US3882126A - 2-amino(and 2-aminomethyl)-2-quinolylthioacetamides - Google Patents

2-amino(and 2-aminomethyl)-2-quinolylthioacetamides Download PDF

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US3882126A
US3882126A US346488A US34648873A US3882126A US 3882126 A US3882126 A US 3882126A US 346488 A US346488 A US 346488A US 34648873 A US34648873 A US 34648873A US 3882126 A US3882126 A US 3882126A
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pyridyl
thioacetamide
dimethylamino
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L Martin Brenner
Bernard Loev
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SmithKline Beecham Corp
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    • 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
    • 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
    • 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
    • C07D213/54—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

Definitions

  • This invention also includes pliarmaceuticallv ac- This invention relates to new 2-amino(and Z- ceptiible acid addition salts of the compounds of Foraminomethyl)-2-heterocvclic-thioacetamide CUHF mula l Pounds having Phllrmlmplegicill activity Particulan Preferred compounds of this invention are repre lhcse (mmpounds inhibit gastric acid sccrction' sented by Formula I in which R is Z-pvridyl.
  • the compounds of this invention produce inhibition py py y q m LIMHZQLVI m of gastric acid secretion. This activity is demonstrated minim-H ring. Said rings being Optional)
  • compounds which produce an increase in the gastric in which:
  • R is an alkali metal.
  • R" is lower alkyl or (CH I,,- cycloalkyl.
  • R is NH-(lower alkyl). Ntlower alkyh or NH-(Cl-lg -cycloalkyl.
  • R is NH-( lovver alkyl or NH- tcHfl -cycloalkyl. said cycloalkyl groups having 36 carbon atoms and n is as defined above.
  • a hetcrocycliccarboxaldehyde an amine and an alkali metal cyanide are reacted. preferably in the presence of acid. to give a 2-amino-2-heterocyclic-acetonitrile which is converted to a Z-amino-2-heterocyclic-thioacetamide of this invention by reacting with hydrogen sulfide in the presence ofa 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 Z-heterocyclicacetamide is reacted with an equimolar amount of formaldehyde and an equimolar amount of an amine to give a 2-aminomcthyl-2-heterocyclic-acetamide which is treated with phosphorus pentasulfide to give a 2- aminomethyl-2-heterocyclic-thioacetamide of this invention.
  • Reacting with an appropriate amine gives the corresponding N-substituted thioacetamides of this invention.
  • a 2-heterocyclicacetonitrile is reacted with formaldehyde and an amine to give a 2-aminomethyl-2-heterocyclic-acetonitrile which is converted to a 2-aminomethyl-2-heterocyclicthioacetamide 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 to prepare the N-substituted compounds of this invention.
  • the N- unsubstituted thioacetamides are reacted with the appropriate amine.
  • the 2-aminomethyl 2-heterocyclicacetamide intermediate in procedure ll 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-heterocyclic-acetic 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-tCH- l -cycloalkyl thioamides prepared by procedures Ill and IV may be converted to the corres onding N-unsubstituted compounds by treating with ammonium hydroxide.
  • the pharmaccutically 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.
  • 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 ap limbate 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.
  • Exemplary of liquid carriers are syrup. peanut oil. olive oil. sesame oil. propylene glycol. polyethylene glycol (mol. wt. 200400) 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 dis tearate alone or with a wax.
  • compositions can be employed.
  • 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.
  • lower alkyl and lower alkoxy where used herein denote groups having 1-4 carbon atoms and halogen denotes chloro. bromo or fluoro.
  • 2-Dimethylamino-2-(Z-pyridyl)acetonitrile (1 L4 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 Z-dimethylamino-IZ-(Z- pyridyHthioacetamide. m.p. ll33C. (dec.).
  • Phosphorus pentasulfide (2.3 g.) is added to 2.0 g. of 3-dimethylamino-2-t 2-pyridyl)propanamide in 25 ml. of pyridine. The mixture is heated on a steam bath for 2 hours. then 250 ml. of water and i0 ml. of 5 percent 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-2-(2-pyridyl)thiopropanamide.
  • Example 8 By the procedure of Example 8, 0.02 mole of N- cyclopropyl-I-(Z-pyridyl)thioacetamide is warmed on a steam bath with 0.02 mole of formaldehyde and 0.02 mole of diniethylamine in methanol for minutes to give. after removing the solvent and recrystallizing the residue. N-cyclopropyl-3-dimethylamino'2-(2- pyridyl lthiopropanamide.
  • EXAMPLE 1 A mixture of 7.5 g. of Z-dimethylamino-Z-(Z- pyridyhthioacetamide and [5 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-methyl-2-(Z-pyridyl)thioacetamide.
  • EXAMPLE l8 A mixture of Z-dimethylamino-Z-l 2- pyridyl )thioacetamide and 40 percent aqueous solution of cyclopropylamine is heated at reflux for 45 minutes and worked up by the procedure described in Example 1 l to give N-cyclopropyl-Z-dimethylamino-Z-t 2- pyridyl )thioacetamide.
  • EXAMPLE 21 ethanol/ether to give Z-dimethylamino-Z-t 2- pyridyl)thioacetamide dihydroehloridev Similarly. using N-cyclopropyl-Z-dimethylamino-2 (Z-pyridyl)thioacetamide. the dihydrochloride salt of N-cyclopropyl-2-dimethylamino-2-( 2- pyridyl)thioacetamide is prepared.
  • n (l or I;
  • R is a Z-quinolyl ring. said ring being optionally nonsubstituted by halogen. lower alkyl or lower alkoxy;
  • R and R are lower alkyl or taken together with the R and R are hydrogen or lower alkyl and n is or nitrogen atom to which they arc attached form a l or a pharmaccutically acceptable acid addition pipcridino pyrrolidino or N-lowcr alkylpipcrazino salt tilCl'fZOf ring; 2.
  • a compound according to claim I. said compound n being Nmyclopropyl3 dimcthylamino-2-(2-quinolyl)- or NH-tCHy -cycloalkyh said cycloalkyl having 3-6 thiopropanamidc. carbon atoms;

Abstract

The compounds are 2-amino(and 2-aminomethyl)-2-heterocyclicthioacetamides which are inhibitors of gastric acid secretion.

Description

Brenner et al.
2-AMlNO(AND 2-AMlNOMETHYL)-2- QUINOLYLTHIOACETAMIDES Inventors: L. Martin Brenner, Upper Darby;
Bernard Loev, Broomall, both of Pa.
Assignee: SmithKline Corporation,
Philadelphia, Pa.
Filed: Mar. 30, 1973 Appl. No.: 346,488
Related U.S. Application Data Division of Ser No. 236,593, March 21, 1972, Pat. No. 3,740,409.
[451 May 6, 1975 [56] References Cited UNITED STATES PATENTS 2,086,822 6/1937 Schubert et al r. 260/287 R 2,456,911 12/1948 Bruce 260/287 R 2,876,222 3/1959 Bloom .r 260/287 R 3,245,997 4/1966 Yonau 260/287 R 3,483,206 12/1969 Werner 260/287 R Primary ExaminerDonald G. Daus Assistant Examiner-David E. Wheeler Attorney, Agent, or Firm-Joan S. Keps; Richard D. Foggio; William H. Edgerton [57] ABSTRACT The compounds are 2amino(and 2-aminomethyl)-2- heterocyclic-thioacetamides which are inhibitors of gastric acid secretion.
4 Claims, N0 Drawings 1 2 2-AMINO(AND or NH-((H l -cvcloalkyl, said cycloalkvl having 3-(1 Z-AMINOMETHYLl-Z- carbon atoms. QLINOLYLTHIOACETAMIDES R and R.; are hydrogen or lower alkyl and n is (i or This is a division of application Ser. No. 236.593 filed 1. Mar IL 1972 now US. Pat, No 3.740.409. 5 This invention also includes pliarmaceuticallv ac- This invention relates to new 2-amino(and Z- ceptiible acid addition salts of the compounds of Foraminomethyl)-2-heterocvclic-thioacetamide CUHF mula l Pounds having Phllrmlwohlgicill activity Particulan Preferred compounds of this invention are repre lhcse (mmpounds inhibit gastric acid sccrction' sented by Formula I in which R is Z-pvridyl. R and R The p of this im'cmhm rcprcscmcd l' are methyl or ethyl or taken together with the nitrogen the follllwlng fmmulill atom to which thev are attached form a piperidino or FORMULA l p vrrolidino ring and R, is NH NH-(lower alkyl NH- 8 cyclopropvl. NH-cvclohutyl. NH-CH- cyclopropvl or R -CH-l Z-R NH-(Hi -cyclohut vl.
( 2) Advantageous compounds of this invention are repl m resented by Formula I in which R is 2-pyridvl. R and R;, are methyl and R is NH NH-methvl. NH 1 cyclopropvl. NH-c clobutyl NH-CH- -cyclopropvl or NH-CH -cyclobutvl.
The compounds of this invention produce inhibition py py y q m LIMHZQLVI m of gastric acid secretion. This activity is demonstrated minim-H ring. Said rings being Optional) Substi o v administration to pylorus ligated rats doses of tuted by halogenlower itlkvl or lower alkos); about 50 i l "l Also i actlvliy demun R2 and R" are lower ulkyl or take" mgethcr with thc 35 strated by administration to chronic gastric fistula rats (Brodie etaL. Amer. J. Physiol. 201812-814. 1962) at doses of about 50 mg./kg. orally In these procedures. compounds which produce an increase in the gastric in which:
in is 0 or I; 20 R is a Z-p vridvl. Z-pyrimidvl. 4-pyrimidyl 2- nitrogen atom to which the are attached form a piperidino. pyrrolidino or N-lower alkvlpiperazino rin g as pH or a decrease in the volume of gastric juice or both a in 11 so are Considered active.
36 The compounds of this invention are prepared by the following procedures:
f i ll R -CH0 im\R a'-ca n -izii-cn R -pI-c-RB a ea-c41 11. i i l -CH -Nfl CHZO Bll\ R -(llll-c-lm RI'E- R112 -9 R -fH-CR R Cl! III. IV-
"a f": f g). 1
v. f i RI-CHZ-QI c11 0 im\ a -cii-cit -9 m -cii-c-itii ----a n -fu-c-x "a I 2 i: f:
II it 11 \R3 l n n n The terms in. R.. R and R are as defined above. R is an alkali metal. R" is lower alkyl or (CH I,,- cycloalkyl. R is NH-(lower alkyl). Ntlower alkyh or NH-(Cl-lg -cycloalkyl. R is NH-( lovver alkyl or NH- tcHfl -cycloalkyl. said cycloalkyl groups having 36 carbon atoms and n is as defined above.
According to procedure I. a hetcrocycliccarboxaldehyde. an amine and an alkali metal cyanide are reacted. preferably in the presence of acid. to give a 2-amino-2-heterocyclic-acetonitrile which is converted to a Z-amino-2-heterocyclic-thioacetamide of this invention by reacting with hydrogen sulfide in the presence ofa 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 ll. a Z-heterocyclicacetamide is reacted with an equimolar amount of formaldehyde and an equimolar amount of an amine to give a 2-aminomcthyl-2-heterocyclic-acetamide which is treated with phosphorus pentasulfide to give a 2- aminomethyl-2-heterocyclic-thioacetamide of this invention. Reacting with an appropriate amine gives the corresponding N-substituted thioacetamides of this invention.
By procedure lll. a 2-heterocyclic-N-substituted thioacetamide is reacted with an equimolar amount of formaldehyde and an equimolar amount of an amine to give the corresponding 2-aminomethyl compounds of this invention.
According to procedure IV. an aminoalkylheterocycle is reacted with strong base such as butyl or phcnyl lithium and then with an appropriate isothiocyanate to give N-substituted thioacetamides of this invention.
According to procedure V. a 2-heterocyclicacetonitrile is reacted with formaldehyde and an amine to give a 2-aminomethyl-2-heterocyclic-acetonitrile which is converted to a 2-aminomethyl-2-heterocyclicthioacetamide 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-heterocyclicacetamide intermediate in procedure ll 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-heterocyclic-acetic 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-tCH- l -cycloalkyl thioamides prepared by procedures Ill and IV may be converted to the corres onding N-unsubstituted compounds by treating with ammonium hydroxide.
The pharmaccutically 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 ap propriate 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. 200400) 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 dis tearate 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 percent aqueous solution. 0.2 mole) and the solution is neutralized with concentrated hydrochloric acid. To the stirred neutralized solution is added l4.4 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 -20C. for 18 hours. then filtered. The filtrate is concentrated and distilled in vacuo to give 2- dimethylamino-Zl Z-pyridyl lacetonitrile.
2-Dimethylamino-2-(Z-pyridyl)acetonitrile (1 L4 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 Z-dimethylamino-IZ-(Z- pyridyHthioacetamide. m.p. ll33C. (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 l-dimethylamino-Z-t 2- pyridyl)thioacetamide dihydrochloride.
EXAMPLE 2 By the procedure of Example I. using in place of 2- dimethylamino-2-('l-pyridyllacetonitrile the following substituted acetonitriles:
2-diethylamino-2-( Z-pyridyl )acetonitrile 2-pyrrolidino-2-( Z-pyridyl )acetonitrile Z-piperidino-Z-t Z-pyridyl )acetonitrile 2-dimethylamino-2-( o-methyll-pyridyl )acetonitrile the products are. respectively:
2-diethylamino-2-( Z-pyridyl )thioacetamide 2-pyrrolidino-2-( Z-pyridyl )thioacetamide 2-piperidino-2-( 2-pyridyl )thioacetamide 2-dimethylamino-2-(6-methyl-2- pyridyl)thioacetamide.
EXAMPLE 3 Using 0.07 mole of 2-dimethylamino-2-( Z-quinolyhacetonitrile in place of Z-dimethylamino-Z-(Z- pyridyhacetonitrile in the procedure of Example 1 gives Zdimethylamino-ZJZ-quinolyl)thioacetamide.
Similarly. using Z-piperidino-Z-(Z- quinolyl)acetonitrile. the product is 2-piperidino-2-(2- quinolyl )thioacetamide.
EXAMPLE 4 To 270 g. of Z-pyrimidinecarboxaldehyde and l 1.3 g. of dimcthylamine (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-(Z-pyrimidyl)acetonitrile.
Using 2-dimethylamino-2-(Z-pyrimidyl)acetonitrile in place of Z-dimethylamino-Q-tZ-pyridyl)acetonitrile in the procedure of Example 1 gives Z-dimethylamino- 2-(Z-pyrimidyl)thioacetamide.
EXAMPLE 5 By the procedure of Example l. using in place of 2- pyridinecarboxaldehyde. the following carhoxaldehydes:
2-pyrrolecarhoxaldehyde IZ-pyrazinecarboxaldehyde 4-pyrimidinecarboxaldehyde Z-thiazolecarhoxaldehyde 4-thiazolecarboxaldehyde the products are. respectively:
2-dimethylamino-2-( 2-pyrrolyl )thioacetamide 2-dimethylamino 2-( Z-pyrazinyl )thioacetamide 2-dimethylamino-2-(4-pyrimidyl)thioacetamide 6 2-dimethylamino-2-( Z-thiazolyl )thioacetamide 2-dimethylamino-2-( 4-thiazolyl )thioacetamide.
EXAMPLE 6 By the procedure of Example 1. using dipropylamine in place of dimethylamine the product is 2- dipropylamino-2-( Z-pyridyl )thioacetamide.
Similarly. using dibutylamine. the product is 2- dibutylamino-2-( 2-pyridyl )thioacetamide.
EXAMPLE 7 By the procedure of Example I. 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-methylpiperazin0)-2-(2- pyridyhacetonitrile in 200 ml. of dry pyridine and 5 m]. of anhydrous triethylamine for 7 hours. The mixture is then stirred for I? hours. This procedure is repeated for 5 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 alltylpiperazines:
N-ethylpiperazine N-propylpiperazine N-hutylpiperazine the products are. respectively:
Z-t4-ethylpiperazino)-2-(Z-pyridyl)thioacetamide 2-( 4-propylpiperazino )-2-( Z-pyridyl )thioacetamide 2-( 4-hutylpiperazino )-2-( Z-pyridyl )thioacetamide.
EXAMPLE 8 To 4.] g. (0.03 mole) of .'Z-(2-pyridyl)acetamide dissolved in 60 ml. of methanol is added 2.52 g. of 37 percent aqueous formaldehyde solution (().()3 mole of formaldehyde) dissolved in 15 ml. of methanol and 1.35 g. (0.03 mole) of dimethylamine dissolved in IS 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 -dimethylamino-2-( 2- pyridyl )propanamide.
Phosphorus pentasulfide (2.3 g.) is added to 2.0 g. of 3-dimethylamino-2-t 2-pyridyl)propanamide in 25 ml. of pyridine. The mixture is heated on a steam bath for 2 hours. then 250 ml. of water and i0 ml. of 5 percent 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-2-(2-pyridyl)thiopropanamide.
EXAMPLE 9 By the procedure of Example 8. using in place of dimethylamine. the following:
diethylamine dipropylamine dibutylamine pyrrolidine piperidine 7 N-mcthylpiperaxine the products are. respectively:
3-diethy lamino-2-t Z-pyridyl lthiopropanamide 3-dipropylamino24 lpyridyl lthiopropanamide 3-dihutylaminoQ-t Z-py ridyl )thiopropanamide 3pyrrolidino-I -l Z-pyridyl )thiopropanamide 3-pipcridino-2l 2-pyridyl ttliio ropanamidc 3-t 4methylpiperazino |-2-( 2-py ridyl )thiopropanamide.
EXAMPLE l By the procedure of Example 8. using 2-(5-ethyl2- pyridyhacetamide. the product is 3--dimethylamino-Z- tS-ethylQ-pyridyl)thiopropanamide.
EXAMPLE ll A solution of 7.6 g. i005 mole) of pyridyl Ithioacetarnide in a 40 percent 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-Z-(Z- pyridyl)thioacetamide.
By the procedure of Example 8. 0.02 mole of N- cyclopropyl-I-(Z-pyridyl)thioacetamide is warmed on a steam bath with 0.02 mole of formaldehyde and 0.02 mole of diniethylamine in methanol for minutes to give. after removing the solvent and recrystallizing the residue. N-cyclopropyl-3-dimethylamino'2-(2- pyridyl lthiopropanamide.
Similarly. using in the above procedure the following cycloalkylamines:
cyclohutylamine cyclopentylamine cyclohesylamine the products are. respectively:
N-cyclohuty|-3-dimethylamino Z-(Z-pyridylJthiopropanamide Ncyclopentyl-B-dimethy[amino-24 Z-pyridyl )thio propanamide N-cyclohexyl-3-dimethylamino-2-(1-pyridyl)thio propanamide.
EXAMPLE l2 Cyclopropanemethylamine hydrochloride (6.02 g, 0.056 mole} and 4.71 g. [01156 mole) of sodium bicarbonate are dissolved in 75 ml. ofvvater and the solution is added to 4.35 g. I002) mole) of Z-(Z- pyridyllthioacetamide. The reaction mixture is heated on a steam hath with stirring for four hours. The mixture is then cooled and 25 ml. of water is added. The reaction mixture is estracted 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- cyclopropanemethy l-Z-t 2-pyridyl lthioacetamidc.
By the procedure of Example 8. 0.01 mole of N- cyclopropanemethyl-Z-( Z-pyridyl )thioacetamide is warmed on a steam hath with (Mil mole of formaldehyde and (H11 mole of diniethylamine in methanol for l5 minutes to give. after removing the solvent and recrystallizing the residue. N-cyclopropancmethyl-3- dimethylaniino-ll Z-pyridyl )thiopropanamide.
Similarly. using in place of cyclopropanemethylamine hydrochloride the following:
cyclohutanemethylamine hydrochloride cyclopentanemethylamine hydrochloride cyclohesanemethylamine hydrochloride the products are, respectively:
N-cyclohutanemethyl-3dimethylamino--2-(2- py ridyl )thiopropanamide N-cyclopentanemethyl3-dimethylamino-2-( 2 p ridyl lthiopropanamide N-cyclohexanemethyl-3 dimethylamino2-t2- pyridyl )thiopropanamide.
EXAMPLE 13 By the procedure described in Example ll, the following thioaeetamides are reacted with formaldehyde and dimethylamine:
NmethylQ-(lpyridyl)thioacetamide N-methyl-2-( Z-quinolyl )thioacetamide N-ethyl-2(fi-methyli-pyridyl)thioacetamide N-propyl-2-[o-methylfl-pyridyl)thioacetamide N-hutyl-2-(fi-methyl-l-pyridyl)thioacetamide Nmethyl-2-( 4ethoxy Z-pyridyl lthioacetamide N,Ndimethyl-2 (2-pyridyl)thioacetamide N,N-diethyl-2-((i-rnethyl'l-pyridyllthioacetamide to give the following products. respectively:
3-dimethylamino-N-methyl-'.2-( Z-pyridyl )thio propanamide 3-dimethylamino-N-methyl-2-tZ-quinolyllthiopropanamide 3-dimethylamino-N-ethyl-3-( fi-methyllpyridyl )thiopropanamide 3-dimcthylamino-N-propyl-2-(6-methyl-2-pyridyllthiopropanamide N-hutyl-3-dimcthylamino-2-(fi-methyl-Z-pyridyl)thiopropanamide 3 dimethylaminwN-methyl-Zi4-ethoxy-2-pyridyl)- thiopropanamide 3dimethylamino-N.N dimethyl-2-(l-pyridyhthio propanamide B-dimethylamino-N.N-diethyl-Z-t(i-mCthyI-Z- pyridyl lthiopropanamide.
EXAMPLE l4 By the procedure of Example I l, using cyclopropylamine and the following thioacetamides:
2-4 Z-pyrazinyl )thioacetamide 2- Lpyrrolyl )thioacctamide 2-(Z-quinolyl)thioacetamide the products are. respectively.
N-cyclopropyl-3-dimethylamino-2-(lpyrazinyllthiopropanamide N-cyelopropyl-3-dimethylamino-2-(lpyrrolynthiopropanamide N-cyclopropyl-B-dimethylamino-Z-tZ-quinolyhthiopropanamide.
EXAMPLE l5 By the procedure of Example 11. using cyclopropanemethylamine hydrochloride and the following thioacetamides:
9 2-( 2-pyrazinyl )thioacetamide 2-( 2-pyrrolyl )thioaeetamide 2-( 2-quinolyl )thioacetamide the products are. respectively:
N-cyclopropanemethyl-3-dimethylamino-2-( 2- pyrazinyl)thiopropanamide N-cyclopropanemethyl-3-dimethylamino-2-(2- pyrrolyl)thiopropanamide N-cyclopropanemethyl-Il-dimethylamino-Z-t 2- quinolyl)thiopropanamide.
EXAMPLE l6 By the procedure of Example I. using 4-chloro-2- pyridinecarboxaldehyde in place of 2- pyridinecarboxaldehyde. the product is 2-(4-chloro-2- pyridyll-2-(dimethylamino)thioacetamide.
EXAMPLE 1? A mixture of 7.5 g. of Z-dimethylamino-Z-(Z- pyridyhthioacetamide and [5 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-methyl-2-(Z-pyridyl)thioacetamide.
By the same procedure. using the appropriate lower alkylamine. Z-dimethylamino-N-ethyl-2-(2- pyridyl)thioacetamide and the corresponding N-propyl and N-butyl compounds are prepared.
Similarly. using the appropriate di-(lower alky|)- amine. 2-dimethylamino-N.N-dimethyl-2-( 2 pyridyl)thioacetamide and the corresponding N.N- diethyl. N.N-dipropyl and N.N-dibutyl compounds are prepared.
Also. using 2-dimethylamino-2-t 2- pyrimidyl)thioacetamide and methylamine. the product is Z-dimethylamino-N-methyl-2-(2- pyrimidyl)thioacetamide. Similarly, using dimethylamine. the product is Z-dimcthylamino-N.N-dimethyl-Z- (Z-pyrimidyl)thioacetamide.
EXAMPLE l8 A mixture of Z-dimethylamino-Z-l 2- pyridyl )thioacetamide and 40 percent aqueous solution of cyclopropylamine is heated at reflux for 45 minutes and worked up by the procedure described in Example 1 l to give N-cyclopropyl-Z-dimethylamino-Z-t 2- pyridyl )thioacetamide.
By the same procedure. using 2-piperidino-2-( 2- pyridyl )thioacetamide. the product is N-cyclopropyl-Z- piperidino-2-( Z-pyridyl)thioacetamide.
EXAMPLE 19 To 5 .65 g. of Z-dim ethylamino2-( 2- pyridyUthioacetamide is added 6.02 g. of cyclopropanemethylamine hydrochloride and 4.7! 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- cyclopropanemethyl-2-dimethylamino-2-( 2- pyridyl )thioacetamide.
By the same procedure. using cyclopentanemethylamine hydrochloride. the product is N- cyelopentanemethyl-2-dimethylamino-2-( 2- pyridyl )thioacetamide.
EXAMPLE 20 5 Alternatively. N-cyclopropanemethyl-Z- dimethylamino-2-(Z-pyridyl)thioacetamide is prepared by the following procedure.
A solution of 13.6 g. (0.l mole) of 2-(dimethylaminomethyl)pyridine in 50 ml. of anhydrous benzene is added dropwise at C. to 8.7 g. (0.1 mole) of phenyl lithium in 100 ml. of anhydrous benzene. After the addition. the reaction is stirred for minutes and [L3 g. (0.1 mole) of cyclopropanemethyl isothiocyanate in 50 ml. of anhydrous benzene is added dropwise. 5 The mixture is stirred at 25C. 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 )thioacctamide.
EXAMPLE 21 ethanol/ether to give Z-dimethylamino-Z-t 2- pyridyl)thioacetamide dihydroehloridev Similarly. using N-cyclopropyl-Z-dimethylamino-2 (Z-pyridyl)thioacetamide. the dihydrochloride salt of N-cyclopropyl-2-dimethylamino-2-( 2- pyridyl)thioacetamide is prepared.
EXAMPLE 23 2-Dimethylamino-2-(Q-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. 2-dimethylamino-2-( Z-pyridyl )thioacetamide maleate.
In the same manner. using citric acid. 2- dimethylamino-2-(2-pyridyl)thioacetamide citrate is prepared.
What is claimed is: l. A compound of the formula:
in which:
m is (l or I;
R is a Z-quinolyl ring. said ring being optionally nonsubstituted by halogen. lower alkyl or lower alkoxy;
1 1 12 R and R are lower alkyl or taken together with the R and R are hydrogen or lower alkyl and n is or nitrogen atom to which they arc attached form a l or a pharmaccutically acceptable acid addition pipcridino pyrrolidino or N-lowcr alkylpipcrazino salt tilCl'fZOf ring; 2. A compound according to claim 1, said compound R being Z-dimcthylaminoJJZ-quinolyl)thioacetamide. 5 3. A compound according to claim 1, said compound N bcing 3-dimcthylamino-N-methyl-2-(2-quinolyl)thio- R propanamidc.
4. A compound according to claim I. said compound n being Nmyclopropyl3 dimcthylamino-2-(2-quinolyl)- or NH-tCHy -cycloalkyh said cycloalkyl having 3-6 thiopropanamidc. carbon atoms;

Claims (4)

1. A COMPOUND OF THE FORMULA:
2. A compound according to claim 1, said compound being 2-dimethylamino-2-(2-quinolyl)thioacetamide.
3. A compound according to claim 1, said compound being 3-dimethylamino-N-methyl-2-(2-quinolyl)thiopropanamide.
4. A compound according to claim 1, said compound being N-cyclopropyl-3-dimethylamino-2-(2-quinolyl)thiopropanamide.
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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
US3933811A (en) * 1972-06-26 1976-01-20 Smithkline Corporation N-aminomethyl-2-amino(and 2-amino-methyl)-2-(2-quinolyl)-thioacetamides
US4001241A (en) * 1973-08-09 1977-01-04 Smithkline Corporation 2-alkoxy(and 2-alkoxyalkyl)-2-quinolyl-thioacetamides

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Publication number Priority date Publication date Assignee Title
US2086822A (en) * 1932-11-01 1937-07-13 Gen Aniline Works Inc Process for producing aromatic asymmetrical thiourea derivatives
US2456911A (en) * 1945-05-04 1948-12-21 Wyeth Corp Disubstituted acetamidyl derivatives of amino quinolines
US2876222A (en) * 1956-10-18 1959-03-03 Pfizer & Co C 1,2,3,4-tetrahydroquinolyl and 1, 2, 3, 4-tetrahydroisoquinolyl derivatives of 1, 3-diazacyclohexene-2
US3245997A (en) * 1963-07-17 1966-04-12 Searle & Co 3-substituted 1-(1, 2, 3, 4-tetrahydro-2-isoquinolyl) alkyl-2-thioureas
US3483206A (en) * 1967-12-15 1969-12-09 Ciba Geigy Corp N-isoquinolylalkanoyl-n-arylamines

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2086822A (en) * 1932-11-01 1937-07-13 Gen Aniline Works Inc Process for producing aromatic asymmetrical thiourea derivatives
US2456911A (en) * 1945-05-04 1948-12-21 Wyeth Corp Disubstituted acetamidyl derivatives of amino quinolines
US2876222A (en) * 1956-10-18 1959-03-03 Pfizer & Co C 1,2,3,4-tetrahydroquinolyl and 1, 2, 3, 4-tetrahydroisoquinolyl derivatives of 1, 3-diazacyclohexene-2
US3245997A (en) * 1963-07-17 1966-04-12 Searle & Co 3-substituted 1-(1, 2, 3, 4-tetrahydro-2-isoquinolyl) alkyl-2-thioureas
US3483206A (en) * 1967-12-15 1969-12-09 Ciba Geigy Corp N-isoquinolylalkanoyl-n-arylamines

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
US3933811A (en) * 1972-06-26 1976-01-20 Smithkline Corporation N-aminomethyl-2-amino(and 2-amino-methyl)-2-(2-quinolyl)-thioacetamides
US4001241A (en) * 1973-08-09 1977-01-04 Smithkline Corporation 2-alkoxy(and 2-alkoxyalkyl)-2-quinolyl-thioacetamides

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