US3419555A - 2-aryl-tetrahydropyran-3-amines - Google Patents

Description

United States Patent 0 3,419,555 Z-ARYL-TETRAHYDROPYRAN-3-AMINES Herndon Jenkins, Richmond, Va., assignor to A. H. Robins Company Incorporated, Richmond, Va., a

corporation of Virginia No Drawing. Filed Oct. 24, 1965, Ser. No. 505,010 25 Claims. (Cl. 260-247.2)

The present invention relates to certain novel aryl-substituted heterocyclic compounds, and is more particularly concerned with Z-aryItetrahydropyran-3-amines.

The invention is especially concerned with novel compounds having the formula:

T RI! wherein Ar is selected from the group consisting of phenyl, lower-alkylphenyl, hydroxyphenyl, lower-alkoxyphenyl, halophenyl, trifluoromethylphenyl, and naphthyl, wherein is selected from the group consisting of amino, N-loweralkylamino, N,N dilower alkylamino, N phenylloweralkylamino, morpholinoethyl, N- (hydroxylower alkyl)- amino, N,N di (hydroxylower-alkyl) amino, N-lOWeralkyl-N-(hydroxylower alkyl) amino, and a saturated monocyclic heterocyclic radical having up to a maximum of twelve carbon atoms and having up to a maximum of two hetero atoms in the ring and selected from the group consisting of morpholino, N-oxazolidone, piperidino, pyrrolidino and piperazino radicals, and wherein R" is selected from the group consisting of hydrogen and lower alkyl, and acid addition and quaternary ammonium salts thereof.

The basic compounds of the invention may be converted to either acid addition salts with pharmaceutically acceptable acids such as hydrochloric, fumaric acid, etc., or to quaternary salts with alkyl halides such as methyl bromide, etc.

The compounds falling within the general Formula I may exist in more than one form due to the possibility of stereo-isomerism resulting from at least two centers of asymmetry. It is also to be understood that the foregoing Formula I includes the possible racemates as well as the individual optically active forms.

The 2-aryltetrahydropyran-3-amines of the invention are useful as vasopressors, CNS stimulants, antidepressants, appetite suppressants, and nasal decongestants. In addition, certain of the compounds have been found to cause sedation in mice.

It is accordingly an object of the present invention to provide new and useful 2-aryltetrahydropyran-3-amines, compositions thereof, and methods of making and using the same. Other objects of the invention will be apparent to one skilled in the art.

In the definition of symbols in the foregoing Formula I and where they appear elsewhere throughout the specification and claims, the terms have the following significance.

The term lower-alkyl as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like. Lower alkoXy has the formula O1ower-alkyl. The term cycloalkyl as used herein includes primarily cyclic alkyl radicals containing three up to nine carbon atoms inclusive and encompasses 3,419,555 Patented Dec. 31, 1968 such groups as cyclopropyl, cyclobutyl, cyclohexyl, cyclo pentyl, methylcyclohexyl, propylcyclohexyl, ethylcyclopentyl, propylcyclopentyl, dimethylcyclohexyl, cycloheptyl, and cyclooctyl. Included in the term phenylloweralkyl are groups such as benzyl, phenethyl, methylbenzyl, phenpropyl, and the like.

When halogen is referred to herein, preferably but not necessarily a halogen of atomic weight in excess of nineteen but not greater than eighty is employed. Of the halogens, chlorine is preferred.

Among the suitable amino radicals included within the symbol are primary, secondary and tertiary amino radicals, such as unsubstituted amino (NH lower-alkyl-amino; dilower-alkyl-amino; phenylamino; phenyllower-alkylamino; di(phenyllower-alkyl) amino; lower-cycloalkylamino; dilower-cycloalkylamino; (hydroxylowenalkyl)amino; di- (hydroxylower-alkyl)-amino; 1ower-alkyl--(hydroxyloweralkyl)-amino; basic saturated monocyclic heterocyclic radicals having up to a maximum of twelve carbon atoms, as exemplified by piperidino; lower-alkyl-piperidino, e.g., 2-, 3-, or 4-lower-alkyl-piperidino; or 2,4-, 2,6-, or 3,5-dilower-alkyl-piperidino; lower-alkoxy-piperidino; pyrrolidino; lower-alkyl-pyrrolidino; lower-alkoxy-pyrrolidino; morpholino; lower-alkyl-morpholino; piperazino; loweralkyl-piperazino (e.g., C- or N -methyl-piperazino); N (lower-alkyl)-C-(lower-alkyl)-piperazino; N (hydroxylower-alkyl)-piperazino; N-lower-aliphatic acyloxy-loweralkyl) and especially N-(lower-alkanoyloxy-lower-alkyl)- piperazino [e.g., N-(acetoxy-, isobutyroxy-, or octanoyloxyethyl or propyl)-piperazino]; lower-alkoxy-piperazino; N lower alkoxy-lower-alkylpiperazino, e.g., N'-ethoxyethylpiperazino; and lower-carbalkoxy-piperazino.

The compounds of Formula I may be converted to and are most conveniently employed in the form of non-toxic pharmaceutically acceptable acid addition or quaternary ammonium salts. Such salts also have improved watersolubility. 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 acid addi tion salt. The free basic compounds of Formula I may be conveniently converted to their quaternary ammonium or acid addition salts by reaction of the free base with the selected acid or acid ester, e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl or aralkyl halide, sulfate or sulfonate, preferably in the presence of an organic solvent inert to the reactants and reaction products under the conditions of the reaction. 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 anions of which 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, hydriodic acid, nitric acid, sulfuric acid, and phosphoric acid; and organic acids such as acetic acid, citric acid, lactic acid, fumaric acid, and tartaric acid. The quaternary ammonium salts are obtained, e.g., by the addition of alkyl, cycloalkyl, alkenyl, cycloalkenyl, or aralkyl esters of inorganic acids or organic sulfonic acids, to the free base form of the selected tertiary amino compound. The alkyl, cycloalkyl, alkenyl, cycloalkenyl, or aralkyl esters so used include such compounds as methyl chloride, methyl 3 bromide, methyl iodide, ethyl bromide, propyl chloride, allyl chloride, allyl bromide, dimethyl sulfate, methyl benzene-sulfonate, methyl p-toluene sulfonate, benzyl halides such as p-chlorobenzyl chloride and p-nitrobenzyl chloride, and the like.

The acid addition salts are prepared either by dissolving the free base in an aqueous solution containing the ap propriate acid and isolating the salt by evaporating the solution, or by 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, illustratively ethyl acetate or benzene, drying the extract and evaporating to dryness or fractionally distilling, or in other conventional manner.

General method for the preparation of 2-aryl-tetrahydropyran-3-amines A 2-aryl-3-bromo (or chloro) tetrahydropyran (1 mole) is treated with an excess of the appropriate primary or secondary amine or ammonia (2 to moles; ca. 5 moles preferred) either without solvent or in a solvent which dissolves the reactants but does not itself enter the reaction (e.g., lower alcohols such as 2-propanol, aromatics such as toluene, ethers such as ethylene glycol dimethyl ether or other suitable solvents; 2-propanol being especially useful). The reaction mixture is heated from 5 to 100 hours at elevated temperatures usually in the range of 110 to 190 C. (24 hours at 150 C. being typical). The product formed in this reaction may be isolated in a manner suitable for organic bases. For example, the basic product may be taken up in acid, neutral material separated from it by extraction of the aqueous solution with an organic solvent (e.g., ether, ethyl acetate or toluene) and the basic product liberated from the acid solution by making the solution strongly basic. The basic product thus liberated may be taken up in an organic solvent (e.g., ether, chlorofrom, ethyl acetate or toluene), dried over an anhydrous salt which will form a hydrate (e.g., sodium sulfate, potassium carbonate or calcium sulfate), concentrated and distilled in vacuo. A salt may be formed by treatment of the basic product with the appropriate acid. The amines may be separated into optical isomers through separation of their diastereoisomeric salts formed with optically active acids (e.g., d-tartaric, l-malic acids, etc.).

The 2-aryl tetrahydropyran-El-amines of the invention which are primary or secondary amines may be further reacted to form novel compounds having desirable pharmacological properties. One such method for further reaction is acylation, of which the following is a suitable general description. The compounds are anti-depressants and sedatives.

The 2-aryl-tetrahydropyran-3-amines which are primary or secondary amines may be acylated by the following general method. The 2-aryl-tetrahydropyran-3-amine (1 mole) in an unreactive solvent (e.g., chloroform or tetrahydrofuran) is treated dropwise (e.g., over 0.5 hour) with the desired acylating agent (1 equivalent) (e.g., acetic anhydride, ethyl chloroforrnate, diphenylcarbamoyl chloride or phenyl isocyanate) and, in those cases where an acid is liberated (e.g., the first 3 acylating agents listed) may be treated simultaneously with a base (1 equivalent) (e.g., sodium hydroxide or pyridine). After addition is complete, the product may be isolated by methods used in the art. For example, a chloroform solution of the product can be washed with acid, base and water, dried and concentrated and the crude product purified by fractional distillation or crystallization,

The following preparations are given by Way of illustration only and are not to be construed as limiting.

Preparation 1.3-bromo-2-phenyltetrahydropyran Bromine (430 g., 2.69 moles) was added dropwise to a solution of dihydropyran (227 g., 2.69 moles) in absolute ethyl ether (250 ml.) at about -20 C. with vigorous stirring. This solution was added slowly with stirring to a solution of phenylmagnesium bromide (3.00 moles) in absolute ethyl ether (1 liter) at about 2025 C. The reaction mixture was refluxed for one hour after the addition was completed and cautiously mixed with water (1 liter). The water layer was discarded and the ether layer washed again with water, dried over sodium sulfate, concentrated and distilled. 3-bromo-2-phenyltetrahydropyran (448 g., 1.86 moles) was obtained in a 69% yield based on dihydropyran; B.P. 143-148 C. at 22 mm. pressure. The 3-br0mo-2-phenyltetrahydropyran crystallized on standing and was recrystallized from isooctane giving white crystals melting at 41.5-42.5 C. Cf. [R. Paul, Bull. Soc. Chem. (5), 2, 311-322 (1935)] Preparation 2.3-bromo-2- 3-methoxyphenyl) tetrahydropyran 3-bromo-2- 3-methoxyphenyl tetrahydropyran was prepared from bromine, dihydropyran and 3-methoxyphenylmagnesium bromide in the same manner as described in Preparation 1. After working up the reaction mixture in the usual manner, there was obtained a yield of 59% of the theoretical amount of 3-bromo-2-(3-methoxyphenyl) tetrahydropyran. The product boiled at 116120 C. at 0.2 mm. pressure; n 1.5632.

Preparation 3.-3-bromo 2-( l-naphthyl)tetrahydropyran Bromine (58 g., 0.36 mole) was added dropwise to a solution of dihydropyran (30.6 g., 0.36 mole) in absolute ethyl ether ml.) at about -15 C. with vigorous stirring. This solution was added slowly with stirring to a solution of l-naphthylmagnesium bromide [prepared from 1-br0m0naphthalene (100 g., 0.48 mole) and magnesium (12.2 g., 0.50 mole) in absolute ether (200 ml.) at about 20-25 C.]. The reaction mixture was refluxed two hours and hydrolyzed with dilute hydrochloric acid. The ether layer was separated, washed with water, dried over sodium sulfate, concentrated and distilled. 3-bromo- 2-(l-naphthyl)tetrahydropyran (73 g., 0.25 mole) boiling at to 169 C. at 0.15 mm. pressure was obtained in a 69% yield based on the dihydropyran.

Preparation 4.3 bromo 2 (3-trifluoromethylphenyl) tetrahydropyran 3-trifluoromethylphenylmagnesium bromide was added to the product resulting from the addition of bromine to dihydropyran in the same manner as described in Preparation 1 to give 3-bromo-2-(3-trifiuoromethylphenyl)tetrahydropyran in 69% of theoretical yield. The product boiled at 134139 C. at 22 mm. pressure; n 1.5011.

Preparation 5.3-bromo-2-p-tolyltetrahydropyran 3-bromo 2 p-tolyltetrahydropyran was prepared in 44% of the theoretical yield in the same manner as described in Preparation 1 for the synthesis of 3-bromo-2- phenyltetrahydropyran except that ptolylmagnesium. bromide was used in place of phenylmagnesium bromide. The 3-bromo-2-p-tolyltetrahydropyran was distilled at 90-94 C. at 0.05 mm. pressure; n 1.5573.

Preparation 6..3-bromo-4-methyl-2-phenyltetrahydropyran Bromine (1 mole) was added dropwise to a solution of 4-methyl-2,3-dihydro-4H-pyran [W. E. Parham and H. E. Holmquist, JACS, 73, 913 (1951)] (1 mole) in absolute ether (250 cc.) at about 20 C. with vigorous stirring. The resultant solution was added dropwise over 30 minutes to a stirred solution of phenylmagnesium bromide (1.3 moles) in absolute ether (1.5 liters) at 20 25 C. The reaction mixture was refluxed for one hour after the addition was completed and was then cautiously decomposed with an excess of dilute hydrochloric acid. The aqueous layer was discarded and the ether layer was washed with water, dried over anhydrous sodium sulfate, concentrated and distilled in vacuo giving 3-brorno- 4-methyl-2-phenyltetrahydropyran.

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 difierent 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, 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 present in a compound, other dilower-alkylamino compounds are prepared in the same manner starting only with the selected dilferent dilower-alkylamino compound. In the same manner, ortho and meta substituted compounds are produced instead of the para by utilizing the selected ortho or meta substituted starting compound, and vice versa. Similarly, other molecular changes are readily made.

The following examples are given by way of illustration only and are not to be construed as limiting.

Example 1.2-phenyltetrahydropyran-3-amine bimaleate 3-bromo-2-phenyltetrahydropyran (48.2 g., 0.20 mole) in sufiicient 2-propanol (210 ml.) to make a solution was saturated with ammonia at 0-10" C. and this mixture was stirred and heated for 48 hours in a closed stainless steel autoclave at about 145 C. The contents of the autoclave were then concentrated at reduced pressure to a pasty mass and partitioned between isopropyl ether and sufficient 2 N hydrochloric acid to produce a strongly acidic aqueous layer. The isopropyl ether layer was discarded and the aqueous layer was made strongly basic with 50% aqueous sodium hydroxide. An oil separated and was taken up in chloroform, washed with water, dried over sodium sulfate, concentrated and distilled. 2-phenyltetrahydropyran-3-amine (17.4 g., 0.098 mole) was collected, boiling at l35-141 C. at 25 mm. pressure; 11 1.5465. The neutralization equivalent found was 179.3, compared with 177.2 calculated. The yield was 49% of the theoretical. The base was treated with an equimolar quantity of maleic acid in ethanol to give a crystalline salt. Recrystallization from a mixture of absolute ethyl alcohol and ethyl acetate gave 2-phenyltetrahydropyran- 3-amine bi-maleate as white crystals melting at 14015- 14l.5 C.

Analysis.Ca1c. for C14H19N05 C, H, Found: C, 61.77; H, 6.54.

Utilizing the method of Example 1, 3-bromo-2-(3- chlorophenyl)tetrahydropyran is reacted with ammonia to produce 2 (3-chlorophenyl)tetrahydropyran-3-amine.

Example 2.2- 3-methoxyphenyl) tetrahydropyran-3- amine hydrochloride The preparation of 2-(3-methoxyphenyl)tetrahydropyran-3-arnine was carried out in the same manner as given in Example 1 by the reaction of ammonia and 3- bromo-2-(3rnethoxyphenyl)tetrahydropyran in 2-propanol solvent. The product, 2-(3-methoxyphenyl)tetrahydropyran-3-arnine was obtained in 44% yield, boiling at 133-136 C. at 0.22 mm. pressure; 11 1.5513. The 2-(3-methoxyphenyl)tetrahydropyran-B-amine was treated with an excess of an ether solution of hydrogen chloride to give a crystalline hydrochloride salt. The 2-(3-rnethoxyphenyl)tetrahydropyran-3 amine hydrochloride thus obtained was recrystallized from a mixture of 2-propanol and ligroin giving white crystals :melting at l83l84 C.

Analysis.--Calc. for C H ClNO C, 59.13; H, 7.44; N, 5.75. Found: C, 59.14; H, 7.52; N, 5.66.

The corresponding 2-(3-hydroxyphenyl)tetrahydropyran-3-amine is prepared by splitting of the methoxy group to the hydroxy group with ethanolic HBr.

Example 3 .-N -methyl-2-( l-naphthyl) tetrahydropyran-3'amine hydrochloride 3-bromo-2-(l-naphthyl)tetrahydropyran (72.5 g., 0.25 mole) and methylamine (45 g., 1.45 moles) in sufficient 2-propanol to give a total volume of 175 uml. Were heated at 140 to 145 C. for 24 hours in a closed steel vessel. The cooled reaction mixture was then concentrated in vacuo and partitioned between isopropyl ether and dilute aqueous hydrochloric acid. The acid layer was made strongly basic with 50% aqueous sodium hydroxide and extracted with chloroform. The chloroform solution was dried over sodium sulfate, concentrated and distilled. N- methyl-Z- l-naphthyl)tetrahydropyran-3-arnine (11.0 g., 0.046 mole, 18% of theory) was isolated; B.P. 121- 137" C. at 0.2 mm. pressure.

The base dissolved in ether was treated with an excess of ethereal hydrogen chloride and the white crystalline product thus obtained was recrystallized from a mixture of ethyl alcohol and ethyl acetate. The white crystals of Nmethyl-2-( 1-naphthyl)tetrahydropyran-3-amine hydrochloride melted with decomposition at 238 to 245 C.

Analysis.-Calc. for C H ClNO: C, 69.18; H, 7.26; N, 5.04. Found: C, 69.18; H, 7.22; N, 4.97.

The same manner, the corresponding N-hydroxyethylamino compound is prepared by substituting N-hydroxyethylamine for the methylarnine of the preceding example, as further indicated below:

N- (Z-hydroxyethyl -Z-phenyltetrahydropyran-3-amine Ethanolamine (121 g., 2.0 moles) and 24.1 g. (0.1 mole) of 3-brorno-2-phenyltetrahydropyran was heated 18 hours at 173 C. The excess ethanolamine was distilled from the reaction mixture and the residual oil distilled to give 9.0 g. (40.7%) of product, B.P. 109-113 C. at 0.1 mm. pressure. The maleate salt melted at 96.5 C.

Analysisr Calc. for C H NO C, 60.52; H, 6.87; N, 415. Found: C, 60.32; H, 6.79; N, 4.08.

Example 4.-N-methyl-2-phenyltetrahydropyran- 3-amine hydrochloride 3-bromo-2-phenyltetrahydropyran (48 g., 0.20 mole) and methylamine (31 g., 1.00 mole) in Z-propanol (200 ml.) were heated at C. for 18 hours in a closed steel vessel. The cooled reaction mixture was concentrated in vacuo and then partitioned between isopropyl ether and dilute aqueous hydrochloric acid. The acid layer was made strongly alkaline with 50% aqueous sodium hydroxide and the separated oil was extracted into chloroform. The chloroform extract was dried over anhydrous sodium sulfate, concentrated in vacuo and distilled. N- methyl-2-phenyltetrahydropyran- 3 amine (19 g., 0.10 mole, 50% of theory) was isolated; B.P. 133134 C. at 22 mm. pressure; 12 1.5356. The base was dissolved in ether and treated with ethereal hydrogen chloride. Two recrystallizations from acetonitrile yielded white crystals of N-methyl-Z-phenyltetrahydropyran-3-amine hydrochloride, melting at 216.5218.5 C.

Analysis.--Calc. for C H ClNO: C, 63.28; H, 7.97; N, 6.15. Found: C, 63.15; H, 7.78; N, 6.01.

Example 5.-N,N-dimethyl-Z-phenyltetrahydropyran- 3-arnine hydrochloride 3-bromo-2-phenyltetrahydropyran (96 g., 0.40 mole) and dimethylamine (90 g., 2.0 moles) in 2-propanol (150 ml.) were heated 25 hours at 125 C. in a closed steel vessel. The cooled reaction mixture was concentrated in vacuo and partitioned between dilute aqueous hydrochloric acid and isopropyl ether. The acid layer was made strongly basic with 50% aqueous sodium hydroxide and the oil which separated was extracted into chloroform. The chloroform layer was dried over anhydrous sodium sulfate, concentrated and distilled. N,N-dimethyl-2-phenyltetrahydropyran-3-amine (11.0 g., 0.054 mole, 13% of theory) was isolated; B.P. 146151 C. at 25 mm. pressure; n 1.5313. The equivalent weight by anhydrous perchloric acid titration gave 205.7; 205.3 calculated. The base was treated with ethereal hydrogen chloride to give N,N-dimethyl-2-phenyltetrahydropyran 3 amine hydrochloride as white crystals. Two recrystallizations from absolute ethanol gave white crystals, melting point 195- 196.5 C.

Analysis.-Calc. for C H ClNO: C, 64.58; H, 8.34; N, 5.79. Found: C, 64.55; H, 8.36; N, 5.78.

In the same manner, the corresponding N,N-di(hydroxyethyl)amino and N-methyl N hydroxyethylamino compounds are prepared by substituting N,N-di(hydroxyethyl)amine or N-methyl-N-hydroxyethylamine for the dimethylamine of the preceding example.

Example 6.N,N-dimethyl-2-phenyltetrahydropyran- 3-amine N-methyl-2-phenyltetrahydropyran-3-amine (19 g., 0.10 mole), formic acid (26 g. of 90% aqueous formic acid, 0.50 mole) and formaldehyde (22.5 g. of 40% aqueous solution, 0.30 mole) were heated at 80 C. for 17 hours. The solution was then cooled, concentrated in vacuo and partitioned between ether and dilute aqueous hydrochloric acid. The hydrochloric acid solution was made strongly basic and extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, concentrated and distilled. N,N-dimethyl-2-phenyltetrahydropyran-3-amine (19 g., 0.093 mole, 93% of theory) was isolated; B.P. 140143 C. at 22 mm. pressure. The free base was identical with that prepared in Example 5.

Example 7.N- 2-morpholinoethyl -2-phenyltetrahydropyran-3-amine dihydrochloride monohydrate 3-bromo-2-phenyltetrahydropyran (24 g., 0.10 mole) and 4-(2-aminoethyl)-morpholine (65 g., 0.50 mole) were heated together for 55 minutes at 200 C. without a solvent. The reaction mixture was partitioned between dilute aqueous sodium hydroxide solution and isopropyl ether. The isopropyl ether solution was dried, concentrated and distilled giving N-(Z-morpholinoethyl)-2-phenyltetrahydropyran (12.0 g., 41% of theory) boiling at 145- 150 C. at 0.1 mm. pressure; n 1.5336. Equivalent weight by titration was 144 compared with a calculated equivalent weight of 145. The base was dissolved in ether and treated with an excess of ethereal hydrogen chloride. The precipitated solid was recrystallized twice from 2- propanol giving white crystals of N-(2-morpholinoethyl)- Z-phenyltetrahydropyran-3-amine dihydrochloride monohydrate, melting at 226 to 228.5 C.

Analysis.Calc. for C I-I Cl N O -H O: C, 53.54; H, 7.93; N, 7.34; H O, 4.74. Found: C, 53.42; H, 8.04; N, 7.28; H O, 4.84.

Example 8.Additional amine compounds Utilizing the method of Examples 1 through 7, 3- bromo-phenyltetrahydropyran or other starting material from said examples is reacted with a suitable amine reactant to provide the corresponding compounds according to the invention wherein the group is piperidino, 4-methylpiperidino, 3,5-diethylpiperidino, 4-methoxypiperidin0, pyrrolidino, 3-methylpyrrolidino, 3-methoxypyrrolidino, 3-methylmorpholino, 3-methoxymorpholino, piperazino, N -methylpiperazino, N -methyl-2-methylpiperazino, N-(hydroxyethyl)piperazino, N- acetoxyethyl) piperazino, 3-methoxypiperazino, N-ethoxyethylpiperazino, and 3-(carbethoxy)piperazino.

Example 9.N-methyl-2- 3-trifiuoromethylphenyl) tetrahydropyran-3-amine hydrochloride 3-bromo-2-(3 trifiuoromethylphenyl)tetrahydropyran (61 g., 0.20 mole) and methylamine (40 g., 1.3 moles) in 2-propanol (150 ml.) were heated 19 hours at 140 C. in a closed steel vessel. The reaction mixture was concentrated in vacuo and partitioned between dilute aqueous hydrochloric acid and isopropyl ether. The acid layer was made strongly basic with aqueous sodium hydroxide and the separated oil was taken up in chloroform. The chloroform extract was dried over sodium sulfate, concentrated and distilled. N-methyl-2-(3-trifluoromethylphenyl)tetrahydropyran-3-amine (26 g., 50% of theory) was isolated boiling at 128 to 133 C. at 22 mm. pressure; n 1.4853. The oil was dissolved in ether and treated with ethereal hydrogen chloride to give a crystalline salt. Two recrystallizations from a mixture of 2- propanol and isopropyl ether gave N-methyl-2-(3-trifiuoromethylphenyl tetrahydropyran-3-amine hydrochloride as white crystals melting at 206 to 207 C.

Analysis.Calc. for C H ClF NO: C, 52.79; H, 5.80; N, 4.74. Found: C, 53.01; H, 5.82; N, 4.91.

Example 10.N,N-dimethyl-2-phenyltetrahydropyran- 3-amine methobromide N,N-dimethyl-Z-phenyltetrahydropyran-3-amine (19 g., 0.093 mole) was dissolved in methyl ethyl ketone ml.) and a solution of methyl bromide (29 g., 0.30 mole) in methyl ethyl ketone (100 ml.) was added while maintaining the temperature at 25 C. Crystals formed and were removed by filtration after standing overnight at room temperature. Two recrystallizations of the crystals from a mixture of ethyl acetate and ethyl alcohol gave N,N-dimethyl 2 phenyltetrahydropyran-3-amine methobromide (22 g., 79% of theory) as white crystals; M.P. 199200.5 C.

Analysis.Calc. for C H BrNO: C, 56.00; H, 7.39; N, 4.66. Found: C, 56.08; H, 7.46; N, 4.80.

Example 11.3-rnorpholino-3 p -toly1tetrahydropyran 3-bromo-2-p-tolytetrahydropyran (40 g., 0.16 mole) and morpholine (68 g., 0.78 mole) were mixed and then refluxed for 5 hours. The excess morpholine was distilled off in vacuo. The residue was partitioned between dilute aqueous hydrochloric acid and isopropyl ether. The acid layer was made strongly basic with 50% aqueous sodium hydroxide and the oil which separated was taken up in chloroform. The chloroform layer was dried over sodium sulfate and distilled. The material boiled at 117 to C. at 0.01 mm. pressure and crystallized in the receiver (7.0 g., 17% of the theoretical yield). Five recrystalli- 9 zations from isopropyl ether gave 3-morpholino-2-p-tolyltetrahydropyran, M.P. 88.5 to 90 C.

Analysis.-Calc. for C H NO C, 73.53; H, 8.87; N, 5.36. Found: C, 73.58; H, 9.08; N, 5.51.

Example 12.--N- 2-phenylethyl -2-phenyltetrahydropyran-B-amine hydrochloride A mixture of 3-bromo-2-phenyltetrahydr0pyran (27 g., 0.11 mole) and phenethylamine (121 g., 1.0 mole) was refluxed 20 hours and the excess phenethylamine distilled ofi in vacuo. The cooled solution was partitioned between dilute hydrochloric acid and isopropyl ether. The acid layer was made strongly basic with 50% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform solution was dried over sodium sulfate, concentrated and distilled. The material boiling at 140-147 C. at 0.2 mm. pressure (17 g., 54% of theory) was collected and converted to the hydrochloride salt in the usual manner. Two recrystallizations from absolute ethanol gave N-(Z-phenylethyl)-2-phenylt-etrahydropyran-3-amine hydrochloride melting at 248.5- 250 C.

Analysis-Cale. for C H ClNO: C, 71.79; H, 7.61; N, 4.41. Found: C, 71.61; H, 7.58; N, 4.31.

Example 13.N-isopropyl-2-phenyltetrahydropyran- 3-amine hydrochloride 3-bromo-2-phenyltetrahydropyran (48.2 g., 0.2 mole) and isopropylamine (59 g., 1.0 mole) were placed in a sealed steel vessel and the temperature raised to 140 C. After maintaining the temperature at this level for 17 hours, the reaction mixture was cooled. The reactor was opened and the solution made strongly basic with dilute aqueous sodium hydroxide. The organic material was extracted into isopropyl ether, dried over sodium sulfate and distilled. The distillate was dissolved in dilute aqueous hydrochloric acid, extracted with ether and the acid layer made basic with aqueous sodium hydroxide. The organic material was extracted into ether, dried over sodium sulfate and distilled (14.1 g., 32% yield); B.P. 145-151 C. at 22 mm. pressure; r1 1.5151. The hydrochloride salt prepared in the usual manner was recrystallized from ethyl acetate to give N-isopropyl-2phenyltetrahydropyran-3-amine hydrochloride; M.P. 246247.5 C.

Analysis.Ca1c. for C H CINO: C, 65.74; H, 8.67; N, 5.48. Found: C, 65.84; H, 8.67; N, 5.71.

Example 14.-2-phenyltetrahydropyran-3-amine 3-chloro-2-phenyltetrahydropyran [R. Paul, Compt.

rend. 218, 1124 (1944)] (30.0 g., 0.153 mole) in sulficient 2-propanol (60 ml.) to make a solution was treated with ammonia (26 g., 1.53 moles) at about -20 C. and this solution was heated and stirred for 72 hours at 175 C. in a closed stainless steel vessel. The reaction mixture was worked up in the same manner as described in Example 1 to give Z-phenyltetrahydropyran-3-amine (9.5 g., 0.054 mole, 35% of theory). This material was shown to be identical with that obtained in Example 1.

Example 15.-4-methyl-2-phenyltetrahydropyran-3-amine A solution of 3-bromo-4-methyl-Z- henyltetrahydropyran (0.5 mole) in 2-propanol (400 ml.) was saturated with ammonia at to C. and the solution was stirred and heated 48 hours in a closed stainless steel vessel at 150-160 C. The reaction mixture was cooled, concentrated in vacuo and partitioned between water and dilute hydrochloric acid. The aqueous layer was made strongly basic with 50% aqueous sodium hydroxide and the oil which separated was extracted into ether. The ether solution was dried over anhydrous sodium sulfate, concentrated and distilled in vacuo giving 4-metl1yl-2-phenyltetrahydropyrarr -3-amine.

The following examples illustrate useful derivatives of the 2-aryltetrahydropyran-3-arnines of the invention, prepared by subsequent acylation, having the formula:

Wherein R is selected from the group consisting of hydrogen, lower-alkyl, phenyl, phenyllower-alkyl, lowercycloalkyl, and hydroxylower-alkyl,

Wherein Ar is selected from the group consisting of phenyl, lower-alkylphenyl, hydroxyphenyl, lower-alkoxyphenyl, halophenyl, trifluoromethylphenyl, and naphthyl,

Wherein R is selected from the group consisting of hydrogen and lower-alkyl, and

Wherein R is selected from the group consisting of lower-alkyl, lower-alkoxy phenyllower-alkyl, amino, N- lower-alkylamino, N,N-dilower-alkylamino, phenylamino, diphenylamino, lower cycloalkylamino, dilower cycloalkylamino, phenyllower-alkylamino, and di(phenyllower-alkyl) amino.

Example 16.N-acetyl-2-phenyltetrahydropyran-3-amine 2-phenyltetrahydropyran-3-amine (18 g., 0.10 mole) in isopropyl ether ml.) was treated with acetic anhydride (20.4 g., 0.20 mole) and triethylamine (10.1 g., 0.10 mole) for 10 minutes at 50 C. On cooling a white precipitate formed which was recrystallized from a mixture of 2-propanol and ligroin giving N-acetyl-Z-phenyltetrahydropyran-3-amine (13 g., 0.060 mole, 60% of theory) as white crystals; M.P. 11S.5117 C.

Analysis-Calc. for C H NO C, 71.13; H, 7.81: N, 6.39. Found: C, 71.23; H, 7.84; N, 6.28.

Example 17.-N-carbethoxy-Z-phenyltetrahydropyran-3- amine 2-phenyltetrahydropyran-3-amine (10 g., 0.056 mole) and pyridine (4.7 g., 0.06 mole) in chloroform (100 ml.) were treated dropwise during 25 minutes with a solution of ethyl chloroformate (6.5 g., 0.06 mole) in chloroform (50 ml.) at 0 C. When addition of the chloroformate was completed, the reaction mixture was stirred 30 minutes at 25 C., washed with water, dried over anhydrous sodium sulfate, concentrated and distilled; B.P. 124127 C. at 0.3 mm. pressure. The product (10.0 g, 0.04 mole) was obtained in a 74% yield and crystallized on standing Two recrystallizations from ligroin gave white crystals of N-carbethoxy-2-phenyltetrahyd-royran- 3-amine melting at 72.5 to 74 C.

Analysis.-Calc. for C H NO C, 67.44; H, 7.68 N, 5.62. Found: C, 67.49; H, 7.62; N, 5.46.

Example 18.-N-(N,N'-diphenylcarbamoyl)- phenyltetrahydropyran-3 -amir1e 2-phenyltetrahydropyran-3-amine (17.7 g., 0.10 mole) in tetrahydrofuran 100 ml.) was treated dropwise during twenty minutes with diphenylcarbarnoyl chloride (23 g., 0.10 mole) in tetrahydrofuran (100 ml.). During the last half of the addition of the diphenylcarbarnoyl chloride, sodium hydroxide (4.0 g., 0.10 mole) in water (50 ml.) was added simultaneously. Ether (100 ml.) was then added and the ether layer separated, dried over sodium sulfate and concentrated to give a white crystalline solid. Two recrystallizations from 2-propanol gave N-(N,N- diphenylcarbarnoyl) 2 phenyl-tetrahydropyran-3-amine (24 g., 50% of theory) as white crystals melting at 148.5 C.

Analysis.Calc. for C H N O C, 77.38; H, 6.49; N, 7.52. Found: C, 77.12; H, 6.64; N, 7.35.

in dry benzene (100 ml.) at 10 C. was treated dropwise during 30 minutes with phenylisocyanate (12 g., 0.10

mole) in dry benzene (100 ml.) while stirring and cooling. The reaction mixture was warmed to 30 C. for 30 minutes, and chilled and the product removed by filtration. 2 phenyl-N-(phenylcarbamoyl)tetrahydropyran-3-amine (27 g., 0.09 mole) was obtained in 90% yield; M.P. 182.5-184" C. Two recrystallizations from 2-propanol gave the pure product as white crystals melting at l83184 C.

Analysis.Calc. for C H N O C, 72.95; H, 6.80; N, 9.45. Found: C, 72.87; H, 6.91; N, 9.49.

Using the procedure described above, the following compounds are prepared from the selected starting materials.

(l) N-methyl-N-(benzylcarbamoyl) 2 (p-methylphenyl)tetrahydropyran-3-amine (2) N-methyl-N-(ethylcarbamoyl) 2 (p-hydroxyphenyl)tetrahydropyran-3-amine (3) N-benzyl-N-(diethylcarbamoyl) 2 (p-ethoxyphenyl) tetrahydropyran-3-amine (4) N-cyclohexyl-N-(phenacetyl) 2 (p-chlorophenyl)tetrahydropyran-3-arnine (5) N-(Z-hydroxyethyl)-N-(cyclohexylcarbamoyl) 2- m-trifluoromethylphenyl) -tetrahydropyran-3 -amine (6) N-methyl-N-(dicyclohexylcarbamoyl) 2 (1- naphthyl)tetrahydropyran-3-amine (7) N-methyl-N-(dibenzylcarbamoyl) 4 methyl-2- phenyltetrahydropyran-3-amine (8) N-carbamoyl 2 phenyltetrahydropyran-3-amine.

Example .-N- 2-phenyl-3-tetrahydropyranyl oxa'zolidinone Fourteen grams (0.0634 mole) of N-(2-hydroxyethyl) 2-phenyltetrahydropyran3-amine and g. (0.25 mole) of diethyl carbonate and a small piece of sodium was mixed with 500 ml. of toluene. The toluene was distilled off over a two hour period, reducing the toluene volume to approximately 70 ml. The mixture was quenched with ice and the basic materials extracted with dilute hydrochloric acid. The toluene solution was dried and concentrated to an oil which crystallized spontaneously. The solid was recrystallized from ethyl acetate to give 7.3 g. (43.5%) of material melting at l30l3l.5 C.

Analysis.Calc. for C H NO C, 67.99; H, 6.93; N, 5.66. Found: C, 67.86; H, 6.87; N, 5.53.

Where the foregoing examples 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 fiuoro compounds, are prepared starting from the appropriate halogenated starting material. Similarly, where methoxy or other lower-alkoxy group is present, 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 present in a compound, other diloweralkylamino compounds are prepared in the same manner starting only 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, and vice versa. Similarly other molecular changes within the scope of the invention are readily made.

Formulation and administration.Effective quantities of any of the foregoing pharmacologically active compounds 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 in the form of sterile solutions. The free basic amino compounds, While effective, are preferably formulated and administered in the form of their non-toxic acid-addition or quaternary ammonium salts for purposes of convenience of crystallization, increased solubility, and the like.

Although very small quantities of the active materials of the present invention, even as low as 0.1 milligram, 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, e.g., anorectic or sedative, desired. Five to fifty milligrams appears optimum per unit dose, while usual broader ranges appear to be one to milligrams per unit dose. The active agents of the invention may be combined with other pharmacologically active agents, or with buffers, antacids or the like, 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 Example 21 are representative for the pharmacologically active compounds of the invention, but have been especially designed to embody as active ingredient N-lower-alkyl-2-phenyltetrahydropyran- 3-amines, or their hydrochlorides, hydrobromides, methiodides, or like pharmaceutically acceptable salts.

Example 2 l .-Formulations -(1) Capsules.-Capsules of 5 ing., 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

Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows:

100 mg 250 mg. 500 mg. Ingredients per per per capsule capsule capsule Active ingredient, as salt 100.0 250.0 500. O Lactose 231. 5 126. 5 31. 1 Starch 99. 2 54. 2 13. 4 Magnesium stearate". 4. 3 4. 3 5. 5

Total 435. 0 435. 0 550. 0

Per tablet, mg.

( 1) Active ingredient 5.0 (2) Corn starch 13.6 (3) Corn starch (paste) 3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate 0.9

Total 170.1

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

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 2.2

Total 540.0

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 mesh screen. The wet granules are dried at 140-160 degrees Fahrenheit overnight. The dried granules are passed through a number ten mesh screens. 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

Uniformly blend the active ingredient, corn starch, Carbowax 6000, lactose, 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 granulator. These granules are then blended with the remainder of the magnesium stearate and the lubricated granules are then converted into tablets on a suitable tablet press.

14 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

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 degrees Fahrenheit. The dried granules are passed through a number ten mesh screen. The dried granules and weighed amounts of corn starch and cal-cium stearate are uniformly blended and these lubricated granules are compressed on a suitable tablet press.

(3) Injectable-2% sterile solution.

Per cc. Active ingredient mg 20 Preservative, e.g., chlorobutanol percent wt./vol 0.5 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.

Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, compositions, methods, and procedures of the present invention without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.

I claim:

1. An aryltetrahydropyranamine selected from the group consisting of (1) compounds of the formula:

T RI! wherein Ar is selected from the group consisting of phenyl, lower-alkylphenyl, hydroxyphenyl, lower-alkoxyphenyl, halophenyl, trifluoromethylphenyl, and naphthyl, wherein is selected from the group consisting of amino, N-loweralkylamino, N,N-dilower-alkylamino, N-phenylloweralkylamino, 2-morp holinoethyl, N (hydroxylower alkyl)-amino, N,N di(hydroxylower alkyl) amino, N-lower-alkyl-N-(hydroxylower-alkyl)-amino,. and a saturated monocyclic heterocyclic radical having up to a maximum of twelve carbon atoms and having up to a maximum of two hetero atoms in the ring and selected from the group consisting of morpholino, N-oxazolidinone, piperidino, pyrrolidino, and piperazino, and wherein R" is selected from the group consisting of hydrogen and lower-alkyl, and (2) non-toxic pharmaceutically acceptable acid addition and quaternary ammonium salts thereof. 2. 2-(lower-alkoxyphenyl)tetrahydropyran-S-amine. 3. Nlower-alkyl-2-phenyltetrahydropyran-3-amine. 4 N,N dilower alkyl 2-phenyltetrahydropyran-3- amine.

5. 2-(lower-alkylphenyl)tetrahydropyran-3-amine.

6. Z-phenyl(lower-alkyltetra'hydropyran)-3-amine.

7. 2-phenyltetrahydropyran-3-amine bimaleate.

8. 2-(3-methoxyphenyl)tetrahydropyran 3 amine hydrochloride.

9. N-methyl-2-(l-naphthyl)tetrahydropyran-3 amine hydrochloride.

10. N-methyl-2-phenyltetrahydropyran 3 amine hydrochloride.

11. N,N-dimethyl-2-phenyltetrahydropyran 3 amine hydrochloride.

12. N,N-dimethyl-2-phenyltetrahydropyran-3-amine.

13. N-(Z-morpholinoethyD-Z phenyltetrahydropyran- 3-amine dihydrochloride monohydrate.

14. N-methyl-2-(3 trifluoromethylphenyl)tetrahydropyran-3-amine hydrochloride.

15. N,N-dimethyl-2-phenyltetrahydropyran 3 amine methobromide.

16. 3-morpholino-2-p-tolyltetrahydropyran.

17. N-(Z-phenylethyl) 2 phenyltetrahydropyran 3- amine hydrochloride.

18. N-isopropyl-Z-phenyltetrahydropyran-3-amine drochloride.

19. 4-methyl-2-phenyltetrahydropyran-3-amine.

20. A compound having the formula:

wherein R is selected from the group consisting of hydrogen, lower-alkyl, phcnylloWer-alkyl, lower-cycloalkyl, and hydroxylower-alkyl,

wherein Ar is selected from the group consisting of phenyl, loWer-alkylphenyl, hydroxyphenyl, lower-alkoxyphenyl, halophenyl, trifluoromethylphenyl, and naphthyl,

wherein R" is selected from the group consisting of hydrogen and lower-alkyl, and

wherein R is selected from the group consisting of lower-alkyl, lower-alkoxy, phenyllower-alkyl, amino, N-lower-alkylamino, N,N-dilower-alkylamino, phenylamino, diphenylamino, cycloalkylamino, dicycloalkylamino, phenyllower-alkylamino, and di(phenylloweralkyl)amino. 21. N-acetyl-Z-phenyltctrahydropyran-3-amine. 22. N-carbethoxy-Z-phenyltetrahydropyran-3-arnine. 23. N N',N diphenylcarbamoyl) 2 phenyltetrahydropyran-S-amine.

24. 2-phenyl-N-(phenylcarbamoyl)tetrahydropyran 3- amine.

25. N-(Z-phenyl-3-tetrahydropyranyl)-0Xazolidinone.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner.

JOSE TOVAR, Assistant Examiner.

US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,419,555 December 31, 196E Herndon Jenkins It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below: Column 6, line 39, "The should read In the line 53, "N, 415.

should read N, 4. l5 Column 8, line 64, morpholino3-pshould read morpholino-2p- .Column 9, line 51, "ll24" should read 122-4 Column 10, line 47 "standing" should read standing. line 48, "phenyltetrahydroyran" should read phenyltetrahydropyran line 53, "diphenylcarbamoyl)phenyltetra should read diphenylcarbamoyl-Z- phenyltetra Column 16, line 18, "N-N'" should read Nw(N' Signed and sealed this 10th day of March 1970.

(SEAL) Attest: Edward M. Fletcher, 11'. WILLIAM E. SCHUYLER, JR.

Commissioner of Patents Attesting Officer

Claims (3)

1. AN ARYLTETRAHYDROPYRANAMINE SELECTED FROM THE GROUP CONSISTING OF (1) COMPOUNDS OF THE FORMULA:

13. N-(2-MORPHOLINOETHYL)-2-PHENYLTETRAHYDROPYRAN3-AMINE DIHYDROCHLORIDE MONOHYDRATE.

20. A COMPOUND HAVING THE FORMULA: