US3471520A - 4-aryl-isoflavanoids - Google Patents

Description

United States Patent O 3 7 Int. Cl. C07d 7/119, 27/00, 87/50 US. Cl. 260345.2 30 Claims ABSTRACT OF THE DISCLOSURE For effecting a relatively low estrogenic activity and a relatively high anti-fertility eflect, there are provided compounds of the following formula, physiologically compatible acid addition salts thereof and quaternary ammonium compounds thereof:

Q g Y wherein 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,

or together with a nitrogen atom a heterocyclic 5- or 6-membered ring,

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, therefore, is to provide novel and unobvious 4-aryl-isoflavanoids.

Other objects are to provide one or more processes for producing isoflavanoids, and to provide novel and valuable intermediates for use in such processes.

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.

3,471,520 Patented Oct. 7, 1969 Upon further study of the specification and claims, other objects and advantages of the present invention will become apparent.

To attain the objects of this invention, there are provided 4-aryl fiavanoids of Formula I, as follows:

wherein 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,

Q represents OH or, together with R, a ring C=C double bond,

R represents H or, together with Q, a ring C=C double bond,

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, and

n represents 2 or 3, as Well as the physiologically compatible salts with acids or bases, and the quaternary ammonium salts of these compounds.

These compounds possess only a minor estrogenic activity, but exhibit at the same time a good anti-fertility effect, which has not been found as yet in any compound of the isoflavanoid type. Thus, when tested according to a method similar to that described in Journal of Reproduction and Fertility, volume 5, page 239 (1963) 4-[p-(2- pyrrolidinoethoxy) phenyl] 7 methoxy-3-isoflavene-hydrochloride (applied orally in a concentration of 1 mg./ 100 g. to rats) exhibited a 100% anti-fertility effect and simultaneously a 33% estrogenic efliect (when tested in the same concentration in the Allen-Doisy-test). Under the same conditions, the known l-{2-[p-(3,4-dihydro-6- methoxy 2 phenyl-l-naphthyl)-phenoxy]-ethyl}-pyrrolidine-hydrochloride showed a 100% anti-fertility effect and a estrogenic efiect.

Moreover, the new isoflavanoids possess gonadotropininhibiting, contraceptive and/or ovulation-stimulating effects.

To produce 4-aryl-fiavanoids of Formula I, as well as the physiologically compatible salts thereof with acids or bases, and the quaternary ammonium salts thereof, a process is provided comprising the following steps:

(A) an isofiavanone of Formula II o R. R; X

wherein 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;

(B) the thus-obtained products are subsequently optionally treated with agents which split off water, and/ or one or both residues R and R7 are optionally converted into the residues R and R in such a manner that (1) protected hydroxy groups are liberated by treatment with hydrolyzing or hydrogenolyzing agents,

(2) or free hydroxy groups are alkylated or acylated by treatment with alkylating or acylating agents,

(3) or a carboxylic acid or carboxylic acid alkyl ester group is converted into a carboxylic acid amide group by treatment with aminating agents,

(C) and/or that optionally compounds of Formula I are converted, by treatment with acids or bases, or alkylating agents, respectively, into the physiologically compatible salts or quaternary ammonium compounds, respectively.

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. In this connection, 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. As the isoflavanones of Formula H, the following are preferred:

oro-, 2-methyl-7-(tetrahydropyranyl-(2)-oxy)-2'-fluoro-, 2-ethyl-7- (tetrahydropyranyl- (2 -oxy) -2'-fluoro-, 7- (tetrahydropyranyl-(Z)-oxy-4-fiuoro-, 2-methyl-7-(tetrahydropyranyl- (2) -oxy -4'-fluoro-, 2-ethyl-7- (tetrahydropyranyl- (2)-oxy)-4-fiuoro-isoflavanone.

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)-ether, p-iodophenyl-tetrahydropyranyl-(2)- ether.

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. In some cases, the addition of a Lewis acid, such as, for example, magnesium bromide, suitable for complex formation, is advantageous. Normally, 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. For terminating the reaction, the reaction mixture can additionally be heated for a period of time until the solvent used is boiling.

After the reaction is terminated, the reaction product is hydrolyzed, if desired after the solvent has been evaporated and recovered. If the hydrolysis is conducted with water or under acidic conditions, for example with the aid of aqueous ammonium chloride solution or dilute hydrochloric acid in the cold state, normally no water is split off, and there are obtained the carbinols of Formula I (Q =OH, R=H).

In contradistinction thereto, if it is desired to obtain the dehydration products of Formula 1V it is possible to dehydrate the carbinols of Formula I (Q=0H, R=H). This can be done by treatment with acids under mild conditions. For example, 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. It is also possible to employ other conventional processes by which 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. For example, 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. If desired, 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.

In a compound of Formula I, it is possible to convert one or both residues R and R into residues R and R (which are different from R and R respectively). Such conversions can basically be conducted according to methods which are known or described in the literature.

Thus, it is possible to liberate protected hydroxy groups by hydrolysis or hydrogenolysis. For example, 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. Likewise, 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.

It is furthermore possible to alkylate or acylate free hydroxy groups. As a special case of an alkylation, attention is directed to the 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. In this connection, one of the conventional inert solvents, such as acetone or methylethyl ketone, can also be present.

An important reaction is the conversion of phenolic hydroxy groups into substituents of the formula correspondingly, 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, 3-piperidinopropyl, 3-morpholinopropyl halogenides, or with the corresponding alcohols. 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). However, it is likewise possible to react the free phenols with the corresponding alcohols, or substituted aminoalcohols in the presence of 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. In addition to the free acids, particularly suitable for this purpose are the corresponding 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.

The 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. In this reaction, 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.

In a compound of Formula I wherein R and/or R represent OCH COOH or -OCH COOAlkyl, 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. For this reaction, such acids are to be considered which yield physiologically acceptable salts. Thus, there can be used 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.

Alternatively, it is possible to convert such compounds of Formula I wherein R and/or R are OSO H or OPO H by conventional treatment with a base, into the metallic or ammonium salt thereof. For these reactions, all bases can be utilized yielding physiologically acceptable salts. Thus, organic or inorganic bases, such as, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, as Well as the corresponding carbonates can be used, and further ammonia, mono-, di-, and triethanolamine.

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.

According to the invention, the following groups of compounds are preferred, referring to Formula I:

Compounds wherein 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.

Particularly valuable are compounds of the following groups, referring again to Formula 1:

Compounds wherein R is H, CH or C H R is H, OH, OCH Z-dimethylaminoethoxy, 2-diethylaminoethoxy, Z-piperidinoethoxy, or 2-pyrrolidinoethoxy, and

Q, R, W, 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;

Compounds wherein R1 is H, CH3, Or C2H5,

R is H, OH, or OCH R is H, OH, or OCH Q is OH,

R is hydrogen, and

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;

Compounds wherein R2 is H, OH, Or OCH3,

R is H, OH, or OCT-I Q and R represent a ring C C bond, and

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.

The compounds of this invention can be employed in mixture with conventional pharmaceutical excipients used in the human or veterinary medicine. 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.

For parenteral application, there are particularly suitable solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. For enteral application there can furthermore be employed tablets, dragees, and the like. For topical application, 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. With respect to enteral 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. For topical administration, 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.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the specification and claims in any way whatsoever.

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.

Analogously, the following 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. and C.; 4-phenyl-7-methoxy-2-fluoro-, 2- rnethyl-4-anisyl-, 2-ethyl-4-anisyl-, 4-anisyl-2-fluoro-, 4- anisyl-4-fiuoro-, 4-anisyl-7-methoxy, 2-methyl-4-anisyl-7- methoxy-, 2-ethyl-4-anisyl-7-methoxy-, M.P. IDS-106 C. and 4-anisyl-7-methoxy-2-fluor0-4-hydroxy-isoflavane.

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).

Analogously, the following 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. 1l9121 C.; 2-'metl1yl-4.-anisyl, 2-ethyl-4-anisyl-, 4-anisyl-2fluoro-, 4-anisyl-4-fiuoro-, 4- anisyl-7-methoxy-, M.P. 162165 C.; 2-methyl-4- anisyl- 7-methoxy-, 2-ethyl-4-anisyl-7-methoxy-, and 4-anisy1-7 methoxy-2-fluoro-3-isoflavene.

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.

Analogously, the following 4-hydroxy-7-(tetrahydropyranyl-(Z)-oxy)-isoflavanes are obtainable from the corresponding isoflavanones: 2-methyl-4-phenyl-, 2-ethyl- 4.-phenyl-, 4-anisyl-, 2-methyl-4-anisyl-, and 2-ethyl-4- anisyl 4 hydroxy 7 (tetrahydropyranyl (2) oxy)- isoflavane.

Analogously, there are obtainable from p-(tetrahydropyranyl-(2)-oxy)-phenyl-magnesium bromide and the corresponding isollavanones, 4-(p-tetrahydropyranyl-(2)- oxy)-4-hydroxy-isofiavane and the following derivatives thereof: 2-methyl-, 2-ethyl-, 2'-fluoro-, 4-fluoro-, 7- methoxy-, 2-methyl-7-methoxy-, 2-ethyl-7-methoxy-, 7- methoxy-2-fluoro-, and 7-methoxy4-fluoro-.

(b) 2 g. 4-phenyl-4-hydroxy-7-(tetrahydropyranyl-(2)- oxy)-isoflavane are boiled under reflux for 2 /2 hours in 50 ml. aqueous-ethanolic hydrochloric acid. After cooling, the mixture is worked up in the usual manner with chloroform and water, 4-phenyl-7-hydroxy-3-isoflavene being obtained.

Analogously, the following 7-hydroxy-3-isoflavenes are obtainable: 2-methyl-4-phenyl-, 2-ethyl-4-phenyl-, 4-anisyl-, 2-methyl-4-anisyl-, and 2-ethyl-4-anisyl-.

Likewise in an analogous manner, 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.

Analogously, the following 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-.

The following 4-hydroxy-7-benzyloXy-isoflavanes are obtainable from the corresponding 7-benzyloxy-isoflavanones: 4-phenyl-, 2-methyl-4-phenyl-, 2-ethyl-4-phenyl-, 4-anisyl-, 2-methyl-4-anisyl-, and 2-ethyl-4-anisyl-.

(b) 2 g. 4-(p-benzyloxyphenyl)-4-hydroxy-isoflavane are dissolved in 200 ml. ethyl acetate and agitated, on 5% palladium charcoal at room temperature and normal pressure, with hydrogen. The reaction solution is filtered off, concentrated, and chromatographed on silica gel. By eluation with benzene, amorphous 4-(p-hydroxyphenyl)- 4-hydroxy-isoflavane is obtained which is immediately processed further.

Analogously, the following 4-(phydroxyphenyl)-4- hydroxy-isoflavanes are obtained by hydrogenolysis of the 10 corresponding benzyloxy compounds: 2-methyl-, 2-ethyl-, 2'-fluoro-, 4'-fiuoro-, 7-methoxy-, M.P. 173 C.; 2-methyl- 7-methoxy-, 2-ethyl-7-methoxy- (two isomers, M.P. 112 C. and ISO-152 C., respectively), 7-methoxy-2'-fluoro-, and 7-methoxy-4-fluoro-.

as well as the following 4,7-dihydroxy-isofiavanes: 4- phenyl-, 2-methyl-4-phenyl-, 2-ethyl-4-phenyl-, anisyl-, 2-methyl-4-anisyl-, 2-ethyl-4-anisyl-, 4-(p-2-dimethylaminoethoxyphenyl 2-methyl-4- (p-2-dimethylaminoethoxyphenyl)-, 2-ethyl-4-( p 2 dimethylaminoethoxyphenyl)-, 4-(p-2-diethylaminoethoxyphenyl)- 2-methyl-4- (p-Z-diethylarninoethoxyphenyl)-, and 2-ethyl-4-(p-2- diethylaminoethoxyphenyl (c) 0.99 g. 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.

In an analogous manner, the following 7-hydroxy-3- isoflavenes are obtainable from the corresponding 4,7-dihydroxy-isoflavanes:

4- (p-2-dimethylaminoethoxyphenyl 2-methy1-4-(p-Z-dimethylaminoethoxyphenyl)-, and 2-ethyl-4- (p-2-dimethylaminoethoxyphenyl) EXAMPLE 6 and the following 4-hydroxy-7-carbomethoxymethoxyisoflavanes: 4-phenyl-, 2-methyl-4-phenyl-, 2-ethyl-4- phenyl-, 4-anisyl-, 2-methyl-4-anisyl-, and 2-ethyl-4- anisyl-.

Also analogously obtainable are the following 7- carbethoxymethoxy-3-isofiavenes: 2-methyl-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 and the following 7-carbomethoxymethoxy-3-isofiavenes: 4-phenyl-, 2-methyl-4-phenyl-, 2-ethyl-4-phenyl-, 4-anisyl, 2-methyl-4-anisyl-, and 2-ethyl-4-anisyl-.

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.

Analogously, the following 4-hydroxy-isoflavanes are obtainable from the corresponding dihydroxy compounds:

4- (p-2-dimethylaminoethoxyphenyl) 2-methyl-4- (p-2-dimethylaminoethoxyphenyl 2-ethyl-4- (p-2-dimethylarninoethoxyphenyl) 4-(p-2-dimethylaminoethoxyphenyl)-2'-fluoro-,

4-(p-2-dimethylaminoethoxyphenyl)-4-fiuoro-,

4-( p-2-dimethylaminoethoxyphenyl) -7-methoxy-,

2-methy1 4 (p 2 dimethylaminoethoxyphenyl) 7 methoxy-,

2-ethyl-4- (p-2-dimethylaminoethoxyphenyl -7-rnethoxy-,

4- (p-2-dimethylaminoethoxyphenyl)-7-methoxy-2-fiuoro-,

4 (p-2 dimethylaminoethoxyphenyl) 7 (tetrahydropy i y),

2-methyl-4- (p-2-dirnethylaminoethoxyphenyl) -7- ({tetrahydropyranyl- 2 -oxy 2-ethyl-4-(p-2-dimethylaminoethoxyphenyl) 7 (tetrahydropyranyl- (2) -oxy) 4-(p-Z-diethylaminoethoxyphenyl)-,

2-rnethyl-4- (p-2-diethylaminoethoxyphenyl) 2-ethyl-4- (p-Z-diethylaminoethoxyphenyl 4- p-2-diethylaminoethoxyphenyl -7-rnethoxy-,

2-methyl-4- (p-2-diethylaminoethoxyphenyl -7-methoxy-,

2-ethyl-4- (p-2-diethylaminoethoxyphenyl -7-methoxy-,

4-(p-2-pyrrolidinoethoxyphenyl)-,

2-methyl-4-(p-2-pyrrolidinoethoxyphenyl)-,

2-ethyl-4- (p-2-pyrrolidinoethoxyphenyl 4- (p-2-pyrrolidinoethoxyphenyl -7-methoxy-,

Z-methyl 4-(p-2-pyrrolidinoethoxyphenyl) 7 methoxy-,

and

2-ethyl-4- (p-2-pyrrolidinoethoxyphenyl -7-methoxy-,

and the following 3-isofiavenes:

4-(p-Z-dirnethylaminoethoxyphenyl)-,

2-methyl-4- (p-2-dimethylaminoethoxyphenyl) 2-ethyl-4-(p-2-dimethy1aminoethoxyphenyl)-,

4- p-2-din1ethy1aminoethoxyphenyl) -2-fluoro-,

4-( p-2-dimethylaminoethoxyphenyl -4-fluoro-,

4- (p-2-dimethylaminoethoxyphenyl) -7-methoxy-,

2 methyl 4 (p 2 dimethylaminoethoxyphenyl) 7 methoxy-,

2-ethyl-4- (p-2-dimethylaminoethoxyphenyl) -7-methoxy-,

4 (p 2 dimethylaminoethoxyphenyl) 7 methoxy-2- fiuoro-,

4 (p 2 dimethylaminoethoxyphenyl) 7 (tetrahydropv y y)-,

2-methyl-4-(p-2-din1ethylaminoethoxyphenyl) -7-(tetrahydropyranyl- (2 oxy) 2-ethyl-4-(p-2-dimethylaminoethoxyphenyl) 7 (tetrahydropyranyl- (2 -oxy) 4- (p-2-diethylaminoethoxyphenyl) 2-rnethyl-4- (p-2-diethylaminoethoxyphenyl) 2-ethyl-4- p-Z-diethylaminoethoxyphenyl 4- (p-2-diethylaminoethoxyphenyl -7-methoXy-,

2-methyl-4- (p-2-diethylaminoethoxyphenyl) -7-methoxy-,

2-ethyl-4- (p-2-diethylaminoethoxyphenyl -7-methoxy-,

2-rnethyl-4- (p-2-pyrrolidinoethoxyphenyl 2-ethyl-4- (p-2-pyrrolidinoethoxyphenyl 4- p-Z-pyrrolidinoethoxyphenyl) -7-methoxy-,

2-methyl-4- (p-2-pyrrolidinoethoxyphenyl) -7-methoxy-,

and

2-ethyl-4-(p-2-pyrrolidinoethoxyphenyl -7-meth0xy-.

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.

In an analogous manner, the following 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-,

1 2 4- (p-Z-dimethylaminoethoxyphenyl) and 2- EXAMPLE 9 7.8 g. 4-phenyl-7-hydroxy-3-isoflavene, dissolved in 105 ml. pyridine, are added to a solution of 21 ml. phosphorus oxychloride in 210 ml. absolute yridine, this being done under stirring at 5 C. within 15 minutes. The mixture is allowed to stand overnight at room temperature, and is then poured onto a mixture of 3 kg. ice and 300 ml. concentrated hydrochloric acid; this mixture is heated for minutes on a steam bath. After cooling, the reaction solution is extracted with ethyl acetate, the extracts are washed with 1 N hydrochloric acid, dried with sodium sulfate, filtered, and evaporated to dryness. There is obtained 4-phenyl-7-hydroxy-3-isoflavene-7-orthophosphate.

Analogously, the following 4,7-dihydroxy-isoflavane- 7-orthophosphates are obtained: 4-phenyl-, 2-methyl-4- pheny1-, 2-ethyl-4-phenyl, 4-anisyl-, 2-methyl-4-anisyl-, 2-ethyl-4-anisyl, 4-(p-Z-dimethylaminoethoxyphenyl)-, 2-methyl-4-(p-2-dimethylarninoethoxyphenyl)-, and 2- ethyl-4- (p-2-dimethylaminoethoxyphenyl) as well as the following 7-hydroxy-3-isofiavene-7-orthophosphates: 2-methyl-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 10 Under stirring, there are suspended at 90 C. in 45 ml. absolute pyridine 6 g. sulfamic acid and then 7.5 g. 4- phenyl-7-hydroxy-3-isofiavene. The suspension is stirred for 90 minutes on a steam bath, cooled, filtered, washed with pyridine, and the filtrate is mixed with several separate portions of absolute ether and decanted. The residue is dried under vacuum, mixed with 75 ml. 12% solution of sodium hydroxide and 53 ml. pyridine, and agitated for 5 minutes. The (upper) pyridine phase is washed several times with ether, then diluted with methanol, and evaporated to dryness. The sodium salt of 4-phenyl-7- hydroxy-3-isofiavene-7-sulfate is recrystallized from methanol.

Analogously, 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)-,

as well as the following 7-hydroxy-3-isofiavene-7-sulfuric acid ester sodium salts: 2-methyl-4-phenyl-, 2-ethyl'4- phenyl-, 4-anisyl-, 2-rnethyl-4-anisyl-, 2-ethyl-4-anisyl-, 4-(p-2-dimethylaminoethoxyphenyl)-, 2Fmethyl-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.

By saponifying the other esters described in Example 6, the following 4-hydroxy-7-carboxymethoxy-isoflavanes are analogously obtainable: 4-phenyl-, 2-methyl-4-phenyl, 2-ethyl-4-phenyl-, 4-anisyl-, 2-methyl-4-anisyl-, 2-ethyl-4- anisyl-,

as well as the following 7-carboxymethoxy-3-isoflavenes: 4-phenyl-, 2-methyl-4-phenyl-, 2-ethyl-4-phenyl-, 4-anisyl-, 2-methyl-4-anisyl-, and 2-ethyl-4-anisyl'.

13 EXAMPLE 12 and the following 7-diethylcarbamoyl-methoxyand 7- pyrrolidino-carbonyl=methoxy-3-isoflavenes: 2-methyl-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 13 2 g. 4(p-2-dimethylaminoethoxyphenyl)-3-isoflavene are dissolved in a small amount of ethanol and mixed with an excess of ethanolic hydrochloric acid. The hydrochloride of the base which precipitates is isolated by filtration.

= EXAMPLE 14 0.5 g. 4-(p-2-dimethylaminoethoxyphenyl)3-isoflavene is dissolved in ether and mixed with an excess of methyl iodide. The reaction mixture is allowed to stand for 24 hours at room temperature, and is then vacuum-filtered; the thus-obtained methoiodide is purified by crystallization from methanol.

The following examples are such for suitable pharmaceutical compositions which can be prepared according to conventional procedures.

EXAMPLE A Tablets: Mg. 4 (p 2 pyrrolidinoethoxy-phenyl)-7-methoxyisoflavene-hydrochloride Lactose 6'0 Highly dispersed silicium dioxide Wheat starch 55 Arrowroot 18 Magnesium stearate 2 Talc 8 EXAMPLE B Coated tablets: Mg. 4 (p 2 pyrrolidinoethoxy-phenyl)-7-methoxyisofiavene-hydrochloride Lactose 90 Tale 5 The coating consists of a mixture of sugar, talc, wheat starch, and tragacanth and weighs about 100 mg.

EXAMPLE C Solution for injections A solution of 1 part 4-(p-Z-pyrrolidinoethoxy-phenyl)- 7-methoxy-isofiavene-hydrochloride in 999 parts of disstilled water is prepared and filled into 1 ml. ampoules in such a manner that each ampoule contains 1 mg. of the active ingredient.

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.

Instead of 4-(p-Z-pyrrolidinoethoxy-phenyl)-7-methoxy-3-isofiavene, other compounds of Formula I as described above as well as their physiologically compatible salts can be used.

The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Consequently, such changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of the following claims.

What is claimed is:

1. A member selected from the group consisting of a compound of the following formula, a physiologically compatible acid addition salt thereof, and a quaternary ammonium compound thereof:

wherein R is H or alkyl of 1-3 carbon atoms,

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,

Q represents OH or together with R a ring carbon-tocarbon double bond,

R represents H or together with Q a ring carbon-tocarbon double bond,

X and Y each represents H or F,

Z represents OH, alkoxy of 1-6 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, with the provision that Q and R together represent a ring, carbonto-carbon double bond only when one or more of the following conditions exists:

(a) R is alkyl of 1-3 carbon atoms; and (b) R is alkanoyloxy of 1-6 carbon atoms,

-OSO3H, OPOgH 0r 2. A member as defined by claim 1, wherein Q represents'OH and R represents H.

3. A member as defined by claim 2, wherein R and R being the same or different, are H, OH,

-OCH 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-piperidinoethoxy, 2-pyrrolidinoethoxy, --OSO H, OPO H 0r -OCH COW, W is OH, OCH OC H NH diethylamino, pyrrolidino, piperidino, or morpholino.

4. A compound as defined by claim 1 wherein 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, and

X and Y have the previously indicated meanings.

5. A member as defined by claim 1 wherein said member is 4-phenyl-4-hydr0xy-7-methoxy-isoflavane.

6. A member as defined by claim 1 wherein said member is 2 ethyl-4-phenyl-4-hydroxy-7-methoxy-isofiavane.

7. A member as defined by claim 1 wherein said member is 4 phenyl-4-hydroxy-7-acetoxy-isoflavane.

8. A member as defined by claim 1 wherein said member is Z-ethyl 4-phenyl-4-hydr0xy-7-acetoxy-isoflavane.

9. A member as defined by claim 1 wherein said member is 4 (p-2-dimethylaminoethoxyphenyl)-4-hydr0xy-isoflavane.

10. A member as defined by claim 1 wherein said member is 2 ethyl-4-(p-2-dimethy1aminoethoxyphenyl)-4-hydroxy-isoflavane.

11. A member as defined by claim 1 wherein said member is 4 (p-2-dimethylaminoethoxyphenyl)-4-hydroxy-7- methoxy-isofiavane.

12. A member as defined by claim 1 wherein said memher is 2 ethyl-4-(p-2-dimethy1aminoethoxyphenyl)-4-hydroxy-7-methoxy-isofiavane.

13. A member as defined by claim 1 wherein said member is 4 (p-Z-dimethylaminoethoxyphenyl)-4-hydroxy-7- acetoxy-isoflavane.

14. A member as defined by claim 1 wherein said member is 2 ethyl-4-(p-2-dimethylaminoethoxyphenyl)-4-hydroxy-7-acetoxy-isoflavane.

15. A member as defined by claim 1 wherein said member is 4 (p 2-diethylaminoethoxyphenyl)-4-hydr0xy-7- methoXy-isofiavane.

16. A member as defined by claim 1 wherein said member is 2 ethyl 4-(p-2-diethylaminoethoxyphenyl)-4-hydroxy-7-methoxy-isoflavane.

17. A member as defined by claim 1 wherein said member is 4 (p-2-pyrro1idinoethoxyphenyl)-4-hydroxy 7 methoxy-isoflavane.

18. A member as defined by claim 1 wherein said member is 2 ethyl-4-(p-2-pyrrolidinoethoxyphenyl) 4-hydroxy-7-methoxy-isoflavane.

19. A member as defined by claim 1 wherein said member is 4 p hydroxyphenyl-4-hydroxy-7-methoxy-isoflavane.

20. A member as defined by claim 1 wherein said member is 2-ethyl 4-p-hydroxyphenyl-4-hydroxy-7-methoxyisofiavane.

21. A member as defined by claim 1 wherein said member is 2 ethyl-4-phenyl-7-methoxy-3-isofiavene.

22. A member as defined by claim 1 wherein said member is 4-phenyl-7-acetoxy-3-isoflavene.

23. A member as defined by claim 1 wherein said member is 2 ethyl-4-phenyl-7-acetoxy-3-isofiavene.

24. A member as defined by claim 1 wherein said member is 2 ethyl-4-(p-Z-dimethylaminoethoxyphenyl)-3-isofiavene.

25. A member as defined by claim 1 wherein said member is 2 ethyl 4-(p-2-dimethylaminoethoxyphenyl)-7- methoxy-3-isoflavene.

26. A member as defined by claim 1 wherein said member is 4 (p 2-dimethylaminoethoxyphenyl)-7-acetoxy- 3-isofiavene.

27. A member as defined by claim 1 wherein said member is 2-ethyl-4-(p-2-dimethylaminoethoxyphenyl)-7acetoxy-3-isoflavene.

28. A member as defined by claim 1 wherein said member is 2 ethyl-4-(p-2-diethylaminoethoxyphenyl)-7-methoxy-3-is0flavene.

29. A member as defined by claim 1 wherein said member is 2 ethyl 4 (p 2-pyrrolidinoethoxyphenyl)-7-methoxy-3-isoflavene.

30. A member as defined by claim 1 wherein said member is Z-ethyl 4 p-hydroXyphenyl-7-methoxy-3-isofiavene.

References Cited UNITED STATES PATENTS 3,142,682 7/1964 De Stevens 260-3452 XR 3,340,276 9/1967 Carney et a1. 260-3452 3,340,277 9/ 1967 Carney et a1. 260-3452 HENRY R. JILES, Primary Examiner JOHN M. FORD, Assistant Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,471, 520 Dated October 7 19 69 Inventor(s) X13115 Irmscher et a1.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

"*1; IN THE CLAIMS;

Claim 1, 5th line after the diagram: (CH )n" should read (CH Claim 3, line 3: "R and R should read -R and R u Claim 27, line 2 "'Zaeetoxy" should read -7-acetoxy- Signed and sealed this 28th day 'of July 1970 EA Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents