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Publication numberUS3062828 A
Publication typeGrant
Publication dateNov 6, 1962
Filing dateFeb 27, 1962
Priority dateFeb 27, 1962
Publication numberUS 3062828 A, US 3062828A, US-A-3062828, US3062828 A, US3062828A
InventorsCarl D Lunsford
Original AssigneeRobins Co Inc A H
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
US 3062828 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent Ofitice 3,062,828 Patented Nov. 5, 1 952 3,062,828 5-(ALKOXYPHENOXYMETHYL)-2- OXAZGLIDONES Carl D. Lunsford, Richmond, Va., assignor to A. H. Robins Company, Inc., Richmond, Va, a corporation of Virginia No Drawing. Filed Feb. 27, 1962, Ser. No. 176,093 8 Claims. (Cl. 260-367) The present invention relates to certain ether-substituted heterocyclic compounds and is more particularly concerned with certain substituted S-aryloxy methyl-Z-oxazolidones and related compounds which may be additionally substituted at the N- or 3-position of the oxazolidone ring. The oxazolidone ring may also be referred to as the oxazolidinone ring. The present application is a continuation-in-part of my prior-filed copending applications Serial No. 680,647, filed August 28, 1957, now abandoned, and Serial No. 821,356, filed June 19, 1959.

The concept of the novel compounds constituting the present invention may be illustrated by the following structural formula:

wherein X is hydrogen or a lower-alkoxy substituent group, such as methoxy, ethoxy, and the like, at least one X being lower-alkoxy, and

R is hydrogen or a hydrocarbon radical such as alkyl (including cycloalkyl) and aralkyl.

The compounds which are the subject of this invention are related in their pharmacological activity to compounds of Well-known therapeutic value which might be characterized as substituted propanediols or glyceryl ethers, for example, 3 (o toloxy) 1,2 propanediol (mephenesin), 3 (o methoxyphenoxy) 1,2 propanediol (glyceryl guaiacolate), 3-(o-toloxy)-2-hydroxypropyl 'carbamate (Tolseram, US. 2,609,386, Lott et al.), Z-methyl- 2-propyl-1,3 propanediol biscarbamate (meprobamate, Equanil, US. 2,724,720, Bergel et al.), and 3-(o-methoxyphenoxy)-2-hydroxypropyl carbamate (Robaxin, US. 2,770,649, Murphey).

In general, the prior art compounds have been found useful for muscle relaxant conditions susceptible to myanesin therapy where the action is central with some slight myoneural depression. The sites of the depression appear to be in the brain stem at the level of the thalamus and below and in the spinal cord. Such action is characterized by producing Weakness and flaccidity of the skeletal muscle. The complementary sedative effects of these compounds as well as their muscle relaxant action are temporary in nature lasting for mephen'esin for a perihave been based on the degree of antagonism to such convulsions. The duration of action of meprobamate or mepromate is reported to be about three times longer than that of mephenesin. The usefulness of many of these compounds, such as mephenesin, has been lessened due example, cycloalkyl, aralkyl and the like.

to their relatively brief duration of action necessitating frequent large doses and as always workers in the art today are striving for increased activity to lessen dosages and to cut down on any untoward side effects.

The patented prior art into which the compounds of the present invention fall can be distinguished. U.S. 2,- 399,118, 2,437,388, 2,437,389, and 2,437,390 to Homeyer describe generally the preparation of 2-oxazolidone compounds in which the 5-position is substituted by alkyl or aryl.

However, 2-oxazolidone ether compounds such as 5- (o-alkoxyphenoxymethyl)-2-oxazolidones have not been described in the prior art to date.

Therefore, it is an object of this invention to provide certain novel extracyclic ether-linked oxazolidone-2 compounds.

It is a further object of the present invention to provide alkoxyphenoxy ethers of oxazolidone-Z compounds wherein the extracyclic other group is attached to a methyl group located at the 5-position of the oxazolidone-Z ring.

It is a further object of this invention to provide such ethers of oxazolidone-Z wherein additionally the N- or 3-position of the oxazolidone ring is substituted by aliphatic, cycloaliphatic, or aromatic radicals.

It is a still further object of this invention to provide processes for the formation of ethers of oxazolidone and intermediate compounds for the formation thereof.

It is an additional object of this invention to provide novel muscle relaxant compounds having satisfactory and advantageous activity when compared with known compounds.

Other objects of the invention will become apparent to those skilled in the art to which this invention pertains.

The novel group of compounds constituting the present invention includes 5-(o-alkoxyphenoxymethyl)-2-ox azolidones in which the N- or 3-position may or may not be substituted by a hydrocarbon radical. Typical of substituent hydrocarbon radicals are alkyl, cycloalkyl, aralkyl, and the like. Preferably the N- or S-position is unsubstituted or substituted by a lower-alkyl radical.

These compounds may also be referred to as 5-(2'-alkoxyphenoxymethyl) 2 oxazolidones. The dialkoxy com pounds are preferably referred to as 5-(2,6-dia1koxyphenoxymethyl)-2-oxazolidones, but generically are also 5-(o-alkoxyphenoxymethyl)-2-oxazolidones. 4 v

It has been found that the S-(o-methoxyphenoxymthyl)-2-oxazolidone compounds are particularly active when the N- or 3-position is hydrogen or methyl, e.g., the 5 (o methoxyphenoxymethyl) 2 oxazolidone, 5- (2,6 dimethoxyphenoxymethyl) 2 oxazolidone, or 5 (0 methoxyphenoxymethyl) N methyl 2 oxazolidone compounds. Other useful though not preferred compounds are those wherein the N- or 3-position is substituted by groups other than lower-alkyl, such as for Typical of other operable N-substituted compounds are the S-(omethoxyphenoxymethyl) N benzyl 2 oxazolidone and 5 (o methoxyphenoxymethyl) N cyclohexyl 2- oxazolidone.

The 5- (o-alkoxyphenoxymethyl) 2 oxazolidones (including the 2,6'-dialkoxy compounds) may be conven iently prepared by reacting a selected 3-(o-alkoxyphenoxy)-1,2-propanediol and urea in approximately 1:2 molar quantities under ring closure conditions at elevated temperatures of approximately to 200 C. These oxazolidones may also be prepared by reacting 1,2-epoxy 3-(o-alkoxyphenoxy)propanes with urea, or with sodium cyanate and hydrochloric acid, or with ethyl carbamate under basic catalysis. 3-(o-alkoxyphenoxy)-l-hydrocarbon substituted amino-Z-propanols may be prepared by opening the ring of the unsubstituted oxazolidone compound by reduction with lithium aluminum hydride 'to produce the corresponding 1'4-rnethylaminopropanol, and then reclosing the ring using an alkyl carbonate such as diethyl carbonate, or carbonyl chloride, thereby forming the desired N-methyl oxazolidonc-Z-compound.

. As an alternative method of preparation, a 3-(o-alkoxyphenoxy)-l-chloro-2-propanol (e.g., glyceryl guaiacol ether chlorinated in the 1 position) and urea may be reacted in at least 1:2 molar quantities to give a -(-oalkoxyphenoxymethyl)-2-o: azolidone. Preparation of compounds substituted in the N-position may be accomplished by aminating the starting chloropropanol with a primary amine such as monomethylamine, cyclohexylamine, or the like, and subsequently effecting ring closure of the resulting aminopropanol to give the desired N- or 3-hydrocarbon substituted-Z-oxazolidone by means of a dialkyl carbonate such as diethyl carbonate, or carbonyl chloride. Alkyl carbonates in general are suitable for effecting the formation of the 2-oxazolidones and typical carbonates found useful in the practice of this step of the process are diethyl carbonate, di-n-propyl carbonate, di-n-butyl carbonate, di-sec-butyl carbonate, and the like. Thus, as a further mode of preparation, the 3-(0- alkoxyphenoxy)-l-chloro-2-propanol may be animated with ammonia or a primary amine prior to ring closure with carbonyl chloride or a dialkyl carbonate. The intermediate compound in the preparation is a 3-(o-alkoxyphenoxy)-1-amino-2-propanol. Subsequent ring closure proceeding from the beta-aminoalcohol produces either the unsubstituted 5-(o-alkoxyphenoxymethyl) 2 oxazolidone or the N- or 3-hydrocarbon substituted derivative, depending upon the exact aminopropanol compound used.

Evaluation of the compounds of the present invention by standard pharmacological tests indicates utility thereof as skeletal muscle relaxants where the compounds are predominantly strychnine antagonists in their anti-convulsant behavior. The 2,6-dialkoxy compounds are useful interneuronal blocking agents or depressants of central synaptic transmission, being extremely effective against electro-shock-induced convulsions, especially the compound 5-(2,6'-din1ethoxyphenoxymethyl)-2-oxazolidone, which activity is indicative of ultimate anticonvulsant, relaxant, tranquilizing, and similar clinical use in human beings.

The following examples illustrate the compositions and processes of the present invention.

EXAMPLE 1 5-(o-Methoxyphenoxymethyl) -2-Oxazolidone Method A.-A mixture of 893 grams (4.5 moles) of glyceryl guaiacol ether (glyceryl guaiacolate) and 542 grams (9.0 moles) of urea was heated for six hours at 175 to 190 C., cooled and dissolved in 1500 ml. of 95% ethanol. This ethanolic solution was filtered while hot, and the reaction product crystallized on cooling. The crystallized product was filtered and recrystallized twice from ethanol in the manner described above to produce the pure 2-oxazolidone. A yield of 320 grams (34%) of 5-(o-methoxyphenoxymethyl) 2 oxazolidone having a melting point between 140.5 and 142 C. was obtained. The compound produced was a White powder which was found to be insoluble in water but soluble in alcohol and propylene glycol. Yields in several additional runs ranged from 25 to 37%. In these runs acetone was used as a substitute for ethanol.

Analysis-Calculated for C H NO C, 59.18; H, 5.87; N, 6.27. Compound produced: C, 59.05; H, 5.81; N, 6.11.

Method B.-The compound of this example was alternately prepared by heating a mixture of 101 grams (0.47 mole) of 3-(o-methoxyphenoxy)-1-chloro-2-propanol and 1.68 grams (2.8 moles) of urea and stirring for 2.5 hours at 180 to 190 C. The reaction mixture was partitioned between water and chloroform. The chloroform extract was dried over sodium sulfate and the solid product was precipitated with petroleum ether (B.P. 65110 C.)

and crystallized from ethanol. The product yield was 45 grams (43%) and the product had a melting point of 143 to 144 C. When the product was mixed with a substantially equal amount of S-(o-methoxyphenoxymethyl)-2-oxazolidone prepared according to method A, the melting point of the mixture was not depressed.

Some of the starting materials of this invention used in the formation of the novel compounds thereof are in themselves new, and a method for their preparation is also included.

EXAMPLE 2 5 (o-Methoxyphenoxym ethyl -3 -Merhyl-2-Oxazolidone Preparation A .-3-(o-methoxyphenoxy) -l-methylamino-2-propanol: A suspension of 37.9 grams (1.0 mole) of lithium aluminum hydride in 200 ml. of dry ether and 800' ml. of dry tetrahydrofuran was stirred and refluxed under anhydrous conditions for 1.5 hours. There was added to this mixture 112 grams (0.5 mole) of 5-(0- methoxyphenoxymethyl) 2 oxazolidone portionwise so that gentle refluxing was maintained. After complete addition, the mixture was stirred and refluxed for two hours, cooled, and excess hydride decomposed with water. About one liter of chloroform was then added and the mixture filtered. The filtrate was concentrated until most of the cholorform was removed, and then diluted with 800 ml. of dry ether. On standing, the product precipitated as white needles. Yield 55.9 grams (53%); M.P. 77.5 to 78 C. The melting point was not elevated by recrystallization from isopropyl ether.

Analysis.Calculated for C H NO C, 62.11; H, 8.11. Compound produced: C, 62.14; H, 7.84.

Preparation B.-3- (o-methoxyphenoxy) -1-methylamino-2-propanol from 3-(o-methoxyphenoxy)-l-chloro-Z- propanol: A solution of 56 grams (0.39 mole) of 3-(0- methoxyphenoxy)-1-chloro-2-propanol and 34 grams (1.1 moles) of monomethylamine in 500 ml. of absolute ethanol was heated in a sealed bottle on the steambath for 22 hours. The excess amine and alcohol were removed by distillation and the product was distilled at 164 C./0.6 mm. and crystallized from isopropyl ether. Yield: 23 grams (29%) of 3-(o-methoxyphenoxy)-1-methylamino-Z-propanol which had a melting point of 78 to 79 C.

FORMATION OF 5-(oMETHOXYPHENOXY)-3-METHYL- 2-OXAZOLIDONE A mixture of 45.5 grams (0.20 mole) of 3-(o-rnethoxyphenoxy)-1-methylamino-2-propanol, 26.6 grams (0.20 mole) of diethyl carbonate, and 0.5 gram of sodium metal in 200 ml. of n-heptane was refluxed under a moisture trap (Dean and Stark) until no more methanol separated from the distillate. The mixture was cooled, causing separation of an oil which was removed and crystallized from absolute ethanol. Yield: 16.5 grams (35%) of 5-(o-methoxyphenoxy)-3-methyl-2-oxazolidone having a melting point of 73 to 75 C. The compound produced was a white crystalline solid found to be soluble in aqueous alcohol and propylene glycol but insoluble in water.

Analysis.-Calculated for C H NO C, 60.75; H, 6.37. Compound produced: C, 60.90; H, 6.15.

When carbonyl chloride was used in place of diethyl carbonate in approximately equimolar quantities, but employing low temperatures, an equivalent yield of the 2- oxazolidone of this example was obtained.

EXAMPLE 3 5 -(0-M ethoxyphenoxymethyl )-3-Cyclohexyl-2-0xazolidone Preparation of 3-(0-meth0xyphen0xy)-1-cycl0hexyl amin0-2-propanol.A mixture of 86.5' grams (0.4 mole)- of 3-(o-methoxyphen0xy)-1-chloro-2-propanol and 158 grams (0.8 mole) of cyclohexylamine was heated on a steambath for 22. hours, cooled, and partitioned between chloroform and water. The chloroform layer was dried over sodium sulfate and concentrated. The residue distilled at 168 C./0.06 mm. Product yield was 53 grams (35%) of the 3-(o-methoxyphenoxy)-1-cyclohexylamino- 2-propanol having a melting point of 61.5 to 62 C. after recrystallization from isopropyl ether.

' FORMATION OF 5-(O-METHOXYPHENOXYMETHYL)- 3-CYCLOHEXYL-Z-OXAZOLIDONE A solution of 28 grams (0.093 mole) of 3-(o-methoxyphenoxy)-1-cyclohexylamino-2-propanol, as prepared above, and 11 grams (0.093 mole) of diethyl carbonate in 250 ml. of n-heptane was stirred and heated for three hours so that the ethanol formed was distilled from the mixture. At the beginning of each hour, a 0.1 gram piece of sodium metal was added to the mixture. When the reaction was complete, the mixture was cooled and the heptane was decanted from the precipitated product. A few ml. of ethanol was added, and the material was taken up in chloroform. The chloroform solution was washed and dried over sodium sulfate and concentrated. The residue was crystallized from iso-octane and recovered as 5-(o-methoxyphenoxymethyl)-3-cyclohexyl-2- oxazolidone. This compound was isolated in the form of clear prismatic crystals having a melting point of 68 to 69 C. The crystalline material was found to be soluble in ethanol and insoluble in water.

Analysis-Calculated for C17H23NO4: 4.65% N. Compound produced: 4.59% N.

The 5-(o-methoxyphenoxymethyl)-3-cyclohexyl-2-oxazolidone may also be prepared by using equimolar quantitles of carbonyl chloride in place of diethyl carbonate, as in Example 2.

EXAMPLE 4 5 -(-M ethoxyphenoxymethyl -3-Benzy I-Z-Oxazolidone In the manner set forth in Example 3, the intermediate compound 3-(o-methoxyphenoxy)-1benzy1amino-2-propanol was prepared by the use of benzylamine and converted to the compound -(o-methoxyphenoxymethyl)-3- benzyl-Z-oxazolidone. This 2-oxazolidone compound upon crystallization had a clear prismatic crystalline form and a melting point of 59 to 59.5 C. The compound was found to be soluble in ethanol and slightly soluble (1 to 2%) in 50% polyethylene glycol-300.

Analysis.Calculated for C H NO Compound produced: N, 4.59%.

EXAMPLE 5 5 -(2,6'-Dimethoxyphenoxymethyl )-2-0xazolid0ne A mixture of 35 grams (0.153 mole) of 3-(2,6-dimethoxyphenoxy)-1,2-propanediol and 18.3 grams (0.306 mole) of urea was heated rapidly to 170 C. and maintained at 170190 C. for five hours. The resulting mixture was poured into water and extracted with chloroform. The chloroform extract was dried over sodium sulfate, filtered and concentrated, and the residue was distilled at reduced pressure. The main fraction boiled at 238-245 C./0.22 mm. This was crystallized from ethyl acetate and yielded 21 grams (54%); melting point l13115 C. After two recrystallizations from ethyl acetate, the melting point was constant at 117-118.5 C.

Analysis-Calculated for C H NO C, 56.91; H, 5.97; N, 5.53. Found: C, 57.16; H, 6.01; N, 5.70.

EXAMPLE 6 5-(2,6'-Diprop0xyphenoxymethyl) -2-oxaz0lid0ne This compound is prepared in the manner of Example 5, by reacting 3-(2,6'-dipropoxyphenoxy)-,2-propanedio1 (or the corresponding l-chloro-2-propanol or 2-hydroxyl-propyl-carbamate) with urea and separating, working up the product, and purifying it in the usual manner.

Standary pharmacological tests in animals of compounds of this invention have indicated that such compounds are of definite value in relieving severe skeletal muscle spasms. Additionally, these compounds have ex- TABLE 1.--ORAL PROTECTIVE DOSAGE (PDro) IN RATS AFTER STATED ABSORPTION TIME BEFORE A CHAL- LENGI NG INJECTION OF STRYCHNINE Minutes 30 60 120 5-(o-Methoxyphenoxymethyl)-2-oxazolidone,

mg. 135 5-(o-Methoxyphenoxymethyl)-3-methyl-2- oxazolidone, mgJag 230 174. 6 Mephenesin, rug/kg 312 633 Tolseram, mgJ 171 433 The results indicate that the amount of 5-(o-methoxyphenoxymethyl)-2-oxazolidone required to protect (PD at the 30-minute absorption interval is only about onethird the amount of mephenesin required, and at the 120-minute absorption interval is only about one-seventh of the amount of mephenesin and one-quarter of the amount of mephenesin carbamate (Tolseram) required. The results also indicate that the amount of 5-(o-methoxyphenoxymethyl)-3-methy1-2-oxazolidone required at the 30-minute absorption interval is only about two-thirds of the amount of mephenesin required. The results finally indicate both increased potency and improved duration of effect over the known mephenesin and mephenesin carbamate.

The lack of effectiveness of these compounds of the invention in protecting against metrazol shock together with the high degree of effectiveness against strychnine in animal experiments indicates that the locus operandi of these compounds is predominantly on the spinal cord and presumably is an internuncial type of depression.

As a test for measuring the effectiveness of these compounds as strychinne antagonists, the following standardized method was used:

The compound (e.g., (a) 5-(o-methoxyphenoxymethyl)-2-oxazolidone or (b) 5-(o-methoxyphenoxymethyl)- 3-methyl-2-oxazolidone) was suspended in a 0.5% methylcellulose suspension, using the Potter glass homogenizer to obtain a stable, even suspension. Female white rats (Rockland Farms) weighing from -420 grams were used throughout the study. Graded oral doses of the drug were given to ten rats per dose level, with three to five dose levels being studied per drug. The volume of all oral doses of the drug was maintained at 4 ml. per 100 grams body weight. At intervals of 30 and minutes after the oral administration of the drug, the animals were challenged with an intraperitoneal dose of 3 mg./kg. of strychnine in a volume of 1 ml. per 100 grams body weight. In a few instances, a challenge was also made at 60 and 90 minutes. For each time interval, the 50% protective dose (PD was calculated by the method of Litchfield and Wilcoxon. Survivals of three hours or more were taken as evidence of protection.

By this method, the oral protective dose for 50% of the rats was found for (a) to be mg./kg. when an interval of 30 minutes was allowed between administration of the drug and the strychnine; and 86 mg./kg. when an interval of 120 minutes was allowed between administration of the drug and the strychnine. Under the same test conditions, the oral protective dose for 50% of the animals, in the case of mephenesin, was 312 mg./kg. at 30 minutes and 603 mg./kg. at 120 minutes. A similar comparison was made with mephenesin carbamate (Tolseram) and the figures in this case were found to be 171 mg./kg. at 30 minutes and 483 mg./kg. at 120 minutes. The derivatives of this invention may be embodied in For example, 5-(o- P. at

the same pharmaceutical forms as 3-(ortho-toloxy)-l,2-

propanediol, e.g., capsules, tablets, solutions and elixirs; and may be administered in the same manner and in substantially reduced doses.

It is to be understood that the invention is not limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

I claim:

1. -(o-lower-alkoxyphenoxymethyl)-2-oxazolidine.

2. 5 (o methoxyphenoxymethyl) 3 methyl 2- oxazolidone.

3. 5 (o methoxyphenoxymethyl) 3 benzyl 2- oxazolidone.

4 5 (o methoxyphenoxymethyl) 3 -cyclohexyl 2- oxazolidone.

' 5. A 2 oxazolidone compound of the following formula:

wherein: X is selected from the group consisting of hydrogen and lower-alkoxy, and at least one X is loweralkoxy, and R is selected from the group consisting of hydrogen, lower-alkyl, cyclohexyl, and benzyl.

6. A process of preparing S-(o-methoxyphcnoxymethyl)-2-oxazolidone which comprises heating a mixture of about two molar equivalents of urea and one molar equivalent of a substance selected from the group consisting of the guaiacol ether of glycerol and the guaiacol ether of glyceryl chlorhydrin at a temperature of at least C. for a period of at least three hours to form said oxazolidone, dissolving said oxazolidone, in a suitable solvent and crystallizing and recovering said oxazolidone.

7. 5-(o-methoxyphenoxymethyl)-2-oxazolidone.

8. 5-(2,6-dimethoxyphenoxymethyl)-2-oxazolidone.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,062,828 November 6, 1962 Carl D Lunsford It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, lines 8 and 9, for "(-o-alkoxyphenoxymethyl" read (0-alkoxyphenoxymethyl line 23, for "animated" read aminated column 4, line 26, for "cholorform" read chloroform column 5, line 67, for ",2-" read l,2- column 7, line 12, for "oxazolidine" read oxazolidone column 8, line 12, after "oxazolidone", second occurrence, strike out the comma.

Signed and sealed this 23rd day of April 1963,,

(SEAL) Attest:

ERNEST w. SWIDER DAVID LADD Attesting Officer Commissioner of Patents

Non-Patent Citations
1 *None
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3268546 *May 12, 1964Aug 23, 1966Mcneilab IncCertain 2-benzoxazolinone compounds having methoxy and halo substituents
US4188323 *May 11, 1978Feb 12, 1980A. Menarini S.A.S.Derivatives of 2-oxazolydone and methods for preparing the same
US7998992 *Mar 27, 2008Aug 16, 2011Institute Of Medicinal Molecular Design, Inc.Oxazolidinone derivative having inhibitory activity on 11β-hydroxysteroid dehydrogenase type 1
EP0086403A2 *Feb 3, 1983Aug 24, 1983MERCK PATENT GmbH2-Oxazolidine-ones
WO2008120655A1Mar 27, 2008Oct 9, 2008Inst Med Molecular Design IncOxazolidinone derivative having inhibitory activity on 11β-hydroxysteroid dehydrogenase type i
U.S. Classification548/232
International ClassificationC07D263/24
Cooperative ClassificationC07D263/24
European ClassificationC07D263/24