US3740409A - 2-amino(and 2-aminomethyl)-2-heterocyclic-thioacetamides - Google Patents

2-amino(and 2-aminomethyl)-2-heterocyclic-thioacetamides Download PDF

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US3740409A
US3740409A US00236593A US3740409DA US3740409A US 3740409 A US3740409 A US 3740409A US 00236593 A US00236593 A US 00236593A US 3740409D A US3740409D A US 3740409DA US 3740409 A US3740409 A US 3740409A
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pyridyl
thioacetamide
dimethylamino
thiopropanamide
procedure
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L Brenner
B Loev
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Smith Kline and French Laboratories Ltd
GlaxoSmithKline LLC
SmithKline Beecham Corp
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • C07D213/57—Nitriles
    • 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
    • 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
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to new 2-amino(and 2-aminomethyl)-2-heterocyclic-thioacetamide compounds having pharmacological activity.
  • these compounds inhibit gastric acid secretion.
  • R is a 2-pyridyl, Z-pyrimidyl, 4-pyrimidyl, 2-pyrazinyl, 2-pyrrolyl, Z-quinolyl, Z-thiazolyl or 4-thiazolyl ring, said rings being optionally substituted by halogen, lower alkyl or lower alkoxy;
  • R and R are lower alkyl or taken together with the nitrogen atom to which they are attached form a piper idino, pyrrolidino or N-lower alkylpiperazino ring;
  • R and R are hydrogen or lower alkyl and n is 0 or 1.
  • This invention also includes pharmaceutically acceptable acid addition salts of the compounds of Formula 1.
  • Preferred compounds of this invention are represented by Formula I in which R is Z-pyridyl, R and R are methyl or ethyl or taken together with the nitrogen atom to which they are attached form a piperidino or pyrrolidino ring and R is NH NH(lower alkyl), NH- cyclopropyl, NHcyclobutyl, NHcl-l yclopropyl or NHCH cyclobutyl.
  • R is Z-pyridyl
  • R and R are methyl and R is NH NHmethyl, l IH-cyclopropyl, NHcyclobutyl, NH-CH cyclopropyl or NHCH --cyclobutyl.
  • 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 50 mg./kg. orally. Also, this activity is demonstrated by administration to chronic gastric fistula rats (Brodie et al., Amer. J. Physiol. 202:812814, 1962) at doses of about 50 mg./ kg. orally. In these procedures, compounds which produce an increase in the gastric pH or a de- Patented June 19, 1973 ice crease in the volume of gastric juice or both are considered active.
  • the compounds of this invention are prepared by the following procedures:
  • R1-CHO HN 2-heterocyclic-thioacetamide of this invention by reacting with hydrogen sulfide in the presence of a base such as an amine or by reacting with ammonium polysulfide.
  • the N-substituted thioacetamides of this invention are prepared by reacting the N-unsubstituted compounds with the appropriate amine.
  • a 2-heterocyclic-acetamide is reacted with an equimolar amount of formaldehyde and an equimolar amount of an amine to give a Z-aminomethyl-Z-heterocyclic-acetamide which is treated with phosphorus pentasulfide to give a Z-aminomethyl-2-heterocyclic-thioacetamide of this invention.
  • Reacting with an appropriate amine gives the corresponding N-substituted thioacetamides of this invention.
  • a Z-heterocyclic-acetonitrile is reacted with formaldehyde and an amine to give a 2-an'1inomethyl-2-heterocyclic-acetonitrile which is converted to a 2-aminomethyl-Z-heterocyclic-thioacetamide of this invention by reacting with hydrogen sulfide in the presence of a base such as an amine or by reacting with ammonium polysulfide.
  • a base such as an amine
  • ammonium polysulfide reacting with ammonium polysulfide.
  • the N-unsubstituted thioacetamides are reacted with the appropriate amine.
  • the 2-aminomethyl-2-heterocyclic-acetamide intermediate in procedure II may be prepared by reacting a lower alkyl ester of a Z-heterocyclic-acetic acid with formaldehyde and an amine and reacting the resulting lower alkyl ester of a 2-aminomethyl-2-heterocyclicacetic acid with ammonia.
  • the 2-aminomethyl-2-heterocyclic-acetamide thus prepared may be dehydrated to give the 2 aminomethyl 2 heterocyclic-acetonitrile intermediates in procedure V.
  • NH-lower alkyl and NH-(CH -cycloalkyl thioamides prepared by procedures III and IV may be converted to the corresponding N-unsubstituted compounds by treating with ammonium hydroxide.
  • 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, 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. 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.
  • compositions 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.
  • lower alkyl and lower alkoxy where used herein denote groups having 1-4 carbon atoms and halogen denotes chloro, bromo or fluoro.
  • Z-dimethylamino 2 (2-pyridyl)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 17 hours. This procedure is repeated for five 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 dimethylarnino-2-(Z-pyridyl)thioacetamide, M.P. 133' C. (dec.).
  • the product is Z-dibutylamino-2-(2-pyridyl)thioacetamide.
  • EXAMPLE 8 To 4.1 g. (0.03 mole) of 2-(2-pyridyl)acetamide dissolved in 60 ml. of methanol is added 2.52 g. of 37% aqueous formaldehyde solution (0.03 mole of formaldehyde) dissolved in ml. of methanol and 1.35 g. (0.03 mole) of dimethylamine dissolved in 15 ml. of methanol. The resulting solution is warmed on a steam bath for 15 minutes. The solvent is then removed under reduced pressure and the residue is recrystallized from acetone to give 3-dimethylarnino-2-(2-pyridyl)propanamide.
  • Phosphorus pentasulfide (2.3 g.) is added to 2.0 g. of 3-dimethylamino-2-(2-pyridyl)propanamide 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 is added. The mixture is extracted with chloroform and the extracts are dried and concentrated and the residue is recrystallized to give 3-dimethylamino-Z- (Z-pyridyl) thiopropanamide.
  • EXAMPLE 11 A solution of 7.6 g. (0.05 mole) of 2-(2-pyridyl)thioacetamide in a 40% aqueous solution of cyclopropylamine is refluxed for 45 minutes. After cooling, approximately 30 ml. of water is added. The reaction mixture is extracted three times with chloroform. The extracts are combined and dried over magnesium sulfate. The solvent is removed under reduced pressure. The residue is recrystallized twice from ethyl acetate/hexane to give N- cyclopropyl-2- (2-pyridyl thioacetamide.
  • 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. The product is recrystallized from ethyl acetate/ hexane to give N-cyclopropanemethyl-Z-(2-pyridyl)-thioacetamide.
  • EXAMPLE 17 A mixture of 7.5 g. of Z-dimethylamino-Z-(Z-pyridyl)- thioacetamide and 15 ml. of 30% aqueous methylamine is heated for 30 minutes, then cooled and 25 m1. of 5% 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 Z-dimethylamino-N-methyl-2-(2-pyridyl)thioacetamide.
  • the product is 2-dimethylamino- N-methyl-Z-(Z-pyrimidyl)thioacetamide.
  • the product is 2-dimethyla-mino-N,'N-dimethyl-Z- (2-pyrimidyl thioacetamide.
  • EXAMPLE 18 A mixture of 2-dimethylamino-2-(2-pyridyl)thioacetamide and 40% aqueous solution of cyclopropylamine is heated at reflux for 45 minutes and worked up by the procedure described in Example 11 to give N-cyclopropyl- 2-dimethylamino-2- Z-pyridyl thioacetamide.
  • the product is N-cyclopentanemethyl-2-dimethylamino-Z-(2-pyridyl) thioacetamide.
  • n is or 1;
  • R is a 2-pyridyl ring, said ring being optionally substituted by halogen, lower alkyl or lower alkoxy;
  • R and R are lower alkyl or taken together with the nitrogen atom to which they are attached form a piperidino, pyrrolidino or N-lower alkylpiperazino ring;
  • R4 is N/ or NH(CH cycloalky1, said cycloalkyl having 3 6 carbon atoms;
  • R and R are hydrogen or lower alkyl and n is 0 or 1 or a pharmaceutically acceptable acid addition salt thereof.
  • R is 2-pyridyl
  • R and R are methyl or ethyl or taken together with the nitrogen atom to which they are attached form a piperidino or pyrrolidino ring and R is NH NH(loWer alkyl), NH-cyclopropyl, :NHcyclobutyl, NH-CH cyclopropyl or NHCH cyclobutyl.
  • R is Z-pyridyl
  • R and R are methyl and R is NH NHmethyl, NH-cy clopropyl, NHcyclobutyl, NHCH cyclopropyl or NHCH cyclobutyl.

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US00236593A 1972-03-21 1972-03-21 2-amino(and 2-aminomethyl)-2-heterocyclic-thioacetamides Expired - Lifetime US3740409A (en)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3853865A (en) * 1972-06-26 1974-12-10 Smithkline Corp N-aminomethyl-2-amino(and 2-amino-methyl)-2-heterocyclic-thioacetamides
US3860592A (en) * 1973-01-10 1975-01-14 Smithkline Corp 2-alkoxy-3-amino-2-heterocyclic-thiopropanamides
US3898228A (en) * 1972-05-22 1975-08-05 Smithkline Corp N-alkenyl and N-alkynyl 2-pyridine thioacetamides
US3915965A (en) * 1973-01-10 1975-10-28 Smithkline Corp 2-Alkoxy(and 2-amino)-3-amino-2-heterocyclic-thiopropanamides
US3933811A (en) * 1972-06-26 1976-01-20 Smithkline Corporation N-aminomethyl-2-amino(and 2-amino-methyl)-2-(2-quinolyl)-thioacetamides
US3948892A (en) * 1973-01-10 1976-04-06 Smithkline Corporation 2-Alkoxy(and 2-amino)-3-amino-2-heterocyclic-thiopropanamides
US3950522A (en) * 1974-04-12 1976-04-13 Smithkline Corporation Pharmaceutical compositions and methods of inhibiting gastric acid secretion
US4118567A (en) * 1972-06-23 1978-10-03 Smithkline Corporation 3-Morpholino-2-heterocyclic-thiopropanamides
US4249012A (en) * 1975-11-18 1981-02-03 John Wyeth & Brother Ltd. Certain 4-formamidothiazoles
US4272534A (en) * 1979-03-30 1981-06-09 Rhone-Poulenc Industries 2-(Pyrid-2-yl)tetrahydrothiophene derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA836241B (en) * 1982-09-02 1985-03-27 Ici Australia Ltd Herbicidal cyclohexane-1,3-dione derivatives

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3898228A (en) * 1972-05-22 1975-08-05 Smithkline Corp N-alkenyl and N-alkynyl 2-pyridine thioacetamides
US4118567A (en) * 1972-06-23 1978-10-03 Smithkline Corporation 3-Morpholino-2-heterocyclic-thiopropanamides
US3853865A (en) * 1972-06-26 1974-12-10 Smithkline Corp N-aminomethyl-2-amino(and 2-amino-methyl)-2-heterocyclic-thioacetamides
US3933811A (en) * 1972-06-26 1976-01-20 Smithkline Corporation N-aminomethyl-2-amino(and 2-amino-methyl)-2-(2-quinolyl)-thioacetamides
US3860592A (en) * 1973-01-10 1975-01-14 Smithkline Corp 2-alkoxy-3-amino-2-heterocyclic-thiopropanamides
US3915965A (en) * 1973-01-10 1975-10-28 Smithkline Corp 2-Alkoxy(and 2-amino)-3-amino-2-heterocyclic-thiopropanamides
US3948892A (en) * 1973-01-10 1976-04-06 Smithkline Corporation 2-Alkoxy(and 2-amino)-3-amino-2-heterocyclic-thiopropanamides
US3950522A (en) * 1974-04-12 1976-04-13 Smithkline Corporation Pharmaceutical compositions and methods of inhibiting gastric acid secretion
US4249012A (en) * 1975-11-18 1981-02-03 John Wyeth & Brother Ltd. Certain 4-formamidothiazoles
US4272534A (en) * 1979-03-30 1981-06-09 Rhone-Poulenc Industries 2-(Pyrid-2-yl)tetrahydrothiophene derivatives

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