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
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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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Abstract

THE COMPOUNDS ARE 2-AMINO(AND 2-AMINOMETHYL)-2HETEROCYCLIC-THIOACETAMIDES WHICH ARE INHIBITORS OF GASTRIC ACID SECRETION.

Description

United States Patent 3,740,409 2-AMINO(AND Z-AMINOMETHYD-Z-HETERO CYCLlC-THIOACETAMIDES L. Martin Brenner, Upper Darby, and Bernard Loev,
Broomall, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa. No Drawing. Filed Mar. 21, 1972, Ser. No. 236,593 Int. Cl. C07d 31/50 US. Cl. 260294.8 E 3 Claims ABSTRACT OF THE DISCLOSURE The compounds are 2-amino(and 2-aminomethyl)-2- heterocyclic-thioacetamides which are inhibitors of gastric acid secretion.
This invention relates to new 2-amino(and 2-aminomethyl)-2-heterocyclic-thioacetamide compounds having pharmacological activity. In particular, these compounds inhibit gastric acid secretion.
The compounds of this invention are represented by the following formula:
FORMULA I ll R1-OHCR4 I 2)m R2 R3 in which:
in is 0 or 1;
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;
or NI-I--(CH cycloalky1, said cycloalkyl having 3-6 carbon atoms;
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.
Advantageous compounds of this invention are represented by Formula I in which 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.
According to procedure 11, 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.
By procedure III, a 2-heterocyclic-N-substituted-thioacetamide is reacted with an equimolar amount of formaldehyde and an equirnolar amount of an amine to give the corresponding Z-aminomethyl compounds of this invention.
According to procedure IV, an aminoalkyl-heterocycle is reacted with strong base such as butyl or phenyl lithium and then with an appropriate isothiocyanate to give N-substituted thioacetamides of this invention.
According to procedure V, 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. To prepare the N-substituted compounds of this invention, the N-unsubstituted thioacetamides are reacted with the appropriate amine.
Alternatively, 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.
Also, the 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. 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, 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 employed, 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.
The terms lower alkyl and lower alkoxy where used herein denote groups having 1-4 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 To cold Z-pyridinecarboxaldehyde (21.4 g., 0.2 mole) is added dimethylamine (22.5 g. of a 40% aqueous solution, 0.2 mole) and the solution is neutralized with concentrated hydrochloric 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 chloroform. 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 20 C. for 18 hours, then filtered. The filtrate is concentrated and distilled in vacuo to give 2-dimethylamino-2-(Z-pyridyl)-acetonitrile.
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.).
One gram of 2 dimethylamino-2(2-pyridyl)thioacetamide in ether is added to ethereal hydrogen chloride. The resulting precipitate is filtered off, washed with ether and recrystallized from ethanol/ ether to give 2-dimethylamino 2 (2-pyridyl)thioacetamide dihydrochloride.
EXAMPLE 2 By the procedure of Example 1, using in place of 2-dimethylamino-Z-(2-pyridyl)acetonitrile the following substituted acetonitriles:
2-diethylamino-2- (2-pyridyl) acetonitrile 2-pyrrolidino-2- Z-pyridyl) acetonitrile 2-pip eridino-2- (2-pyridyl acetonitrile 2-dimethylamino-2- 6-methyl- 2-pyridy1) acetonitrile the products are, respectively:
2-diethylamino-2- (2-pyridyl) thioacetamide 2-pyrrolidino-2- (2-pyridyl) thioacetamide 2-piperidino-2- (Z-pyridyl thioacetamide 2-dimethylamino-2- 6 -methyl-2-pyridyl) thioacetamide.
EXAMPLE 3 Using 0.07 mole of 2-dimethylamino-2-(2-quinolyl)- acetonitrile in place of 2-dimethylamino-2-(2 pyridyl)- acetonitrile in the procedure of Example 1 gives 2-dimethylamino-Z- (2- quinolyl) thioacetamide.
Similarly, using 2-piperidine-2-(2-quinolyl)-acetonitrile, the product is Z-piperidino-Z-(2-quinolyl)thioacetamide.
EXAMPLE 4 To 27.0 g. of 2-pyrimidinecarboxaldehyde and 11.3 g. of dimethylamine (neutralized with hydrochloric acid) is added, with stirring and cooling, 17.9 g. of potassium cyanide in a small amount of water. The mixture is allowed to stand overnight and ether is added. Concentrating and distilling the residue gives 2-dimethylamino- 2- (2-pyrimidyl acetonitrile.
Using 2-dimethylamino-2-(2-pyrimidyl)acetonitrile in place of 2-dimethylamino-2-(Z-pyridyl)acetonitrile in the procedure of Example 1 gives 2 dimethylamino 2 (2- pyrimidyl) thioacetamide.
EXAMPLE 5 By the procedure of Example 1, using in place of Z-pyridinecarboxaldehyde, the following carboxaldehydes:
2-pyrrolecarboxaldehyde 2-pyrazinecarboxaldehyde 4 pyrimidinecarboxaldehyde 2-thiazolecarboxaldehyde 4-thiazolecarboxaldehyde the products are, respectively:
2-dimethylamino-2- 2-pyrrolyl) thioacetamide 2-dimethylamino-2- 2-pyrazinyl) thioacetamide Z-dimethylamino-Z- 4-pyrimidyl thioacetamide 2-dimethylamino-2- 2-thiazolyl thioacetamide 2-dimethylamino-2- 4-thiazolyl thioacetamide.
EXAMPLE 6 By the procedure of Example 1, using dipropylamiue in place of dimethylamine the product is 2-dipropylamino- 2- 2-pyridyl thioacetamide.
Similarly, using dibutylamine, the product is Z-dibutylamino-2-(2-pyridyl)thioacetamide.
EXAMPLE 7 By the procedure of Example 1, Z-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 1 to give 2-(4- methylpiperazino -2- (2-pyridyl) thioacetamide.
Similarly, using in place of N-methylpiperazine the following lower alkylpiperazines:
N-ethylpiperazine N-propylpiperazine N-butylpiperazine the products are, respectively:
2- (4-ethylpiperazino -2- (Z-pyridyl thioacetamide 2- 4-propylpiperazino -2- (2-pyridyl) thioacetamide 2- (4-butylpiperazino -2- (Z-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 9 By the procedure of Example 8, using in place of dimethylamine, the following:
diethylamine dipropylamine dibutylamine pyrrolidine piperidine N-methylpiperazine the products are, respectively:
3-dimethylamino-2- 2-pyridyl thiopropanamide 3-dipropylamino-2- (2-pyridyl thiopropanamide 3-dibutylamino-2- 2-pyridyl thiopropanamide 3-pyrrolidino-2- 2-pyridyl thiopropanamide 3-piperidino-2- 2-pyridyl) thiopropanamide 3-(4-methy1piperazino)-2-(2-pyridy1)thiopropanamide.
EXAMPLE 10 By the procedure of Example 8, using 2(5-ethyl-2- pyridyl)acetamide, the product is 3-dimethylamino-2-(5- ethyl-2-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.
By the procedure of Example 8, 0.02 mole of N-cyclopropyl-2-(2-pyridyl)thioacetamide is warmed on a steam bath With 0.02 mole of formaldehyde and 0.02 mole of dimethylamine in methanol for 15 minutes to give, after removing the solvent and recrystallizing the residue, N- cyclopropyl-3-dimethylamino-2-(2 pyridyl)thiopropanamide.
Similarly, using in the above procedure the following cycloalkylamines cyclobutylamine cyclopentylamine cyclohexylamine the products are, respectively:
N-cyclobutyl-3-dimethylamino-2- (Z-pyridyl) thiopropanamide N-cyclopentyl-3-dimethylamino-2- 2-pyridyl) thiopropauamide N-cyclohexyl-3-dimethylamino-2- (2-pyridyl) thiopropanamide EXAMPLE 12 Cyclopropanemethylamine hydrochloride (6.02 g, 0.056 mole) and 4.71 g. (0.056 mole) of sodium bicarbonate are dissolved in 75 ml. of water and the solution is added to 4.35 g. (0.029 mole) of 2-(2-pyridy1)thio acetamide. 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. The product is recrystallized from ethyl acetate/ hexane to give N-cyclopropanemethyl-Z-(2-pyridyl)-thioacetamide.
By the procedure of Example 8, 0.01 mole of N-cycloprop-anemethyl-Z-(2-pyridyl)thioacetamide is warmed on a steam bath with 0.01 mole of formaldehyde and 0.01
mole of dimethylamine in methanol for 15 minutes to give, after r-n1oving the solvent and recrystallizing the residue, -N cyclopropanemethyl-3-dimethylamino-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-3-dimethylamino-2-(2-pyridyl)- thiopropanamide N-cyclopentanemethyL3-dimethylamino-2-(2-pyridyl)- thiopropanamide N-cyclohexanemethyl-3 -dimethylamino-2- (2-pyridyl) thiopropanamide.
EXAMPLE 13 By the procedure described in Example 11, the follow ing thioacetamides are reacted with formaldehyde and dimethylamine N-methyl-2- Z-pyridyl thioacetamide N-methyl-2-(2-quinoly1)thioacetamide N-ethyl-2- 6 -methy1-2-pyridyl thioacetamide N-propyl-2- 6-methyl-2-pyridyl thioacetamide N-butyl-2- (6-methyl-2-pyridyl) thioacetamide N-methyl-2- (4-ethoxy-2-pyridyl) thio acetamide N,N-dimethyl-2- (2-pyridyl) thioacetamide N,N-diethyl-2-( 6-methyl-2rpyridyl) thio acetamide to give the following products, respectively:
3-dimethylamino-N-methyl-Z- 2-pyridyl) thiopropanamide 3-dim ethylamino-N-methy1-2- (2-quinoly1) thiopropanamide 3 -dimethylamino-N-ethyl-2- 6-methy1-2-pyridyl) thiopropanamide 3 -dimethylamiuo-N-propyl-Z- 6-methy1-2-pyridyl) thiopropanamide N-butyl-3 -dimethylamino-2-(6-methy1-2-py1idy1)thiopropanamide 3 -dimethylamino-N-rnethyl-Z- (4-eth'oxy-2-pyridyl)thiopropanamide 3-dimethylamino-N,N- dimethy1-2- 2-pyridyl) thiopropanamide 3 -dimethylamino-N,N-diethyl-2- (-6-methyl-2-pyridyl) thiopropanamide.
EXAMPLE 14 By the procedure of Example 1i1, using cyclopropylamine and the following thioacetamides:
2- (Z-pyrazinyl) thioacetamide 2- (2-pyrrolyl) thioacetamide 2- (2-quino1yl) thioacetamide the products are, respectively:
N-cyc1opropyl-3 -dimethylamino-2-(2-pyrazinyl)thiopropanamide -N-cyclopropyl-3-dimethylamino-Z- (2-pyrro1yl) thiopropanamide N-cyclopropyl-3-dimethylamino-2(2-quinolyl)thiopropanamide.
EXAMPLE 15 By the procedure of Example 12, using cyclopropanemethylarnine hydrochloride and the following thioacetamides:
2- 2-pyrazinyl) thioacetamide 2- 2-pyrroly1) thio acetamide 2- Z-quinolyl) thioacetamide the products are, respectively N-cyclopropanemethyl-3-dimethylamino-2- (2-pyrazinyl thiopropanamide 8 N-cyclopropanemethyl-3-dimethylamino-2-(2-pyrro1yl)- thio-propanamide N-cyclopropanemethyl-3-dimethylamino-2-(2-quino1yl)- thiopropanamide.
EXAMPLE 16 By the procedure of Example 1, using 4-chloro-2- pyridinecarboxaldehyde in place of 2-pyridinccarboxaldehyde, the product is 2-(4-chloro-2-pyridyl)-2-(dimethy1 amino) 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.
By the same procedure, using the appropriate lower alkylamine, 2 dimethylamino-N-ethyl-Z-(2-pyridyl)thioacetamide and the corresponding N-propyl and N-butyl compounds are prepared.
Similarly, using the appropriate di(lower alkyD-amine, 2-dimethylamino-N,N-dimethyl 2 (2-pyridyl)thioacetamide and the corresponding N,N-diethyl, N,-N-dipropyl and lN,N-dibutyl compounds are prepared.
Also, using 2-dimethylamino-2-(2-pyrimidyl)thioacetamide and methylamine, the product is 2-dimethylamino- N-methyl-Z-(Z-pyrimidyl)thioacetamide. Similarly, using dimethylamine, 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.
By the same procedure, using 2-piperidino-2-(Z-pyridyl) thioacetamide, the product is N-cyclopropyl-2-piperidino- 2-(2-pyridyl)thioacetamide.
EXAMPLE 19 To 5.65 g. of Z-dimethylamino-Z-(Z-pyridyl)thioacetamide is added 6.02 g. of cyclopropanemethylamine hydrochloride and 4.71 g. of sodium bicarbonate which are dissolved in 75 ml. of water and the resulting mixture is heated with stirring on a steam bath for four hours to give, after working up by the procedure described in Example 12, N-cyclopropane methyl-2-dimethylamino-2- (2-pyridyl)thioacetamide.
By the same procedure, using cyclopentanemethylamine hydrochloride, the product is N-cyclopentanemethyl-2-dimethylamino-Z-(2-pyridyl) thioacetamide.
EXAMPLE 20 Alternatively, 'N cyclopropanemethyl 2 dimethylamino-Z-(2-pyridyl)thioacetamide is prepared by the following procedure.
A solution of 13.6 g. (0.1 mole) of Z-(dimethylaminomethyl) pyridine in 50 ml. of anhydrous benzene is added dropwise at 25 C. to 8.7 g. 0.1 mole) of phenyl lithium in ml. of anhydrous benzene. After the addition, the reaction is stirred for 30 minutes and 11.3 g. (0.1 mole) of cyclopropanemethyl isothiocyanate in 50 ml. of anhydrous benzene is added dropwise. The mixture is stirred at 25 C. for 15 hours, then decomposed with dilute hydrochloric acid. The layers are separated and the aqueous layer is basified with aqueous sodium carbonate solution. Extraction with chloroform, removal of the chloroform from the extract and recrystallization gives N- cyclopropanemethyl 2 dimethylamino 2 (Z-pyridyl) thioacetamide.
9 EXAMPLE 21 By the procedure of Example 20, using Z-(piperidinomethyl)pyridine in place of 2-(dirnethylaminomethyl) pyridine, the product is N-cyclopropanemethy1-2-piperidino-2-(Z-pyridyl)thioacetamide.
EXAMPLE 22 2-dimethylamino-2-(2-pyridyl)thioacetamide (2 g.) in ethanol is treated with an equimolar amount of maleic acid in ethanol to give, after removing the solvent in vacuo, Z-dimethylamino 2 (2-pyridyl)thioacetamide maleate.
In the same manner, using citric acid, 2-dimethylamino-2-(2-pyridyl)thioacetarnide citrate is prepared.
What is claimed is:
1. A compound of the formula:
S R;-OHl-B4 It z a in which:
m is or 1;
R is a 2-pyridyl ring, said ring being optionally substituted by halogen, lower alkyl or lower alkoxy;
10 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.
2. A compound of claim 1 in which 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.
3. A compound of claim 1 in which R is Z-pyridyl, R and R are methyl and R is NH NHmethyl, NH-cy clopropyl, NHcyclobutyl, NHCH cyclopropyl or NHCH cyclobutyl.
References Cited UNITED STATES PATENTS 3,290,318 12/1966 Sause 260-2948 E 3,624,085 11/1971 Malen et al. 260294.8 E 3,686,190 8/1972 Malen et al. 260-2948 E ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.
260-250 R, 256.4 R, 268 H, 283 S, 293.68, 293.69, 302 R, 326.5 S, 32682; 424-250, 251, 258, 263, 267, 270, 274
US00236593A 1972-03-21 1972-03-21 2-amino(and 2-aminomethyl)-2-heterocyclic-thioacetamides Expired - Lifetime US3740409A (en)

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US3860592A (en) * 1973-01-10 1975-01-14 Smithkline Corp 2-alkoxy-3-amino-2-heterocyclic-thiopropanamides
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US3860592A (en) * 1973-01-10 1975-01-14 Smithkline Corp 2-alkoxy-3-amino-2-heterocyclic-thiopropanamides
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