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

2-aryl-tetrahydropyran-3-amines Download PDF

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US3419555A
US3419555A US505010A US50501065A US3419555A US 3419555 A US3419555 A US 3419555A US 505010 A US505010 A US 505010A US 50501065 A US50501065 A US 50501065A US 3419555 A US3419555 A US 3419555A
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amine
phenyltetrahydropyran
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alkyl
tetrahydropyran
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Jenkins Herndon
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AH Robins Co Inc
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AH Robins Co Inc
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Priority to NL6614056A priority patent/NL6614056A/xx
Priority to CH1516666A priority patent/CH468378A/de
Priority to SE14205/66A priority patent/SE303760B/xx
Priority to GB47023/66A priority patent/GB1169014A/en
Priority to BR183868/66A priority patent/BR6683868D0/pt
Priority to SE14456/66A priority patent/SE320675B/xx
Priority to DE1620222A priority patent/DE1620222C3/de
Priority to FR1602629D priority patent/FR1602629A/fr
Priority to GB47693/66A priority patent/GB1140803A/en
Priority to DE19661543840 priority patent/DE1543840A1/de
Priority to NL6615029A priority patent/NL6615029A/xx
Priority to FR81396A priority patent/FR1497423A/fr
Priority to BR183952/66A priority patent/BR6683952D0/pt
Priority to CH1538066A priority patent/CH487140A/de
Priority to BE688765D priority patent/BE688765A/xx
Priority to FR81395A priority patent/FR6041M/fr
Priority to AT992866A priority patent/AT265256B/de
Priority to FR92057A priority patent/FR6717M/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical

Definitions

  • 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:
  • 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
  • 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.
  • certain of the compounds have been found to cause sedation in mice.
  • 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.
  • cycloalkyl as used herein includes primarily cyclic alkyl radicals containing three up to nine carbon atoms inclusive and encompasses 3,419,555 Patented Dec.
  • cyclopropyl such as cyclopropyl, cyclobutyl, cyclohexyl, cyclo pentyl, methylcyclohexyl, propylcyclohexyl, ethylcyclopentyl, propylcyclopentyl, dimethylcyclohexyl, cycloheptyl, and cyclooctyl.
  • phenylloweralkyl are groups such as benzyl, phenethyl, methylbenzyl, phenpropyl, and the like.
  • halogen 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.
  • 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-
  • 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 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.
  • 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 limbate 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.
  • 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.
  • the product formed in this reaction may be isolated in a manner suitable for organic bases.
  • 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).
  • a base e.g., sodium hydroxide or pyridine
  • the product may be isolated by methods used in the art. For example, a chloroform solution of the product can
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • N-hydroxyethylamino compound is prepared by substituting N-hydroxyethylamine for the methylarnine of the preceding example, as further indicated below:
  • 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.
  • Example 5 3-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.
  • 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.
  • 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.
  • 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.
  • a suitable amine reactant to provide the corresponding compounds according to the invention wherein the group is piperidin
  • 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.
  • 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.
  • 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.
  • Example 13N-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.
  • R is selected from the group consisting of hydrogen, lower-alkyl, phenyl, phenyllower-alkyl, lowercycloalkyl, and hydroxylower-alkyl
  • Ar is selected from the group consisting of phenyl, lower-alkylphenyl, hydroxyphenyl, lower-alkoxyphenyl, halophenyl, trifluoromethylphenyl, and naphthyl,
  • R is selected from the group consisting of hydrogen and lower-alkyl
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • dilower-alkylamino group such as the dimethylamino group
  • other diloweralkylamino compounds are prepared in the same manner starting only with the selected different dilower-alkylamino compound.
  • ortho and meta products are produced instead of the para by utilizing the selected ortho or meta substituted starting material, and vice versa.
  • other molecular changes within the scope of the invention are readily made.
  • 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.
  • 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.
  • 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.
  • Typical blend for encapsulation Per capsule, mg.
  • Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows:
  • 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
  • Preservative e.g., chlorobutanol percent wt./vol 0.5 Water for injection q.s.
  • 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.
  • An aryltetrahydropyranamine selected from the group consisting of (1) compounds of the formula:
  • 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,.
  • 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-(lower-alkoxyphenyl)tetrahydropyran-S-amine 3.
  • Nlower-alkyl-2-phenyltetrahydropyran-3-amine. 4 N,N dilower alkyl 2-phenyltetrahydropyran-3- amine.
  • R is selected from the group consisting of hydrogen, lower-alkyl, phcnylloWer-alkyl, lower-cycloalkyl, and hydroxylower-alkyl
  • Ar is selected from the group consisting of phenyl, loWer-alkylphenyl, hydroxyphenyl, lower-alkoxyphenyl, halophenyl, trifluoromethylphenyl, and naphthyl,
  • R" is selected from the group consisting of hydrogen and lower-alkyl
  • 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.
  • NICHOLAS S. RIZZO Primary Examiner.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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US505010A 1965-10-24 1965-10-24 2-aryl-tetrahydropyran-3-amines Expired - Lifetime US3419555A (en)

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US505010A US3419555A (en) 1965-10-24 1965-10-24 2-aryl-tetrahydropyran-3-amines
US504992A US3470189A (en) 1965-10-24 1965-10-24 Heterocyclic substituted acetic acid derivatives,intermediates therefor,and production and use thereof
NL6614056A NL6614056A (enrdf_load_html_response) 1965-10-24 1966-10-05
CH1516666A CH468378A (de) 1965-10-24 1966-10-19 Verfahren zur Herstellung heterocyclisch substituierter Derivate der Essigsäure
SE14205/66A SE303760B (enrdf_load_html_response) 1965-10-24 1966-10-19
GB47023/66A GB1169014A (en) 1965-10-24 1966-10-20 Aryl-Substituted Tetrahydropyrans
BR183868/66A BR6683868D0 (pt) 1965-10-24 1966-10-21 Compostos hetero-ciclicos aril substituidos
SE14456/66A SE320675B (enrdf_load_html_response) 1965-10-24 1966-10-21
FR1602629D FR1602629A (en) 1965-10-24 1966-10-22 Arylpyranamine derivs
DE1620222A DE1620222C3 (de) 1965-10-24 1966-10-22 3-Pyrrolidinyloxy-substituierte Diphenylessigsäurederivate und Verfahren zu deren Herstellung
GB47693/66A GB1140803A (en) 1965-10-24 1966-10-24 Heterocyclic substituted acetic acid derivatives, intermediates therefor, and production and use thereof
NL6615029A NL6615029A (enrdf_load_html_response) 1965-10-24 1966-10-24
FR81396A FR1497423A (fr) 1965-10-24 1966-10-24 Procédé de production de dérivés hétérocycliques d'acide acétique
BR183952/66A BR6683952D0 (pt) 1965-10-24 1966-10-24 Processo para a producao de derivados de acido acetico substituidos heterociclicos
CH1538066A CH487140A (de) 1965-10-24 1966-10-24 Verfahren zur Herstellung von in 2-Stellung durch einen Arylrest substituierten 3-Amino-tetrahydropyranen
BE688765D BE688765A (enrdf_load_html_response) 1965-10-24 1966-10-24
DE19661543840 DE1543840A1 (de) 1965-10-24 1966-10-24 Verfahren zur Herstellung von arylsubstituierten heterocyclischen Verbindungen
AT992866A AT265256B (de) 1965-10-24 1966-10-24 Verfahren zur Herstellung neuer 2-Aryltetrahydropyran-3-amine und ihrer Salze
FR81395A FR6041M (enrdf_load_html_response) 1965-10-24 1966-10-24
FR92057A FR6717M (enrdf_load_html_response) 1965-10-24 1967-01-20

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3669992A (en) * 1968-04-18 1972-06-13 Phillips Petroleum Co Preparation of aminotetrahydropyrans
US5252735A (en) * 1990-06-29 1993-10-12 The Upjohn Company Antiatherosclerotic and antithrombotic 2-amino-6-phenyl-4H-pyran-4-ones
US5302613A (en) * 1990-06-29 1994-04-12 The Upjohn Company Antiatheroscleroic and antithrombotic 2-amino-6-phenyl-4H-pyran-4-ones

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DE2951634A1 (de) * 1979-12-21 1981-07-16 C.H. Boehringer Sohn, 6507 Ingelheim Neue substituierte 4-amino-2,6-diaryl-tetrahydrothiopyrane, deren saeureadditionssalze, verfahren zu ihrer herstellung, ihre verwendung und pharmazeutische zusammensetzungen
WO2000031078A1 (fr) * 1998-11-20 2000-06-02 Banyu Pharmaceutical Co., Ltd. Derives de 1-acetylazetidine

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US3128277A (en) * 1964-04-07 Lower alkyl-a
US2708194A (en) * 1952-12-10 1955-05-10 Univ Michigan 2-(1-methyl) polymethyleniminylmethyl benzhydryl ethers and preparation thereof
US3280196A (en) * 1962-05-25 1966-10-18 S B Penick & Company Benzhydryl-dihaloalkane ethers

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3669992A (en) * 1968-04-18 1972-06-13 Phillips Petroleum Co Preparation of aminotetrahydropyrans
US5252735A (en) * 1990-06-29 1993-10-12 The Upjohn Company Antiatherosclerotic and antithrombotic 2-amino-6-phenyl-4H-pyran-4-ones
US5302613A (en) * 1990-06-29 1994-04-12 The Upjohn Company Antiatheroscleroic and antithrombotic 2-amino-6-phenyl-4H-pyran-4-ones

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GB1169014A (en) 1969-10-29
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FR1602629A (en) 1971-01-04
US3470189A (en) 1969-09-30
FR6041M (enrdf_load_html_response) 1968-05-20
CH468378A (de) 1969-02-15
FR1497423A (fr) 1967-10-06
GB1140803A (en) 1969-01-22
BR6683952D0 (pt) 1973-12-26
BE688765A (enrdf_load_html_response) 1967-03-31
AT265256B (de) 1968-10-10
DE1620222C3 (de) 1975-06-05
NL6615029A (enrdf_load_html_response) 1967-04-25
DE1620222A1 (de) 1972-04-06
NL6614056A (enrdf_load_html_response) 1967-04-25
SE303760B (enrdf_load_html_response) 1968-09-09
BR6683868D0 (pt) 1973-12-27
DE1620222B2 (de) 1974-10-03
CH487140A (de) 1970-03-15

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