US3853865A - N-aminomethyl-2-amino(and 2-amino-methyl)-2-heterocyclic-thioacetamides - Google Patents

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

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Publication number
US3853865A
US3853865A US00266024A US26602472A US3853865A US 3853865 A US3853865 A US 3853865A US 00266024 A US00266024 A US 00266024A US 26602472 A US26602472 A US 26602472A US 3853865 A US3853865 A US 3853865A
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United States
Prior art keywords
pyridyl
thioacetamide
amino
dimethylamino
morpholino
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Expired - Lifetime
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US00266024A
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English (en)
Inventor
L Brenner
B Loev
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SmithKline Beecham Corp
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SmithKline Corp
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Priority to US00266024A priority Critical patent/US3853865A/en
Priority to JP48051547A priority patent/JPS4949955A/ja
Priority to US05/507,107 priority patent/US3933811A/en
Priority to US507093A priority patent/US3896233A/en
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Publication of US3853865A publication Critical patent/US3853865A/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
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen 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
    • C07D213/59—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
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • a particularly advantageous compound ofthis inven- 5 tion is 3-morpholino-N-morpholinomethyl-2-(2- pyridyl)-thiopropanamide.
  • the compounds of this invention produce inhibition
  • This invention relates to new N-aminomethyl-2- amino-(and Z-aminomethyl)-2-heterocyclicthioacetamides having pharmacological activity.
  • these Compounds mhlblt gasmc Seem of gastric acid secretion. This activity is demonstrated tlonby administration topylorus ligated rats at doses of The compounds of thls "Wentlon are represented about 10 to about 50 mg./kg. orally. Also, this activity the followmg formulai is demonstrated by administration to chronic gastric fistula rats; (Brodie et aL, Amer. J. Physiol.
  • R -YI-FC-NH C11 0 l-l-R R ?H-CNH-CH -R R and R are di-lower alkylamino, N-lower alkyl-N-
  • m, R R and R are as defined above.
  • This invention also includes pharmaceutically ac- According to precedure I, a 2-amino(0r 2- eeptable acid addition salts of the compounds of Foraminomethyl)-2-heterocyclic-thioacetamide is reacted mula I. with formaldehyde and an amine.
  • the reaction is pref-
  • the pharmacologically active compounds of this inerably carried out in an organic solvent, such as a lower vention have the basic structure of Formula I. Howalkanol, for example methanol.
  • the reaction is carried ever, it is apparent to one skilled in the art that well out at about -40C. to about 90C.
  • a heterocyclic thioacetaalkoxy or halogen may be incorporated on the heteromide is reacted with two molar equivalents of formalcyclic rings of R and the phenyl rings. These comdehyde and two molar equivalents of an amine to give pounds are used as are the parent compounds.
  • compounds of this invention in which m is l and R and Preferred compounds of this invention are repre- R are the same.
  • R andR are as defined above and R is an Most preferably, in the compounds of Formula I, R alkali metal. is pyridyl.
  • R alkali metal. is pyridyl.
  • a heterocyclic- Advantageous compounds of this invention are repcarboxaldehyde, an amine and an alkali metal cyanide resented by Formula I in which R, is Z-pyridyl, mis 0 are reacted, preferably in the presence of acid, to give a 2-amino-2heterocyclic-acetonitrile which is converted to a 2-amino-2heterocyclic-thioacetamide by reacting with hydrogen sulfide in the presence of a base such as an amine or by reacting with ammonium po1y-
  • The- 2-aminomethyl-2heterocycliothioacetamide starting materials are prepared by reacting a Z-heterocyclic-thioacetamide, Z-he
  • the pharrnaceutically acceptable, acid addition salts of the compounds of Formula 1 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.
  • 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.
  • the carrier or diluent may in clude 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.
  • the yellow eluant is collected, the solvent removed and the residual liquid applied to an ethyl acetate slurried Florisil (magnesia-silica gel) column. Again the yellow eluant is concentrated and the residual viscous liquid is triturated with ethyl acetate and left at 20C. for 18 hours. The resulting precipitate is filtered and washed with cold ethyl acetate to give S-morpholino-N- morpho1inomethyl-2-( 2-pyridy1)thiopropanamide.
  • 2-Dimethylamino-2-(2-pyridyl)acetonitrile (11.4 g., 0.07 mole) is dissolved in 200 ml. of dry pyridine containing 5 m1. of anhydrous triethylamine. Hydrogen sultide is bubbled into the stirred solution for 7 hours and the solution is then stirred for 17 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 Z-dimethylamino-Z-(Z- pyridyl)thioacetamide, m.p. 133C. (dec.).
  • 2-Morpholino-2-(2-pyridyl)thioacetamide (1.0 g., 0.0042 mole) is dissolved with heating in 30 ml. of 5 methanol. To the warm solution is added 1.0 g. (0.012 mole) of morpholine and 1.84 g. (0.022 mole) of 37 aqueous formaldehyde solution. The resulting solution is refluxed three hours and then stirred for 17 hours. The solvent is evaporated and the residue is recrystallized from methanol/ether to give 2-morpholino-N- morpholinomethyl-2-(2-pyridyl)thioacetamide, m.p. l44l47C. (dec.).
  • the product is 2- dipropylamino-N-morpholinomethyl-2-(2- pyridyl )thioacetamide.
  • the product is 2-dibutylamino-N-morpholinomethyl-2-(2- 5 pyridyl)-thioacetamide.
  • EXAMPLE 12 A solution of 3.0 g. (0.019 mole) of 2-(2-pyridyl)- thioacetamide in 40 ml. of anhydrous methanol is treated at -40C. with l.7 g. (0.0l9 mole) of morpholine in ml. of methanol and 1.6 ml. of 37% formalin solution. The resulting mixture is kept at C. for 36 hours.
  • the product is 3-(N ethyl-N-phenylamino )-N-( N-ethyl-N- phenylaminomethyl )-2-(2-pyridyl )thiopropanamide.
  • the products are B-(N-propyl-N- phenylamino)-N-(N-propyl-N-phenylaminomethyl)-2- (2-pyridyl )-thiopropanamide and 3 -(N -butyl-N- phenylamino)-N-(N-butylN-phenylaminomethyl)2- (Z-pyridyl )thiopropanamide.
  • R is dimethylamino or m is 1 and R is morpholino,
  • R is dimethylamino, diethylamino, piperidino or pyr- 4.
  • a compound of claim 1, said compound being 3- rolidino or m is l and R is morpholino, and R is di- 5 morpholino-N-morpholinomethyl-2-(2-pyridyl)thiolower alkylamino, piperidino, pyrrolidino or morphopropanamide. lino.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
US00266024A 1972-06-26 1972-06-26 N-aminomethyl-2-amino(and 2-amino-methyl)-2-heterocyclic-thioacetamides Expired - Lifetime US3853865A (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US00266024A US3853865A (en) 1972-06-26 1972-06-26 N-aminomethyl-2-amino(and 2-amino-methyl)-2-heterocyclic-thioacetamides
JP48051547A JPS4949955A (en:Method) 1972-06-26 1973-05-09
US05/507,107 US3933811A (en) 1972-06-26 1974-09-18 N-aminomethyl-2-amino(and 2-amino-methyl)-2-(2-quinolyl)-thioacetamides
US507093A US3896233A (en) 1972-06-26 1974-09-18 Pharmaceutical compositions and methods of inhibiting gastric acid secretion

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Application Number Priority Date Filing Date Title
US00266024A US3853865A (en) 1972-06-26 1972-06-26 N-aminomethyl-2-amino(and 2-amino-methyl)-2-heterocyclic-thioacetamides

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3931162A (en) * 1972-06-26 1976-01-06 Smithkline Corporation N-Aminomethyl heterocyclic thioacetamides
US4289766A (en) * 1977-12-27 1981-09-15 Eli Lilly And Company Heterocyclic carbothioamides
US4375547A (en) * 1980-10-02 1983-03-01 Eli Lilly And Company N-Methyl-N'-2-([(2-dimethylaminomethyl)-4-thiazolyl]methylthio)ethyl 2-nitro-1,1-ethenediamine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2100970A1 (en:Method) * 1970-07-30 1972-03-24 Fujisawa Pharmaceutical Co
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
US3749728A (en) * 1972-02-15 1973-07-31 Smith Kline French Lab N-cycloalkyl and n-cycloalkane-alkylthioamides

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3726878A (en) * 1969-07-08 1973-04-10 Takeda Chemical Industries Ltd Pyridine thioacetamide derivatives
FR2100970A1 (en:Method) * 1970-07-30 1972-03-24 Fujisawa Pharmaceutical Co
US3686190A (en) * 1970-08-07 1972-08-22 En Nom Collectif Science Union 2-pyridinethioacetamides
US3749728A (en) * 1972-02-15 1973-07-31 Smith Kline French Lab N-cycloalkyl and n-cycloalkane-alkylthioamides
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
US3931162A (en) * 1972-06-26 1976-01-06 Smithkline Corporation N-Aminomethyl heterocyclic thioacetamides
US4289766A (en) * 1977-12-27 1981-09-15 Eli Lilly And Company Heterocyclic carbothioamides
US4375547A (en) * 1980-10-02 1983-03-01 Eli Lilly And Company N-Methyl-N'-2-([(2-dimethylaminomethyl)-4-thiazolyl]methylthio)ethyl 2-nitro-1,1-ethenediamine

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