or the Fries transportation reaction, known from the literature.
  • esterfied hydroxy groups can be hydrolyzed in a basic, neutral, or acidic medium.
  • the bases are principally aqueous, aqueous-alcoholic, or alcoholic sodium or potassium hydroxide, whereas the acids are preferably hydrochloric acid or sulfuric acid. If compounds of Formula II containing ester groups are employed a starting materials, the hydroxy groups can be liberated by hydrolysis after reaction with the organometallic compound III.
  • hydroxy groups ether-tied in the manner of an acetal can be acid hydrolyzed; benzyl ethers can be split hydrogenolytically, preferably with hydrogen on a platinum or palladium catalyst in the presence of an inert solvent, such as methanol, ethanol, ethyl acetate, or acetic acid.
  • an inert solvent such as methanol, ethanol, ethyl acetate, or acetic acid.
  • alkylate or acylate free hydroxy groups It is furthermore possible to alkylate or acylate free hydroxy groups.
  • esterification of a compound of Formula I wherein R and/ or R represent OCH COOH Etherification can be conducted, for example, by reaction with corresponding alkyl halogenides, sulfates, or lower alkyl esters in the presence of alkali, such as sodium or potassium hydroxide or carbonate.
  • alkali such as sodium or potassium hydroxide or carbonate.
  • one of the conventional inert solvents such as acetone or methylethyl ketone, can also be present.
  • the phenolic starting compounds can be reacted, for example, with methyl iodide, dirnethyl sulfate, ethyl, propyl, isopropyl, n-butyl, isobutyl, amyl, isoamyl, hexytl, or isohexyl halogenides, Z-dialkylaminoethyl halogenides, such as Z-dimethylaminoethyl, 2-diethylaminoethyl, Z-methylethylaminoethyl halogenides, 2-pyrrolidinoethyl, 2-piperidinoethyl, Z-morpholinoethyl, or 3- dialkylaminopropyll halogenides, such as 3 di-methylaminopropyl, 3-diethyl aminopropyl, 3-pyrroli dinopropyl
  • Suitable halogenides are the chlorides, bromides, tor iodides.
  • Such etherification processes are conducted, for example, in accordance with the principle of a Williamson Synthesis, the starting compounds being the corresponding alkali phenolates (sodium or potassium phenolates).
  • acidic catalysts such as sulfuric acid, phosphoric acid, or p-toluenesulfonic acid.
  • the residue -OCH COZ can be provided by etherification of the phenolic OH-groups with bromoacetic acid or chloroacetic acid or the derivatives thereof.
  • methyl and ethyl esters, amides, and dialkylamides such as, for example, methyl or ethyl chloroacetate, chloroacetamide, or N,N-diethylchloroacetarnide.
  • Acylation of the hydroxy groups can be carried out by heating with an anhydride or halogenide of such acids as acetic, propionic, butyric, isobutyric, valeric, isovaleric, or caproic acid.
  • the reaction is advantageously conducted in the presence of a base, such as pyridine, or an alkali salt of the corresponding acid, or also of a small quantity of a mineral acid, such as sulfuric acid or hydrochloric acid.
  • Phosphoric acid esters are advantageously obtained by esterification with phosphorus oxychloride in pyridine; and sulfuric acid esters are preferably produced by reaction with sulfamic acid or sulfur trioxide in pyridine and subsequent alkali hydrolysis.
  • esterification processes of carboxymethoxy groups are conducted in a conventional manner by reaction with the corresponding alcohol, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert.-butanol, amyl alcohol isoamyl alcohol, n-hexanol, or isohexanol, in the presence of an acid, for example, sulfuric acid, hydrochloric acid, or p-toluenesulfonic acid.
  • an acid for example, sulfuric acid, hydrochloric acid, or p-toluenesulfonic acid.
  • an additional inert solvent can be present, such as benzene, toluene, methylene chloride, or dichlorethane, the water which is formed being preferably distilled ofi azeotropically.
  • An esterification can also be accomplished, of course, likewise with diazoalkanes, for example diazomethane, in ether, tetrahydrofuran, or dioxane.
  • the carboxylic acid or carboxylic acid alkyl ester group can be converted into a carboxylic acid amide group 'by treatment with ammonia, ammonium salts, or alkyl or dialkylamines, if desired after previously converting the compound into the corresponding acid chloride or bromide.
  • These reactions can be conducted in the presence of an inert solvent, preferably in benzene or chloroform. However, it is also possible to employ an excess of the aminating agent as the solvent.
  • An amino derivative obtained according to the process of this invention can be converted into the acid addition salt thereof by an acid, in a conventional manner.
  • such acids are to be considered which yield physiologically acceptable salts.
  • organic and inorganic acids 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, diethylacetic 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, methanesulfonic acid, ethanedisulfonic acid, fi-hydroxyethanesulfonic acid, p-toluenesulfonic acid, naphthalenemonoand disulfonic acids, sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric, hydrobromic or hydriodic acids, or phosphoric acids, such as orthophosphoric acid, etc.
  • Isoflavanoids of Formula I containing basic groups such as, for example, amino or imino can be converted into their physiologically compatible quaternary ammonium compounds by treatment with alkylating agents, such as methyl iodide, dimethyl sulfate, or ethyl halogenides.
  • alkylating agents such as methyl iodide, dimethyl sulfate, or ethyl halogenides.
  • R and R being the same or different, are H, OH, OCH;,, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2 piperidinoethoxy, 2 pyrrolidinoethoxy, OSO H, OPO H or OCH COW,
  • W is OH, OCH OC H NH diethylamino, pyrrolidino, piperidino, or morpholino, and
  • Q, R, X, and Y have the previously indicated meanings, as well as the physiological acid addition salts of these compounds and the quaternary ammonium compounds thereof.
  • R1 is H, CH3, Or C2H5,
  • R is H, OH, or OCH
  • R is H, OH, or OCH
  • Q is OH
  • R is hydrogen
  • X and Y have the previously indicated meanings, as well as the physiological acid addition salts of these compounds and the quaternary ammonium compounds thereof;
  • R is H, OH, or OCT-I Q and R represent a ring C C bond
  • X and Y have the previously indicated meanings, as well as the physiological acid addition salts of these compounds and the quaternary ammonium compounds thereof.
  • Carrier substances can be such organic or inorganic substances suitable for parenteral, enteral, or topical application, and which of course do not deleteriously react with the novel compounds, such as, for example, water, vegetable oils, polyethylene glycols, gelatin, lactic sugar, amylose, magnesium stearate, talc, vaseline, cholesterol, etc.
  • parenteral application there are particularly suitable solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants.
  • suitable solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants.
  • enteral application there can furthermore be employed tablets, dragees, and the like.
  • salves, liniments, creams, and the like which are, if desired, sterilized or mixed with auxiliary agents such as preservatives, stabilizers, or wetting agents, or salts for influencing the osmotic pressure, or with buffer substances, can be employed.
  • the substances of the invention are preferably administered to mammals in a dosage of 0.1 to 500 mg., preferably 1 to mg., per unit dosage.
  • Ampoules are considered to bc a dosage unit for parenteral application.
  • tablets are considered unit dosages, said tablets usually being formulated with at least one carbohydrate. If a liquid is used for enteral application, a sweetened vehicle is customarily employed.
  • an ointment vehicle is to be used, said ointment vehicle being defined as a viscous to semi-solid vehicle of the kind customarily used in liniments, pastes, salves, and the like.
  • EXAMPLE 1 0.66 g. isofiavanone, dissolved in 30 ml. absolute benzene, are added dropwise to an ethereal Grignard solution of 0.23 g. magnesium and 2.2 g. p-bromo-anisole. The ether is distilled off, and the mixture is boiled for 16 hours. Then, the mixture is cooled, decomposed with 100 ml. 10% hydrochloric acid, and the benzene layer is separated; this benzene layer is washed with water, then with 10% solution of sodium hydroxide, and again with water, dried over sodium sulfate, and the solvent is removed. The thusobtained 4-anisyl-4-hydroxy-isofiavane is recrystallized from chloroform/ether, M.P. 144-145 C.
  • 4-hydroxy-isoflavanes are obtainable from the corresponding isoflavanones: 4- phenyl-, M.P. 121-123 C.; 4-phenyl-2'-fluoro-, 4-phenylphenyl-, M.P. l21l23 C.; 4-phenyl-2-fiuoro-,4-phenyl- 4-fluoro-, 4-phenyl-7-methoxy-, M.P. 151-152 C.; 2- methyl 4 phenyl 7 methoxy-, 2-ethyl-4-phenyl-7-methoxy-, two isomers having the respective melting points of 158 C.
  • EXAMPLE 2 0.68 g. isofiavanone, dissolved in 30 ml. absolute benzene, is mixed dropwise with an ethereal solution of 4 millimols of phenyl lithium. The mixture is further processed as described in Example 1. There is obtained 4- phenyl-4-hydroxy-isoflavane, M.P. 127-131" C.
  • EXAMPLE 3 As in Example 2, isofiavanone is reacted with phenyl lithium in benzene/ ether. The mixture is Worked up as in Example 1, but is heated, after the addition of the 10% hydrochloric acid, on the steam bath for 5 hours. In this manner, 4-phenyl-3-isoflavene is obtained having the melting point of 130l32 C. (from ether/ petroleum ether).
  • 3-isoflavenes are obtainable from the corresponding isoflavanones: 2-methyl-4- phenyl-, 2-ethyl-4-phenyl-, 4-phenyl-2'-fluoro-, 4-phenyl-4'- fiuoro, 4-phenyl-7-methoxy, 2 methyl-4-phenyl-7-methoxy-, Z-ethyl-4-phenyl-7-methoxy-, 4-phenyl-7-methoxy- 2-fiuoro-, 4-anisyl-, M.P.
  • EXAMPLE 4 (a) Analogously to Example 1, there is obtained from 7-(tetrahydropyranyl-(2)-oxy) isofiavanone and phenyl magnesium bromide, the 4-phenyl-4-hydroxy-7- (tetrahydropyranyl-(Z)-oxy)-isoflavane; however, the decomposition step is conducted with aqueous ammonium chloride solution in place of hydrochloric acid. A small quantity of 4-phenyl-4, 7-dihydroxy-isoflavane can be obtained from the sodium hydroxide washing solution by acidification and extraction.
  • 4-(p-hydroxyphenyl)-3-isoflavene (M.P. 188-189 C.) and the following derivatives thereof are obtainable: 2-methyl-, 2-ethyl-, 2-fluoro-, 4-fluoro-, 7-meth0Xy-, M.P. 118 C.; Z-methyl- 7-methoxy-, 2-ethyl-7-methoxy-, 7-methoxy-2-fluoro-, and 7-methoxy-4'-fluoro-.
  • EXAMPLE 5 (a) Analogously to Example 1, there is obtained from isoflavanone and p-benzyloxyphenyl-rnagnesium bromide, 4-(p-benzyloxyphenyl)-4-hydroxyisoflavane, MP. 122- 123 C.
  • 4-(p-benzyloxyphenyl)-4- hydroxy-isoflavanes are obtainable: 2-methyl-, Z-methyl- 7-methoxy-, 2-ethyl-, 2'-fluoro-, 4fluoro-, 7-methoxy-, 2-ethyl-7-methoxy- (two isomers having the melting point of 126 C. and 137 C., respectively), 7-methoxy-2'- fluoro-, and 7-methoxy-4'-fluoro-.
  • 4-(p-hydroxyphenyl)-4-hydroxy-isoflavane are heated with a mixture of 0.7 ml. concentrated sulfuric acid and 13 ml. dioxane for 5 hours on a steam bath. Then, the mixture is cooled, poured on ice, extracted with chloroform, and washed with water; the chloroform layer is dried over sodium sulfate, concentrated, and the thusobtained 4-(p-hydroxyphenyl)-3-isoflavene is recrystallized from ether/petroleum ether, M.P. 188-189 C.
  • EXAMPLE 7 1 g. 4-(p-hydroxyphenyl)-3-isoflavene and 4 g. 2- pyrrolidinoethyl chloride are boiled with 1.2 g. anhydrous potassium carbonate in 40 ml. absolute acetone for 20 minutes under stirring. The mixture is concentrated, water and ether are added thereto, and the layers are separated; the reaction solution is dried over potassium hydroxide, concentrated by evaporation, and chromatographed on aluminum oxide. With the aid of chloroform, 4-(p-pyrrolidinoethoxyphenyl)-3-isoflavene is eluated and subsequently recrystallized from acetone/ether; MP. 98- 99 C.
  • EXAMPLE 8 1 g. 4-phenyl-7-hydroxy-3-isofiavene is heated, together with ml. pyridine and 5 ml. acetic anhydride, for 5 hours to 50 C. After the mixture has been cooled oil, it is worked up in the usual manner with water and chloroform; there is obtained 4-phenyl-7-acetoxy-3-isofiavene.
  • 4-hydroxy-7- acetoxy-isoflavanes are obtained byacetylation of the corresponding hydroxy compounds: 4-phenyl-, 2-methy1-4- phenyl-, 2-ethyl-4-phenyl-, 4-anisyl-, 2-methyl-4-anisyl-, 2-ethyl-4-anisyl-, 4-(p-2-dimethylaminoethoxyphenyl)-, 2- methyl-4-(p-2-dimethylaminoethoxyphenyl)-, and Z-ethyl- 4-(p-2-dimethylaminoethoxyphenyl as well as the following 7-acetoxy-3-isoflavenes: Z-methyl- 4-phenyl-, 2-ethyl-4-phenyl-, 4-anisyl-, 2-methyl-4-anisyl-,
  • the sodium salts of the following 4,7- dihydroxy-isoflavane-7-sulfuric acid esters are obtainable: 4-phenyl-, 2-rnethyl-4-phenyl-, 2-ethyl-4-phenyl, 4-anisyl- 2-methyl-4-anisyl-, 2-ethyl-4-anisyl-, 4-(p-2-dimethylaminoethoxyphenyl 2-methyl-4- (p-2-dimethylaminoethoxyphenyl)-, and 2-ethyl-4-(p-2-dimethylaminoethoxyphenyl)-,
  • EXAMPLE 11 2 g. 4-phenyl-7-carbethoxymethoxy-3-isoflavene are boiled under reflux with 30 ml. 2 N ethanolic potassium hydroxide solution for 3 hours. Upon acidifying the solution with dilute sulfuric acid, 4-phenyl-7-carboxymethoXy-3-isofiavene is obtained.
  • hydrochloride instead of the hydrochloride, other physiologically oompatible salts of 4-(p-2-pyrrolidinoethoxy-phenyl)-7- methoxy-3-isoflavene or the free base itself can be incorporated into similar pharmaceutical preparations.
  • R and R each represents H, OH, alkoxy of l-6 carbon atoms, alkanoyloxy of l-6 carbon atoms, -O-(CH )nNR R OPO3H2, OI -OCH COZ,
  • R and R each represents alkyl of 1-4 carbon atoms, or R and R together with the N atom represent pyrrolidino, piperidino, morpholino, or piperazino,
  • R represents H or together with Q a ring carbon-tocarbon double bond
  • Z represents OH, alkoxy of 1-6 carbon atoms, -NH
  • alkyl portion is of 1-6 carbon atoms
  • R is alkyl of 1-3 carbon atoms; and (b) R is alkanoyloxy of 1-6 carbon atoms,
  • R and R being the same or different, are H, OH,
  • W is OH, OCH OC H NH diethylamino, pyrrolidino, piperidino, or morpholino.
  • R is H, CH or C H R is H, OH, or OCH R is H, OH, or OCH Q is OH,
  • R is hydrogen
  • a member as defined by claim 1 wherein said member is 4-phenyl-4-hydr0xy-7-methoxy-isoflavane.
  • a member as defined by claim 1 wherein said member is Z-ethyl 4-phenyl-4-hydr0xy-7-acetoxy-isoflavane.
  • a member as defined by claim 1 wherein said member is 4 (p-2-dimethylaminoethoxyphenyl)-4-hydr0xy-isoflavane.
  • a member as defined by claim 1 wherein said member is 4 (p-2-dimethylaminoethoxyphenyl)-4-hydroxy-7- methoxy-isofiavane.
  • a member as defined by claim 1 wherein said memher is 2 ethyl-4-(p-2-dimethy1aminoethoxyphenyl)-4-hydroxy-7-methoxy-isofiavane.
  • a member as defined by claim 1 wherein said member is 4 (p 2-diethylaminoethoxyphenyl)-4-hydr0xy-7- methoXy-isofiavane.
  • a member as defined by claim 1 wherein said member is 2 ethyl 4-(p-2-diethylaminoethoxyphenyl)-4-hydroxy-7-methoxy-isoflavane.
  • a member as defined by claim 1 wherein said member is 4 (p-2-pyrro1idinoethoxyphenyl)-4-hydroxy 7 methoxy-isoflavane.
  • a member as defined by claim 1 wherein said member is 2-ethyl 4-p-hydroxyphenyl-4-hydroxy-7-methoxyisofiavane.
  • a member as defined by claim 1 wherein said member is 4-phenyl-7-acetoxy-3-isoflavene.
  • a member as defined by claim 1 wherein said member is 2-ethyl-4-(p-2-dimethylaminoethoxyphenyl)-7acetoxy-3-isoflavene.

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SE (1) SE350040B (sh)

Cited By (26)

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US4053626A (en) * 1973-03-13 1977-10-11 Merck Patent Gesellschaft Mit Beschrankter Haftung Cholesterol level-lowering phenoxyacetic acids
US4093631A (en) * 1975-06-03 1978-06-06 Beecham Group Limited 7-Aminopropoxy chromane and chromenes
US4133883A (en) * 1975-06-03 1979-01-09 Beecham Group Limited Polycyclic chromenes useful as antidepressants and anorexics
WO1993010741A2 (en) * 1991-12-02 1993-06-10 Endorecherche Inc. Sex steroid activity inhibitors
US5254568A (en) * 1990-08-09 1993-10-19 Council Of Scientific & Industrial Research Benzopyrans as antiestrogenic agents
US5389646A (en) * 1993-12-30 1995-02-14 Zymogenetics, Inc. Methods for treatment and prevention of bone loss using 2,3-benzopyrans
US5686465A (en) * 1988-10-31 1997-11-11 Endorecherche Inc. Sex steroid activity inhibitors
US6060503A (en) * 1991-12-02 2000-05-09 Endorecherche, Inc. Benzopyran-containing compounds and method for their use
EP1153020A1 (en) * 1999-02-15 2001-11-14 Novogen Research Pty. Ltd. Production of isoflavone derivatives
US20020035074A1 (en) * 1997-05-01 2002-03-21 Novogen, Inc. Treatment or prevention of menopausal symptoms and osteoporosis
US20030018060A1 (en) * 1996-08-30 2003-01-23 Novogen Research Pty Limited Therapeutic methods and compositions involving isoflavones
US20030078214A1 (en) * 1992-05-19 2003-04-24 Novogen Research Pty. Ltd. Dietary supplements comprising soy hypocotyls containing at least one isoflavone
US6599536B1 (en) 1998-03-26 2003-07-29 Novogen Research Pty Ltd Therapy of estrogen-associated disorders
US20030157225A1 (en) * 2000-01-21 2003-08-21 Husband Alan James Food product and process
US20040106595A1 (en) * 2001-01-24 2004-06-03 Maurizio Delcanale 2H-1-benzopyran derivatives processes for their preparation and pharmaceutical compositions thereof
US20040147551A1 (en) * 1999-09-06 2004-07-29 Novogen Research Pty Ltd. Compositions and therapeutic methods involving isoflavones and analogues thereof
US20040152761A1 (en) * 2001-03-08 2004-08-05 Andrew Heaton Dimeric isoflavones
US20050036962A1 (en) * 1997-12-24 2005-02-17 Novogen Research Pty. Ltd. Compositions and method for protecting skin from UV induced immunosuppression and skin damage
US20050119301A1 (en) * 2001-03-16 2005-06-02 Alan Husband Treatment of restenosis
US7033621B1 (en) 1997-04-28 2006-04-25 Novogen, Inc. Isoflavone compositions produced from legumes
JP2008513376A (ja) * 2004-09-21 2008-05-01 ノボジェン リサーチ ピーティーワイ リミテッド 置換クロマン誘導体、医薬品、および治療における使用
US20090233999A1 (en) * 1999-09-06 2009-09-17 Novogen Research Pty Ltd Compositions and therapeutic methods involving isoflavones and analogues thereof
US20090317490A1 (en) * 2004-09-21 2009-12-24 Novogen Research Pty Ltd. Substituted chroman derivatives, medicaments and use in therapy
US8461361B2 (en) 2004-09-21 2013-06-11 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies

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US3142682A (en) * 1961-11-21 1964-07-28 Ciba Geigy Corp Tertiary amino derivatives of chromans and homo-chromans
US3340276A (en) * 1964-04-01 1967-09-05 Ciba Geigy Corp 3, 4-diphenyl-chromans
US3340277A (en) * 1964-06-24 1967-09-05 Ciba Geigy Corp Phenyl-chromenes

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4053626A (en) * 1973-03-13 1977-10-11 Merck Patent Gesellschaft Mit Beschrankter Haftung Cholesterol level-lowering phenoxyacetic acids
US4093631A (en) * 1975-06-03 1978-06-06 Beecham Group Limited 7-Aminopropoxy chromane and chromenes
US4133883A (en) * 1975-06-03 1979-01-09 Beecham Group Limited Polycyclic chromenes useful as antidepressants and anorexics
US5395842A (en) * 1988-10-31 1995-03-07 Endorecherche Inc. Anti-estrogenic compounds and compositions
US5840735A (en) * 1988-10-31 1998-11-24 Endorecherche Inc. Sex steroid activity inhibitors
US5686465A (en) * 1988-10-31 1997-11-11 Endorecherche Inc. Sex steroid activity inhibitors
US5254568A (en) * 1990-08-09 1993-10-19 Council Of Scientific & Industrial Research Benzopyrans as antiestrogenic agents
WO1993010741A3 (en) * 1991-12-02 1994-02-03 Endorecherche Inc Sex steroid activity inhibitors
US6060503A (en) * 1991-12-02 2000-05-09 Endorecherche, Inc. Benzopyran-containing compounds and method for their use
WO1993010741A2 (en) * 1991-12-02 1993-06-10 Endorecherche Inc. Sex steroid activity inhibitors
US20040048812A1 (en) * 1992-05-19 2004-03-11 Novogen Research Pty. Ltd. Health supplement
US20070179099A1 (en) * 1992-05-19 2007-08-02 Novogen Research Pty Ltd. Methods of cholesterol reduction using isoflavones
US7045155B2 (en) 1992-05-19 2006-05-16 Novogen Research Pty Ltd. Dietary supplements comprising soy hypocotyls containing at least one isoflavone
US6987098B2 (en) 1992-05-19 2006-01-17 Novogen Research Pty. Ltd. Health supplement
US20030078214A1 (en) * 1992-05-19 2003-04-24 Novogen Research Pty. Ltd. Dietary supplements comprising soy hypocotyls containing at least one isoflavone
USRE40792E1 (en) 1992-05-19 2009-06-23 Novogen Research Pty Ltd Health supplements containing phyto-oestrogens, analogues or metabolites thereof
US20040106561A1 (en) * 1992-05-19 2004-06-03 Novogen Research Pty. Ltd. Health supplement
US5389646A (en) * 1993-12-30 1995-02-14 Zymogenetics, Inc. Methods for treatment and prevention of bone loss using 2,3-benzopyrans
US20050059616A1 (en) * 1996-08-30 2005-03-17 Kelly Graham Edmund Therapeutic methods and compositions involving isoflavones
US20030018060A1 (en) * 1996-08-30 2003-01-23 Novogen Research Pty Limited Therapeutic methods and compositions involving isoflavones
US7202273B2 (en) 1996-08-30 2007-04-10 Novogen Research Pty Ltd Therapeutic methods and compositions involving isoflavones
US7033621B1 (en) 1997-04-28 2006-04-25 Novogen, Inc. Isoflavone compositions produced from legumes
US20020035074A1 (en) * 1997-05-01 2002-03-21 Novogen, Inc. Treatment or prevention of menopausal symptoms and osteoporosis
US20050036962A1 (en) * 1997-12-24 2005-02-17 Novogen Research Pty. Ltd. Compositions and method for protecting skin from UV induced immunosuppression and skin damage
US6599536B1 (en) 1998-03-26 2003-07-29 Novogen Research Pty Ltd Therapy of estrogen-associated disorders
US20080038387A1 (en) * 1998-03-26 2008-02-14 Novogen Research Pty Ltd Therapy of estrogen-associated disorders
EP1153020A4 (en) * 1999-02-15 2002-08-21 Novogen Res Pty Ltd PREPARATION OF ISOFLAVONE DERIVATIVES
EP1153020A1 (en) * 1999-02-15 2001-11-14 Novogen Research Pty. Ltd. Production of isoflavone derivatives
US7488494B2 (en) 1999-09-06 2009-02-10 Novogen Research Pty Ltd. Compositions and therapeutic methods involving isoflavones and analogues thereof
US20040147551A1 (en) * 1999-09-06 2004-07-29 Novogen Research Pty Ltd. Compositions and therapeutic methods involving isoflavones and analogues thereof
US20060106220A1 (en) * 1999-09-06 2006-05-18 Novogen Research Pty. Ltd. Compositions and therapeutic methods involving isoflavones and analogues thereof
US20090233999A1 (en) * 1999-09-06 2009-09-17 Novogen Research Pty Ltd Compositions and therapeutic methods involving isoflavones and analogues thereof
US20030157225A1 (en) * 2000-01-21 2003-08-21 Husband Alan James Food product and process
US6951883B2 (en) * 2001-01-24 2005-10-04 Chiesi Farmaceutici S.P.A. 2H-1-benzopyran derivatives processes for their preparation and pharmaceutical compositions thereof
US20040106595A1 (en) * 2001-01-24 2004-06-03 Maurizio Delcanale 2H-1-benzopyran derivatives processes for their preparation and pharmaceutical compositions thereof
US20040152761A1 (en) * 2001-03-08 2004-08-05 Andrew Heaton Dimeric isoflavones
US20050119301A1 (en) * 2001-03-16 2005-06-02 Alan Husband Treatment of restenosis
US9198895B2 (en) 2004-09-21 2015-12-01 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US20090317490A1 (en) * 2004-09-21 2009-12-24 Novogen Research Pty Ltd. Substituted chroman derivatives, medicaments and use in therapy
US8084628B2 (en) 2004-09-21 2011-12-27 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8461361B2 (en) 2004-09-21 2013-06-11 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8697891B2 (en) 2004-09-21 2014-04-15 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8957109B2 (en) 2004-09-21 2015-02-17 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US9138478B2 (en) 2004-09-21 2015-09-22 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
JP2008513376A (ja) * 2004-09-21 2008-05-01 ノボジェン リサーチ ピーティーワイ リミテッド 置換クロマン誘導体、医薬品、および治療における使用
US9381186B2 (en) 2004-09-21 2016-07-05 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US9708283B2 (en) 2010-11-01 2017-07-18 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9981936B2 (en) 2010-11-01 2018-05-29 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10105346B2 (en) 2010-11-01 2018-10-23 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10369132B2 (en) 2010-11-01 2019-08-06 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10973799B2 (en) 2010-11-01 2021-04-13 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US11583514B2 (en) 2010-11-01 2023-02-21 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US11723893B2 (en) 2010-11-01 2023-08-15 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies

Also Published As

Publication number Publication date
GB1102987A (en) 1968-02-14
DE1518002B2 (de) 1974-04-11
DK111268B (da) 1968-07-15
DE1518002C3 (de) 1975-01-23
SE350040B (sh) 1972-10-16
DE1518002A1 (de) 1969-06-19
CH469697A (de) 1969-03-15
BR6576150D0 (pt) 1973-09-06
FR5046M (sh) 1967-05-02
BE674534A (sh) 1966-06-30
IL24787A (en) 1969-11-30
NL6517021A (sh) 1966-07-04

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