US3860592A - 2-alkoxy-3-amino-2-heterocyclic-thiopropanamides - Google Patents

2-alkoxy-3-amino-2-heterocyclic-thiopropanamides Download PDF

Info

Publication number
US3860592A
US3860592A US322572A US32257273A US3860592A US 3860592 A US3860592 A US 3860592A US 322572 A US322572 A US 322572A US 32257273 A US32257273 A US 32257273A US 3860592 A US3860592 A US 3860592A
Authority
US
United States
Prior art keywords
pyridyl
methoxy
thiopropanamide
methyl
morpholino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US322572A
Inventor
Bernard Loev
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Corp filed Critical SmithKline Corp
Priority to US322572A priority Critical patent/US3860592A/en
Priority to ZA739612A priority patent/ZA739612B/en
Priority to AU63873/73A priority patent/AU472060B2/en
Priority to BE139525A priority patent/BE809403A/en
Priority to JP49005188A priority patent/JPS49100075A/ja
Priority to GB60174A priority patent/GB1401167A/en
Priority to FR7400512A priority patent/FR2221131A1/fr
Priority to DE2401109A priority patent/DE2401109A1/en
Priority to US05/514,684 priority patent/US3948892A/en
Priority to US514353A priority patent/US3898335A/en
Priority to US514519A priority patent/US3915965A/en
Application granted granted Critical
Publication of US3860592A publication Critical patent/US3860592A/en
Assigned to SMITHKLINE BECKMAN CORPORATION reassignment SMITHKLINE BECKMAN CORPORATION CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). EFFECTIVE DATE: 03/04/82 Assignors: SMITHKLINE CORPORATION
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—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
    • C07D213/59—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 at least one of the bonds being to sulfur
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—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

Definitions

  • R is Z-pyridyl, Z-pyrimidyl, 4-pyrimidyl, 2-pyrazinyl, Z-pyrrolyl, 2-quinolyl, 2-thiazolyl or 4-thiazolyl;
  • R is lower alkoxy, allyloxy, cyclopropane methoxy
  • R is di-lower alkylamino, piperidino, pyrrolidino, N-
  • R is NH-(lower alkyl), N(lower alkyl) Nl-l-phenyl, Nl-l-(CH ),,-cycloalkyl, said cycloalkyl having 3-6 carbon atoms, or NH-R n is O or 1 and R is allyl or propargyl optionally substituted by methyl or ethyl groups, said R having 36 carbon atoms.
  • This invention also includes pharmaceutically acceptable acid addition salts of the compounds of Formula l.
  • the pharmacologically active compounds of this invention have the basic structure of Formula I. However, it is apparent to one skilled in the art that well known nuclear substituents such as lower alkyl, lower alkoxy or halogen may be incorporated on the heterocyclic rings. These substituted compounds are used as are the parent compounds.
  • R is morpholino. Also, preferably R, is 2-pyridyl. R is preferably lower alkoxy.
  • Preferred compounds of this invention are represented by Formula I in which R is 2-pyridyl, R is methoxy, R is morpholino and R is NH-methyl, NH- ethyl, NH(CH ),,-cycloalkyl or NH-allyl.
  • a particularly advantageous compound of this invention is 2-methoxy-N-methyl-k3-morpholino-2-(2- pyridyl)-thiopropanamide.
  • the compounds of this invention produce inhibition of gastric acid secretion. This activity is demonstrated by administration to pylorus ligated rats at doses of about mg./kg. to about 50 mg./kg. orally. in this procedure, compounds which produce an increase in gastric pH or a decrease in the volume of gastric juice or both are considered active.
  • the compounds of this invention are prepared by the following procedures:
  • R -R are as defined above.
  • a 2-alkoxy(or 2-amino)-2- heterocyclic, thioacetamide is reacted with formaldehyde and an amine.
  • the reaction is preferably carried out by reacting the thioamide with a slight excess of formaldehyde and amine in alcoholic solution, preferably at elevated temperature, for example at reflux temperature.
  • R is lower alkoxy, allyloxy or cyclopropanemethoxy
  • R is lower alkyl, phenyl, (CH ),,-cycloalkyl or R R is NH- (lower alkyl), NH-phenyl, NH-(CH ),,-cycloalkyl or NH-R
  • n and R are as defined above.
  • the vinyl group of a vinyl heterocycle is oxidized to the ethylene oxide ring and the resulting compound is reacted with an amine to give a 2-heterocyclic-Z-hydroxyethylamine.
  • the hydroxy group is converted to an ether (R by standard procedures and the resulting 2-alkoxy compound is re acted with a strong base such as phenyl or butyl lithium and then with an appropriate isothiocyanate to give N substituted 2-alkoxy-3-amino-2-heterocyclicthiopropanamides of this invention.
  • R R R R, R and R are as defined above;
  • R is lower alkyl, preferably methyl or ethyl;
  • R' is an alkali metal; and
  • R is di-lower alkylamino, piperidino, pyrrolidino, N-lower alkylpiperazino or morpholino.
  • the alkoxymethyl-heterocycles are prepared by reacting a halomethyl-heterocycle with an alkoxide, such as sodium alkoxide, or alternatively, by reacting a heterocyclic-methanol with an appropriate halide, for example a lower alkyl, allyl or 'cyclopropanemethyl chloride or bromide, in the presence of a base such as, sodium hydride.
  • an alkoxide such as sodium alkoxide
  • a heterocyclic-methanol for example a lower alkyl, allyl or 'cyclopropanemethyl chloride or bromide
  • a lower alkyl Z-heterocyclic-acetate is converted to the 2-alkoxy compound by reacting with N-bromo or N-chlorosuccinimide and reacting the resulting 2-bromo or 2-chloro compound with a sodium alkoxide; the resulting lower alkyl 2- alkoxy-Z-heterocyclic-acetate is converted to the corresponding acetamide by reacting with ammonium hydroxide; the acetamide is dehydrated to give the corresponding nitrile and the nitrile is converted to a 2- alkoxy-Z-heterocyclic-thioacetamide by reacting with hydrogen sulfide in the presence of a base such as an amine or by reacting with ammonium polysulfide or, alternatively, the acetamide is reacted with phosphorus pentasulfide to give the corresponding thioacetamide.
  • the N-substituted thioacetamides maybe prepared by react
  • the lower alkyl 2-alkoxy-Z-heterocyclic-acetate intermediates in procedure B may also be prepared by reacting an alkoxymethyl-heterocycle (which is an intermediate in procedure A) with astrong base such as phenyl lithium and a lower alkyl chloroformate.
  • N-substituted Z-alkoxythioacetamide starting materials may be prepared by the following procedures:
  • a heterocycliccarboxaldehyde, an amine and an alkali metal cyanide are reacted, preferably in the presence of acid, to give a 2- amin0-2-heterocyclic-acetonitrile which is converted to a 2-amino-2-heterocyclic-thioacetamide by reacting with hydrogen sulfide in the presence of base such as an amine or by reacting with ammonium polysulfide.
  • the corresponding N-substituted thioacetamides are prepared by reacting the N-unsubstituted compounds with the appropriate amine.
  • the pharmaceutically acceptable, acid addition salts of the compounds of Formula I are formed with organic and inorganic acids by methods known to the art.
  • the base is reacted with an organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly.
  • aqueous miscible solvent such as acetone or ethanol
  • aqueous immiscible solvent such as ethyl ether or chloroform
  • Exemplary of the salts which are included in this invention are maleate, fumarate, succinate, oxalate, benzoate, methanesulfonate, ethanedisulfonate, benzenesulfonate, acetate, propionate, tartrate, citrate, camphorsulfonate, hydrochloride, hydrobromide, sulfate, sulfamate, phosphate and nitrate salts.
  • the compounds of this invention are administered internally either parenterally, rectally or, preferably, orally in an amount to produce the desired biological activity.
  • the compounds are administered in conventional dosage forms prepared by combining an appropriate dose of the compound with standard pharmaceutical carriers.
  • the pharmaceutical carrier may be for example a solid or a liquid.
  • solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia or cocoa butter.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 gm.
  • liquid carriers are syrup, peanut oil, olive oil, sesame oil, propylene glycol, polyethylene glycol (mol. wt.
  • the carrier or diluent may include a time delay material well known to the art such as, for example, glyceryl monostearate or glyceryl distearate alone or with a wax.
  • a wide variety of pharmaceutical forms can be em- 5 ployed, for example the preparation may take the form of tablets, capsules, powders, suppositories, troches, lozenges, syrups, emulsions, sterile injectable liquids or liquid suspensions or solutions.
  • compositions are prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the compounds of this invention have an asymmetric carbon atom and thus may be present as optical isomers.
  • the connotation of the formulas presented herein is to include all isomers, the separated isomers as well as mixtures thereof.
  • the optically active thiopropanamides are prepared by the use of optically active strong acids, such as camphorsulfonic acid, dibenzoyltartaric acid or phenethylsulfamic acid, to separate the optical isomers of the thiopropanamides.
  • lower alkyl and lower alkoxy where used herein denote groups having 14 carbon atoms and halogen denotes chloro, bromo or fluoro.
  • 2-(methoxymethyl)pyridine is prepared by the following alternative procedure.
  • a mixture of 10.9 g of Z-pyridinernethanol and 2.4 g. of sodium hydride in ml. of dimethylsulfoxide is warmed on a steam bath for '15 minutes, then cooled to room temperature.
  • Methyl 5O iodide (14.2 g.) is added and then the mixture is heated at 40C. for one hour.
  • Water (150 ml.) is then added and the mixture is extracted with ether. The extractsare dried, concentrated and distilled to give 2-(methoxymethyl)pyridine.
  • EXAMPLE 4 A mixture of 6.3 g. of Z-pyrrolemethanol and 25 ml. of thionyl chloride is heated on a steam bath for four hours. The mixture is then concentrated under reduced pressure and the residue is dissolved inwater, basified with 5 percent aqueous sodium bicarbonate solution and extracted with ether. The extracts are dried, concentrated and distilled to give 2- (chloromethyl)pyrrole.
  • N-cyclopropanemeth'yl-Z methoxy-Z- (2-pyridyl)thioacetamide is prepared by the following.
  • N-cyclopropyl-2-methoxy-3-morpholino-2-(2- pyrrolyl )-thiopropanamide N-cyclopropyl-2-rnethoxy-3-morpholino-2-(2- quinolyl)-thiopropanamide
  • N-cyclopropyl-2-methoxy-3-morpholino-2-(3- methyl-2-pyrazinyl)thiopropanamide N-cyclopropyl-2-methoxy-3-morpholino-2-(3- methyl-2-pyrazinyl)thiopropanamide.
  • EXAMPLE l1 2-(Methoxymethyl)pyridine (1.85 g., 0.015 mole) in 15 ml. of dry benzene is added dropwise to a chilled solution of phenyl lithium (8.1 ml. of 2.1 molar solution, 0.017 mole) in 15 ml. of dry benzene. After the addition is complete, the mixture is stirred at C. for 1 hour. Phenyl isothiocyanate (2.03 g., 0.015 mole) in 15 ml. of dry benzene is added dropwise and the mixture is allowed to come to room temperature gradually, then the mixture is stirred overnight. The mixture is diluted with 50 ml. of water and acidified with dilute hydrochloric acid. The layers are separated and the organic EXAMPLE 12 In the procedure of Example 1, using the following in place of methyl isothiocyanate:
  • EXAMPLE 13 A mixture of 18.1 g. of methyl 2-methoxy-2-(2- pyridyl)acetate and 10 g. of dimethylamine in ethanol is stirred at room temperature for 26 hours. The mixture is concentrated, dissolved in chloroform and extracted with brine. The organic phase is dried over magnesium sulfate and filtered and the solvent is removed under reduced pressure to give 2-methoxyN,N- dimethyl-2-(2-pyridyl)acetamide.
  • 2-methoxy-N,N-dimethyl-2-(2- pyridyl)acetamide is prepared by the'following procedure.
  • chloroform is added dropwise and with cooling to 50 g. of dimethylamine in 100 ml. of chloroform. The mixture is stirred for four hours, then 50 ml. of 5 percent aqueous sodium hydroxide is added and the chloroform solution is dried and concentrated to give 2-methoxy-N,N-dimethyl 2-(Z-pyridyl)acetamide.
  • Phosphorus pentasulfide (4g.) is added to 9.7 g. of 2-methoxy-N,N-dimethyl-2-(2-pyridyl)acetamide in 25 ml. of pyridine. The mixture is heated on a steam bath for two hours, then 250 ml. of water and 10 ml. of 5% aqueous sodium hydroxide solution are added. The mixture is extracted with chloroform and the extracts are dried and concentrated and the residue is recrystallized to give 2methoxyN,N-dimethyl-2-(2-pyridyl)- thioacetamide.
  • N,N-diethylthiocarbamoyl chloride N,N-dipropylthiocarbamoyl chloride N,N-dibutylthiocarbamoyl chloride the products are, respectively:
  • EXAMPLE 16 A solution of 9.95 g. (0.081 mole) of 2-(methoxyrnethyl)pyridine in 80 ml. of dry benzene is added dropwise to a chilled solution of 40 ml. (0.084 mole) of phenyl lithium in 80 ml. of dry benzene. The mixture is stirred at 0C. for 1 hour after the addition is complete. Then 8.02 g. of allyl isothiocyanate in 50 ml. of benzene is added dropwise and the mixture is allowed to come to room temperature gradually. The mixture is then diluted with 500 ml. of water and acidified with 10 percent hydrochloric acid. The layers are separated and the organic layer is washed several times with water.
  • aqueous layers are combined neutralized with 10 percent aqueous sodium hydroxide solution and then brought to pH 9 with percent aqueous sodium bicarbonate solution, then extracted with chloroform.
  • the chloroform extracts are washed once with brine and dried over magnesium sulfate.
  • the solvent is removed and the residue is chromatographed on a silica gel column, eluting with ethyl acetate.
  • the fractions containing the product are combined and evaporated and the residue is recrystallized from ethyl acetate/hexane to give N-allyl-2-methoxy-2-(2- pyridyl)thioacetamide, m.p. 59.560C.
  • the product is 2- methoxy-N-methyl-3-pyrrolidino-2-(2-pyridyl)thiopropanamide.
  • the product is 2-methoxy-N-methyl-3-(4- methylpiperazino)-2-(Z-pyridyl)thiopropanamide.
  • EXAMPLE 21 One gram of 2methoxy-N-methyl3-morpholino-2- (2-pyridyl)thiopropanamide in ether is added to ethereal hydrogen chloride. The resulting precipitate is filtered off and recrystallized from ethanol/ether to give 2-methoxy-N-methyl-3-morpholino-2-(2-pyridyl)thiopropanamide hydrochloride.
  • EXAMPLE 23 To cold Z-pyridinecarboxaldehyde (21.4 g., 0.2 mole) is added dimethylamine (22.5 g. of a 40 percent aqueous solution, 0.2 mole) and the solution is neutralized with concentrated hydrochloride acid. To the stirred neutralized solution is added 14.4 g. (0.22 mole) of potassium cyanide. The mixture is stirred overnight, then diluted with water, transferred to a separatory funnel and repeatedly extracted with chloreform. The combined chloroform extracts are washed three times with water, once with brine and dried over magnesium sulfate. The mixture is filtered, the solvent is removed under reduced pressure and methanol is added to the residue. The mixture is allowed to stand at 20C.
  • a mixture of 7.5 g. of 2-dimethylamino-2-(2- pyridyl)thio'acetamide and 15 ml. of 30 percent aqueous methylamine is heated for 30 minutes, then cooled and 25 ml. of 5 percent aqueous sodium carbonate solution is added. The solution is extracted with chloroform, the organic solution is dried and concentrated and the residue is recrystallized to give 2* dimethylamino-N-methyl2-(2-pyridyl)thioacetamide.
  • EXAMPLE 24 In the procedure of Example 23, using 2- dimethylamino-2-(2quinolyl)acetonitrile in place of 2-dimethylamino-2-(2-pyridyl)acetonitrile, the product is 2-dirnethylamino-N-methyl-3-morpholino-2-(2- quinolyl )thiopropanamide.
  • Hydrogen sulfide is bubbled into a stirred solution of 12.0 g. of 2-(4-methylpiperazino)-2-( 2- pyridyl)acetonitrile in 200 ml. of dry pyridine and 5 ml. of anhydrous triethylamine for seven hours. The mixture is then stirred for 17 hours. This procedure is repeated for five days and the mixture is worked up as in Example 23 to give 2-(4-methylpiperazino)-2-(2- pyridyl)-thioacetamide.
  • the product is 2- dibutylamino-N-methyl-3-morpholino-2-(2-pyridyl)- thiopropanamide.
  • EXAMPLE 29 EXAMPLE 30 To 5.65 g. of 2-dimethylamino-2-(2- pyridyl)thioacetamide is added 6.02 g. of cyclopropanemethylamine hydrochloride and 4.71 g. of sodium bicarbonate which are dissolved in ml. of water and the resulting mixture is heated with stirring on a steam bath for four hours. The mixture is cooled and 25 ml. of water is added. The mixture is extracted with chloroform, dried and then concentrated. The residue is chromatographed and recrystallized to give N- cyclopropanemethyl-2-dimethylamino-2-(2- pyridyl)thioacetamide.
  • the product is N- cyclopcntanemethyl-2-dimethylamino-3-piperidino-2- (2-pyridyl )thiopropanamide.
  • R is Z-pyridyl or 2quinoly1;
  • R is lower alkoxy, allyloxy or cyclopropanemethoxy;
  • R is di-lower alkylamino, piperidino, pyrrolidino or morpholino;
  • R is NH-(lower alkyl), N(lower alkyl) NH-phenyl, NH-(CH ),,-cycloalkyl, said cycloalkyl having 3-6 carbon atoms, or NH-R n is 0 or 1 and R is an ally] or propargyl group optionally substituted by methyl or ethyl groups, said R having 3-6 carbon atoms or a pharmaceutically acceptable acid addition salt thereof.
  • R is Z-pyridyl, R is methoxy, R is morpholino and R,, is NH-methyl, NH-ethyl, NH-(CH ),,-cycloalkyl or NH-allyl.
  • a compound of claim 1 said compound being 2- methoxy-N-methyl-3-m0rpholino-2-(2-pyridyl)thiopropanamide.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

The compounds are 2-alkoxy(and 2-amino)-3-amino-2-heterocyclicthiopropanamides, for example 2-methoxy-N-methyl-3-morpholino-2(2-pyridyl)thiopropanamide, which are inhibitors of gastric acid secretion.

Description

United States Patent [1 1 Loev [451 Jan. 14, 1975 1 2-ALKOXY-3-AMlNO-Z-HETEROCYCLIC- THIOPROPANAMlDES I751 lnventor: Bernard Loev, Broomall, Pa.
[73] Assignec: SmithKline Corporation,
Philadelphia, Pa.
221 P1160; .lan.10, 1973 211 Appl.N0.:322,572
[58] Field ofSearch; 260/247.1 M, 294.8 E, 26(1/295 AM, 288 R [56] References Cited UNITED STATES PATENTS 2,953,562 9/1960 Schuler et al. 260/247.1 M
3,686,190 8/1972 Malen et a1. 260/2948 E 3,726,878 4/1973 Kanai et a1. 260/2471 M 3,740,409 6/1973 Brenner et a1. EGO/294.8 E
FOREIGN PATENTS OR APPLICATIONS Primary Examiner-James A. Patten Assistant ExaminerMichael Shippen Attorney, Agent, or Firm-Joan S. Keps; Richard D. Foggio; William H. Edgerton [57] ABSTRACT The compounds are 2-alk0xy(and 2-amino)-3-a min0- Z-heterdcyclic-thioprepanamides, for example 2- methoxy-N-methyl-3-m0rph0lino-2-(2-pyridy1)thi0- propanarriide, which are inhibitors of gastric acid secretion.
6 Claims, N0 Drawings 2/1964 Gr at Britain :60 195 AM Z-ALKOXY-3-AMINO-2-HETEROCYCLIC- THIOPROPANAMIDES FORMULA I in which:
R is Z-pyridyl, Z-pyrimidyl, 4-pyrimidyl, 2-pyrazinyl, Z-pyrrolyl, 2-quinolyl, 2-thiazolyl or 4-thiazolyl;
R is lower alkoxy, allyloxy, cyclopropane methoxy,
di-lower alkylamino, piperidino, pyrrolidino, N- lower alkylpiperazino or morpholino;
R is di-lower alkylamino, piperidino, pyrrolidino, N-
lower' alkylpiperazino or morpholino;
R is NH-(lower alkyl), N(lower alkyl) Nl-l-phenyl, Nl-l-(CH ),,-cycloalkyl, said cycloalkyl having 3-6 carbon atoms, or NH-R n is O or 1 and R is allyl or propargyl optionally substituted by methyl or ethyl groups, said R having 36 carbon atoms.
This invention also includes pharmaceutically acceptable acid addition salts of the compounds of Formula l.
The pharmacologically active compounds of this invention have the basic structure of Formula I. However, it is apparent to one skilled in the art that well known nuclear substituents such as lower alkyl, lower alkoxy or halogen may be incorporated on the heterocyclic rings. These substituted compounds are used as are the parent compounds.
In the compounds of Formula 1, preferably R is morpholino. Also, preferably R, is 2-pyridyl. R is preferably lower alkoxy.
Preferred compounds of this invention are represented by Formula I in which R is 2-pyridyl, R is methoxy, R is morpholino and R is NH-methyl, NH- ethyl, NH(CH ),,-cycloalkyl or NH-allyl. I
A particularly advantageous compound of this invention is 2-methoxy-N-methyl-k3-morpholino-2-(2- pyridyl)-thiopropanamide.
The compounds of this invention produce inhibition of gastric acid secretion. This activity is demonstrated by administration to pylorus ligated rats at doses of about mg./kg. to about 50 mg./kg. orally. in this procedure, compounds which produce an increase in gastric pH or a decrease in the volume of gastric juice or both are considered active.
These compounds show antiulcer activity, for example in the restraint-stress method in which on oral administration to rats these compounds inhibit the development of experimental ulcers.
The compounds of this invention are prepared by the following procedures:
The terms R -R are as defined above.
According to procedure I, a 2-alkoxy(or 2-amino)-2- heterocyclic, thioacetamide is reacted with formaldehyde and an amine. The reaction is preferably carried out by reacting the thioamide with a slight excess of formaldehyde and amine in alcoholic solution, preferably at elevated temperature, for example at reflux temperature.
. H-R3 E 2 R cH-cu a ea-cs ti -cu on The terms R and R are as defined above; R is lower alkoxy, allyloxy or cyclopropanemethoxy; R is lower alkyl, phenyl, (CH ),,-cycloalkyl or R R is NH- (lower alkyl), NH-phenyl, NH-(CH ),,-cycloalkyl or NH-R ;,and n and R are as defined above.
According to procedure I], the vinyl group of a vinyl heterocycle is oxidized to the ethylene oxide ring and the resulting compound is reacted with an amine to give a 2-heterocyclic-Z-hydroxyethylamine. The hydroxy group is converted to an ether (R by standard procedures and the resulting 2-alkoxy compound is re acted with a strong base such as phenyl or butyl lithium and then with an appropriate isothiocyanate to give N substituted 2-alkoxy-3-amino-2-heterocyclicthiopropanamides of this invention.
The thioacetamide starting materials in the above procedure are prepared by the following procedures:
The terms R R R R, R and R are as defined above; R is lower alkyl, preferably methyl or ethyl; R' is an alkali metal; and R is di-lower alkylamino, piperidino, pyrrolidino, N-lower alkylpiperazino or morpholino.
According to procedure A, an alkoxymethyl or aminomethyl heterocycle is reacted with a strong base such as phenyl or butyl lithium and then with an appropriate isothiocyanate to give the N-substituted 2-alkoxy(and Z-amino)-2-heterocyclic-thioacetamides.
The alkoxymethyl-heterocycles are prepared by reacting a halomethyl-heterocycle with an alkoxide, such as sodium alkoxide, or alternatively, by reacting a heterocyclic-methanol with an appropriate halide, for example a lower alkyl, allyl or 'cyclopropanemethyl chloride or bromide, in the presence of a base such as, sodium hydride.
According to procedure B, a lower alkyl Z-heterocyclic-acetate is converted to the 2-alkoxy compound by reacting with N-bromo or N-chlorosuccinimide and reacting the resulting 2-bromo or 2-chloro compound with a sodium alkoxide; the resulting lower alkyl 2- alkoxy-Z-heterocyclic-acetate is converted to the corresponding acetamide by reacting with ammonium hydroxide; the acetamide is dehydrated to give the corresponding nitrile and the nitrile is converted to a 2- alkoxy-Z-heterocyclic-thioacetamide by reacting with hydrogen sulfide in the presence of a base such as an amine or by reacting with ammonium polysulfide or, alternatively, the acetamide is reacted with phosphorus pentasulfide to give the corresponding thioacetamide. The N-substituted thioacetamides maybe prepared by reacting the N-unsubstituted compounds with the appropriate amine.
The lower alkyl 2-alkoxy-Z-heterocyclic-acetate intermediates in procedure B may also be prepared by reacting an alkoxymethyl-heterocycle (which is an intermediate in procedure A) with astrong base such as phenyl lithium and a lower alkyl chloroformate.
Alternatively, the N-substituted Z-alkoxythioacetamide starting materials may be prepared by the following procedures:
a. reacting a lower alkyl 2-alkoxy-2-heterocyclicacetate with the appropriate substituted amine and treating the resulting N-substituted 2-alkoxy-2-heterocyclic-acetamide with phosphorus pentasulfide;
b. reacting an alkoxymethyl-heterocycle with a strong base such as phenyl lithium and a N,N-di-lower alkylcarbamoyl chloride and treating the resulting N,N- di-lower alkyl-Z-alkoxy-Z-heterocyclic-acetamide with phosphorus pentasulfide;
c. reacting an alkoxymethyl-heterocycle with a strong base such as phenyl lithium and a N,N-di-lower alkyl-thiocarbamoyl chloride.
According to procedure C, a heterocycliccarboxaldehyde, an amine and an alkali metal cyanide are reacted, preferably in the presence of acid, to give a 2- amin0-2-heterocyclic-acetonitrile which is converted to a 2-amino-2-heterocyclic-thioacetamide by reacting with hydrogen sulfide in the presence of base such as an amine or by reacting with ammonium polysulfide. The corresponding N-substituted thioacetamides are prepared by reacting the N-unsubstituted compounds with the appropriate amine.
The pharmaceutically acceptable, acid addition salts of the compounds of Formula I are formed with organic and inorganic acids by methods known to the art. For example, the base is reacted with an organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly. Exemplary of the salts which are included in this invention are maleate, fumarate, succinate, oxalate, benzoate, methanesulfonate, ethanedisulfonate, benzenesulfonate, acetate, propionate, tartrate, citrate, camphorsulfonate, hydrochloride, hydrobromide, sulfate, sulfamate, phosphate and nitrate salts.
, The compounds of this invention are administered internally either parenterally, rectally or, preferably, orally in an amount to produce the desired biological activity.
Preferably, the compounds are administered in conventional dosage forms prepared by combining an appropriate dose of the compound with standard pharmaceutical carriers.
The pharmaceutical carrier may be for example a solid or a liquid. Exemplary of solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia or cocoa butter. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 gm. Exemplary of liquid carriers are syrup, peanut oil, olive oil, sesame oil, propylene glycol, polyethylene glycol (mol. wt.
200-400) and water. The carrier or diluent may include a time delay material well known to the art such as, for example, glyceryl monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be em- 5 ployed, for example the preparation may take the form of tablets, capsules, powders, suppositories, troches, lozenges, syrups, emulsions, sterile injectable liquids or liquid suspensions or solutions.
The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
It will be apparent to one skilled in the art that the compounds of this invention have an asymmetric carbon atom and thus may be present as optical isomers. The connotation of the formulas presented herein is to include all isomers, the separated isomers as well as mixtures thereof. Preferably, the optically active thiopropanamides are prepared by the use of optically active strong acids, such as camphorsulfonic acid, dibenzoyltartaric acid or phenethylsulfamic acid, to separate the optical isomers of the thiopropanamides.
The terms lower alkyl and lower alkoxy" where used herein denote groups having 14 carbon atoms and halogen denotes chloro, bromo or fluoro.
The following examples are not limiting but are illustrative of the compounds of this invention and processes for their preparation.
EXAMPLE 1 2-(Chloromethyl)pyridine hydrochloride (16.3 g., 0.1 mole) is dissolved in 100 ml. of methanol. Freshly prepared sodium methoxide (5 g., 0.22 mole of sodium dissolved in 150 ml. of methanol) is added dropwise. The resulting mixture is heated at reflux for 18 hours, then filtered. The filtrate is concentrated. Water and ether are added, the aqueous phase is extracted with ether and the combined ethereal phases are washed with water and saturated aqueous sodium chloride, then dried over magnesium sulfate, concentrated and distilled to give 2-(methoxymethyl)pyridine.
Alternatively, 0.1 mole of 2-(chloromethyl)pyridine and 0.l1 mole of sodium methoxide are used in the above procedure to give 2-(methoxymethyl)pyridine.
Also, 2-(methoxymethyl)pyridine is prepared by the following alternative procedure. A mixture of 10.9 g of Z-pyridinernethanol and 2.4 g. of sodium hydride in ml. of dimethylsulfoxide is warmed on a steam bath for '15 minutes, then cooled to room temperature. Methyl 5O iodide (14.2 g.) is added and then the mixture is heated at 40C. for one hour. Water (150 ml.) is then added and the mixture is extracted with ether. The extractsare dried, concentrated and distilled to give 2-(methoxymethyl)pyridine.
2-(Methoxymethyl)pyridine (4.4 g., 0.036 mole), dissolved in 25 ml. of dry benzene, is added dropwise to 20 ml. of 2M phenyl lithium (0.04 mole) in benzene/ether with cooling. The mixture is stirred for 30 minutes, then methyl isothiocyanate (2.6 g.-, 0.03 mole), dissolved in 40 ml. of dry benzene, is added dropwise with cooling. The resulting solution is stirred overnight. An equal volume of water is added and the solution is cooled and made acidic with 10 percent hy- 65 drochloric acid. The phases are separated, the organic phase is washed with water and the combined aqueous phases are made basic to about pH 9, then extracted with chloroform. The chloroform extracts are washed with water and dried over magnesium sulfate. Filtration and removal of solvent gives a residue which is recrystallized from isopropyl ether/ethanol to give 2- methoxy-N-methyl-2-(2-pyridyl)thioacetamide, m.p. 104105C.
A solution of 1.96 g. (0.01 mole) of 2-methoxy-N- methyl-2-(2-pyridyl)thioacetamide in 20 ml. of methanol is treated with 1.3 g. (0.015 mole) of morpholine.
and 0.45 g. (0.015 mole) of formaldehyde. The mixture is refluxed for 48 hours. The solvents are removed in vacuo. The residue is recrystallized twice from 2- propanol to give 2-methoxy-N-methyl-3-morpholino-2- (2-pyridyl)thiopropanamide, mp. 'l28-l32C.
EXAMPLE 2 By the procedure of Example 1, using in place of sodium methoxide, the following sodium alkoxides:
sodium e thoxide sodium propoxide sodium butoxide sodium allyloxide sodium cyclopropanemethoxide EXAMPLE 3 By the procedure of Example 1, using in place of (chloromethyDpyridine, the following:
2-(chloromethyl)pyrazine 2-(chloromethyl)quinoline 2-(chloromethyl)thiazole 4-(chloromethyl)thiazole the following thioacetamides are obtained respectively: 2-methoxy-N-methyl-2-(Z-pyrazinyl)thioacetamide 2-methoxy-N-methyl-2-(Z-quinoyl)thioacetamide 2-methoxy-N-methyl-2-(Z-thiazolyl)thioacetamide 2-methoxy-N-methyl-2-(4-thiazolyl)thioacetamide. The above prepared thioacetamides are reacted with formaldehyde and morpholine by the procedure of Example l. to give the following products, respectively: 2-methoxy-N-methyl- 3-morpholino-2-(2-pyrazinyl)- thiopropanamide 2-methoxy-N-methyl-3-morpholino-2-(2-quinolyl)- thiopropanamide 2-methoxy-N-methyl-3-morpho1ino-2-(2-thiazolyl)- thiopropanamide 2-methoxy-N-methyl-3 -morpholino-2-(4-thiazoly1)- thiopropanamide.
EXAMPLE 4 A mixture of 6.3 g. of Z-pyrrolemethanol and 25 ml. of thionyl chloride is heated on a steam bath for four hours. The mixture is then concentrated under reduced pressure and the residue is dissolved inwater, basified with 5 percent aqueous sodium bicarbonate solution and extracted with ether. The extracts are dried, concentrated and distilled to give 2- (chloromethyl)pyrrole.
Using 2-(chloromethyl) in place of 2- converting 2- EXAMPLE 5 4-Pyrimidinecarboxylic acid is reduced using lithium aluminum hydride in ether to give 4- pyrimidinemethanol.
4-Pyrimidinemethanol is converted to 4- (chloromethyl)pyrimidine by the procedure of Example 4.
Using 4-(chloromethyl)pyrimidine in the procedure of Example 1, the product is 2-methoxy-N-methyl-3- morpholino-2-(4-pyrimidyl)thiopropanamide.
EXAMPLE 6 To a solution containing 12.1 g. (0.08 mole) of methyl 2-(2-pyridyl)acetate in 120 ml. of carbon tetrachloride is added 14.8 g. (0.084 mole) of N- bromosuccinimide and 0.3 g. of dibenzoylperoxide. The solution is irradiated by meansof a sun-lamp source until essentially all the solid (succinimide) has risen to the top (about 10-15 minutes).
The solution is filtered and the solvent removed under reduced pressure and without heat to give methyl 2-bromo-2-(2-pyridyl)acetate.
The above prepared 2-bromo compound is dissolved in 100 ml. of dry methanol and freshly prepared sodium methoxide (0.09 mole) in 100 ml. of dry methanol is added dropwise. Then the mixture is stirred for three hours at room temperature. The solvent is removed under reduced pressure and without heatto give methyl 2-methoxy-2-(2-pyridyl)acetate.
The above prepared 2-methoxy compound is dissolved in 65 ml. of concentrated ammonium hydroxide and the solution is stirred for 6.5 hours. The mixture is then concentrated, dissolved in chloroform and extracted twice with brine. The organic phase is dried over magnesium sulfate and filtered and solvent is removed under reduced pressure to give 2-methoxy-2(2- pyridyl-acetamide.
To 20 ml. of dry 1,2-dichloroethane containing 2.0 g. of sodium chloride is added 3.32 g. of 2-methoxy-2-(2- pyridyl)acetamide. After stirring at room temperature for minutes, 1.7 ml. of phosphorus oxychloride is to 2-(chloromethyl)pyrimidine added. The solution is refluxed for 18 hours. The solution is then cooled and made basic with 10 percent aqueous sodium hydroxide solution. The aqueous phase is extracted three times with chloroform and the combined chloroform extracts are washed three times with water and once with brine and dried over magnesium sulfate. Filtration, removal of solvent and distillation in vacuo gives 2-methoxy-2-(2- pyridyl)acetonitrile, b.p. 7276C./0.2 mm.
In 125 ml. of dry pyridine containing 4 ml. oftriethylamine is dissolved 2.65 g. (0.018 mole) of Z-methoxy- 2-(2 pyridyl)acetonitrile. Hydrogen sulfide is bubbled through the solution for 5.5 hours. The solvent is evaporated under reduced pressure and chloroform is added to the residue. The mixture is allowed to stand at 20C. for 18 hours. The precipitate is filtered off and recrystallized from isopropanol to give 2-methoxy- 2-(2-pyridyl)thioacetamide, m.p. l57159C.
A solution of 9.1 g. of 2-methoxy-2-(2-pyridyl)- thioacetamide in a 40 percent aqueous solution of cyclopropylamine is heated at reflux for 45 minutes. The mixture is cooled and 30 ml. of water is added. The mixture is extracted with chloroform and the extracts are dried over magnesium sulfate and concentrated to give after recrystallizing the residue, N-cyclopropyl-2- methoxy-2-( 2-pyridyl)thioaceta'mide.
By the procedure of Example 1, reacting the above prepared thioacetamide with formaldehyde and morpholine gives N-cyclopropyl-Z-methoxy-3-morpholino- 2-(2-pyridyl)thiopropanamide.
By the same procedure, using the following cycloalkylamines:
cyclobutylamine cyclopentylamine cyclohexylamine the products are, respectively:
N-cyclobutyl-2-methoxy-3-morpholino-2-(2- pyridyl)thiopropanamide N-cyclopentyl-2-methoxy 3-morpholino-2-(2- pyridyl)thiopropanamide N-cyclohexyl-2-methoxy-3-morpholino-2-(2- pyridyl)thiopropanamide.
EXAMPLE 7 Using cyclopropanemethyl isothiocyanate in place of methyl isoth-iocyanate in the procedure of Example 1 gives N-cyclopropanemethyl-2-methoxy-3- morpholino-2-(2-pyridyl)thiopropanamide.
EXAMPLE 8 Alternatively, N-cyclopropanemeth'yl-Z methoxy-Z- (2-pyridyl)thioacetamide is prepared by the following.
procedure.
A solution of 6.0 g. of cyclopropanemethylamine hydrochloride and 4.7 g. of sodium bicarbonate in 75 ml. of water is added to 5.4 g. of 2-methoxy-2-(2-pyridyl)- thioacetamide. The reaction mixture is heated on a steam bath with stirring for four hours. The mixture is then cooled and 25 ml. of water is added. The reaction mixture is extracted three times with chloroform. The chloroform extracts are combined, dried over magnesium sulfate and then evaporated. The residue is purified by dry-column chromatography on silica gel, using ethyl acetate as solvent. Recrystallization gives N-cyclopropanemethyl-2-methoxy-2-(2- pyridyl)thioacetamide.
Reacting the above prepared thioacetamide with formaldehyde and morpholineby the procedure of Example 1 gives N-cyclopropanemethyl-2-methoxy-3- morpholino-2-(2-pyridyl)thiopropanamide.
Similarly, using in place of cyclopropanemethylamine hydrochloride, the following:
cyclobutanemethylamine hydrochloride cyclopentanemethylamine hydrochloride cyclohexanemethylamine hydrochloride the products are, respectively:
N-cyclobutanemethyl-Z-methoxy-3-morpholino-2- (2-pyridyl)thiopropanamide N-cyclopentanemethyl-2-methoxy-31morpholino 2- (2-pyridyl)thiopropanamide N-cyclohexanemethyl-2-methoxy-3-morpholino-2- (2-pyridyl)thiopropanamide.
EXAMPLE 9 By the procedure of Example 6, using in place of methyl 2-(2-pyridyl)acetate the following:
methyl 2-(2-pyrrolyl)acetate ethyl 2-(2-quinolyl)acetate ethyl 2-(4-thiazolyl)acetate ethyl 2-(4-methyl-2-thiazolyl)acetate ethyl 2-(3-methyl-2-pyrazinyl)acetate the products are, respectively: 4
N-cyclopropyl-2-methoxy-3-morpholino-2-(2- pyrrolyl )-thiopropanamide N-cyclopropyl-2-rnethoxy-3-morpholino-2-(2- quinolyl)-thiopropanamide N-cyclopropyl-2-methoxy-3-morpholino-2-(4- thiazolyl)-thiopropanamide N-cyclopropyl-Z-methoxy-3-morpholino-2-(4- methyl-Z-thiazolyl)thiopropanamide N-cyclopropyl-2-methoxy-3-morpholino-2-(3- methyl-2-pyrazinyl)thiopropanamide.
Similarly, the corresponding N-cyclobutyl, N- cyclopentyl and N-cyclohexyl compounds are prepared.
EXAMPLE 10 By the procedure of Example 8, using the appropriate 2-alkoxy-2-heterocyclic-thioacetamide, prepared from the corresponding lower alkyl heterocyclicacetate by the procedure of Example 6, the following products are obtained:
N-cyclopropanemethyl-2-methoxy-3-morpholino-2- (2-pyrrolyl)thiopropanamide N-cyclopropanemethyl-2-methoxy-3-morpholino-2- (Z-quinolyl)thiopropanamide N-cyclopropanemethyl-Z-methoxy-3-morpholino-2- (4-thiazo1yl)thiopropanamide.
EXAMPLE l1 2-(Methoxymethyl)pyridine (1.85 g., 0.015 mole) in 15 ml. of dry benzene is added dropwise to a chilled solution of phenyl lithium (8.1 ml. of 2.1 molar solution, 0.017 mole) in 15 ml. of dry benzene. After the addition is complete, the mixture is stirred at C. for 1 hour. Phenyl isothiocyanate (2.03 g., 0.015 mole) in 15 ml. of dry benzene is added dropwise and the mixture is allowed to come to room temperature gradually, then the mixture is stirred overnight. The mixture is diluted with 50 ml. of water and acidified with dilute hydrochloric acid. The layers are separated and the organic EXAMPLE 12 In the procedure of Example 1, using the following in place of methyl isothiocyanate:
ethyl isothiocyanate propyl isothiocyanate butyl isothiocyanate the products are, respectively:
N-ethyl-2-methoxy-3-morpholino-2-(2-pyridyl)thiopropanamide 2-methoxy-3-morpholino-N-propyl-2-( Z-pyridyl )thiopropanamide N-butyl-2-methoxy-3-morpholino-2-(2-pyridyl)thiopropanamide.
EXAMPLE 13 A mixture of 18.1 g. of methyl 2-methoxy-2-(2- pyridyl)acetate and 10 g. of dimethylamine in ethanol is stirred at room temperature for 26 hours. The mixture is concentrated, dissolved in chloroform and extracted with brine. The organic phase is dried over magnesium sulfate and filtered and the solvent is removed under reduced pressure to give 2-methoxyN,N- dimethyl-2-(2-pyridyl)acetamide.
Alternatively, 2-methoxy-N,N-dimethyl-2-(2- pyridyl)acetamide is prepared by the'following procedure. 2-Methoxy-2-(2-pyridyl)acetyl chloride hydrochloride, 22 g., [prepared by reacting 2-methoxy-2-(2- pyridyl)acetic acid in benzene with thionyl chloride] in m1. of chloroform is added dropwise and with cooling to 50 g. of dimethylamine in 100 ml. of chloroform. The mixture is stirred for four hours, then 50 ml. of 5 percent aqueous sodium hydroxide is added and the chloroform solution is dried and concentrated to give 2-methoxy-N,N-dimethyl 2-(Z-pyridyl)acetamide.
Phosphorus pentasulfide (4g.) is added to 9.7 g. of 2-methoxy-N,N-dimethyl-2-(2-pyridyl)acetamide in 25 ml. of pyridine. The mixture is heated on a steam bath for two hours, then 250 ml. of water and 10 ml. of 5% aqueous sodium hydroxide solution are added. The mixture is extracted with chloroform and the extracts are dried and concentrated and the residue is recrystallized to give 2methoxyN,N-dimethyl-2-(2-pyridyl)- thioacetamide.
By the procedure of Example 1, reacting the above prepared thioacetamide with formaldehyde and morpholine gives 2-methoxy-N,N-dimethyl-3-morpholino- 5 2-(2-pyridyl)-thiopropanamide.
EXAMPLE 14 Alternatively, 2-methoxy-N,N-dimethyl-2-(2- pyridyl)thioacetamide is prepared by the following procedures.
To 0.10 mole of phenyl lithium in 100 ml. of benzene/ether at C. is added dropwise 10.6 g. (0.084 mole) of 2-(methoxymethyl)pyridine dissolved in 75 ml. of benzene. To this mixture is added dropwise 10.0 g. (0.081 mole) of N.N-dimethylthiocarbamoyl chloride in 100 ml. of benzene. The resulting mixture is stirred at room temperature overnight, then poured into 100 ml. of water and acidified. The organic phase is extracted once with dilute aqueous acid. The combined aqueous phases are extracted twice with ether, then made basic to about pH 10 and extracted three times with chloroform. The combined chloroform extracts are dried over magnesium sulfate and the solvent is removed by evaporation. The residue is chromatographed, then distilled in vacuo to give 2-methoxy- N,N-dimethyl-2-(2-pyridyl)thioacetamide.
Alternatively, using N,N-dimethylcarbamoyl chloride in the above procedure gives 2-methoxy-N,N- dimethyl-2-(2-pyridyl)acetamide which is converted to the thioacetamide by'reaction with phosphorus pentasulfide by the procedure described in Example 13.
Also. by the procedure of Example 1, reacting 2- methoxy-N.N-dimethyl-2-(2-pyridyl)thioacetamide with formaldehyde and morpholine. the product is 2- methoxy-N.N-dimethyl-B-morpholino-2-(2-pyridyl)thiopropanamide.
EXAMPLE 15 Using the following N,N-di-lower alkylthiocarbamoyl chloride compounds in the procedure of Example 14:
N,N-diethylthiocarbamoyl chloride N,N-dipropylthiocarbamoyl chloride N,N-dibutylthiocarbamoyl chloride the products are, respectively:
N,N-diethyl-2-methoxy-3-morpholino-2-(2-pyridyl)- thiopropanamide 2-methoxy-N,N-dipropyl-3-morpholino-2-(2 pyridyl)thiopropanamide N.N-dibutyl-2-methoxy-3-morpholino-2-(2-pyridyl)- thiopropanamide.
EXAMPLE 16 A solution of 9.95 g. (0.081 mole) of 2-(methoxyrnethyl)pyridine in 80 ml. of dry benzene is added dropwise to a chilled solution of 40 ml. (0.084 mole) of phenyl lithium in 80 ml. of dry benzene. The mixture is stirred at 0C. for 1 hour after the addition is complete. Then 8.02 g. of allyl isothiocyanate in 50 ml. of benzene is added dropwise and the mixture is allowed to come to room temperature gradually. The mixture is then diluted with 500 ml. of water and acidified with 10 percent hydrochloric acid. The layers are separated and the organic layer is washed several times with water. The aqueous layers are combined neutralized with 10 percent aqueous sodium hydroxide solution and then brought to pH 9 with percent aqueous sodium bicarbonate solution, then extracted with chloroform. The chloroform extracts are washed once with brine and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a silica gel column, eluting with ethyl acetate. The fractions containing the product are combined and evaporated and the residue is recrystallized from ethyl acetate/hexane to give N-allyl-2-methoxy-2-(2- pyridyl)thioacetamide, m.p. 59.560C.
Reacting N-allyl-2-inethoxy-2-(2- pyridyl)thioacetamide with formaldehyde and morpholine by the procedure of Example 1 gives N-allyl-2- methoxy-3-morpholino-2-(2-pyridyl)thiopropanamide.
EXAMPLE 17 in 100 ml. of dry methanol and freshly prepared sodium methoxide (0.09 mole) in 100 ml. of dry methanol is added dropwise. Then the mixture is stirred for three hours at room temperature. The solvent is removed under reduced pressure and without heat to give methyl 2-methoxy-2-(2-pyridyl)acetate.
The above prepared Z-methoxy compound is dissolved in ml. of concentrated ammonium hydroxide and the solution is stirred for 6.5 hours. The mixture is then concentrated, dissolved in chloroform and cxtracted twice with brine. The organic phase is dried over magnesium sulfate and filtered and solvent is rcmoved under reduced pressure to give 2-methoxy-2-( 2- pyridyl)acetamide.
To 20 ml. of dry 1,2-dichloroethanc containing 2.0 g. of sodium chloride is added 3.32 g. of 2-methoxy-2-(2- pyridyl)acetamide. After stirring at room temperature for 15 minutes, 1.7 ml. of phosphorus oxychloride is added. The solution is refluxed for 18 hours. The solution is then cooled and made basic with 10 percent aqueous sodium hydroxide solution. The aqueous phase is extracted three times with chloroform and the combined chloroform extracts are washed three times with water and once with brine and dried over magnesium sulfate. Filtration, removal of solvent and distillation in vacuo gives 2-methoxy-2-(2- pyridyl)acetonitrile, b.p. 72-76C./0.2 mm.
In ml. of dry pyridine containing 4 ml. of triethylamine is dissolved 2.65 g. (0.018 mole) of 2-methoxy- 2-(2-pyridyl)acetonitrile. Hydrogen sulfide is bubbled through the solution for 5.5 hours. The solvent is evaporated under reduced pressure and chloroform is added to the residue. The mixture is allowed to stand at 20C. for 18 hours. The precipitate is filtered off and recrystallized from isopropanol to give 2-methoxy- 2-(2-pyridyl)thioacetamide, m.p. 157159C.
To 4.4 g. (0.026 mole) of 2-methoxy-2-(2- pyridyl)thioacetamide in 20 ml. of water at 0C. is added 2.9 g. (0.053 mole) of propargylamine with stirring and the resulting suspension is allowed to stand overnight at 5C. Ethanol (5ml.) is added and the mixture is stirred for five hours, then extracted with dichloromethane. The extracts are dried and concentrated. The residue is chromatographed on a silica gel drycolumn, using 1:10 ethyl acetate/ether as the eluant. The product fraction is treated with charcoal, filtered, concentrated and the residue is recrystallized from benzene/ligroin to give Z-methoxy-N-propargyl-2-(2 pyridyl)thioacetamide.
The above prepared thioacetamide is reacted with formaldehyde and morpholine by the procedure of Example l to give Z-methoxy-3morphrlino-N-propargyl- 2-(2-pyridyl)thiopropanamide.
By the same procedure, using in place of propargylamine, the following amines:
l-methylallylamine 2-ethylallylamine I Z-butenylamine 4-methyl-2-pentenylamine I 2-butynylamine 2-pentynylamine 1ethyl-lmethyl-Z-propynylamine the products are, respectively:
2-rnethoxy-N-(1methylallyl)-3 morpholino-2-(2- pyridyl)thiopropanamide N-(Z-ethylallyl)2-rnethoxy-3-morpholino-2-(2- pyridyl)thiopropanamide N-(2-butenyl)-2-methoxy pyridyl)-thiopropanamide 2-methoxy-N-( 4-methyl-2-pentenyl )-3-morpholino- 2-(2-pyridyl)thiopropanamide N-(Z-butynyl)-2-methoxy-3-morpholino-2-(2- pyridyl)-thiopropanamide Z-methoxy-3-morpholino-N-(2-pentynyl)-2-(2- pyridyl )thiopropanamide N-(1ethyl-lmethyl-Z-propynyl)-2-methoxy-3- morpholino-2-(Z-pyridyl)thiopropanamide.
EXAMPLE 18 Using piperidine in place of morpholine in the proce dure of Example 1, the product is 2-methoxy-N- methyl-3-piperidino-2-(Z-pyridyl)thiopropanamide.
Similarly, using pyrrolidine, the product is 2- methoxy-N-methyl-3-pyrrolidino-2-(2-pyridyl)thiopropanamide.
By the same procedure, using l-methylpiperazine, the product is 2-methoxy-N-methyl-3-(4- methylpiperazino)-2-(Z-pyridyl)thiopropanamide.
EXAMPLE 19 Using diethylarnine in place of morpholine in the procedure of Example 1, the product is 3-diethylamino-2- methoxy-N-methyl-2 (2-pyridyl)thiopropanamide.
Similarly, using the following amines:
20 -3-morpholino-2-( 2- dimethylamine 5O dipropylamine dibutylamine the products are, respectively:
3dimethylamino-Z-methoxy-N-methyl-2-(2- pyridyl)thiopropanamide 3-dipropylamino-2-methoxy-N-methyl-2-(2-pyridyl)- thiopropanamide 3-dibutylamino-2-methoxy-N-methyl-2-(2-pyridyl)- thiopropanamide.
By the procedure Similarly, using in place of diethylamine the followpiperidine pyrrolidine l-methylpiperazine the products are, respectively:
2-methoxy-N-methyl-3-piperidino2-(2-quinolyl)thiopropanamide 2-methoxy-N-methyl-3pyrrolidino-2-(2-quinolyl)- thiopropanamide 2-methoxy-N-methyl-3-( 4-methylpiperazino)-2-(2- quinolyl)thiopropanamide.
EXAMPLE 21 One gram of 2methoxy-N-methyl3-morpholino-2- (2-pyridyl)thiopropanamide in ether is added to ethereal hydrogen chloride. The resulting precipitate is filtered off and recrystallized from ethanol/ether to give 2-methoxy-N-methyl-3-morpholino-2-(2-pyridyl)thiopropanamide hydrochloride.
By the same procedure, the hydrochloride salt of 2- methoxy-N-methyl-3-morpholino-2-(2-quinolyl)thiopropanamide is prepared.
EXAMPLE 22 Two grams of 2-methoxy-N-methyl-3-morpholino-2-' (2-pyridyl)thiopropanamide in ethanol is treated with an equimolar amount of maleic acid in ethanol to give, after removing the solvent under reduced pressure, 2- methoxy-N-methyl-3-morpholino-2-(2-pyridyl)thio- 1 propanamide maleate. v
By the same procedure, using citric acid, the citrate salt of 2-methoxy-N-methyl-3-morpholino-2-(2- pyridyl)thiopropanamide is prepared.
EXAMPLE 23 To cold Z-pyridinecarboxaldehyde (21.4 g., 0.2 mole) is added dimethylamine (22.5 g. of a 40 percent aqueous solution, 0.2 mole) and the solution is neutralized with concentrated hydrochloride acid. To the stirred neutralized solution is added 14.4 g. (0.22 mole) of potassium cyanide. The mixture is stirred overnight, then diluted with water, transferred to a separatory funnel and repeatedly extracted with chloreform. The combined chloroform extracts are washed three times with water, once with brine and dried over magnesium sulfate. The mixture is filtered, the solvent is removed under reduced pressure and methanol is added to the residue. The mixture is allowed to stand at 20C. for 18 hours, then filtered. The filtrate is concentrated and distilled in vacuo to give 2- dimethylamino-2-(2pyridyl )acetonitrile' 2-Dimethylamino-2'(2'pyridy1)acetonitrile (11.4 g., 0.07 m.) is dissolved in 200 ml. of dry pyridine containing 5 ml. of anhydrous triethylamine. Hydrogen sulfide is bubbled into the stirred solution for seven hours and the solution is then stirred for l7 hours. This procedure is repeated for 5 days. Then the mixture is stirred for an additional 48 hours. The solvent is then removed under reduced pressure and the residue is recrystallized from ethanol to give 2-dimethylamino-2-(2 pyridyl)thioacetamide, m.p. l30-l33C. (dec.).
A mixture of 7.5 g. of 2-dimethylamino-2-(2- pyridyl)thio'acetamide and 15 ml. of 30 percent aqueous methylamine is heated for 30 minutes, then cooled and 25 ml. of 5 percent aqueous sodium carbonate solution is added. The solution is extracted with chloroform, the organic solution is dried and concentrated and the residue is recrystallized to give 2* dimethylamino-N-methyl2-(2-pyridyl)thioacetamide. A mixture of 19.5 g. of 2-dimethylamino-N-methyl-Z- (2-pyridyl)thioacetamide in 200 ml. of methanol, 13 g. of morpholine and 4.5 g. of formaldehyde is heated at reflux for 48 hours. The mixture is concentrated in vacuo and the residue is recrystallized from isopropyl ether to give 2-dimethylamino-N-methyl-3- morpholino-2-(2-pyridyl)thiopropanamide.
EXAMPLE 24 In the procedure of Example 23, using 2- dimethylamino-2-(2quinolyl)acetonitrile in place of 2-dimethylamino-2-(2-pyridyl)acetonitrile, the product is 2-dirnethylamino-N-methyl-3-morpholino-2-(2- quinolyl )thiopropanamide.
EXAMPLE 25 By the procedure of Example 23, using in place of 2- dimethylamino-2-(2-pyridyl)acetonitrile the following substituted acetonitriles:
2-diethylamino-2-(2-pyridyl)acetonitrile 2-pyrrolidin0-2-(2-pyridyl)acetonitrile 2-piperidino-2-(2-pyridyl)acetonitrile 2-dimethylamino-2-(6-methyl-2-pyridyl)acetonitrile the products are, respectively:
2-diethylamino-N-methyl-3-morpholino-2 (2- pyridyl)-thiopropanamide N-methyl-3-morpholino-2-pyrrolidino-2-(2-pyridyl)- thiopropanamide N-methyl-3-morpho|ino-2-piperidino-2-(Z-pyridyl)- thiopropanamide Z-dimethylamino-N-methyl-3-morph0lino-2-(6- methyl-Z-pyridyl)thiopropanamide.
EXAMPLE 26 By the procedure of Example 23, 2- pyridinecarboxaldehyde is reacted with N-methylpiperazine and potassium cyanide to give 2-(4- methylpiperazino)-2(2-pyridyl)acetonitrile.
Hydrogen sulfide is bubbled into a stirred solution of 12.0 g. of 2-(4-methylpiperazino)-2-( 2- pyridyl)acetonitrile in 200 ml. of dry pyridine and 5 ml. of anhydrous triethylamine for seven hours. The mixture is then stirred for 17 hours. This procedure is repeated for five days and the mixture is worked up as in Example 23 to give 2-(4-methylpiperazino)-2-(2- pyridyl)-thioacetamide.
The above prepared thioacetamide is reacted with methylamine and the resulting N-methyl compound is reacted with formaldehyde and morpholine by the procedure of Example 23 to give N-methyl-2-( 4- methylpiperazino)-3-morpholino-2-(2-pyridyl)thiopropanamide.
Similarly, using in place of N-methylpiperazine the following lower alkylpiperazines:
N-ethylpiperazine N-propylpiperazine N-butylpiperazine the products are, respectively:
2-(4-ethylpiperazino)-N-methyl3-morpholino-2-(2- pyridyl)thiopropanamide N-methyl-3-morpholino-2-(4-propylpiperazino)-2- (2-pyridyl)thiopropanamide 2-(4-butylpiperazino)-N-methyl-3-morph0lino-2-(2- pyridyl)thiopropanamide.
EXAMPLE 27 By the procedure of Example 23, using dipropylamine in place of dimethylamine the product is 2- dipropylamino-N-methyl-3morph0lino(2-pyridyl)thiopropanamide.
Similarly, using dibutylamine, the product is 2- dibutylamino-N-methyl-3-morpholino-2-(2-pyridyl)- thiopropanamide.
EXAMPLE 28 By the procedure of Example 23, using in place of 2- pyridinecarboxaldehyde, the following carboxaldehydes:
2-pyrimidinecarboxaldehyde 2-pyrrolecarboxaldehyde 2-pyrazinecarboxaldehyde 4-pyrimidinecarboxaldehyde 2-thiazolecarboxaldehyde I 4-thiazolecarboxaldehyde the products are, respectively:
2-dimethylamino-N-methyl-3-morpholino-2-(2- pyrimidyl)thiopropanamide 2-dimethylamino-N-methyl-3-morpholin0-2-(2- pyrrolyl)thiopropanamide Z-dimethylamino-N-methyl-3-morpholino-2-(2- pyrazinyl)thiopropanamide Z-dimethylamino-N-methyl-3-morpholino-2-(4- pyrimidyl)thiopropanamide Z-dimethylamino-N-mcthyl-3-morpholin0-2-(2- thiazolyl)thiopropanamide Z-dimethylamino-N-methyl-3-morpholino-2-(4- thiazolyl)thiopropanamide.
EXAMPLE 29 EXAMPLE 30 To 5.65 g. of 2-dimethylamino-2-(2- pyridyl)thioacetamide is added 6.02 g. of cyclopropanemethylamine hydrochloride and 4.71 g. of sodium bicarbonate which are dissolved in ml. of water and the resulting mixture is heated with stirring on a steam bath for four hours. The mixture is cooled and 25 ml. of water is added. The mixture is extracted with chloroform, dried and then concentrated. The residue is chromatographed and recrystallized to give N- cyclopropanemethyl-2-dimethylamino-2-(2- pyridyl)thioacetamide.
Reacting the above prepared thioacetamide witih formaldehyde and piperidine by the procedure of Ex- 7 ample 1 gives N-cyclopropanemethyl-Z- dimethylamino-3-piperidino-2-(2-pyridyl)thiopropanamide.
By the same procedure, using cyclopentanemethylamine hydrochloride, the product is N- cyclopcntanemethyl-2-dimethylamino-3-piperidino-2- (2-pyridyl )thiopropanamide.
What is claimed is:
l. A compound of the formula:
R It) R -l R in which:
R is Z-pyridyl or 2quinoly1; R is lower alkoxy, allyloxy or cyclopropanemethoxy; R is di-lower alkylamino, piperidino, pyrrolidino or morpholino;
R is NH-(lower alkyl), N(lower alkyl) NH-phenyl, NH-(CH ),,-cycloalkyl, said cycloalkyl having 3-6 carbon atoms, or NH-R n is 0 or 1 and R is an ally] or propargyl group optionally substituted by methyl or ethyl groups, said R having 3-6 carbon atoms or a pharmaceutically acceptable acid addition salt thereof.
2. A compound of claim 1 in which R is 2-pyridyl.
3. A compound of claim 1 in which R is morpholino.
4. A compound of claim 1 in which R is lower alkoxy.
5. A compound of claim 1 in which R is Z-pyridyl, R is methoxy, R is morpholino and R,, is NH-methyl, NH-ethyl, NH-(CH ),,-cycloalkyl or NH-allyl.
6. A compound of claim 1 said compound being 2- methoxy-N-methyl-3-m0rpholino-2-(2-pyridyl)thiopropanamide.

Claims (5)

  1. 2. A compound of claim 1 in which R1 is 2-pyridyl.
  2. 3. A compound of claim 1 in which R3 is morpholino.
  3. 4. A compound of claim 1 in which R2 is lower alkoxy.
  4. 5. A compound of claim 1 in which R1 is 2-pyridyl, R2 is methoxy, R3 is morpholino and R4 is NH-methyl, NH-ethyl, NH-(CH2)n-cycloalkyl or NH-allyl.
  5. 6. A compound of claim 1 said compound being 2-methoxy-N-methyl-3-morpholino-2-(2-pyridyl)thiopropanamide.
US322572A 1973-01-10 1973-01-10 2-alkoxy-3-amino-2-heterocyclic-thiopropanamides Expired - Lifetime US3860592A (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US322572A US3860592A (en) 1973-01-10 1973-01-10 2-alkoxy-3-amino-2-heterocyclic-thiopropanamides
ZA739612A ZA739612B (en) 1973-01-10 1973-12-20 Pharmacologically active compounds
AU63873/73A AU472060B2 (en) 1973-01-10 1973-12-20 2-alkoxy (and2-amino)-3-amino-2-heterocyclic -thiopropanamides
BE139525A BE809403A (en) 1973-01-10 1974-01-04 2-ALCOXY (ET 2-AMINO) -3-AMINO-2-HETEROCYCLOTHIOPROPANAMIDES AND PHARMACEUTICAL COMPOSITIONS IN CONTAINER
GB60174A GB1401167A (en) 1973-01-10 1974-01-07 Heterocyclic substituted thiopropanamides
JP49005188A JPS49100075A (en) 1973-01-10 1974-01-07
FR7400512A FR2221131A1 (en) 1973-01-10 1974-01-08
DE2401109A DE2401109A1 (en) 1973-01-10 1974-01-10 THIOPROPANAMIDE, YOUR PHARMACOLOGICALLY COMPATIBLE ACID ADDITIONAL SALTS, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
US05/514,684 US3948892A (en) 1973-01-10 1974-10-15 2-Alkoxy(and 2-amino)-3-amino-2-heterocyclic-thiopropanamides
US514353A US3898335A (en) 1973-01-10 1974-10-15 Pharmaceutical compositions and methods of inhibiting gastric acid secretion
US514519A US3915965A (en) 1973-01-10 1974-10-15 2-Alkoxy(and 2-amino)-3-amino-2-heterocyclic-thiopropanamides

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US322572A US3860592A (en) 1973-01-10 1973-01-10 2-alkoxy-3-amino-2-heterocyclic-thiopropanamides

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US514353A Continuation-In-Part US3898335A (en) 1973-01-10 1974-10-15 Pharmaceutical compositions and methods of inhibiting gastric acid secretion
US05/514,684 Division US3948892A (en) 1973-01-10 1974-10-15 2-Alkoxy(and 2-amino)-3-amino-2-heterocyclic-thiopropanamides

Publications (1)

Publication Number Publication Date
US3860592A true US3860592A (en) 1975-01-14

Family

ID=23255468

Family Applications (1)

Application Number Title Priority Date Filing Date
US322572A Expired - Lifetime US3860592A (en) 1973-01-10 1973-01-10 2-alkoxy-3-amino-2-heterocyclic-thiopropanamides

Country Status (8)

Country Link
US (1) US3860592A (en)
JP (1) JPS49100075A (en)
AU (1) AU472060B2 (en)
BE (1) BE809403A (en)
DE (1) DE2401109A1 (en)
FR (1) FR2221131A1 (en)
GB (1) GB1401167A (en)
ZA (1) ZA739612B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3917593A (en) * 1972-05-22 1975-11-04 Smithkline Corp N-alkenyl and N-alkynyl (2-quinolyl)thio-acetamides
US4001241A (en) * 1973-08-09 1977-01-04 Smithkline Corporation 2-alkoxy(and 2-alkoxyalkyl)-2-quinolyl-thioacetamides
USRE31588E (en) * 1977-06-03 1984-05-22 Bristol-Myers Company Imidazolylmethylthioethyl alkynyl guanidines

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2953562A (en) * 1958-04-12 1960-09-20 Degussa Basic unsaturated carboxylic acid amides and their preparation
US3686190A (en) * 1970-08-07 1972-08-22 En Nom Collectif Science Union 2-pyridinethioacetamides
US3726878A (en) * 1969-07-08 1973-04-10 Takeda Chemical Industries Ltd Pyridine thioacetamide derivatives
US3740409A (en) * 1972-03-21 1973-06-19 Smith Kline French Lab 2-amino(and 2-aminomethyl)-2-heterocyclic-thioacetamides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2953562A (en) * 1958-04-12 1960-09-20 Degussa Basic unsaturated carboxylic acid amides and their preparation
US3726878A (en) * 1969-07-08 1973-04-10 Takeda Chemical Industries Ltd Pyridine thioacetamide derivatives
US3686190A (en) * 1970-08-07 1972-08-22 En Nom Collectif Science Union 2-pyridinethioacetamides
US3740409A (en) * 1972-03-21 1973-06-19 Smith Kline French Lab 2-amino(and 2-aminomethyl)-2-heterocyclic-thioacetamides

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3917593A (en) * 1972-05-22 1975-11-04 Smithkline Corp N-alkenyl and N-alkynyl (2-quinolyl)thio-acetamides
US4001241A (en) * 1973-08-09 1977-01-04 Smithkline Corporation 2-alkoxy(and 2-alkoxyalkyl)-2-quinolyl-thioacetamides
USRE31588E (en) * 1977-06-03 1984-05-22 Bristol-Myers Company Imidazolylmethylthioethyl alkynyl guanidines

Also Published As

Publication number Publication date
AU472060B2 (en) 1976-05-13
DE2401109A1 (en) 1974-07-18
GB1401167A (en) 1975-07-16
JPS49100075A (en) 1974-09-20
BE809403A (en) 1974-07-04
AU6387373A (en) 1975-06-26
ZA739612B (en) 1974-11-27
FR2221131A1 (en) 1974-10-11

Similar Documents

Publication Publication Date Title
EP0177353B1 (en) Thiazolidinedione derivatives, their production and use
KR890000566B1 (en) 1-heteroaryl-4(2.5-pyrrolidinedion-iylalkyl)piperazine derivatives and their preparation
EP0040696B1 (en) Aminothiadiazoles as gastric secretion inhibitors
DE3689924T2 (en) Phenoxyalkylisoxazoles substituted by a heterocyclic group and their use as antiviral agents.
GB2177395A (en) Thiazole derivatives
DE69430752T2 (en) TETRACYCLIC COMPOUNDS
CZ20032452A3 (en) N-phenyl arylsulfonamide compound, pharmaceutical composition in which the compound is comprised as an active component, synthetic intermediate for this compound and process of its preparation
EP0508740B1 (en) Thiazolidinedione derivatives, their production and their use
US3898335A (en) Pharmaceutical compositions and methods of inhibiting gastric acid secretion
US20080070946A1 (en) Hydroxymethylbenzothiazoles Amides
US3860592A (en) 2-alkoxy-3-amino-2-heterocyclic-thiopropanamides
JPH0753716B2 (en) Imidazol carboxamide derivative
US3740409A (en) 2-amino(and 2-aminomethyl)-2-heterocyclic-thioacetamides
US3825547A (en) N-alkenyl and n-alkynyl thioamides
US3923809A (en) 5-Alkoxy-5-heterocyclic-1,2,3,6-tetrahydro-4(5H)-pyrimidinethiones
US3915965A (en) 2-Alkoxy(and 2-amino)-3-amino-2-heterocyclic-thiopropanamides
US3749728A (en) N-cycloalkyl and n-cycloalkane-alkylthioamides
US3956494A (en) Pharmaceutical compositions and methods of inhibiting gastric acid secretion
US3948892A (en) 2-Alkoxy(and 2-amino)-3-amino-2-heterocyclic-thiopropanamides
US3931162A (en) N-Aminomethyl heterocyclic thioacetamides
US4001241A (en) 2-alkoxy(and 2-alkoxyalkyl)-2-quinolyl-thioacetamides
NL8102099A (en) 2-GUANIDINOTHIAZOLE DERIVATIVES WITH PHARMACOLOGICAL ACTION.
US3873536A (en) 2-(2-Pyridyl)-N-tertiary amino methylthioacetamides
US3917593A (en) N-alkenyl and N-alkynyl (2-quinolyl)thio-acetamides
US3880860A (en) N-cycloalkyl and N-cycloalkanealkylthioamides

Legal Events

Date Code Title Description
AS Assignment

Owner name: SMITHKLINE BECKMAN CORPORATION

Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769

Effective date: 19820304

Owner name: SMITHKLINE BECKMAN CORPORATION, PENNSYLVANIA

Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769

Effective date: 19820304