IL28125A - 5-(aryldehydropiperidinyl-(and aryldehydropyrrolidinyl)-lower-alkyl)-2-oxazolidinones - Google Patents

Description

P.A. 08125/11 the same*, Of special interest are compounds designated dehydropyrrolidinyl)-ethyl7-2-oxazolidinonest and acid addition salts thereof.

, .;. . ·. . ■ ' , . . · , / . . : · The invention is especially concerned with 5- ('. 601(1 ^-phenyl-*dehydropiperidinyl- and 3-phen¾dehydropyrrolidinyl ;· lower^all.yj^-2-oxazolidi^ having the, formulat m - CR'R« - Ctt··-' '(CHR»)n - A (l) wherein n is selected from the group consisting of 1 and 2, wherein R is selected from the group consisting of hydrogen, lower*-alky1 , cycloalkyl, alkylcycloalkyl, phenylalkyl, and substituted phenyl-alkyl wherein the eubstltuents are selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, trifluoro-methyl, lower-alkyl-thio, di-lower-alkylamino , and nitro, wherein R' is selected from the group consisting of hydro en and methyl, wherein Rw is selected from the group consisting of hydrogen and methyl, P.A. 28125/11 wherein A la phenyl or substituted phenyl attached to a carbon atom of the ring double bond and in the 3 o ^ position of the heterocyclic ring, remaining vaienoes of the carbon atoms of thfc heterocyclic ring being satisfied by hydrogen and zero through four, methyl groups, wherein substituted phenyl substituents are. selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, tri luorq-methyl, lower-alkyl-thio, di-lower-alkylamino, nitro, and hydroxy,.\ and (B) acid addition salts thereof. Since els-trans geometric Isomerism can exist,' due to. the presence of the heterocyclic ring, the foregoing formula and the present invention is Intended to include and cover individual isomers of the compounds as well as isomeric mixtures thereof* The compounds of Formula I are primarily useful as major tra quilizers. Compounds .which block aggressive behavior in fighting mice may be classified as major tranquilizers [Yen, C.Y., et al . , Arch. Int. Pharmacodn .123, 179 (1959)]. The compounds of the pre sent invention possess this property to a high degree and are therefore classified as such.

It is accordingly an object of the present invention to provide novel and useful compounds, compositions thereof, methods of producing the same, and methods for the utilization thereof. Add tional objects will become apparent hereinafter and still others will be apparent to one skilled in the art.

In the definition of: symbols in the formulas hereof and wher they appear elsewhere throughout this specification, the terms have the following significance.

A "substituted phenyl" radical is a phenyl radical substitut by aay. radical or radicals which are not reactive or otherwise interfering under the conditions of reaction, such as nitro, lowe thio alkoxy, lower-alkyliaeseapfee, lower-alkyl, di-lower-alkylamino, hydroxy, trifluoromethyl, halo, «« -·fefee—l-i-k-e-. The substituted phenyl radicals have preferably no more, than one to three sub-stituents such as those given above and, furthermore, these sub-stituents can be in various available positions of the phenyl nucleus and, when more than one substituent is present, can be th same or different and can be in various position combinations relative to each other. The lower-alkyl, lower-alkoxy, lower- thio alkyl»e¾?e«P'fe METHOD OF PREPARATION The compounds of the foregoing Formula I may be prepared according to the following general scheme: A starting oxazolidinone compound of the formula: RN - CR'R* - CH - (CHR")n - CHR" - X (X) wherein R, R', and R" have the meanings assigned in Formula or a tosyl group n is 1 or 2, and X is a halogen atom/ is reacted in a conventiona halogen displacement reaction with a compound of the formula: H— -* ΰ A (XI) wherein - N u 4- A is the remainder of the molecule which is desir to be introduced into the alkyl chain at the 5 position of the oxazolidinone ring, to split out a hydrogen halide.

A further procedure for preparing the compounds of the pre-sent invention (I.) comprises the step of dehydrating a compound of the fo A1-IR-39A ' wherein R, R1 and R" all have the values previously assigned wherein - ^s is a saturated heterocyclic ring selected from pyrrolidin^lfa^nddpigeridinyl, wherein A is phenyl or substituted phenyl/ attached to a carbon atom in the 3 or 4 position of the heterocyclic ring, wherein OH is attached to the same carbon atom as A, the remaining valences of the carbon atoms of the heterocycl ring being satisfied by hydrogen and zero through four methyl groups, at least one of the ring carbon atoms adjacent the carbon atom bearing the A and OH groups having at least one hydrogen .atom attached thereto, with an acid to cause splitting out of water and formation of a compound having the Formula (I) hereinbefore given. These starting compounds are prepared from the. corresponding saturated hydroxy cyclic amine and the selected 5-(2~haloalkyl) -2-oxazolidin'one (X), also according to the conventional halogen replacement reaction. Further details of both the halogen replace ment and hydrolysis procedures will be given hereinafter..

In the event R in Formula XX is benzyl, the R group may if desired be converted from benzyl to hydrogen with an alkali metal, e.g. , sodium, and liquid ammonia. The procedure of this step may be generally described as a process for the production of a starting compound of Formula XX, wherein R is hydrogen, and acid addition salts thereof, which comprises the step of subjecting a starting compound of said Formula XX, wherein R is a benzyl radica to debenzylation .

Starting compound X is provided in any one of a variety of ways. It -is preferably provided by reacting a 3-pyrrolidinol with phosgene and then subjecting the intermediate reaction product to reaction with a tertiary amine, e.g., pyridine or other tertiary heterocyclic amine, dlmethylaniline or other di Ikylarylamine , or trlethylamlne or other tria Ikyln iine , to produce the desired starting 5 - (ha loa Ikyl) -oxazolidlnone (X). This novel procedure A1-IR-39A - 'J " starting materials, and is adaptable to considerable variations i the molecule. The starting 3-pyrrolidinols wherein R' and R" are other than hydrogen may be obtained by the procedure of Ryan et a J. Org. Chem. 27., 2901-2905 (1962) or according to Lunsford U. S. Patent 2,830,997 and other sources cited therein.

-HALOALKYL-2 -OXAZOLIDINONE PRODUCTION As a general procedure for this reaction, the following is representative : A solution of 1-1.25 parts of carbonyl dihallde, e.g., phos- gene (carbonyl dichloride) or carbonyl dibromide, dissolved in chloroform, toluene, benzene, tetrahydrofuran, or other non- reactive · organic solvent is prepared in a suitable container such as a three-neck, round-bottom flask equipped with mechanical stir dropping funnel, pot thermometer and condenser, and to this solution is added one part of the properly substituted 3-pyrroli- dinol.

The reaction mixture is cooled in an ice. bath and the additi is at such a rate that the pot temperature is kept between zero and 25°C. or with sufficient cooling to control the exothermic re action. After the addition of 3-pyrrolidinol is complete, stirri is continued at the above temperature for one-half to one hour. Then, with continued cooling and stirring, two parts of a tertiar amine such as pyridine or other tertiary heterocyclic amine, di~ methylaniline or other dialkylarylamine , or triethylamine or othe trialkylamine, is added and the mixture allowed to warm to room temperature. The solution is extracted with dilute acid, then ■ dilute base, and finally with water. The organic layer is dried ■ over sodium sulfate or other suitable drying agent and the solven removed at reduced pressure. The residual neutral material may then either be distilled in vacuo or purified by crystallization from a non-polar organic solvent. The yield of the purified pro AHR-39A *' details.

HALOGE REPLACEMENT The halogen of the starting 5- (2-haloalkyl) -2-oxazolidinones (Formula X) may be replaced by reaction of the selected starting compound with any one of various reactants H - as alread indicated previously.

Compounds of Formula (X) wherein X is halogen other than chlorine may also be employed and are prepared by allowing the chloro compound to react with halide salts such as sodium iodide or bromide in an appropriate solvent such as acetone or methyl-ethyl ketone .

To replace the halogen in a compound of Formula (X) with the selected amine H - ^^^" the haloalkyl oxazolidinone (X) may be heated at reflux either with a large excess of the appropriate amine or with a small excess of the amine in an appropriate solven such as ethanol. The time required for these reactions usually ranges from about 3 to 18 hours. The solvent or excess amine may then be removed at reduced pressure and the residue partitioned between chloroform and dilute aqueous base. The chloroform solution may be dried over an appropriate drying agent such as sodium sulfate and the solvent removed at reduced pressure. Salts of th residual amine may then be prepared by dissolving the free base in an appropriate solvent such as alcohol and adding an acid such as anhydrous hydrochloric acid, maleic acid, or fumaric acid.

In general, the 5- (aminoalkyl) -2 -oxazolidinone compounds are prepared by heating a solution of the selected 5- (2-haloalkyl) -2-oxazolidinone and the selected amine in a suitable reaction solven e.g., ethanol, a higher boiling alcohol such as butanol, a hydrocarbon solvent such as toluene, or the amine itself may be the solvent in some cases. A reaction temperature from about, room temperature to about 120°C. is usually employed, preferably 100 AHR-39A the speed of reaction, while temperatures below 100°C. frequently require undesirably lengthy reaction periods. The amine may be employed in excess, or an inorganic base such as potassium carbon can be used as a hydrogen acceptor. The resulting solution of th amine reaction product is concentrated, as in vacuo, and the amin product isolated, usually as the crystalline hydrohalide salt corresponding to the halogen in the starting haloalkyl compound. In some cases the hydrohalide salt, e.g., the hydrochloride, crys tallizes as the hydrate. In cases where a crystalline salt is difficult or impossible to obtain, the free basic amine itself ma be distilled and crystallized from a solvent or solvent mixture or alternatively isolated as an oil by fractional distillation. Extraction of the reaction product with a suitable solvent, e.g., ether, benzene, toluene, or ethyl acetate, frequently assists in recovering all of the available product for isolation by crystallization and aqueous acid, e.g., two Normal HC1, or anhydrous ketones, e.g., methyl ethyl ketone, are frequently of value as th solvent or medium from which crystallization or recrystallization is effected. Where the free base is desired, this may be obtaine conventionally by neutralizing the reaction product or a solution of the isolated salt with a base such. as ammonia, ammonium hydroxide, sodium carbonate, or other suitable alkaline material, extracting the liberated base with a suitable solvent such as ethyl acetate or benzene, drying the extract and evaporating to dryness in vacuo or fractionally distilling, or in other conventional-manner. Numerous acid addition salts may be prepared from the free bases, either isolated or without isolation from th reaction product. Reference should be made to the appropriate examples for further particulars and details.

According to the hydrolysis procedure, a compound of Formula I is produced by hydrolysis of a compound of Formula XX, which AHR-39A stituent in the 3 or 4 position thereof, namely, in the same position as the phenyl or substituted phenyl substituent, with a acid, including the use of a compound which is capable of formin an acid in situ in the reaction mixture in question. It is advantageous to use a strong mineral or organic acid such as a hydrogen halide, e.g., hydrochloric acid, or sulfuric acid, eith concentrated or dilute, or in admixture with acetic acid, or sulfonic, benzenesulfonic, p. toluene sulfonic acid, or trichlor acetic acetic, or a compound which is capable of forming a stron acid in the reaction mixture, the dehydration thereby proceeding especially readily and smoothly. As an example, of such latter type compounds may be mentioned inorganic acid halides such as thionyl chloride, sulfuryl chloride, and phosphoric acid halides, such as phosphorus oxychloride and phosphorus trichloride, organ acid halides such as acetyl chloride and benzoyl chloride, and acid anhydrides such as sulfur trioxide, and the like.

In addition, weaker acids or compounds which are capable of forming weaker acids in the reaction mixture may sometimes be us to effect the dehydration. As examples may be mentioned phospho acids, especially dilute phosphoric acid, dichloroacetic acid, monochloroacetic acid, oxalic acid, succinic acid, citric acid, boric acid, boric acid triacetate, and the like.

The said dehydration may" in many cases be effected even wi very small amounts of the said acids or acid-forming compounds a according to; a specially convenient modification of the procedur such an acid or compound is used in the dehydration step in an amount substantially smaller than that equivalent to the saturat hydroxy-substituted starting material. In this manner, the formation of byproducts which might otherwise result from the dehydration is avoided or limited.

Further, it has been found that the dehydration proceeds AHR-39A such as acetic acid anhydride or the like.

Likewise, it is sometimes advantageous to undertake the dehydration step in the presence of a solvent. Examples of suitab solvents are' hydrocarbons , especially aromatic hydrocarbons such as benzene, toluene, or xylene, . halogenated hydrocarbons such as chloroform, a lkanols such as methanol and ethanol, ethers, acetic acid, and the like.

The dehydration in many cases proceeds smoothly even at roo temperature and, especially in cases where the dehydration is effected by a strong acid or a compound capable of forming such strong acid in the reaction mixture in question, in an amount approximately equivalent to the amount of saturated hydroxy-sub-stituted starting material or in excess, it is advantageous in some cases to carry out the dehydration while cooling in- order t limit the formation of byproducts . .

In order to secure a reasonable time of reaction, it may, be convenient in other cases to omit cooling of the reaction mixtur or even to undertake the dehydration at an increased temperature, e.g., in the vicinity of the boiling point of a solvent chosen for the dehydration step, e.g., up to about 120°C. However, no substantial amounts of byproducts are or need be formed even at such increased temperatures, it only being necessary that the acid or acid-providing compound be used in case of higher temperatures in an amount substantially less than that equivalent to the starting saturated hydroxy compound.

Chain Extension: In the event it is desired that the carbon cha at the 5 position of the oxazolidlnone nucleus be greater than t carbon atoms, this is conveniently accomplished by starting with the appropriate two. carbon atom side-chain omeg -ha loa lkyl compound and preparing the omega -nitrile . This nitrile may then be converted to the acid, which in turn may be converted to the aci AHR-39A hydroxys Ikyl compound by reduction, the ester with sodium and alc hol, or the acid halide with sodium borohydride, in accord with c ventional procedure. The 5 - (omega -hydroxya lkyl) compound is then reacted with a suitable halogenating agent, e.g., thionyl chlorid phosphorus trichloride, or the corresponding bromo reagents,, to r place the hydroxy group by a halogen atom and produce the corresponding omega -haloa lkyl compound. This in turn may be reacted w an alkali metal cyanide to again produce the nitrile, in each cas having a side-chain containing one carbon atom more than the star ing 5- (omega -haloalkyl) ~2 -oxazolidinone with which the reaction s quence originates, if desired. Alternatively, the tosylate may b produced from the omega -hydroxya lkyl compound and para -toluene sulfonyl chloride. Either the omega -haloalkyl or the omega -tosyl compound may be reacted with the selected secondary cyclic amine give the desired amine compound having a propyl side chain.

The 5- (omega -cyanoa lkyl) -2-oxazolidinones are prepared in co ventional manner by reaction of the selected 5 -ha loa lkyl-2-oxazolidinone with an alkali metal cyanide, e.g., sodium cyanide, usually by heating the reactants together in a suitable organic solvent, preferably dimethylformamide . T^^^©eed4H?e- --4ga-mma-he¾ee¾kyi)--eeffip«¾ft^¾ - .t¾- eoeh- cose-^^HL-nt^r k-c^-1-4Te"^ry^ The 5 - (omega -carboxya lkyl) -2-oxazolidinones are prepared by conventional acid hydrolysis of the corresponding 5 - (omega -cyano-alkyl) -2 -oxa.zolidinones , employing a concentrated mineral acid reagent « A reaction period of 24 hours and a temperature not in excess of 100 degrees is usually adequate.

The 5- (omega -carbalkoxya lkyl) -2-oxazolidinones are prepared from the 5- (omega -carboxya lkyl) -2-oxazolidinones by standard AHR- 39A hydrogen chloride, sulphuric acid, cation exchange resins, or an aromatic sulphonlc acid such as benzene or p-toluene sulfonic aci preferably with removal of either the ester product or water of r action if optimum yields are desired. Alternatively, the acid ma reacted with a diazoalkane, e.g., diazomethane, in excellent yie or an alkyl halide may be reacted with an alkali metal salt of t acid, in usual manner. Moreover, the acid may first be converted to an acid halide as by treatment with thionyl chloride or bromi or phosphorus trichloride or tribromide, in the accepted manner f such type reactions, and the acid chloride then reacted with a selected alkanol or phenol or alkali metal salt thereof to give high yields of the desired ester.

The following Preparations and Examples are given by way of Illustration only and are not to be construed as limiting: Preparation I: 5 - (2-Chloroethyl) -3-methyl-2-oxazolidinone AHR-1 To 198 grams (2 moles) of phosgene, dissolved in 800 ml. of cold chloroform contained in a three liter, three-necked, round-bottomed flask equipped with a mechanical stirrer, dropping funne pot thermometer and condenser was added 204 grams (2 moles) of 1-methyi- 3-pyrrolidinol in 450 ml. of chloroform. The reaction mixture was cooled in an ice bath and the addition was at such a rate that the pot temperature was kept below 10°C. After the addition of pyrrolidinol was completed, stirring was continued i the cold for 0 . 75 hour. Then, with continued cooling and stirri 270 ml. (2 mole) of triethylamine was added and the reaction mix ture allowed to warm to room temperature. The chloroform soluti was extracted with dilute HCl, then dilute NaOH and finally wate The chloroform layer was dried over sodium sulfate. The chlorof was removed at reduced pressure on a rotary evaporator. Weight the neutral residual oil was 238 grams. This product was distil in vacuo (0 . 3 to 0 .6 mm.). (During the distillation there was e AHR-39A amount, of crystalline solid was collected, which was redistilled using a 6-inch heated column. The product (I) boiled at 120°C. a 0.2 mm., wt. 169 grams (52% yield).

Anal: Calc. for C6H10 02C1: C, 44.04; H, 6.16; N, 8.56 Found . : C, 44.59; H, 6.31; N, 8.41 Preparations II through VII are carried out in the same mann as Preparation I. The corresponding 2-bromoethyl compounds are prepared using . carbonyl' dibromide . Table I indicated the structu and other pertinent information for these Preparations.

II 1045 -C2H5 H H 120-122 0.2 III 1205 -n-C H9 H H 134-141 0.2 IV 1158 cyclohexyl H H 56-59 V 1060 benzyl H H 51-52 VI 1206 -CH3 CH3 H 125-130 1.5 VII 1207 -CH H -CH3 112-122 0.

TABLE I CONTINUED Analytical Data Prepara - Calculated for Found tion No C · H N C H N II 47.33 6.81 7.88 47.31 6.92 7.73 III 6.81 6.82 IV 57.01 7.83 6.04 57.18 7.84 6.16 V 60.12 5.89 5.84 60.11 5.76 5.87 VI 7.89 7.94 VII 7.89 7.87 Preparation VIII: 3-Benzyl-5 "(2 -iodoethyl) -2 -oxazolidinone AHR- : - - - - AHR-39A (0.07 mole) of sodium iodide in 100 ml. of acetone was heated at gentle reflux with mechanical stirring for 20 hours. The reactio mixture was cooled and a white precipitate was separated by filtration and washed with acetone. The precipitate weighted 2.8 grams (95.5% of theoretical yield of sodium chloride). The combined filtrate and acetone wash were concentrated on a rotary evaporator. A brown oil remained, weight .16.8 grams. The oil wa repeatedly extracted with hot isopropyl ether leaving a dark insoluble residue. The isopropyl ether solution deposited on cooling a slightly colored solid which on recrystallization from isopropyl ether yielded 5.0 grams of a white crystalline solid, m.p. 42-43°C. Also, 3.5 grams of a slightly discolored solid was recovered, m.p. 42-43°C. Yield 51.57c , Anal: Calc. for C1 H N0 I: N, 4.23 12 14 2 Found : 'N, 4.44 « In the same manner, the corresponding bromo compound is prepared, using sodium bromide instead of sodium iodide.

Preparation IX: 3-Benzyl-5- (2-chloroethyl) -4, -dimethy1-2 - oxazolidinone l-Benzyl-2, 2-dimethyl-3-pyrrolidinol [prepared according to the method of Ryan et al., J. Org. Chem. 27., 2901-5 (1962) but using benzylamine rather than methylamine] is reacted with phosgene as described in Preparation I to produce the above-identifi compound.

Preparation X: Other chloroethyl compounds prepared by the same method as above are disclosed below and the pyrrolidinols from which' they are derived are indicated. These pyrrolidinols are also prepare by the method of Ryan et al. 3-Benzyl-5- (l-chloro- -propyl) -2-oxazolidinone is produced from 1-benzyl-4 -methyl- 3-pyrrolidinol and phosgene.

- - - - - - - - „ AHR-39A\ l-benzyl-2-methyl-4-pyrrolidinol and. phosgene.

Where the foregoing Preparations produce a compound having a methyl or other lower-alkyl group, it is to be understood that compounds containing other lower-alkyl groups of straight or branched nature, and containing up to eight carbon atoms inclusive such as methyl, ethyl, propyl, isopropyl, butyl, sec. -butyl, t.-butyl, amyl, isoamyl, hexyl, heptyl, and octyl, are prepared in the same manner by substitution . in the process of the appropriate different lower-alkyl starting material. Likewise, where chloro or other halogen atom is present, although chlorine is preferred, further halogen compounds including iodo, bromo, chloro, and fluo compounds . are prepared starting from the appropriate halogenated starting material. Substituted phenyl may be present in place of phenyl. Similarly, other molecular changes are readily made. Preparation XI: 5 - (2-Cyanoethyl) -3-methyl-2-oxazolidi,none AHR-12 A mixture of 8.2 grams (0.05 mole) of 5- (2 -chlo'roethyl) -3-methyl-2-oxazolidinone and 3.8 grams (0.075 mole) of sodium cyani in 50 ml. of dimethyl sulfoxide was heated on a steam bath overnight. The reaction mixture was filtered to remove the insoluble inorganic salts and most of the dimethyl sulfoxide was distilled at reduced pressure. The residue was. dissolved in approximately 60 ml. of water and the solution was extracted with chloroform. The chloroform solution was dried with sodium sulfate and the sol vent, removed on a rotary evaporator. The weight of the residual oil was 7.6 grams (99% yield). This oil was distilled in. vacuo and 4.2 grams of slightly yellow oil, b.p. 165-175°C. at 0.2 - 0. mm. was collected. . The oil crystallized on standing for several days exposed to air and was recrystallized from a mixture of isopropyl alcohol and isopropyl ether. Yield: 2.8 grams (36.57»); m.p. 44-45°C.

Anal:' Calc. for N, 18.18 AHR-39A Preparation XII: 3~Benzyl-5 - (2-cyanoethyl) -2 -oxazolidinone 3-Benzyl-5- (2-chloroethyl) -2-oxazolidinone is reacted with sodium cyanide in the same manner as described for the preparatio of AHR-1214 (Preparation XI) to produce the above-identified compound .

Preparation XIII: 3-Benzyl-2-oxazolidinone-5-propionlc acid and alkyl esters thereof.

A mixture of 3-benzyl-5- (2-cyanoethyl) -2-oxazolidinone and a large excess of 70% sulfuric acid is stirred and heated at 80-90° for 24 hours and poured into ice and water. The precipate is separated and crystallized from an appropriate solvent and found to be the desired compound.

Preparation XIV: 3-Benzyl-2 -oxazolidinone-5 -propionyl chloride A suspension of 3-benzyl-2-oxazolidinone-5 -propionic acid in benzene is treated dropwise with approximately 2 molar equivalent of thionyl chloride with stirring. The resulting solution is heated for 1 hour at reflux and concentrated in vacuo. The resid is purified by crystallization from a nonpolar solvent or otherwise worked up to yield the desired compound.

Preparation XV: 3 -Benzyl-5 - (3-hydroxypropyl) -2 -oxazolidinone To a . suspension of sodium borohydride in dry dioxane is rapi ly added with stirring a solution of 3-benzy.l-2-oxazolidinone-5-propionyl chloride or bromide in dry dioxane. The resulting mixture is stirred at reflux for 4 hours, cooled to room temperature and water is carefully added. The mixture is then partitio ed between water and chloroform. The chloroform solution is drie with anhydrous sodium sulfate and concentrated in vacuo . The residue may be purified by crystallizing from an appropriate solvent to yield the above-identified compound.

Preparation XVI: 3-Benzyl-5 - (3-chloropropyl) -2-oxazolidinone A solution of 2 parts of thionyl chloride in chloroform is - - - - d AHR-39A the mixture is heated at reflux for 5 hours, and then cooled in a ice bath. Water is added with stirring and then dilute hydrochlo acid is added until the mixture is acid. The chloroform layer is separated, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue is crystallized in isopropyl ether and use directly in the halogen replacement reaction.

Preparation XVII: 3-Benzyl-5 - [2 - (4-hydroxy-4-phenylpiperidlno) - ethyl J -2-oxazolidlnone A mixture of 35 g. (0.145 mole) of 3-benzyl- - (2-chloroethyl 2-oxazolidinone, 25 g. (0.141 mole) of 4-hydroxy-4-phenylpiperidi and 20 g. (0.145 mole) of potassium carbonate in 300 ml. of n-butanol was refluxed under a n5rtrogen atmosphere for 16 hours.

After cooling the salts were filtered off and the filtrate was evaporated under reduced pressure to an oil. Trituration with dry ether gave 38.6 g. (72.57°) of crude product. Recrystallizati from benzene-isooctane gave 36 g. o pure product melting at 108- 110°C.

Anal: Calc. for ¾Η28Ν2°3: °' 72'6Ό> Η' 7 Λ2> Ν> 7'36 Found : C, 72.51; Η, 7.34; Ν, 7.26 Preparation XVIII: 5 - [ 2 - (4-Hydroxy-4-phenylpiperldino) -ethyl ] - 2-oxazolidinone A suspension of 26 g. (0.0685 mole) of 3~benzyl-5-[2-(4-hydroxy-4-phenylpiperidino) ethyl] -2-oxazolidinone in 30 ml. of dry tetrahydrofuran (THF) was added slowly to a stirred solution of 3.3 g. (0.143 mole) of sodium in 200ml. of liquid ammonia. A heavy precipitate formed during addition. Before addition was complete the characteristic blue color disappeared so an additio 1.5 g. of sodium was added to the mixture. After addition was co plete, the mixture was stirred an additional 3 hours, whereafter the ammonia was allowed to evaporate slowly. The resulting solid was treated with 300 ml. of THF then slowly with 50 ml. of iso-propanol followed by 300 ml. of salt water. The organic layer AHR-39A ^ sulfate and concentrated. Addition of dry ether caused the product to precipitate, yield 13.5 g. (68%); m.p. 180-183°C. Recry tallization from benzene-absolute alcohol did not change the mel ing point .

Anal: Calc. for C16H22 203: C, 66.18; H, 7.64; N, 9.65 Found : C, 66.29; H, 7.73; N, 9.54 Example 1: 5-12 - ( -Phenyl-3 ,,4-dehydropiperidiny1) -ethyl ] -2 - oxazolldinone . (A¾R-1531) ' A mixture of 20 g. (0.133 mole) of 5- (2-chloroethyl) -2-oxazolidinone, 21.2 g. (0.133 mole) of 4-phenyl-l, 2, 3, 6-tetra-hydropyridine, and 27 g. of sodium bicarbonate in 150 ml. of 2-butanol was refluxed with stirring under a nitrogen atmosphere for 48 hours. The suspension was filtered hot to remove the salts and on cooling 19 g. of crude product slowly precipitated. Recrystallization from methanol, filtration, and evaporation of the filtrate gave a solid which was repeatedly recrystallized from benzene-isooctane . The pure product, (5~[2~(4-phenyl-3,4-dehydropiperidinyl) -ethyl ] -2-oxazolidinone) , 5.7 g. (16%), o o melted at 143-145 C. (141-143 C. from another run) and gave IR and NMR (nuclear magnetic resonance) spectra consistent with the proposed structure.

Anal: Calc. for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29 Found : C, 70.65; H, 7.36; N, 10.24 Example 2: 3-Methyl-5 - [2- (4-phenyl-3 , 4-dehyd,ropiperldinyl) - ethyl J -2-oxazolidinone. (AHR-1680) A stirred mixture of 8.35 g. (0.05 mole) of 3-methyl-5- (2-chloroethyl) -2-oxazolidinone, 10 g. (0.05 mole) of 4-phenyl-l, 2 , 3, 6-tetrahydropyridine hydrochloride, and' 20 g. of sodium bicarbonate in 75 ml. of 2-butanol was- refluxed under nitrogen for 24 hours. The mixture was cooled and the precipitate was removed b filtration. The solid precipitate was added to water and the insoluble product (8.9 g.) was filtered off and washed with wate AHR-39A in benzene and dried. over magnesium sulfate. The hot benzene solution was treated with isooctane and after cooling yielded 2. g. of additional product. Total yield 11.8 g. (82%); m.p. 101- 103°C. The combined product was recrysta llized from alcohol-water and gave 10.7 g. of product which melted at 102-104°C.

Anal: Calc. for C H N 0 : C, 71.30; H, 7.74; N, 9.78 17 22 2 2 Found : C, 71.29; H, 7.72; N, 9.71 Example 3: 3 , 4-Dimethyl-5- [2- (4-phenyl-3 , 4-dehydropiperidinyl) ethylJ~2"-oxazolidinone. (AHR-1733 and 1734) A stirred mixture of 9.75 g. (0.05 mole) of 4-phenyl -1, 2 , 3 , tetrahydropyridine hydrochloride, 8.85 g. (0.05 mole) of 3,4-dimethyl-5- (2 -chloroethyl) -2 -oxazolidinone, and 20 g. of sodium bicarbonate in 75 ml. of 2-butanol was allowed to reflux for 24 hours'. The mixture was filtered and the filtrate was evaporate under reduced pressure to a solid. Recrystallization from iso-propyl ether gave as a first crop 2.5 g. of product enriched in one isomer (m.p. 108-111°C.)\ The enriched product was triturat with hot ether to help remove more of the more soluble isomer, then recrystallized again from isopropyl ether, m.p. 112-114°C; 1 g. An NMR spectrum indicated that' the product was approximatel 90% one isomer. . This isomer (Isomer A) was labeled AHR-173 The filtrate from the first crop was concentrated and yield 9.0 g. of a nearly 50:50 mixture of cis-trans isomers, m.p. 93-103°C. The mixture (of Isomer A and Isomer B) was labeled AHR-1733. The total yield of product was 11.5 g. (77%).

Anal: Calc. for C H /N 0 : C, 71.97; H, 8.05; N, 9.32 Found : C, 71.71; H, 8.22; . N, 9.38 Example 4: 5 - [ 2 - (3-Phenyl-3.4-dehydropyrrolidinyl) -ethyl ] -2 - oxazolidinone . TAHR-1707) and the 2,3-dehydrcT analog A stirred mixture of 7.35 g. (0.05 mole) of 5- (2-chloroethy 2-oxazolidinone, 8 g. (0.05 mole) of 3-phenyl-3-pyrrolidinol, an 14 g. of sodium bicarbonate in 50 ml. of 2-butanol was allowed t AHR-39A crude oil was dissolved in 50 ml. of 6N HC1 and heated on a stea bath for thirty minutes. (The dehydration was followed by thin-layer chromatography.) The acidic solution was cooled in ice, diluted with 100 ml. of ice-x^ater, and treated slowly with cold 257o. NaOH until basic. The resulting gum was extracted into chlo form which was dried over magnesium sulfate and then evaporated under reduced pressure to an oil (13 g.) . . The oil was dissolved in a small amount of benzene and chromatographed on 300 g. of 60 100 mesh Florisil (hydrated aluminosilicate adsorbent) . The column was eluted with benzene containing increasing amounts of acetone up to pure acetone. The fractions containing the desire 3,4-dehydro product were combined and concentrated to an oil whi was still slightly impure (7 g.) . The oil crystallized from eth acetate and was recrystallized several times; yield 2.5 g. (20%, based on starting 4-phenyl-4-pyrrolidinol) ; m.p. 105-107°C. The analytical sample melted at 106-108°C; (€max12 , 654) Anal: Calc. for C15H18 202: C, 69.74; H, 7.02; "N, 10.84 Found : C, 69.59 H, 7.13; N, 10.89 A further fraction contained the desired 5-[2- (3-phenyl-2, 3 dehydropyrrolidinyl) -ethyl] -2-oxazolidinone .

Additional compounds (prepared in the manner of Preparation XVII) from the appropriate selected starting materials include: 3~Methyl-5 - [4-hydroxy-4- (2-methylthiophenyl) -piperidinyl ethyl^ -2-oxazolidinone . 3- ethyl-5- 2- [4 -hydroxy -4- (3-diethylaminophenyl) -piperidin ethylj -2-oxazolidinone . 3-Methyl-5- ^2- [4-hydroxy-4- (3-nitrophenyl) -piperidinyl ] - 3 -Ethyl -5 - 2- [4-hydroxy-4- (2 -methylthiophenyl) -piperidinyl ] ethylJ-2-oxazolidinone . 3 -Ethyl -5 - ^2- [4-hydroxy-4- (3-diethylaminophenyl) -piperidiny AHR-39A phenyl-3,4-dehydropiperidinyl compounds are produced by dehydrati in accord with Example 4.

Example 5 : 5- ( - [4- (4-Fluorophenyl) 3.4-dehydropiperidinyl ] - ethyl }-2-oxazoliclinone. (AHR-1703) A stirred mixture of 4.87 g. (0.032 mole) of 5- (2-chloroeth 2-oxazolidinone, 6.9 g. (0.032 mole) of 4- (4-fluorophenyl) -1, 2, 3, tetrahydropyridine hydrochloride, and 15 g. of sodium bicarbonate in 60 ml. of 2-butanol was allowed to reflux for 24 hours. The sodium salts were filtered off from the hot solution and, after cooling, the filtrate yielded 1.5 g. of product. The filtrate wa evaporated to dryness and the residue was dissolved in chlorofor and extracted several times with water. The chloroform layer was dried over magnesium sulfate and evaporated to a solid which afte recrystallization from benzene melted at 138-140°C.; yield 4 g.

The total yield was 5.5 g. (597o) . The analytical sample melted at 140-142°C.

Anal: Calc. for C-^H^F ^: C, 66.19; H, 6.60; N, 9.65 Found : C, 65.97; H, 6.42; N, 9.62 Example 6: 3-Methyl-5 -τ2- [4- (4-fluorophenyl) -3 , -dehydropiperidinyl J -ethyl) -2-oxazolidinone . (AHR-1704) A stirred mixture of 6.1 g. (0.037 mole) of 3-methyl-5- (2-chloroethyl) -2-oxazolidinone, 8 g. (0.037 mole) of 4-(4-fluoro-phenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride, and 18 g. of sodium bicarbonate in 65 ml. of 2-butanol was allowed to reflux under a nitrogen atmosphere for 24 hours. The mixture was filte while still hot and the filtrate was concentrated to an oil. Th oil was dissolved in benzene and the solution was dried over magnesium sulfate. The benzene solution was heated and treated with isooctane. After cooling, 8.8 g. of nearly pure product was collected. The product was charcoaled and recrystallized from benzene-isooctane, yield 7.2 g. (63%); m.p. 98-100°C. A second crop (0.6 g.) melted at 94-96°C.

AHR-39A Example 7: A stirred mixture of 8.35 g. (0.047 mole) of 3, -dimethyl-5- (2-chloroethyl) -2 -oxazolidinone, 10 g. of 4- (4-fluorophenyl) - 1, 2, 3, 6-tetrahydropyridine hydrochloride, and 20 g. of sodium bicarbonate in 75 ml. of 2-butanol was allowed to reflux for 24 hours. The. mixture was cooled, filtered and the filtrate was evaporated to an oil which solidified. The solid was boiled in ether and the undissolved product was filtered off (4.8 g.) . The NMR spectrum indicated the solid was mostly one isomer. Attempts to purify the single isomer as a hydrochloride salt failed due to the formation of a gelatinous precipitate in the several solvents used. The pure isomer (Isomer A) was obtained, however, after several reerystallizations of the product from isopropyl ether; yield 1.5 g. (9%); m.p. 99-101°C. The analytical sample melted at 101-103°C. The single isomer (Isomer A) was labeled AHR-1706.

The original ether filtrate was treated with ethereal HCl and yielded a crystalline salt which melted at 192-196°C. after recrystallization from ethyl acetate-methanol, yield 7.2 g. (43%). This product was a mixture of Isomer A and Isomer B. The NMR spectrum indicated the isomer composition of the salt was approximately 60% of one isomer and 407o of the other. The isomeric mixture was labeled AHR-1705.

Anal: Calc. for C18H24C1F 202 : C, 60.92; H, 6.82; N, 7.90 (Salt) Found : C, 60.97; H, 6.79; N, 7.88 Anal: Calc. for C18H23F 202: C, 67.90; H, 7.28; N, 8.80 (Free base) Found : C, 67.89; H, 7.33; N, 8.74 Example 8: 5 - [ 2- (4-p-tolyl-6-methyl- , 4-dehydropiperidinyl) - ethyl j1-2-oxazolidinone .

In the same manner as given in Example 1, this compound is - - - - AHR-39A ^ Example 9: 5- [2 - (4-p-Trifluoromethylphenyl-3, 4-dehydropiperidlny propylT~2 -oxazolidinone .

In the same manner as given in Example 1, this compound is prepared by the reaction of 5- (2-chloropropyl) -2-oxazolidinone an 4- (p-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine or its hydrochloride.

Example 10: 5- [2 -(4-m-Dlmethylaminophenyl- , -dehydropiperidlnyl) ethyl J -2-oxazolidinone .

In the same, manner as given in Example 1, this compound is prepared by the reaction of 5 - (2 -chloroethyl) -2-oxazolidinone and 4- (m-dimethylaminophenyl) -1, 2, 3, 6-tetrahydropyridine or its hydro chloride.

Example 11: 5- [2- (4-p-Methylmercaptophenyl-3 , 4-dehydropiperldiny ethyl -2 -oxazolidinone .

In the same manner as given in Example 1, this compound is prepared by the reaction of 5- (2 -chloroethyl) -2-oxazolidinone and 4- (p-methylmercaptophenyl) -1,2,3, 6-tetrahydropyridine or its hydrochloride .

Example 12: 5- [ 1- (4-p-Methoxyphenyl-3 , -dehydropiperidinyl) -2- propyl J -2 -oxazolidinone .

In the same manner as given in Example 1, this compound is prepared by the reaction of 5- (l-chloro~2-propyl) -2-oxazolidinone and 4- (p-methoxyphenyl) -1, 2, 3, 6-tetrahydropyridine or its hydro-chloride.

Example 13: 5- [2-(4-p-Njtrophenyl-3, 4-dehydropiperidinyl) - ethyl J -2-oxazolidinone .

In the same manner as given in Example 1, this compound is prepared by the reaction of 5 - (2 -chloroethyl) -2 -oxazolidinone and 4- (p-nitrophenyl) -1, 2, 3, 6-tetrahydropyridine or its hydro-chloride.

Example 14: 3-Cyclohexyl-5 - [ 2- (4-phenyl- , 4-dehydropiperidinyl) - ethyl J -2 -oxazolidinone .

In the same manner as given in Example 2, this compound is prepared by the reaction of 3~cyclohexyl-5- (2-chloroethyl) -2- AHR-39A Example 15: 3 -Benzyl-5 - [ 2- (4-phenyl-3 , 4-dehydroplperidinyl) - ethyl J -2-oxazolldinone .

In the same manner as given in Example 2, this compound is prepared by the reaction of 3-benzyl-5- (2-chloroethyl) -2-oxazolidinone and 4-phenyl-l, 2, 3, 6-tetrahydropyridine or its hydrochloride.

Example 16: 3- (p-Tolylmethyl) -5- [ 2- (4-phenyl-3 , 4-dehydropiperi- dinyl) ethyl J -2-oxazolidinone .

In the same manner as given in Example 2, this compound is prepared by the reaction of 3- (p-tolylmethyl) -5- (2-chloroethyl) - 2-oxazolidinone and 4-phenyl-l, 2, 3, 6-tetrahydropyridine or its hydrochloride .

Example 17: 3- (p-Methoxybenzyl) -5- [2- (4-phenyl-3 , 4-dehydro- piperidinyl) -ethylj -2-oxazolidinone .

In the same manner as given in Example 2, this compound is prepared by the reaction of 3- (p-methoxybenzyl) -5 - (2 -chlproethyl) 2-oxazolidinone and 4-phenyl-l, 2, 3, 6-tetrahydropyridine or its hydrochloride .

Example 18: 3 - (p-Trifluoromethylbenzyl) -5 - [ 2 - (4-phenyl-3,4- dehydropiperidinyl) -ethyl J -2-oxazolidinone .

In the same manner as given in Example 2, this compound is prepared by the reaction of 3- (p-trifluoromethylbenzyl) -5 - (2-chloroethyl) -2-oxazolidinone and 4-phenyl-l, 2,3, 6-tetrahydro-pyridine or its hydrochloride.

Example 19: 4-Methyl-5- [2- (2 -methyl- -phenyl-2 , 3- and 3,4-dehydr pyrrolidinyl) -propyl J -2-oxazolidlnoneT ' In the same -manner as given in Example 4, this compound is prepared by reaction of 4-methyl-5 - (2 -chloropropyl) -2-oxazolidinone and 2-methyl-3-phenyl-3-pyrrolidinol and dehydratio of the resulting hydroxy ring compound to the corresponding 3,4-dehydro compound. A small amount of the 2,3-dehydro compound is also obtained. Both compounds exist in the form. of optical isome as mixtures thereof.

AHR-39A prepared by reaction of 5- (l-chloro-2-propyl) -2-oxazolidinone and 3-phenyl-5-methyl-3-pyrrolidinol and dehydration of the resulting hydroxy ring compound to the corresponding 3, 4-dehydro compound. A small amount of the 2,3-dehydro compound is also obtained. Bot compounds exist in the form of optical isomers as well as mixture thereof.

Example 21: 5- [2- (2 , 2 -Dimethyl-3 -p-tolyl- , -dehydropyrrolidlnyl ethyl J -2-oxazolldinone .

In the same manner as given in Example 4, this compound is prepared by reaction of 5- (2-chloroethyl) -2-oxazolidinone and 2, 2-dimethyl-3- (p-tolyl) -3-pyrrolidinol and dehydration of the resulting hydroxy ring compound to the corresponding 3, 4-dehydro compound ..

Example 22: 5 - [2- (3-p-Trifluoromethylphenyl-2 ,2,5 , 5-tetramethyl- 3 , 4-dehydropyrrolidinyl) -ethyl J -2-oxazolidinone In the same manner as given in Example 4, this compound is prepared by reaction of 5-(2-chloroethyl) -2-oxazolidinone and 3- (p-trifluoromethylphenyl) -2, 2, 5, 5 -tetramethyl-3-pyrrolidinol and dehydration of the resulting hydroxy ring compound to the corresponding 3, 4-dehydro compound.

Example 23: 3 -Benzyl-5 - [ 3 - (3-p-hydroxypheny1-3,4-dehydro- ' pyrrolidinyl) -propyl J -2-oxazolidinone . .

In the same manner as given in Example 4, this compound is prepared by reaction of 3-benzyl-5- (3-chloropropyl) -2-oxazolidino (Preparation XVI) and 3- (p-hydroxyphenyl) -3-pyrrolidinol and dehydration of the resulting hydroxy ring compound to the corresponding 3,.4-dehydro compound.

Example 24: 5- [2- (3-Phenyl-2 , 3- and 3 , 4-dehydropiperidinyl) - ' ethyl J -2-oxazolidinone .

In the same manner as given in Example 4, these compounds are prepared by reaction of 5- (2-chloroethyl) -2-oxazolidinone and 3-phenyl-3 -piperidinol and dehydration of the resulting hydroxy ring compound to a mixture of the two corresponding AHR-39A Example 25: 5- [ 2 - ( -Phenyl-3 , 4-dehydropiperidinyl) -ethyl] -2- oxazolldinone (AHR-1531) In the same manner as given in Example 4, this compound is prepared by dehydration of 5- [2- (4-hydroxy-4-phenylpiperidino) -ethyl ] -2-oxazolidinone (Preparation XVIII) .

Example 26: 3-Benzyl-5- [2- (4-phenyl-3 , 4-dehydropiperidinyl) - ethyl J -2 -oxazolidinone .

In the same manner as given in Example 4, this compound is prepared by dehydration of 3-benzyl-5- [2- (4-hydroxy-4-phenyl-piperidino) -ethyl ] -2-oxazolidinone . (Preparation XVII).

Example , 27 : 3-Benzyl-5- [ 3- (4-phenyl-3 , 4-dehydropiperidinyl) - propyl J -2-oxazo'lidinone . 3-Benzyl-5 - (3-chloropropyl) -2-oxazolidinone (Preparation XVI) is reacted with 4-phenyl-l, 2, 3, 6-tetrahydropyridine or its hydrochloride in the same manner as given in Example 2 to produce the above-identified compound.

Example 28: 3-Methyl-5-[ 2 - (3-methyl-4-phenyl-3 , 4-dehydropiperidinyl) -ethyl] -2-oxazolidinone In the same manner as given in Example 2, this compound is prepared by the reaction of 3-methyl-5- (2-chloroethyl) -2-oxazolidinone and 3-methyl-4-phenyl-l, 2 , 5 , 6-tetrahydropyridine or the hydrochloride salt thereof.

Example 29: 3-Methyl-5 - [ 2- (5 -methyl-4-phenyl-3 , 4-dehydro- p peridinyl) -ethylT- -oxazolidlnone In the same manner as given in Example 2, this compound is prepared by the reaction of 3-methyl-5- (2-chloroethyl) -2-oxazol.idinone and 5 -methyl-4-phenyl-l, 2,5, 6-tetrahydropyridine or the hydrochloride salt thereof.

Example 30: 3-Methyl-5 - [ 2- (5 -methyl-4-o-tolyl-3 , 4-dehydropiperidinyl) ~ethyl J -2-oxazolidinone .

In the same manner as given in Example 2, this compound is prepared by the reaction of 3-methyl-5- (2-chloroethyl) -2-oxazolidinone and 5-methyl-4-o-tolyl-l, 2,5 , 6-tetrahydropyridine or the hydrochloride salt thereof.

AHR-39A prepared by the reaction of 3-methyl-5 - (2 -chloroethyl) -2-oxazolidinone and 3-methyl-4-o-tolyl-l, 2,5 , 6-tetrahydropyridine or the hydrochloride salt thereof.

Still other compounds preparable in the same manner from the appropriate starting materials include: 3-Methyl-5- [2-(3-methyl-4-phenyl-3,4-dehydropyrrolidinyl) -ethyl] -2-oxazolidinone and 3 -methyl-5- [2- (3-methyl-4-o-tolyl-3,4-dehydropyrrolidinyl) -ethyl] -2-oxazolidinone .

Where any of the foregoing Examples produce a compound having a methyl or other lower-alkyl group, it is to be understood that the compounds containing other lower-alkyl groups of straight or branched nature and containing up to eight carbon atoms inclusive, such as methyl, ethyl, propyl, isopropyl, butyl, sec. -butyl, t. -butyl, amyl, isoamyl, hexyl, heptyl, and octyl, are prepared in the same manner by substitution in the process of the appropriate different lower-alkyl starting material. Likewise, where chloro or other halogen atom is present, although chlorine is preferred, further halogen compounds including iodo, bromo, chloro, and fluoro compounds are prepared starting from the appropriate halogenated starting material. Similarly, where methoxy or other lower-alkoxy group is present, compounds having other lower-alkoxy groups containing various lower-alkyl groups having up to eight carbon atoms inclusive are prepared in the same manner from the appropriate different lower-alkoxy starting material. Moreover, when one dilower-alkylamino group, such as the dimethylamino group, is presen in a compound, other dilower-alkylamino compounds are prepared. in the same manner starting onl with the selected different dilower-alkylamino compound. In the same manner, ortho and meta products are produced instead of the para by utilizing the selected ortho or meta substituted starting material. Similarly, other molecular changes within the scope of AHR-39A-' are generally characterized by important pharmacological activit indicative of their use in counteracting certain physiological abnormalities in an animal body. The compounds of Formula I are major tranquilizers.

The activity of the pharmacologically active agents of the present invention, as evidenced by tests in lower animals, is indicative of utility based on their valuable activity in human beings as well as in lower animals. It will be clearly understo however, that the distribution and marketing of any compound or composition falling within the scope of the present invention fo use in human beings will of course have to be predicated upon prior approval by governmental agencies, such as the U.S.t Federa Food and Drug Administration, which are responsible for and auth ized to pass judgment on such questions.

The compounds of the invention have a basic (amino) nitroge atom in the molecule and are usually most conveniently employed in the form of non-toxic acid-addition salts. Such salts also have improved water-solubility. Although the non-toxic salts are preferred, any salt may be prepared for use as a chemical intermediate, as in the preparation of another but non-toxic aci addition salt. The free basic compounds may be conveniently converted to their acid addition salts by reaction of the free base with the selected acid. The acids which can be used to prepare the preferred non-toxic acid addition salts are those which produce, when combined with the free bases, salts the anio of whic are relatively innocuous: to the animal organism in therapeutic doses of the salts, so that beneficial physiological properties inherent in the free bases are not vitiated by side-effects ascribable to the anions .

Appropriate acid-addition salts are those derived from mineral acids such as hydrochloric acid, hydrobromic acid,, hydro - · fumaric acid, maleic acid, and tartaric acid. The preferred acid addition salt is generally the hydrochloride, aleate, or fumarat The acid-addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or b reacting the free base and the selected acid in an organic solvent in which case the salt ordinarily separates directly or can be conventionally recovered by concentration of the solution or the like. Conversely the free base may be- obtained conventionally by neutralizing the acid-addition salt with an appropriate base such as ammonia, ammonium hydroxide, sodium carbonate or the like, extracting the liberated base with a suitable solvent, illustrati ly ethyl acetate or benzene, drying the extract and . evaporating to dryness or fractionally distilling, or in other conventional manner .

When there are two or more basic nitrogen atoms present in the compounds of the invention, poly-acid-addition salts may be obtained by employing the proper increased molar ratios of ester or acid to the free base.

Formulation and Administration; Effective quantities of any of the foregoing pharmacologically active compounds of Formul I may be administered to a living animal body in any one of various ways, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously, e.g., in the form of sterile isotoni solutions. The compounds may be administered alone or in combination with other pharmacologically effective agents, such as ana legisics , sedatives, antacids, other tranquillizing agents, antiappetite or antiulcer drugs, or the like, as well as buffers and usual pharmaceutical carriers . or diluents. The free .basic amino compounds, while effective, are preferably formulated and AHR-39A solubility, and the like . The compounds of Formula I, especially in the form of their acid-addition salts, represent a preferred group of highly active compounds, of which the 4-phenyl-3, 4-dehydropiperidinyl and 3-phenyl-3, 4-dehydropyrrolidinyl compounds are outstandingly active. Preferred groups at the 3-position are hydrogen, methyl or ethyl.

Although very small quantities of the active materials of th present invention are effective when minor therapy is involved or in cases of administration to subjects having a relatively low body weight, unit dosages are usually five milligrams or above and preferably twenty-five, fifty or one-hundred milligrams or even higher, depending of course upon the emergency of the situation and the particular result desired. Five to fifty milligrams appears optimum per unit dose, while usual broader ranges appear to be one to 100 milligrams per unit dose. The active agents of the invention may be combined with other pharmacologically active agents, or with buffers, antacids or the lik for administration and the proportion of the active agent in the compositions may be varied widely. It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages in a particular case will of course be determined according to established medical principles under the direction of a physician or veterinarian. Results upon administration of these novel materials have thus far proved extremely gratifying.

The formulations of the following Example are representative for all of the pharmacologically active compounds of the inventio but have been especially designed to embody as active ingredient -side chain and the 3-R group is preferably hydrogen, methyl or ethyl, especially as the maleate, fumarate, hydrochloride, hydro-bromide, or like pharmaceutically acceptable salt, and particular the compounds of Examples 1 and 4 designated AHR-1531 and 1707 and physiologically acceptable acid addition salts thereof.

Example Formulations 1) Capsules Capsules of 5 mg., 25 mg., and 50 mg. of active ingredient per capsule are prepared. With the higher amounts of active ingredient, reduction may be made in the amount of lactose.

Typical blend for encapsulation Per Capsule, mg.

Active Ingredient, as salt 5.0 Lactose 296.7 Starch 129.0 Magnesium Stearate > 4.3 Total 435.0 mg.

Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows: Ingredients 100 mg. per 250 mg. per 500 mg. pe Capsule Capsule Capsule Active Ingredient, as salt 100.0 250.0 500.0 Lactose 231.5 126.5 31.1 Starch 99.2 54.2 13.4 Magnesium Stearate 4.3 4. 5.5 Total 435.0 mg. 435.0 mg. 550.0 mg. In each case, uniformly blend the selected active ingredient with lactose, starch, and magnesium stearate and encapsulate the blend. 2) Tablets A typical formulation for a tablet containing 5.0 mg; of active ingredient per tablet follows. The formulation may be use AHR-39A Per Tablet, mg. 1. Active Ingredient 5.0 2. Corn Starch 13.6 3. Corn Starch (paste) 3.4 4. Lactose 79.2 . Dicalciura Phosphate 68.0 6. Calcium Stearate 0.9 Total 170.1 mg.

Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 percent paste in water. Granulate the blend with starch paste and pass the wet mass through an eight mesh screen. The wet granulation is dried and sized through a twelve mesh screen. The dried granules are blended with the calcium stearate and compressed.

Additional tablet formulations preferably contain a higher dosage of the active ingredient and are as follows: A. 50 mg. Tablet .

Ingredients Per Tablet, mg.

Active Ingredient, as salt 50.0 Lactose 90.0 Milo Starch 20.0 Corn Starch 38.0 Calcium Stearate 2.0 Total 200.0 mg.

Uniformly blend the active ingredient, lactose, milo starch and corn starch. This blend is granulated using water as a granulating medium. The wet granules are passed through an eight mesh screen and dried at 140 to 160 degrees Fahrenheit overnight. The dried granules are passed through a number ten mesh screen and blended with the proper amount of calcium stearate and this blend is then converted into tablets on a suitable tablet press.

AHR-39A B. 100 mg. Tablet.

Ingredients Per Tablet, mg.

Active Ingredient, as salt 100.0 Lactose 190.0 Dicalcium Phosphate 172.2 Starch 54.0 Milo Starch 21.6 Calcium Stearate Total 540.0 mg.

Uniformly blend the active ingredient, lactose, dicalcium phosphate, starch and milo starch. This blend is granulated with water and the wet mass is passed through a number eight mes screen. The wet granules are dried at 140-160 degrees Fahrenheit overnight. The dried granules are passed through a number ten mesh screen. These dried granules are blended with the proper weight of calcium stearate and the lubricated granules are then converted into tablets on a suitable tablet press.

C. 250 mg. Tablet.

Ingredients Per Tablet, mg.

Active Ingredient, as salt 250.0 Corn Starch 56.0 Carbowax 6000 (polyethylene glycol of M.W. approximately 6000) 25.0 Lactose 35.0 Magnesium Stearate 4.0 Total 370.0 mg.

Uniformly blend the active ingredient, Carbowax 6000, lactos and one-half the weight of magnesium stearate required. This blend is then "slugged" on a suitable tablet press. These "slugs are granulated through a ten mesh screen on an oscillating granu-lator. These granules are then blended with the remainder of the ■ AHR-39A D. 500 mg. Tablet.

Ingredients Per Tablet, mg.

Active Ingredient, as salt 500.0 Corn Starch (wet) 86.4 Milo Starch · 32.4 Calcium Stearate 3.2 Corn Starch (dry) 26.0 Total 648.0 mg.

Uniformly blend the active ingredient, corn starch and milo starch. This blend is wet granulated using water and the wet mass is passed through a number eight mesh screen. These wet granules are dried overnight at 140-160 degrees Fahrenheit. The dried granules afe passed through a number ten mesh screen. The dried granules and weighed amounts of corn starch and calcium stearate are uniformly blended and these lubricated granules are compressed on a suitable tablet press . 3) Injectable - 2% Sterile Solution Per cc .

Active Ingredient 20 mg.

Preservative, e.g., chlorobutanol 0.57o weight/ volume Water for Injection q.s.

Prepare solution, clarify by filtration, fill into vials, seal, and autoclave. 4) The pharmacologically active compounds provided by the present invention may also be administered successfully by embodying an effective quantity thereof in an injectable suspension for injection into an animal body, in oral powders, suspensions or syrups, and in other acceptable dosage forms.

Preparation: 3-Methyl-5- \1- [4- (3-trifluoromethylphenyl) -4-hydroxy- piperldinyrTe^thylj-2-oxazolidinone, Hydrochloride A mixture of 19.5 g. (0.089 mole) of 3-methyl-5- (2-chloro- - - AHR-39A Υ atmosphere of nitrogen for 36 hours. The hot mixture was filtere and the filtrate was evaporated to an oil. The oil was dissolved in benzene and washed several times with water. The benzene solution was dried over magnesium sulfate and evaporated to an oil. The oily product was dissolved in ether and treated with ethereal HC1. After recrysta llization the hydrochloride salt (27.1 g.j 75%) melted at 221-223°C.

Example 32: 3-Methyl -5 -ft- [4-(3-trifluoromethylphenyl) -3 , 4-dehyd A solution of 11.2 g. (0.0275 mole) of 3 -methy1-5 -{2- [4- (3-trifluoromethylphenyl) -4-hydroxypiperidinyl ]ethyl ~2-oxazolidinon hydrochloride in 100 ml. concentrated ^SO^ was stirred for 30 minutes and then poured onto ice. The solution was carefully neutralized with 6N NaOH in the cold and the product was extracte with chloroform. The chloroform. extract was dried over magnesium sulfate and evaporated to an oil (8.2 g.) . The impure oil was dissolved in benzene and chromatographed on 250 g. of 60-100 mesh Florisil using benzene containing increasing amounts of acetone for elution. The oily product (4.2 g.) obtained from the column was dissolved in isopropanol and treated with ethereal HC1. The resulting hydrochloride, 2.9 g. (28%), melted at 206-209°C. An analytical sample melted at 207-209°C. after one recrystallizatio from isopropanol.

Anal: Calc. for : C, 55.31; H, 5.67; N, 7.17 Found : C, 55.14; H, 5.79; N, 7.25 Preparation: 3 -Methyl-5 - ¾2- [4- (4-methoxyphenyl) -4-hydroxypiperid inyl jethyl"]»- -oxazolidinone Appearance: White Powder Anal: Calc. for C18H26 204: C, 64.65; H, 7.84; N, 8.38 Found : C, 64.74; H, 7.86; N, 8.31 Yield: 59% Melting Point: 150-152°C.

- Example 33: 3 -Methyl-5 - j2 - [A-methoxyphenyl-3, 4-dehydropiperidlny ethylj-2-oxazolidinone (AHR 1877) ; A 2.0 g. (0.006 mole) sample of 3-methyl-5- 2- [4-methoxyphen piperidinyl]ethylj-2-oxazolidinone (AHR-1840) in 50 ml. of 6 hydrochloric acid was heated at 95°C . on the steam bath for 3 hou Alkalinization with ammonia water, followed by extraction into chloroform, produced 2.1 g. of extract which crystallized and whi presented after thin layer chromatography (20% methanol-benzene, silica) a major reaction product, a small amount of starting material, and a small amount of a polar reaction product. Four r crystallizations from ethyl acetate gave pure 3 -methyl-5 - 2 - [4-methoxyphenyl-3, 4-dehydropi.peridinyl ]ethyl -2 -oxazolidinone compound, 320 mg., m.p. 118.5°-121°C . after drying at 85°C./0.1 mm.

Chromatography of mother liquor material on magnesium silicate produced 390 mg. of additional material. Total yield wa 710 mg., 38% of theoretical.

Anal: Calc. for C^H^^Og. C, 68.33; H, 7.65; N, 8.85 .

Found : C, 68.32; H, 7.68; N, 8.90 Since asymmetric carbon atoms are present in many of the compounds of the present invention, optical isomers exist in such cases. When two asymmetric centers are present, pairs of diastereoisomers are possible. These dd astereoisomers , together with optically active forms, are included within the scope of the present invention. The two pairs of diastereoisomers may be separated and resolution of the diastereoisomers into their optically active form may be accomplished by combining the basic diastereoisomers with an optically active organic acid and sepa- · rating by fractional crystallization the d- and 1- forms.

Various modifications and equivalents will be apparent to on skilled in the art and may be made in the compounds, compositions, and methods of the present invention without departing from the spirit or scope thereof, and it is therefore to be understood tha

Claims (1)

1. P.A. 28125/11 WHAT IS CLAIMED IS« 1· A process for producing a 5-omega-subatltuted-2-oxazolidinone selected from the group consisting of (A) compounds of the formula! R - CR'R - CH, - (CHR" ) - CHR» 1 N u - A («) CO — wherein n is selected from the group consisting of 1 and 2, wherein R is selected from the group consisting of hydrogen, lower-alkyl, cycloalkyl, alkylcycloalkyl, phenylalkyl, and substituted phenylalk 1 wherein the substituonts are selected from the group consisting of halogen* Agffr cwer-alkyl, lower-alkoxy, trifluoromethyl , lower-alkyl-thio , dl-lower-alkylamlno , and nitro, Wherein R' is selected from the group consisting of hydrogen and methyl, wherein R» * is selected from the group conslting of hydrogen and methyl, wherein - sfu) is a heterocyclic ring selected from 2,3-dohydropyrrolidinyl, 3»^-dehydropyrrolidlnyl , 2,3-dehydro piporidinyl, and 3,¾-dehydropiperidinyl, Wherein A is phenyl or substituted phenyl phenyl attached to a carbon atom of the ring double bond and in the 3 or 4 position of the heterocyclic ring, remaining valences of the carbon atoms of the heterocyclic ring being satisfied by hydrogen and zero through four methyl groups, wherein substituted phenyl substituents are selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, trlfluoro-methyi, lower-alkyl-thio, di-lower- which comprises the step of reacting a compound of the formula H — — T^ A wherein N u — - A has the value hereinbefore assigned, with a 5-haloalkyl-2-oxazolidinone of the formula wherein B, B', B"» and n all have the values previously \ or tosyl assigned, and wherein X is a replaceable halogen atom^ to cause displacement o said atom and formation of a compound having the formula (I) hereinbefore given, or which comp ises the step of dehydratin a compound of ths fo mula BN - CB'fi' - CH - (CHB' V)n - CHB ' ' - wherein B, R', and R" have the values previously assigned, , wherein i^) is a saturated heterocyclic ring selected from the group consisting of pyrro idinyl and piperidinyl,whiein A . (the substituents being as defined above) is selected from phenyl and substituted phenyl/attached to a carbo atom in a position selected from the aad ^ p sitions of the heterocyclic ring, wherein OH is attached to the ame carbon atom as A, remaining valences of the carbon atoms of the heterocyclic ring being satisfied by hydrogen and zero , through four methyl groups, at least one of the ring carbon atoms adjacent the carbon atom bearing the A and OH groups ha ing at least one hydrogen atom attached thereto* with an acid to cause splitting out of water and formation of a compound having the formula (I) hereinbefore given. Qi«HKS£x}ift£ sai-i« ia £0x&«xi$e££ A process for producing a 5-omega-substituted-2-oxazolidinon selected from the group consisting of (A) compounds of the formula RN - CR'R' - CH - (CHR")n - CHR" - ^u^- A (I) CO —0 wherein n is selected from the group consisting of 1 and 2, wherein R is selected from the group consisting of hydrogen, alkylcycloaleyl lower-alkyl, cycloalkyl, /phenylalkyl, and substituted phenylalkyl wherein the substituents are selected from the group consisting -alk l, lower-alkoxy, trifluoromethyl, lower-alkyl-thio raes&apfce, di-lower-alkylamino, and nitro, wherein R' is selected from the group consisting of hydrogen and methyl, wherein R" is selected from the group consisting of hydrogen and methyl, wherein - i^u)is a heterocyclic ring selected from 2,3-dehydropyrrolidinyl, 3, 4-dehydropyrrolidinyl, 2, 3-dehydropiperi-dinyl, and 3, -dehydropiperidinyl, wherein A is phenyl or substituted phenyl attached to a carb atom of the ring double bond and in the 3. or 4 position of the heterocyclic ring, remaining valences of the carbon atoms of the heterocyclic ring being satisfied by hydrogen and zero throug four methyl groups, wherein substituted phenyl substituents are selected from th group consisting of hal<^eilower-alkyl, lower-alkoxy, trifluoro- thio methyl, lower-alkylmetfee-pt-o-; di-lower-alkylamino, nitro, and hydroxy, and (B) acid addition salts thereof, which comprises the step of reacting a compound of the formula AHR-39A $ wherein '^^- ^ ^as t^ie value hereinbefore assigned, with a 5-haloalkyl-2-oxazolidinone of the formula - (CHR")n - CHR" - X (X) wherein R, R1, R", and n all have the values previously or tosyl assigned, and wherein X is a replaceable halogen atom, to cause displacement of said halogen atom and formation of a compound having the formula (I) hereinbefore given. A process for producing a 5-omega -substituted-2-oxazolidinone selected from the group consisting of (A) compounds of the formula RN - CR'R' - CH - (CHR")n - CHR" - A (∑) CO — 0 wherein n is selected from the group consisting of 1 and 2, wherein R is selected from the group consisting of hydrogen, alkylcycloalkyl lower-alkyl, cycloalkyl, /phenylalkyl, and substituted phenylalkyl wherein the substitutents are selected from the group consisting gen of halo lower-alkyl, lower-alkoxy, trifluoromethyl, lower-alkyl- thio me-^e*pfe-», di-lower-alkylamino, nitro, and hydroxy, wherein R1 is selected from the group consisting of hydrogen and methyl, wherein R" is selected from the group consisting of hydrogen and methyl, wherein - ^u^ is a heterocyclic ring selected from 2,3-dehydropyrrolidinyl, 3, 4-dehydropyrrolidinyl, 2,3-dehydro-piperidinyl, and 3, -dehydropiperidinyl, wherein A is phenyl or substituted phenyl attached to a carb atom of the ring double bond and in the 3 or 4 position of the heterocyclic ring, remaining valences of the carbon atoms of the heterocyclic ring being satisfied by hydrogen and zero through four methyl groups, AHR-39A $ •wherein substituted phenyl substituents are selected from the group consisting of halo, lower-alkyl, lower-alkoxy, trifluoro- thio methyl, lower-alkylmerefljMfce, di-lower-alkylamino, nitro, and hydroxy, and (B) acid addition salts thereof, which comprises the step of dehydrating a compound of the formula wherein R, R' , and R" have the values .previously assigned, wherein is a saturated heterocyclic ring selected from the group consisting of pyrrolidinyl and piperidinyl, wherein A is selected from phenyl and substituted phenyl attached to a carbon atom in a position selected from the 3 and 4 positions of the heterocyclic ring, wherein OH is attached' to the same carbon atom as A, the remaining valences of the carbon atoms of the heterocyclic ring being satisfied by hydrogen and zero through four methyl groups, at least one of the ring carbon atoms adjacent the carbon atom bearing the A and OH groups having at least one hydrogen atom attached thereto, with an acid to cause splitting out of water and formation of a compound having the formula (I) hereinbefore given. A 5-omega-substituted 2-oxazolidinone selected from the group consisting of (A) compounds of the formula: wherein n is selected from the group consisting of 1 and 2, wherein R is selected from the group consisting of hydrogen, alk lcycloalkyl lower-alkyl, cycloalkyl/ phenylalkyl, and substituted phenylalkyl wherein the substituents are selected from the group consisting gen AHR-39A thio m&&eepb&, di-lower-alkylamino, nitro, and hydroxy, wherein R\ is selected from the group consisting of hydrogen and methyl, wherein R" is selected from the group consisting of hydrogen and methyl, wherein - l^u^is a heterocyclic ring selected from 2,3-dehydropyrrolidinyl, 3, 4-dehydropyrrolidinyl, 2,3-dehydro-piperidinyl, and 3, 4-dehydropiperidinyl, wherein A is phenyl or substituted phenyl attached to a carbon atom of the ring double bond and in the 3 or 4 position of the heterocyclic ring, remaining valences of the carbon atoms of the heterocyclic ring being satisfied by hydrogen and zero through four methyl groups, wherein phenyl substituents are selected from the group lower-alkyl, lower-alkoxy, trifluoromethyl, di-lower-alkylamino, nitro, and hydroxy, and (B) acid addition salts thereof. A compound of Claim 3- which is 5- [2-(4-phenyl-3, 4-dehydropiperidinyl) -ethyl] -2-oxazolidinone . A compound of Claim 3· which is 5-[2-(4-phenyl-3, 4-dehydropiperidinyl) -ethyl ] -2-oxazolidinone melting at about 141-145°C. A compound of Claim 3 which is 3-methyl-5- [2- (4-phenyl-3, 4-dehydropiperidinyl) -ethyl] -2-oxazolidinone . A compound of Claim 3* which is a 3-lower-alkyl-5- [2- (4-phenyl 3, 4-dehydropiperidinyl) -ethyl ] -2-oxazolidinone . . A compound of Claim 3 which is 3,4-dimethyl-5-[2-(4-phenyl- AHR-39A 4 0 k A compound of Claim 3 which is the 3,4-dimethyl-5-.2-(4-phenyl-3 , -dehydropiperidinyl) ethyl ] -2 -oxazolidinone isomer melting at about 112-114°C. A compound of Claim 3 which is 5- [2- (3-phenyl-3, 4-dehydro-pyrrolidinyl) -ethyl ] -2 -oxazolidinone . A compound of Claim 3 which is 5-^2- [4- (4-fluorophenyl) -3, 4 dehydropiperidinyl ] ethyl j-2-oxazolidinone . A compound of Claim 3 which is 3-methyl-5 -^2- [4- (4-fluorophenyl) -3, 4-dehydropiperidinyl ] -ethyl -2-oxazolidinone . A compound of Claim 3 which is a 3-lower-alkyl-5-{2- [4- (4-fluorophenyl) -3, 4-dehydropiperidinyl] -ethyl^ -2-oxazolidinone . A compound of Claim β which is 3,4-dimethyl-5- 2-[4-(4-fluorophenyl) -3, 4-dehydropiperidinyl ]^ethyl^ -2 -oxazolidinone . A compound of Claim -3 which is the 3, 4-dimethyl-5-^2- [4-(4-fluorophenyl) -3, 4-dehydropiperidinyl ] -ethyl^ -2-oxazolidinone isomer melting at about 101-103°C. A process which comprise ■fs administering to a living animal body for its tranquilizing effect an effective amount of a compound of Claim -3. - A process which comprises administering to a living animal body for its tranquilizing effect an effective amount of a 5 compound of Claim 4. AHR-39A £ ' A composition useful for its tranquilizing effect comprising an effective dose of at least about one milligram of a compound of Claim -3 together with a pharmaceutically acceptable carrier. -§9- . A composition useful for its tranquilizing effect comprising an effective dose of at least about one milligram of a compound of Claim together with a pharmaceutically acceptable carrier. A compound of Claim 3 which is a 3-lower-alkyl-5-£2- [4- (3-trifluoromethylphenyl)-3,4-dehydropiperidenyl]-ethyl -2-oxazolidi-none acid addition salt. A compound of Claim 3 which is a 3-lower-alkyl-5-^2- [4-methoxyphenyl-3,4-dehydropiperidinyl] ethyl - 2-oxazolidinone . DA TED THIS 4t h A