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Publication numberUS2922744 A
Publication typeGrant
Publication dateJan 26, 1960
Filing dateJun 26, 1957
Priority dateJun 26, 1957
Publication numberUS 2922744 A, US 2922744A, US-A-2922744, US2922744 A, US2922744A
InventorsValley Glenns, Mills Jack, Robert C Rathbun
Original AssigneeLilly Co Eli
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Therapeutic processes employing aminobenzodioxane medicaments
US 2922744 A
Abstract  available in
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Description  (OCR text may contain errors)

THERAPEUTIC PROCESSES EMPLOYING AMINO- BENZODIOXANE MEDICAMENTS Jack Mills, Glenns Valley, and Robert C. Rathbun, Greenwood, Ind., assignors to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Application June 26, 1957 Serial No. 668,035

7 Claims. Cl. 167-65) substituted benzodioxanes represented by the following formula:

7 8 1 2 om-nn-m,

wherein R is a hydrogen, or an alkyl or alkenyl group having from 1 to 4 carbon atoms, and R is an alkyl, an alkenyl, an hydroxyalkyl or an alkoxyalkyl radical having from 2 to 6 carbon atoms.

In the above formula, when R is an alkyl or alkenyl group, it can be, illustratively, methyl, ethyl, isopropyl, allyl or butyl. R in the formula can be, illustratively, allyl, n-butyl, isoamyl, hydroxyethyl, methoxypropyl, n-amyl, isobutenyl, ethoxyethyl, isopropyl and sec-butyl.

Examples of aminobenzodioxanes which are useful in carrying out our novel therapeutic processes include 2- ethoxyethylaminomethyl-8-ethoxybenzodioxane, Z-methoxypropylaminomethyl-S-ethoxybenzodioxane, Z-isobutylaminomethyl 8 n propoxybenzodioxane, 2-A -butenylaminomethyl-S-hydroxybenzodioxane, Z-n-propylaminomethyl-S-isopropoxybenzodioxane, 2-ethylaminomethyl-8- n-butoxybenzodioxane, Z-n-amylaminomethyl-8-methoxybenzodioxane, Z-isobutylaminomethyl-8-hydroxybenzodioxane, 2-isoamylaminomethyl-8 methoxybenzodioxane, 2- isopropylaminomethyl-8-methoxybenzo'dioxane, and the An especially useful group of drugs with excellent therapeutic ratios are provided for use in our novel processes when the compound contains an S-hydroxy, an S-methoxy or an S-ethoxy radical. Examples of this preferred group of aminobenzodioxanes include 2-n-butylaminomethyl-8- ethoxybenzodioxane, 2-allylaminomethyl-8-ethoxybenzo dioxane, Z-n-butylaminomethyl-S-methoxybenzodioxane, 2-n-butylaminomethyl-8-hydroxybenzodioxane, 2-isobutylaminomethyl 8 methoxybenzodioxane, Z-n-amylaminomethyl 8 ethoxybenzodioxane and 2-(2-methylbutyl) aminomethyl-S-hydroxybenzodioxane.

The pharmaceutically acceptable acid addition salts of the aminobenzodioxanes embraced by the above formula are also included Within the scope of this invention since such salts are effective for use in our novel therapeutic process because of their content of active aminobenzodioxane. Furthermore, many of the salts have the advantages of water solubility, heat stability, or both, as compared with the free bases from which they are derived. Both organic and inorganic acids can be employed to form pharmaceuticallyacceptable salts with the various aminobenzodioxane bases, illustrative acids being hydrochloric acid, hydrobrornic acid, sulfuric acid, phosphoric acid, maleic acid, acetic acid, benzoic acid, succinic acid, citric acid, ascorbic acid, and the like.

The novel therapeutic processes of this invention employ a group of substituted benzodioxane compounds which are characterized by a physiological action comprising a marked central depressant action of selected character; that is, the compounds employed in the processes have a pronounced activity on the central nervous system in their ability to depress transmission of nerve impulses across synapses mediated by endogenous sympathetic agents. 0n the other hand, in dosage amounts customarily employed for depression of central activity, the compounds are devoid or substantially so, of hypnotic or soporific action.

The selective central depressant activity of the substituted benzodioxane compounds is readily demonstrable by animal experimentation. Thus for example, administration of a compound represented by the above formula to a conditioned animal previously trained to avoid unpleasant or harmful stimuli by manipulation of a mechanical device or by a particular pattern of action, causes a selective loss of the acquired avoidance behavior without concomitant loss of escape activity.

The physiological action possessed by the compounds represented by the above formula makes them especially useful for administration to human beings for alleviation of some of the ills or disturbances of central origin.

Illustratively, the administration of one of the compounds in suitable dose amounts to a disturbed human being relieves the symptoms arising from emotional tension, neurotic anxiety, 'psychomotor hyper-activity, hysterical panic and other similar conditions of central origin. Additionally, administration of one of the compounds to a human being effectively elevates the emetic threshold. Moreover, the administration of one of the compounds to a hypertensive patient lowers the blood pressure of the patient. The hypotensive action evoked difiers in character from that produced by other compounds previously known, which fail to demonstrate the specific central activity characteristic of the compounds described herein, but conversely act through a peripheral type of adrenergic block.

The following procedure exemplifies, in general terms, the process of administering a substituted benzodioxane to patients having symptomotology of the type described above but who are not so disturbed as to need restraint: A capsule or tablet or other pharmaceutical form containing an effective dose of the medicament in the solid state, for example from 5 to 50 mgs., is administered to the patient via the oral route every 4 to 6 hours, or more often if need be. Initially, it is sometimes desirable to give a large dose-for example, one, two or three times the above dose-in order to obtain a pronounced initial effect. With a majority of patients, a dose of from 5 to 10 mgs. or even 20 mgs. 3 to 4 times a day is sufficient to give the required therapeutic effect.

With disturbed psychotics and other patients requiring restraint, a different therapeutic procedure can be used. Thus, in suitable cases the initial and subsequent doses of benzodioxane tranquilizer can be administered parenterally by intramuscular or subcutaneous injection, and an oral dosage form can be used at such time as the psychotic person is sufiiciently rational. .A water-soluble salt of an aminobenzodioxane is particularly useful for purposes of injection. In general, the dose required for parenteral administration is somewhat less than that required to provide an equal elfect by oral administration.

A further mode of evoking tranquilizing action by the administration of an aminobenzodioxane is that of retaining a patient on a small daily maintenance dose of about 5 to 10 mgs. administeredv three or four times a day, but increasing this dose in times of stress. This type of therapeutic treatment is especially valuable when the patient being treated is suffering from a disease which has a partially psychogenic origin, such as is the case in many types of high blood pressure.

The various pharmaceutical forms referred to above are prepared by methods well known to the art. For example, a solid dosage form can comprise a gelatin capsule containing a dose amount of a substituted aminobenzodioxane mixed with a quantity of starch or other solid pharmaceutical extending medium. Alternatively, a binder such as stearic acid or magnesium Sliifll'fi'tfican be added to the mixture of starch and drug and the whole pressed into tablet form. Parenteral dosage forms are obtained by dissolving a water-soluble salt of the active drum in water or saline solution in a' concentration such that 1 cc. of the solution contains from -10 mgs. of active drug. The solution can thenbe filled into 1 cc. ampoules or larger multiple dose ampules. Y

The following examples illustrate the preparation of suitable dosage forms.

Filled gelatin capsules can be prepared by mixing one pound 'of 8-ethoxy-2-n-butylaminomethylbenzodioxane hydrochloride with 64 pounds of starch and filling the mixture into empty telescoping capsules of such'size that each capsule contains 5 mg. of drug.

Tablets can be prepared as follows: 20 parts of 8- ethoxy-2-n-butylaminomethylbenzodioxane, 35 parts of starch, 35 parts of milk sugar, 4 parts of sodium carboxymethyl cellulose and lpart of magnesium stearate (all parts by weight) are thoroughly mixed and the mixture is then compressed into scored 100 mg. tablets, each tablet containing 20 mg. of the active drug.

Ampoules containing an injectable solution are prepared as follows: 50 liters of a solution containing 5 mg. per ml. of 8-ethoxy-2-n-butylaminomethylbenzodioxane in the form of its hydrochloride salt is prepared in distilled water, and 5 mg. of sodium chloride per ml. are dissolved therein to provide a substantially isotonic solution. The solution is sterilized by filtering it through a Seitz filter, and is then filled with aseptic technique into 1 cc. ampoules.

The novel aminobenzodioxanes which are useful in our therapeutic process and which form the active ingredient in our novel pharmaceutical compositions are prepared by the general procedures set forth below.

By way of explanation, no suitable prior art method was available for the preparation of an 8-substituted aminobenzodioxane corresponding to Formula I. Such methods as were available lead only to the formation of a mixture of the 8-substituted and the 5-substituted isomers. The latter isomers not being useful in the processes of this invention, are unwanted. A mixture of the 5- and 8-isomers corresponding to the above formula is very diflicult to separate. It has, therefore, been necessary to develop novel methods for preparing compounds corresponding to Fonnula I. To this end, a method has been devised for preparing a purified S-alkoxy substituted benzodioxanc intermediate which can be converted into the desired Z-alkylamihomethyl-8-substituted benzodioxane. The process comprises the reaction of an o-alkylcatechol with ethyl-u,B-di-bromopropionate, following the method of Koo et al. as described in I. Am. Chem. Soc. 77, 5375 (1955), to provide a mixture of both 5- and 8-alkoxy-2-carboethoxybenzodioxanes. This mixture of isomers is reacted with alcoholic ammonia to yield a mixture of both 5- and 8-alkoxy-Z-carboxamidobenzodioxanes from which the two isomeric amides can be separated on the basis of their difierential solubility in organic solvents. For example, the 5- alkoxyamide is relatively insoluble in ethanol, whereas the" desired 8- alkoxyamide is markedly soluble in this solvent. The 8-alkoxy-2-carboxamidobenzodioxane separated in this fashion can be freed from such minor residual quantity of the S-isomer as may be present, by simple recrystalliaation, chromatography or other equivalent method. The

pure 8-substituted amide is reconverted to the corresponding Z-carboethoxy derivative, which is reduced with lithium aluminum hydride to yield a Z-hydroxymethyl- S-alkoxybenzodioxane. The hydroxymethyl derivative is chlorinated with thionyl chloride forming a 2-chloromethyl-8-alkoxybenzodioxane from which the desired aminobenzodioxane is prepared by the amination method set forth in Example 1 of US. PatenfNo. 2,056,046, issued September 29, 1936. Alternatively, the separated 2-carboethox -8-alkoxybenzodioxane can be reacted with primary amine to yield the corresponding amide which is then reduced with lithium aluminum hydride directly to the desired 2-aliphatic-substituted aminomethyl-S- alkoxybenzodioxane.

The 8-hydroxy-2-aliphatic-substituted aminobenzodioxanes useful in our novel therapeutic process can be readily prepared from the corresponding 8-alkoxy compounds by treating the phenolic ether with an ether-splitting reagent such as 48% hydrobromic acid, or concentrated hydriodic acid. An alternative method of producing these compounds rests'upon the discovery that a mixture of both the 5- and 8-alkoxy-2-aliphatic-snbstituted aminomethylbenzodioxanes, when treated with an ethersplitting reagentffortuitously yields the desired 8-hydroxy- Z-aIiphatic-substituted aminomethylbenzodioxane as an ether-insoluble solid, whereas the unwanted 5 hydroxy compound is an ether-soluble oil. This alternative method of preparing an S-hydroxy-Z-aliphatic-substituted-aminomethylhenzodioxane is preferred since it involves fewer steps and less expensive starting materials. The S-hydroxy compound thus obtained, in addition to being useful in itself, can readily be alkylated to give such 8-alkoxy or S-alkenoxy derivatives as may be desired. Before alkylating an 8-hydroxy-2-aliphatic substituted aminomethylben'zodioxane it is necessary to protect the secondary amine function, as by acetylation and after the S-hydroxy grouphas been alkylated, the protecting group is removed. If the protecting group is an acetyl group, alkaline hydrolysis sufiices fori'ts removal. More simply, when it is desired to produce an aminobenzodioxane having an ether group in the 8-position other than the ethoxy group, it is feasible to react 8-ethoxy-2-chloromethylbenzodioxane, prepared as illustrated above, with an ethersplitting reagent to form 8-hydroxy-2-chloro-methylbenzodioxane which can be alkylated." The 8- alkoxy-2-chloromethylbenzodioxane can be reacted with a primary amine as described above with reference to the 8-ethoxy compounds to yield 'a desired product. The latter route to 8- hydroXy-Z-substituted benzodioxane ofiers certain technical advantages forcommercial production since the acetylation and deacetylation steps are avoided.

After a pure Sfiscmer of any given structure has once been crystallized, it is frequentlypos'sible to employ seed crystals of the isomer to cause selective crystallization of the desired 8-isomer from a sloution containing both the 8- and S-isomrs, as is well known in the art. The 2-substituted benzodioxanes which are useful in our novel process are capable of being resolved into optically active isomers. For example, the reaction of dl-Z- butylaminomethyl-8-hydroxybenzodioxane and d-ohamphor sulfonic acid inethanol yields a mixture ofsalts in which the salt of the l-isomer of the benzodioxane compound is relatively insoluble and is easily crystallized. The salt of the d-isomer remains in the mother liquor and can be recovered by evaporation of the solvent.

This invention is further illustrated by the following examples which disclose the preparation of illustrative compounds useful in this invention.

EXAMPLE 1 Preparation of Z-chloromethyl-8-ethoxybenz0di0xane e ilr fl- -b i e s in e P e ses 959 .981.

potassium carbonate. The procedure of Koo et 'al., JACS, 77, 5375 (1955) for the preparation of Z-carboethoxybenzodioxane, was followed both as to reaction conditions and isolation of the substituted benzodioxane. About 167 g. of a mixture of Z-carboethoxy 5- and 8-ethoxybenzodioxanes were obtained, boiling at about 125135 C. at a. pressure of about 0.07 mm. of mercury.

By following the procedure of Koo et al., I. Am. Chem. Soc. 77, 5375 (1955) the mixture of 2-carboethoxy-5 and 8-ethoxybenzodioxanes was ammonolysed to the corresponding amide as follows: 167 g. of the above isomer mixture was dissolved in about 800 ml. of ethanol and the solution was added to about 2.5 l. of liquid ammonia. The reaction mixture was stirred for about 16 hours while being maintained in the temperature range 30 to -50"- C. Crystals of 2-carboxamido-5-ethoxybenzodioxane which were ethanol insoluble, precipitated during the reaction period and were separated by filtration. The filtrate was evaporated to dryness leaving 2-carboxamido-8- ethoxybenzodioxane as a crystalline residue. This residue was triturated several times with hot benzene to dissolve the 8-ethoxy isomer, the S-ethoxyisomer being insoluble in hot benzene. The resulting benzene triturations containing the S-ethoxy isomer were combined, and were evaporated to dryness. The crystalline 2-carboxamido-8- ethoxybenzodioxane remaining as a residue was recrystallized from a benzene-hexane solvent mixture. Purified 2-carboxamido-8-ethoxybenzodioxane, prepared and then separated from the S-isomer as indicated above, was obtained melting at about 131132 C.

Analysis-Calculated: C, 59.18; H, 5.87. Found: C, 59.40; H, 6.01.

55 g. of 2-carboxamido-8-ethoxybenzodioxane were dissolved in about 1 liter of ethanol. The resulting mixture was saturated with gaseous hydrogen chloride and was then heated at refluxing temperature for about 16 hours in order to convert Z-carboxamido-S-ethoxybenzodioxane back to the corresponding Z-carboethoxy derivative. The reaction mixture was cooled and the ammonium chloride which had precipitated, was removed by filtration. The filtrate was concentrated in vacuo and the resulting residue containing the 2-carboethoxy-8-ethoxybenzodioxane was dissolved in 500 ml. of ether. The ether layer was washed successively with 200 ml. portions of water, 10% (w./v.) aqueous sodium hydroxide and water and was separated and dried. Distillation of the dry solution yielded 54 g. of 2 carboethoxy-8-ethoxybenzodioxane boiling in the range of 125-135 C.; n =1.52l. Upon standing, this distillate deposited crystals which were separated by filtration, and were recrystallized from a benzene-hexane solvent mixture. Purified Z-carboethoxy-8-ethoxybenzodioxane thus obtained melted at about 61-62 C.

Analysis.-Ca.lCulated: C, 61.89; H, 6.39. Found: C, 62.07: H. 6.28.

293 g. of 2-carboethoxy-8-ethoxybenzodioxane were dissolved in 1 liter of anhydrous ether and the solution was added to a suspension of 46 g. of lithium aluminum hydride in 2 liters of anhydrous ether, so as to reduce the carboethoxy group to an hydroxymethyl group. After the addition had been completed, the reaction mixture was stirred for about 16 hours at ambient room temperature, and was then decomposed by the addition, seriatirn, of 48 ml. of water, 36 ml. of 20% sodium hydroxide and 168 ml. of water. The solid inorganic salts which precipitated were separated by filtration. The ethereal filtrate containing the 2 hydroxymethyl 8 ethoxybenzodioxane and crystallized upon standing to yield crystals melting at about 64-65 C. Further purification of this material by recrystallization from a benzene-hexane solvent mixture yielded Z-hydroxymethyl-S-ethoxybenzodioxane melting at about 69-72 C.

Analysis.-Calculated: C, 62.84; H, 6.71. Found: C, 63.10; H, 6.61.

209 g. of 2-hydroxymethyl-8-ethoxybenzodioxane were dissolved in a mixture of 500 ml. of chloroform and 100 successively with about ml. each of 10% hydrochloric.

acid, water, 10% sodium carbonate and water. The organic phase was then separated, dried and distilled. The fraction boiling in the range to 120 C. -at a pressure of about 0.1 .mm. of Hg was collected and comprised 2-chloromethyl-8-ethoxybenzodioxane. This fraction solidified upon standing to yield crystalline 2-chloromethyl-8-ethoxybenzodioxane melting at about 50-52 C. Recrystallization of this material from a benzene-hexane solvent mixture yielded 2-chloromethyl-8-ethoxybenzodioxane melting at about 60-61 C.

Analysis.-Calculated: C, 57.77; H, 5.73. Found: C, 57.75; H,5.87.

EXAMPLE 2 Preparation of 2-n-butylaminomethyI-S-elhoxybenzodioxane A mixture of 30 g. of-2-chloromethyl-8-ethoxybenzodioxane and 44 g. of n-butylamine was refluxed for about three days. About 200 ml. each of 10% hydrochloric acid and ether were then added to the reaction mixture. The resulting organic layer was separated and discarded. The acid aqueous layer containing 2-n-butylaminomethyl-8- ethoxybenzodioxane as a hydrochloride salt was made basic with 10% sodium hydroxide, thus forming 2-n-butylaminomethyl-8-ethoxybenzodioxane free base which was extracted into about 200 ml. of ether. The ethereal solution was washed once with 100 ml. of water, was dried and was evaporated to dryness in vacuo to remove the excess 'n-butylamine, which accompanied the Z-n-butylaminomethyl-S-ethoxybenzodioxane in this purification procedure. The residue comprising Z-n-butylarninomethyl- S-ethoxybenzodioxane, was distilled at a pressure of about 0.1 mm. of Hg 2-n-butylaminomethyl-8-ethoxybenzodioxane boiled in the range to C. at this pressure;

2-n-butylaminomethyl-8-ethoxybenzodioxane prepared as above was dissolved in anhydrous ether and the resulting solution was saturated with gaseous hydrogen chloride, thus forming the hydrochloride salt of 2-n-butylamine methyl-8-ethoxybenzodioxane. This compound melted at about 196-197 C. after recrystallization from an ethanol-ethyl acetate solvent mixture.

Analysis.-Calcu1ated: C, 59.69; H, 8.01. Found: C, 60.11; H, 8.01.

EXAMPLE 3 Preparation 0 2-n-butylaminomethyl-8-eth0xybenzodioxane 15 g. of 2-carboethoxy-8-ethoxybenzodioxane prepared by the method of Example 1 was added to a four-fold molar excess of n-butylamine and the resulting mixture was heated to refluxing temperature for about sixteen hours to form 6-n-butyl 8-ethoxy-benzodioxane-Z-carboxamide. The reaction mixture was evaporated to dryness in vacuo to remove the excess n-butylamine, leaving the carboxamide as a residue. This residue was dissolved in a mixture of ether and 10% hydrochloric acid. The organic layer containing the N-n-butyl S-ethoxybenzodioxane-Z-carboxamide was separated, was washed twice with 10% hydrochloric acid and once with water and was then dried. The ethereal solvent was removed in vacuo and the residue comprising N--n-butyl 8-ethoxybenzodioxane-Z-carboxamide was recrystallized from a henzene-hexane solvent mixture. 10 g. of this recrystallized material, without further purification, was reduced with 7 lithium aluminum hydride to 2-n-butylaminomethyl-8- ethoxybenzodioxane by the reduction procedure of Example 1 as set forth for the reduction of the corresponding Z-carboethoxy compound. However, in isolating the reduced material, advantage was taken of its basic character to extract it into acid, as 2-n-butylaminomethyl-8- ethoxybenzodioxane hydrochloride, from. the ethereal filtrate resulting from the removal of the inorganic lithium aluminum salts. Unreacted amide starting material was recovered from the ethereal layer at this point. The acidic aqueous extract was then made basic and the 2-n-butylaminomethyl-S-ethoxybenzodioxane free base was extracted back into ether. This ethereal layer was washed once with water and was dried. Gaseous hydrogen chloride was passed into this solution in order to prepare the hydrochloride salt of 2-n-butyl-aminomethyl-8-ethoxybenzodioxane which was collected and purified as in Example 2.

. EXAMPLE 4 Preparation of 2-carboethoxy-8-methaxybenzodioxane Following the procedure of Example 1, 3-methoxycatechol was reacted with ethyl-u,B-di-bromopropionate in the presence of anhydrous potassium carbonate to yield a mixture of 2-carboethoxy-S- and S-methoxybenzodioxanes. This mixture boiled in the range of 130 to 140 C. at a pressure of about 0.07 mm. of Hg. Following the procedure of Example 1, the 2-carboethoxy-5- and 8- methoxybenzodioxanes were converted to the corresponding amides with liquid ammonia in ethanol. At the end of the reaction period, crystals of the ethanol-insoluble S-isomer were separated by filtration leaving Z-carboxamido-S-methoxybenzodioxane in the filtrate. The filter cake was triturated with hot benzene to dissolve any of the 8-isomer which might be entrapped by it. The original filtrate was evaporated to dryness and the resulting crystals were triturated with the same benzene used for the previous trituration. The benzene triturate was separated therefrom by decantation. Hexane was added to this benzene solution to the point of incipient precipitation of 2- carboxamide-S-methoxybenzodioxane and the solution was then cooled. Crystalline Z-carboxamide-S-mcthoxybenzodioxane thus obtained melted at about 148-149 C.

Analysis.-Calculated: C, 57.41; H, 5.30. Found: C, 57.90; H, 5.23.

Following the procedure of Example 1, Z-carboxamido- S-methoxybenzodioxane was converted back to Z-carboethoxy-S-methoxybenzodioxane. This compound boiled at about 130-135 C. at a pressure of about 0.05 mm. of Hg.

Analysis.-Calculated: C, 60.50; H. 5.92. FoundrC, 60.35; H, 5.97; n ==1.5258.

EXAMPLE 5 Preparation of 2-allylaminomethyl- 8-methox'ybenz0dioxane1 47 g. of Z-carboxethoxy-8-methoxybenzodioxane were mixed with 200 g. of allylamine and the mixture was heated to refluxing temperature for about 16 hours. The excess allylamine was removed by evaporation in vacuo leaving N-allyl 8-methoxybenzodioxane-Z-carboxamide as a residue. The residue was treated with a mixture of ethyl-ether and 10% hydrochloric acid, whereupon the N allyl 8-methoxybenzodioxane-2-carboxamide dissolved in the ether layer. The ether layer was separated, and was washed twice with 50 ml. portions of 10% of HCl and once with 50 ml. of water, was again separated and dried. The ether was removed therefrom by evaporation in vacuo leaving a solid residue comprising N-allyl 8-methoxyben zodioxane-Z-carboxamide. This compound was recrystallized from a mixture of benzene and hexane and the resulting crystalline product was reduced with lithium aluminum hydride without further purification by the following procedure: About 40 g. of'N allyl8-methdxybenzodioxane-Z-carboxamide were dissolved in 300 ml. of toluene and the solution was added to a suspension of 0.6 mole of lithium aluminum hydride in 1.5 l. of anhydrous diethyl ether. The reduction and isolation of the product were carried out according to the directions set forth in Example 1 for the reduction of 2 carboethoxy-8- ethoxybenz odiox'a'ne to 2-hydroxymethyl8-ethoxybenzodioxane. 2 allylaminomethyl 8 methoxybenzodioxane prepared in this way was distilled andboiled at about 125 C. "at a pressure of about 0.07 mm. of Hg;

Analysis.--Calculated: C, 66.36; H, 7.28. Found: C, 65.76; H, 7.26; n =1.543.

2 allylamino 8 methoxybenzodioxane hydrochloride was prepared from the free base by dissolving the free base in ether, saturating the resulting solution with gaseous hydrogenchloride, separating the precipitated hydrochloride by filtration and then recrystallizing the filter cake from ethanol. 2-allylaminomethyl-S-methoxybenzodioxane hydrochloride thus prepared melted at about 193-494 C.

EXAMPLE 6 Preparation of Z-ethoxyefltylaminomethyl- S-ethaxybenzodioxane Following the procedure of Example 3, a reaction mixture was prepared containing 12 g. of ethoxyethylamine and 18 g. of 2 carboethoxy 8 methoxybenzodioxane. This mixture was heated overnight at refluxing temperature for about sixteen hours in order to prepare N-ethoxyethyl 8-ethoxybenzodioxane-2-carboxamide which was isolated and purified according to the procedure of Example 3. N-ethoxyethyl S-ethoxybenzodioxane-Z-carboxamide thus prepared melted at about 66-68 C.

Analysis.-Calculated: C, 61.00; H, 7.17. Found: C, 61.17; H, 7.17.

Following the procedure of Example 3, N-ethoxyethyl 8-ethoxybenz0dioxaneQ-carboxamide was reduced to the corresponding amine with lithium aluminum hydride and the amine was isolated as such. Z-ethoxyethylaminomethyl-8-ethoxybenzodioxane thus prepared boiled at about l 60-1 65 C. at a pressure of about 0.3 of Hg; n 1.5 16. 2-ethoxyethylaminomethyl 8-ethoxybenzodioxane hydrochloride was prepared by the method of Example 2 and melted at about 135-136" C. after recrystallization from ethanol.

Analysis. Calculated: C, 56.68; H, 7.61. 56.39; H, 7.84.

Found: C,

EXAMPLE 7 Pre'paraiion of Z-isopropylaminomethyl- 8-eth'0xybenzodioxane Found: 0,

EXAMPLE 8 Preparation of Z-n-proplyaminomethyl- 8-eth0xybenzodi0xane The procedure of Example 3 was followed to prepare N-n-propyl 8-ethoxybenzodioxane-2-carboxamide from n-propylamine' and 2-carboethoxy-8-ethoxybenzodioxane.

Q. The amide melted at about 85-86 C. after recrystallization from a mixture of benzene and hexane. Analysis.Calculated: C, 63.38; H, 7.22. Found: C, 63.35; 7.15.

N-n-propyl 8-ethoxybenzodioxane-2-carboxamide was reduced by the procedure of Example 3 to yield 2-n-propylaminomethyI-S-ethoxybenzodioxane which was puriiied as the hydrochloride salt. This salt melted at about 177-178 C. after recrystallization from ethanol.

Analysis.-Calculated: C, 58.43; H, 7.71. Found: C, 58.20; H, 7.68.

EXAMPLE 9 Preparation of Z-n-amylaminomethyZ-8-ethoxybenzodioxane EXAMPLE 10 Preparation of 2-is0amylaminomethyl-8-ethoxybenzodioxane Following the procedure of Example 3, isoamylamine and 2-carboethoxy-8-ethoxybenzodioxane were reacted to form N-isoamyl S-ethoxybenzodioxane-Z-carboxamide melting at about 51-52 C.

Analysis.Calculated: C, 65.50; H, 7.90. Found: C, 64.92; H, 7.84.

The above carboxamide was reduced with lithium aluminum hydride by the process of Example 3. The amine formed in the reduction precipitated during the isolation procedure as the hydrochloride salt at the point where the ether solution containing the free base was contacted with hydrochloric acid and the hydrochloride salt was isolated at this point by filtration. 2-isoamylaminomethyl-8-ethoxybenzodioxane hydrochloride thus obtained melted at about 159160 C. after recrystallization from an ethanol-ether solvent mixture.

Analysis.-Ca.lculated: C, 60.84; H. 8.30. Found: C, 61.56; H, 8.54.

' EXAMPLE 11 Preparation of Z-sec-amylaminomethyl-8-ethoxybenzodioxane Following the procedure of Example 3, Z-carboethoxy- S-ethdxybenzodioxane and sec-amylamine were reacted to form N-sec-amyl-8-ethoxybenzodioxane-Z-carboxamide. The compound was reduced with lithium aluminum hydride by the procedure of the same example to yield Z-sec-amylaminomethyl-S-ethoxybenzodioxane which was purified by distillation. The fraction boiling in the range of 141145 C. at a pressure of about 0.1 mm. of Hg was collected and comprised purified Z-sec-amylaminomethyl- 8-ethoxybenzodioxane.

Analysis.-Calculated: C, 68.78; H, 9.02. Found: C, 68.00; H, 8.96; n =1.512.

The distilled free base was converted to the corresponding hydrochloride salt following the method of Example 2. A crystalline ether-insoluble material precipitated, and was separated by filtration. This crystalline material was one of the two possible racemic pairs of compounds having the same structural formula. It was arbitrarily designated a-Z-sec-amylaminomethyll-8-ethoxybenzodioxane hydrochloride. This compound melted at about 181182 C. after being recrystallized six times from an ether-ethanol solvent mixture.

Analysis-Calculated: C, 60.84; H, 8.30. Found: C, 61.52; H, 8.33.

Preparation of 2-chloromethyl-8-hydr0xybenz0di0xane A mixture containing 57 g. of 2-chlorornethyl-8-ethoxybenzodioxane furnished by the procedure of Example 1, and 250 ml. of 48% hydrobromic acid was heated to refiuxing. temperature. Evolution of ethyl bromide was noted at once. The reaction mixture was heated at such a rate that the ethyl bromide distilled slowly out of the reaction mixture using a short Vigreux column to fractionate the distillate. Heating was continued until the temperature at the top of the fractionating column reached C., the boiling point or" 48% hydrobromic acid. At this point the cleavage of the 8-ethoxy compound to yield 2-chloromethyl-8-hydroxybenzodioxane and ethyl bromide was substantially complete. The reaction mixture was cooled, and was poured into about 1 l. of water. 2-chloromethyl-8-hydroxybenzodioxane being insoluble in water was recovered from the mixture by extraction with two 500 ml. portions of ether. The ether extracts were combined and were washed with water, with 2% sodium bicarbonate solution, and again with water. The ether extracts were then dried and the ether was removed by evaporation in vacuo. The residue comprising 2-chloromethyl-8-hydroxybenzodioxane was distilled under a reduced pressure of about 0.4 mm. 'of Hg and boiled at about -l37 C.

Analysis.--Calculated: C, 53.88; H, 4.52. Found: C, 53.81; H, 4.80; n =1.567.

EXAMPLE 13 Preparation of 2-allylamin0methyl-8-hydr0xybenzodioxane A mixture containing 100 g. of 2-chloromethyl-8- hydroxybenzodioxane and 142 g. of allylamine was heated in a sealed reaction vessel at about C. for about six hours. The reaction mixture was cooled, and the excess allylamine was removed therefrom by evaporation in vacuo.. The residue remaining in the flask com-' prised 2-allylaminomethyl-8-hydroxybenzodioxane formed in the above reaction. It was treated with asolution containing 103.6 g. of potassium carbonate in 500 ml. of water. 2-allylaminomethyl-8-hydroxybenzodioxane was insoluble in this mixture and was extracted therefrom by three succesisve 100 ml. portions of chloroform. The chloroform extracts were combined, were washed wlthwater and were dried. The chloroform was removed by evaporation in vacuo, yielding a crystalline residue which comprised 2-allylaminomethyl-8-hydroxybenzodioxane. This compound melted at about 167 C. after recrystallization from an ethanol-ether solvent mixture.

Analysis.-Calculated: C, 65.14; H, 6.83; N, 6.33. Found: C, 64.76; H, 6.94; N, 6.37. e

1 g. of the above solid was dissolved in a minimum amount of warm anhydrous ethanol. Anhydrous hydrogen chloride gas was passed into the solution to form 2 allylaminomethyl 8-hydroxybenzodioxane hydrochloride which was subsequently precipitated by the addition of anhydrous ether. 2-allylaminomethyl-8-hydroxybenzodioxane hydrochloride thus obtained melted at about 235235.5 C. after recrystallization from ethanol.

EXAMPLE 14 Preparation of Z-n-butylaminomethyl-8-hydroxybenzodioxane ethanol.

hydrochloride was cleaved to the free phenol by refluxing with 48% hydrobromic acid. After the last traces of ethyl bromide had distilled, the reaction mixture was cooled to room temperature and kept at that temperature for about sixteen hours. It was then chilled to about C. During the period when the reaction mixture was being cooled and chilled, a pink crystalline material comprising 2-n-butylaminomethyl-8-hydroxybenz0dioxane hydrobromide deposited. Crystals of this material were separated by filtration, and the filter cake was washed with about 5 ml. of cold acetone. 2n-butylaminomethyl- 8-hydroxybenzodioxane hydrobromide thus purified melted at about 280-281 C.

Analysis.Calculated: C, 49.06; H, 6.33. Found: C, 49.13; H, 6.28.

EXAMPLE 15 Preparation of I-Z-n-butylaminomethyl-8-hydroxybenzodioxane 386 g. of Z-n-butylaminomethyl-S-hydr0xybenzodioxane hydrobrornide were slurried with a mixture containing 4275 ml. of chloroform and 475 ml. of anhydrous A solution containing 204 g. of sodium bicarbonate in 3150 ml. of water was added to the slurry to convert the hydrobromide salt to the corresponding free base. The resulting mixture was stirred for two hours to insure complete neutralization of the hydrobromide salt, and the mixture was filtered. The filter cake which contained the 2-n-butylaminomethyl-S-hydroxybenzodioxane was washed with cold water and was dried; M.P.=168-l69 C.

About 217 g. of 2-n-butylarninomethyl-S-hydroxybenzodioxane comprising a mixture of both d-' and l-isomers, were dissolved in 4800 ml. of anhydrous ethanol. To the solution was added a solution of 212.5 g. of d-camphorsulfonic acid in 500 ml. of anhydrous ethanol, thus forming the d-camphor sulfonate salt of both dand l-2- n-butylaminomethyl-8- hydroxybenzodioxane. The reaction mixture was evaporated to dryness in vacuo leaving the salts as a residue. This residue was dissolved with warming in about 1 l. of anhydrous ethanol. Upon cooling the solution, a crystalline solid precipitated. The precipitate was separated by filtration, and was recrystallized from ethanol. 126 g. of the d-camphor sulfonate salt of l-2-n-butylaminomethyl-8-hydroxybenzodioxane melting at about 200-201.5 C..were obtained. The salt was converted to the corresponding free base by the method described in the first paragraph of this example for the preparation of the dl free base from the dl hydrobromide. l 2 n butylaminomethyl-S-hydroxybenzodioxane thus prepared had an [a]' 89.0 (in ethyl acetate), and melted at about 182183 C. after recrystallization from ethanol.

Analysis.-Calculated: C, 65.80; H, 8.07. Found: C, 65.87; H, 8.26.

l- 2 n-butylaminomethyl-S-hydroxybenzodioxane was converted to the corresponding hydrochloride salt by the method of Example 2. The hydrochloride salt melted at about 270-272 C. with decomposition.

AnaIysis.Calcul-ated: C, 57.03; H, 7.36. 57.24; H, 7.54.

EXAMPLE 16 Preparation of I-Z-n-butylaminomethyM-ethoxybenzodioxane hydrochloride 63 g. of l-2n-butylaminomethyl-8-hydroxybenzodioxane were stirred with about 11. of anhydrous methanol. The mixture was then cooled to about 0 C. while 81.5 g. of acetic anhydride were added dropwise thereto over a period of about one hour. After this period of time had elapsed, the reaction mixture was allowed to warm up to ambient roomternperature at which temperature it was kept for about sixteen more hours- Volatile sub stances were removed from the reaction mixture by Found: 0,

evaporation in vacuo at a temperature of about 100 C. The resulting residue comprising N-acetyl l-2-n-butylaminomethyl-8-hydroxybenzodioxane formed in the above reaction, was dissolved in ether. The ether layer'was washed with aqueous hydrochloric acid, and the washings were discarded. The ether layer was then washed with about 300 ml. of 1 N sodium hydroxide thus forming the sodium salt of N-acetyl l-2n-butylaminomethy1-8-hydroxybenzodioxane. The aqueous alkaline layer was separated, and was acidified with aqueous hydrochloric acid thus precipitating the free phenol, which was extracted into ether. The ether layer was separated, was washed with water and was dried. Removal of the ether from the dried layer by evaporation in vacuo left a residue comprising N-acetyl l-2-n-butylaminomethyl-8-hydroxybenzodioxane which solidified upon cooling. Recrystallization of the solidified residue from a solvent mixture containing benzene and hexane resulted in white crystals of N-acetyl l- Z-n-butylaminomethyl-S-hydroxybenzodioxane melting at about 99-100 C.; [m] =36.9 (in 95% ethanol).

Analysis.Calculated: C, 64.49; H, 7.58. Found: C, 64.59; H, 7.50.

4.6 g. of sodium were dissolved in about 250 ml. of anhydrous ethanol thus forming sodium ethoxide. To the solution were added about 44.5 g. of N-acetyl l-Z-n-butylaminomethyl-S-ethoxybenzodioxane resulting in the formation of the sodium salt of that compound. About 50 g. of ethyl iodide were added dropwise to the mixture forming N-acetyl l-2-n-butylaminomethyl-S-ethoxybenzodioxane. The reaction mixture was heated at refluxing temperature for about eighteen hours. The volatile constituents were removed by evaporation in vacuo, and the resulting residue which contained N-acetyl l-2-n-butylaminomethyl-S-ethoxybenzodioxane, was contacted with an ether-water mixture, the benzodioxane dissolving in the ether and sodium iodide which was formed as a byproduct in the reaction, dissolving in the water. The aqueous layer was separated and discarded, and the ether solution containing the benzodioxane was Washed successively with 10% hydrochloric acid, water, 10% sodium hydroxide and water. The ether layer was dried and the ether removed therefrom by evaporation in vacuo. The residue which contained N-acetyl l-2-nbutylaminomethyl-8-ethoxybenzodioxane was distilled in vacuo and boiled at about 158159 C. at a pressure of about 0.05 mm. of Hg.

Analysis.Calculated: C, 66.42; H, 8.20. Found: C, 66.43; H, 8.36; n =1.523.

37 g. of N-acetyl I-Z-n-butylaminomethyl-S-ethoxybenzodioxane were added to 800 ml. of ethanol which had previously been saturated with anhydrous hydrogen chloride gas at a temperature of about 0 C. The resulting clear solution was heated to refluxing temperature for about 48 hours in order to deacetylate the benzodioxane compound. The volatile constituents were removed by evaporation in vacuo leaving as a crystalline residue the deacetylated material, l-2-n-butylaminoethyl- 8- ethoxybenzodioxane hydrochloride. The residue was recrystallized from ethanol to yield l-2-n-butylarninomethyl-8-ethoxybenzodioxane hydrochloride melting at about 192-193 C.

Analysis-Calculated: C, 59.69; H, 8.01. Found: C, 59.65; H, 8.13; [a] =54.5 (in ethanol).

EXAMPLE 17 Preparation of ethers of 2-chl'oromethyl-8-hydroxybenzodioxane A mixture of 20 g. of 2-chloromethyl-S-hydroxybenzodioxane, 20.6 g. of N-butyl bromide and 20 g. of anhydrous potassium carbonate in ml. of acetone was heated at refluxing temperature for about 24 hours. The reaction mixture was cooled, and 500 ml. of water and 1 l. of other were added. The 2-chloromethyl-8-nbutoxybenzodioxane formed in the reaction was insoluble in aqueous potassium carbonate but dissolved in the ether layer. The ether layer was separated, was washed with 10% sodium hydroxide solution and water, and was dried. The ether was removed by evaporation in vacuo and the residue comprising 2-chloromethyl-8-n-butoxybenzodioxane was distilled. The fraction boiling at about 138-140 C. at a pressure of 0.5 mm. of Hg was collected. It comprised purified 2-chloromethyl-8- butoxybenzodioxane.

Analysis-Calculated: C, 60.81; H, 6.67. Found: C, 60.89; H, 6.82; n =1.533.

Following the same procedure, 2-chloromethyl-8-hydroxybenzodioxane was reacted with allyl bromide to yield 2-chloromethyl-8-allyloxybenzodioxane boiling at about 123-125 C. at a pressure of about 0.1 mm. of Hg.

Analysis.Calculated: C, 59.88; H, 5.44. Found: C, 59.84; H, 5.60; n =l.553.

Following the same procedure, 2-chloromethyl-8-hydroxybenzodioxane was reacted with Z-bromopropane to yield 2-chloromethyl-8-isopropoxybenzodioxane boiling at about 117-120" C. at a pressure of about 0.1 mm. of Hg.

Analysis.Calculated: C, 59.38; H, 6.23. Found: C, 58.58; H, 6.05; n =1.543.

EXAMPLE 18 Preparation of Z-n-butylaminmethyl-8-alk0xybenzodioxane 2-chloromethyl 8 n-butoxybenzodioxane, 2-chloromethyl-S-allyloxybenzodioxane and 2-chloromethyl-8-isopropoxybenzodioxane were reacted with n-butylamine by the procedure of Example 2 to yield respectively, Z-n-butylaminomethyl 8 n butoxybenzodioxane, 2-nbutylaminomethyl-8-allyloxybenzodioxane and Z-n-butylaminomethyl-8-isopropoxybenzodioxane. Other amines such as those employed in Examples 5 to can be employed in place of n-butylamine in the above reaction. Likewise, other lower alkoxy ethers and lower alkenyloxy ethers of 2-chloromethyl-S-hydroxybenzodioxane can be used in place of any of the three ethers specified above.

EXAMPLE 19 Preparation of Z-ethylamin0methy l-8-eth0xybenzodioxane The procedure of Example 3 was followed except that ethylamine was used in place of n-butylamine. N-ethyl 8-ethoxybenzodioxane-Z-carboxamide formed in the reaction melted at about 85-86 C.

Analysis.Calculated: C, 62.13; H, 6.82. Found: C, 61.70; H, 6.76.

Following the procedure of Example 3, N-ethyl 8- ethoxybenzodioxane-Z-carboxamide was reduced with lithium aluminum hydride to form 2-ethylaminomethyl- 8-ethoxybenzodioxane which was converted to its hydrochloride salt and purified as such. Z-ethylaminomethyl- 8-ethoxybenzodioxane hydrochloride melted at about 179-180 C.

Analysis.Calculated: C, 57.03; H, 7.36. Found: C,

EXAMPLE 20 Preparation of Z-crotylaminomethyl-8-methoxy- 'benzodioxane Following the procedure of Example 5, 7.5 g. of 2- carboethoxy-8-methoxybenzodioxane was reacted with 5.6 g. of crotylamine. N-crotyl 8-methoxybenzodioxane- Z-carboxamide was obtained from the reaction mixture as a semi-solid residue following evaporation of the ether solvent used in the extraction procedure. Distillation of this residue yielded purified N-crotyl S-methoxybenzodioxane-Z-carboxamide boiling at 151-153 C. at a pressure of about 0.2 mm. of Hg.

Analysis.-Calculated: C, 63.86; .H, 6.51; N, 5.32. Found: C, 63.80; H, 6.71; N, 5.33; n :1.550.

dioxane hydrochloride was prepared from the free base by the method of Example 5. It melted at about 174- 176 C. Analysis.Calculated: C, 58.84; H, 7.05. Found: C,

EXAMPLE 21 Preparation of Z-crotylaminomethyl-8-eth0xybenzoa'ioxane Following the procedure of Example 3, 12 g. of 2- carboethoxy-8-ethoxybenzodioxane was reacted with 25 g. of crotylamine. The N-crotyl 8-ethoxybenzodioxane- Z-carboxamide was obtained as a semi-solid residue after evaporation of the ether solvent used in the extraction procedure. Distillation of this residue yield purified N-crotyl 8-ethoxybenzodioxane-Z-carboxamide boiling at 155-157" C. at a pressure of about 0.1 mm. of Hg; n =1.542. This amide was reduced with lithium alu minum hydride by the procedure of Example 3 to yield 2-crotylaminomethyl 8 ethoxybenzodioxane boiling at about 138-140 C. at a pressure of 0.15 mm. of Hg.

Analysis.Calculated: C, 60.09; H, 7.40. Found: C, 59.55; H, 7.39; n =l.533. The hydrochloride salt of the above compound prepared by the method of Example 2, melted at about 186-188 C.

EXAMPLE 22 Preparation of 2-allylaminomethyl-8-eth0xybenz0'di0xane EXAMPLE 23 Preparation of 2-(3-ethoxypropyl)aminomethyl-8-ethoxybenzodioxane Following the procedure of Example 2, 2-chloromethyl- S-ethoxybenzodioxane was reacted with 3-ethoxypropylamine to yield 2-(3-ethoxypropyl)aminomethyl-S-ethoxybenzodioxane which was purified by distillation. The distillate was converted to 2-(3-ethoxypropyl)aminomethyl- 8-ethoxybenzodioxane hydrochloride by the procedure of Example 2. This compound melted at about 138-139 C.

2 [3 (2 propoxy)propyl]aminomethyl 8 ethoxybenzodioxane hydrochloride was prepared in the same Way using 3-(2-propoxy)propylamine in place of 3-ethoxypropylamine. This compound melted at about 112 C.

Analysis.Calculated: c, 59.20; H, 7.60. Found: 0,

V EXAMPLE 24 Preparation of 2-(/S-hydroxyethyl)amin0methyl-8-ezhoxybenzodioxane Following the procedure of Example 2, 2-chloromethyl- 8-ethoxybenzodioxane was reacted with ethanolamine to yield Z-(B-hydroxyethyl)aminomethyl 8 ethoxybenzodioxane. This compound was distilled and the distillate was converted to 2 (B hydroxyethyl)aminomethyl-8- ethoxybenzodioxaue hydrochloride by the procedure of Example 2. Z-(fl-hydroxyethyl)aminomethyl-S-ethoxybenzodioxane hydrochloride melted at about 165-166 C. Analysis.Calculated: C, 53.88; H, 6.96. Found: C, 54.10; H, 6.94.

2-(3-hydroxypropyl)aminomethyl 8 ethoxybenzodioxane was prepared in the same way using 3-aminopro panol-l in place of ethanolamine. The compound melted at about 129-130 C.

Analysis.-Calculated: C, 55.35; H, 7.30. Found: C, 55.50; H, 7.45.

EXAMPLE 25 Preparation of Z-chlr0methyl-8-methoxybenzodioxane Following the procedure of Example 1, 2-methoxycatechol was reacted with methyl-a,,8-dichloropropionate in the presence of anhydrous potassium carbonate to yield a mixture of 5- and S-methoxy-Z-carbomethoxybenzodioxanes. The reaction mixture contained, in addition to the above two substances, the corresponding free acids which were formed by hydrolysis during the reaction. The solid potassium carbonate was separated by filtration from the reaction mixture and the filter cake was washed with acetone. The combined washings and filtrate were evaporated to dryness in vacuo leaving the benzodioxane isomer mixture in the residue. This residue was dissolved in ether and water. The ether layer was separated, was washed twice with water, three times with sodium hydroxide and again with water. The ether layer was then dried and distilled. The fraction boiling in the range 140-145 C. at a pressure of about 0.5 mm. of Hg was collected. It was partially crystalline and the crystals proved to he 'S-methoxy-Z-carbomethoxybenzodioxane. The entire distillate was recrystallized from a mixture of benzene and hexane. Recrystallization of the crystals thus obtainedrusing the same solvent mixture yielded purified S-methoxy-Z-carbomethoxybenzodioxane melting at about 7476 C. The 5-methoxy-2-carbomethoxybenzodioxane did not crystallize from this solvent mixture. The alkaline washes obtained above when the ether layer containing the benzodioxane esters was Washed with alkali, were combined and acidified thus converting the 5- and 8- methoxy-Z-carboxybenzodioxane from their sodium salts to the free acids. The free acids were extracted into ether. The ether layer was dried and was evaporated to'dryness. The mixture of acids thus obtained was re-esterified by dissolving them in methanol followed by saturating the resulting solution with gaseous hydrogen chloride. The esterification mixture was heated at refluxing temperature overnight and was then evaporated to dryness leaving the mixture of methyl esters of 5- and S-methoxybenzodioxane-Z-carboxylicacids as a residue. This residue was dissolved in ether and the ether layer was Washed successively with water, 5% sodium hydroxide and water. The ether layer was then dried and the ether was removed therefrom by evaporation in vacuo. Recrystallization of the resulting solid from a mixture of benzene and hexane yielded primarily S-methoxy 2 carbomethoxybenzodioxane which was further purified by crystallization from the same solvent mixture to yield, finally, crystalline ma terial melting at about 78-795 C.

' Next, following the procedure of Example 1, S-methoxy-2-carbomethoxybenzodioxane obtained as above was reduced to 2-hydroxymethyl 8 methoxybenzodioxane using lithium aluminum hydride. This compound was purified by distillation and boiled in the range 130140 C. at a pressure of about 0.05 mm. of Hg. Still following the procedure of Example 1, 2-hydroxymethyl-8-methoxybenzodioxane was chlorinated with thionyl chloride in the presence of pyridine and chloroform to yield 2-chloro-- methyl-8-methoxybenzodioxane. Distillation-of the purified 2-chlorornethyl-8-methoxybenzodioxane yielded materialboiling in the range 110-120" C. at a pressure of about 0.5 mm. of Hg. This distillate later solidified to yield crystalline. 2-chloromethyl-8-methoxybenzodioxane melting at about 65-66 C.

.16 EXAMPLE 26 Preparation of Z-n-amylamino-8-methoxybenzodioxane Following the procedure of Example 2, 2-chloromethyl- S-methoxybenzodioxaneahd n-amylamine were reacted to form 2-n-amylamino-8-methoxybenzodioxane which was isolated as thehydrochloride salt melting at about 176" C.

Analysin-Calculated: C, 59.69; H, 8.01. Found: C, 59.72; H, 7.96.

. Following the same procedure Z-(y-methoxy-n-propylaminomethyl)-8-methoxybenzodioxane hydrochloride was prepared by-us ing 'y-methoxy-n-propylamine in place of n-amylamine. The compound melted at about 19 2- 193 C.

Analysis-Calculated: C, 55.35; H, 7.30. Found: C, 55.74; H, 7.45.

Example 27 Preparaton of salts of 2-n-butylamin0methyl-8- ethoxybenzodioxane 0.1 mol of Z-n-butylaminomethyl-S-ethoxybenzodioxane was dissolved in ether and to the solution were added 0.05 mol of maleic acid dissolved in ether. The precipitate of the maleate salt ofZ-n-butylaminomethyl- S-ethoxybenzodioxane was separated by filtration.

0.1 mol of 2-n-buty laminornethyl-8-ethoxybenzodioxane was dissolved in ethanol, and the solution was added to l00 ml. ofa- 1 -M hydrochloric acid solution. The solventswere removed by. evaporation in vacuo leaving as a residue .2-n-butylaminomethyl-S-ethoxybenzodioxane hydrochloride.

Maleate andhydrochloride salts of other substituted aminobenzodioxanes can be prepared in a manner analogous to that set forth in the preceding paragraphs. Furthermore, other organic and inorganic acids can be substituted for maleic acid and hydrochloric acid. Thus, by following the procedures described above, the following salts are exemplary of those that can be prepared: 2-11- allylaminomethyl-S-hydroxybenzodioxane phosphate, 2-npropylaminomethyLS-methoxybenzodioxane tartrate, 2-nbutylaminomethyl-S-ethoxybenzodioxane hydrobromide. 2-n-isoamylaminomethyl-S-methoxybenzodioxane sulfate, and 2-n-butylaminomethyl-8-ethoxybenzodioxane benzoate.

We claim: I 1

1. The method of alleviating agitative and hyperactive disturbances of central origin in a human being sufliering therefrom which comprises administering to said human being in repeated daily dose amounts of about 510 50 mg., an adrenergic blocking agent with central depressant action, said agent being selected from the class consistingof asubstituted benzodioxane and its pharmaceutically acceptable salts, said substituted benzodioxane being represented by the formula wherein Ris a member of the group consisting of hydrogen and alkyl and alkenyl groups having from 1 to 4 carbon. atoms, R is a radical of the group consisting of alkyl, alkenyl, hydroxyalkyl and alkoxyalkyl radicals having from 2 to. 6 carbon atoms.

2. A therapeutic process according to claim 1 in which Z-n-butylamirlomethyl-8-ethoxybenzodioxalne is administered.

3. A therapeutic process accordingto claim 1 in which 2-n-butylaminomethyl-8-methoxybenzodioxane is administered.

4. A therapeutic process according to claim 1 in which 2-allylaminomethyl-8-ethoxybenzod.ioxane is administered.

5. A therapeutic process according to claim 1 in which 2-n-butylaminomethyl-8-hydroxybenzodioxane is ad ministered.

6. A dosage form adapted for therapeutic administration comprising a medicament of the class consisting of an aminobenzodioxane and a pharmaceutically acceptable salt thereof, said aminobenzodioxane being represented by the formula.

wherein R is a member of the group consisting of hydrogen and alkyl and alkenyl groups having from 1 to 4 carbon atoms and R is a radical of the group consisting of alkyl, alkenyl, hydroxyalkyl and alkoxyalkyl radicals 25 having from 2 to 6 carbon atoms; and a pharmaceutical extending medium.

7. A solid dosage form adapted for therapeutic administration by the oral route comprising an effective dose amount of a pharmaceutically acceptable salt of an aminobenzodioxane represented by the formula CHr-NH-Rr O 10 wherein R is a member of the group consisting of hydrogen and alkyl and alkenyl groups having from 1 to 4 carbon atoms and R is a radical of the group consisting of alkyl, alkenyl, hydroxyalkyl and alkoxylalkyl radicals having from 2 to 6 carbon atoms; and a solid pharma- 15 ceutical extending medium.

References Cited in the file of this patent UNITED STATESTPATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2 922 744 January 26, 1960 Jack Mills et a1.. V

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, line 15,, for drum read drug column 4 line 55 for "sloution" read solution --3 column 5 line 66, after ethoxybenzodioxane insert was washed once with water was dried and was then distilled. The fraction boiling in the range 120 to 130 Ca at a pressure of about Oil mm, of Hg, was collected. This fraction comprised purified 2hydroxy=- methyl-S-ethoxybenzodioxane column 6 line 2, for "wtih" read with ----g line 63 for "-n-butyl" read N-n-butyl column 9, line 17, for "ethoxybenzoidioxane" read ethoxy-=- benzodio'xane line '70 for "amylaminomethyll" read amylaminomethyl column l0 line 52 for "succesisve read ee successive column 16 line 14 for "The" read This Signed and sealed this 26th day of July 1960.

(SEAL) Attest:

KARL H. AXLINE ROBERT C. WATSON Attesting Officer Commissioner of Patents

Non-Patent Citations
Reference
1 *None
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3101345 *Apr 18, 1961Aug 20, 1963Thomae Gmbh Dr K2-hydroxymethyl-8-hydroxy-1,4-benzodioxane
US3131195 *Apr 12, 1960Apr 28, 1964Centre Nat Rech ScientBeta-dimethylaminoethyl ester of parachlorophenoxy acetic acid and its pharmaceutically acceptable acid addition salts
US3140290 *Apr 23, 1962Jul 7, 1964Societe Anoayme dite- hybkoxy -
US3144464 *Feb 25, 1960Aug 11, 1964Bayer AgBeta-phenyl-beta-hydrocarbon-hydracrylic acid-2-nu, nu-diethylamine ethyl esters
US3170933 *Jan 28, 1963Feb 23, 1965Boehringer Sohn Ingelheim2-(gamma-methoxypropyl-aminomethyl)-1, 4-benzodioxane
US5096908 *May 4, 1990Mar 17, 1992Eli Lilly And CompanyMethod of inhibiting gastric acid secretion
US5158956 *May 29, 1991Oct 27, 1992Eli Lilly And CompanyMethod of inhibiting gastric acid secretion with benzodioxanes
US5258379 *Jun 15, 1992Nov 2, 1993Eli Lilly And CompanyMethod of inhibiting gastric acid secretion with n-arylpiperazines
DE1294391B *Jul 17, 1963May 8, 1969Philips NvBasisch substituierte 1, 4-Benzodioxanderivate und deren pharma-kologisch nicht giftige Salze und Verfahren zu deren Herstellung
Classifications
U.S. Classification514/452, 549/366
International ClassificationC07D319/20
Cooperative ClassificationC07D319/20
European ClassificationC07D319/20