Pyridine thioacetamide derivatives
United States Patent [1 1 Kanai et al.  
 [451 Apr. 8, 1975 PYRIDINE THIOACETAMIDE DERIVATIVES [73] Assignee: Takeda Chemical Industries, Ltd.,  
 Osaka, Japan [22] Filed: Jan. 22, 1973 [Zl] App]. No.: 325,438  
 Related US. Application Data [63] Division of Ser. No. 53 ,008,July 7, 1970, Pat. No.  
 [30] Foreign Application Priority Data July 8. 1969 Japan 44-53946 Sept. 27. 1969 Japan 44-77l53 [52] US. CL... 260/294.8 E; 260/247.l; 260/268 C; 260/283 S; 260/286 R; 260/293.69; 424/248; 424/258; 424/263; 424/250; 424/267 [51] Int. Cl C07d 31/50 [58] Field of Search 250/2471, 268 C, 294.8 E,  
 [56] References Cited OTHER PUBLICATIONS Sperber et al.. Chem. Abstracts, Vol. 53. No. 17. Sept. 10. 1959, I7. l22g-l7, 125a.  
 Katritzky, Journal of the Chemical Society, London, pp. 2586-2593, 1955, RS115.  
 Primary E.\&#39;aminerAlan L. Rotman Attorney. Agent, or FirmWenderoth, Lind &amp; Ponack [57] ABSTRACT Compounds of the formula wherein R is hydrogen, lower alkyl, lower alkoxy or halogen and n is an integer of 1 to 4, or wherein (R,),, is a divalent straight chain hydrocarbon radical having 4 carbon atoms which is attached to the 5th and 6th positions of the pyridine ring, each of R and R independently represents hydrogen, lower alkyl, aralkyl or aryl, or R and R together with the nitrogen atom to which they are attached form a heterocyclic ring with a proviso that at least one of R R. and R is other than hydrogen and a pharmaceutically acceptable salt thereof with acids.  
 2 Claims, No Drawings 1 o PYRIDINE THIOACETAMIDE DERIVATIVES This application is a division of SenNo. 53,008, filed July 7, 1970, now US. Pat. No. 3,726,878.  
  This invention relates to a novel pyridine thioacetamide derivative useful for treatment and/or prevention of gastric diseases, and further relates to a method for the production of the pyridine thioacetamide derivative.  
 The present inventors have succeeded in synthesizing a series of novel pyridine thioacetamide derivatives represented by the general formula shown below, and  
 further, with regard to the novel compounds, the inventors have found the following fact.  
  Namely, the pyridine thioacetamide derivative can supress excessive secretion of gastric juice caused by histamine, gastrine or acetylcholine, without producing undesirable effect on digestive secretions&#39;in the other organs such as pancreas, gall bladder and liver, and also without showing uncoupling of oxidative phosphorylation in mytocondoria. Thus, the compound of the present invention can prevent or treat effectively hyperacidity, peptic ulcer and duodenal ulcer without causing any undesirable side effect by oral or parenteral administration.  
  The present invention has been accomplished on the basis of these findings.  
  Thus, the principal object of the present invention is to provide novel pyridine thioacetamide derivatives which are useful for treatment and/or prevention of peptic ulcer, duodenal ulcer or hyperacidity and show low toxicity and no or only a slight side effect.  
  Another object of the present invention is to provide a method for the production of the novel pyridine thioacetamide derivatives. The novel pyridine thioacetamide derivatives of the present invention are represented by the following general formula: I  
  8 era-J wherein R is H, lower alkyl, alkoxy or halogen and n.  
 the same or different and is preferably one having up to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl and tert-butyl. The alkoxy represented by R, is preferably lower alkoxy having up to 4 carbon &#39;atoms such as methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso.-butoxy, sec-butoxy and tert-butoxy. The radical of (R may be a divalent straight chain hydrocarbon having 4 carbon atoms, which is attached to the 5th and 6th positions of the pyridine ring, and this radical is exemplified by Namely in the above is quinolyl, dihydroquinolyl and &#39;tetrahydroquinolyl radical, respectively. The halogen represented by R, includes chlorine, bromine, iodine and fluorine. The aralkyl represented by R or R is preferably phenyl lower alkyl exemplified by benzyl or phenethyl. The aryl represented by R or R is exemplified by phenyl and naphthyl. The heterocyclic ring which is formed with R R and the adjacent nitrogen atom is preferably 5 or 6 membered and may contain additional hetero atoms and is exemplified by six membered ones such as piperazine, piperidine and morpholine, and five memberecl ones such as pyrrolidine.  
  The pyridine thioacetamide derivatives of the above formula (I) form acid addition salts with suitable acids such as inorganic acids (e.g., hydrochloric acid, nitric acid, phosphoric acid, oxalic acid, succinic acid, malic acid, maleic acid, malonic acid, tartaric acid, benzoic acid, toluene sulfonic acid, methane sulfonic acid, etc.), and also can form a quaternary ammonium salt such as l-methyl pyridinium chloride, l-methyl pyridinium bromide, l-ethyl pyridinium chloride, l-ethyl pyridinium bromide, l-methyl pyridinium iodide, lethyl pyridinium iodide, etc..  
  Any of these salts, so far as pharmaceutically acceptable, can be used for the purpose of the present invention.  
  The object compound (I) of the present invention can be produced by one of the methods as summarized below. In the following, the methods of Group (A) can be applied to the production of any of the present compounds; the method of Group (B) can be applied to the production of the present compound (I) whereinboth of R and R are hydrogen or that wherein one of R and R is lower alkyl, aryl or aralkyl and the other is hdyrogen; and the methods of Group (C) can be applied to the production of the present compound (I) wherein both of R and R are hydrogen.  
  Group (A) (the methods applicable to the production of any of the present compounds.)  
 Continued S N CHr-Pl-NHI NHIR (V H (R resultant GHaCN N (wherein R R and n have the same meaning as above).  
  Group (C) (the methods applicable to the production of the present compound (I) wherein both of R and R are hydrogen).  
 (wherein R and n have the same meaning as above, and R is alkyl, and R is lower alkyl, aryl or aralkyl).  
  The object compounds of the present invention are most generally prepared according to the methods of Group (A) ((1), (2) or (3)). Namely, the compound of the formula (II) is allowed to react with a phosphorus sulfide compound or it is at first allowed to react with a halogenating agent and then allowed to react with bydrogen sulfide, and when the resultant is a compound of the formula (I) wherein both R and R are hydrogen, the resultant may be converted to the compound of the formula (l)(ii) by reacting with a primary or secondary amine of the formula In the method (1), the phosphorus sulfide compound employable is exemplified by diphosphorus pentasulfide, tetraphosphorus trisulfide, tetraphosphorus pentasulfide and tetraphosphorus heptasulfide. Among them, diphosphorus pentasulfide is most desirable. An amount of the phosphorus sulfide compound to be used is 0.2 to 2 moles per mole of the compound (II).  
  The reaction is generally conducted in the presence of a suitable inert solvent (e.g. petroleum ether, benzene, toluene, xylene, etc.).  
  In this reaction, it is preferable to use a basic compound such as organic amines (e. g. ethylamine, diethylamine, triethylamine, diethylaniline, picoline, piperidine, morpholine, quinoline, pyridine, etc.).  
  As the compound can take a part also as a reaction solvent, it may be used in a large excess amount with or without other solvent. The reaction temperature generally ranges from about 20C. to about 200C. The pyridine thioacetamide derivatives (I) thus produced can be recovered from the reaction mixture after a per se conventional manner, for example, by evaporating the solvent.  
  In the method (2), the compound (II) is at first allowed to react with a halogenating agent.  
  The halogenating agent employable includes, for example, phosgene, phosphorous halides (e.g., phosphorous oxychloride, phosphorus pentachloride, phosphorus trichloride and tetrachloropyrophosphoric acid), thionyl chloride and sulfuryl chloride. Among them, the phosphorus halides are preferable.  
  The amount of the halogenating agent employed varies depending on the kind of the halogenating agent and generally falls within the range of about 0.1 to about 2 moles per mole of the compound (II). The reaction is conducted generally at a temperature of about 20C. to about 30C, more preferably under cooling, in the presence of a suitable solvent such as ethyl ether, benzene, petroleum ether, pyridine and quinoline.  
  The resultant is then, without separation nor purification, or after suitable separation or purification, allowed to react with hydrogen sulfide.  
 This reaction is generally conducted by introducing hydrogen sulfide gas into the reaction system at a temperature of about 20C to about 50C. An amount of the hydrogen sulfide introduced is not less than about 1 mole, generally excessive, conventionally up to about 20 moles, per mole of the compound (II).  
  The pyridine thioacetamide derivative (I) produced as above can be isolated by per se conventional means, for example, by evaporating the solvent.  
  The starting compound (II) employed in the methods (I) and (2) can be prepared after a conventional manner, a representative of which is summarized in the following scheme.  
  That is to say, the compound (a) is allowed to react with potassium cyanide in an aqueous alcohol under the presence of potassium iodide, and the resulting compound (b) is subjected to the action of hydrogen chloride in alcohol, and finally the resulting compound (C) is allowed to react with the corresponding amine of the formula When the product of the method (1) or (2) is that wherein R and R are hydrogen, this product can be converted, if desired, to the compound of the Formula (I)(ii) by a reaction with a compound of the formula R and R are, same or different, hydrogen, alkyls (e.g. methyl, ethyl, propyl, butyl, etc.), aryls (e.g. phenyl, etc.), aralkyls (e.g. benzyl, phenethyl, etc.) or form, together with the adjacent nitrogen atom, heterocyclic groups (e.g. piperazine, piperidine, pyrrolidine, morpholine, etc.), with a proviso that R and R are not both hydrogen atoms.  
  The reaction is conducted generally in the presence of a suitable solvent such as water, methanol, ethanol, ethyl ether, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide and pyridine. An amount of the amine employed is not less than about 1 mole and conventionally up to about moles per mole of the compound (l)-(i). The reaction temperature generally ranges from about 0C to about 150C.  
 The resultant can be isolated by per se conventional -means, for example, by evaporating the solvent from the reaction system.  
  The object compound of the present invention wherein both R and R or either of R or R are hydrogen atom (i.e. a compound of the formula (Rm-m can be prepared also by the method of Group (B) (method (4) In the method (4), a compound of the general Formula (III) is at first allowed to react with a primary amine of the general formula (wherein R has the same meaning as defined before), and then the resultant is allowed to react with hydrogen sulfide.  
  The reaction of the first step is conducted generally in the presence of a suitable solvent such as methanol, ethanol, ethyl ether, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, pyridine and quinoline. A basic compound such as organic amines (e.g. triethylamine, diethylaniline, quinoline, pyridine, etc.) may be present in the reaction system as a catalyst.  
 The reaction can proceed at a temperature of about 20C to about C, and is preferably conducted under cooling. An amount of the amine to be used is not less than about 1 mole and generally up to about 20 moles per mole of the compound (Ill). The amine is put .into use in a suitable form such as gas, liquid and a solution in a suitable solvent.  
  The resultant of the first step is then, without any separation nor purification or after a suitable separation or purification, allowed to react with hydrogen sulfide.  
 The reaction is generally conducted by introducing hydrogen sulfide into the reaction system at a temperature of about 0C to around room temperature. An amount of the hydrogen sulfide to be introduced is not less than about 1 mole and generally excessive and conventionally up to about 20 moles per mole of the compound (RI).  
  The object compound thus produced can be isolated by per se conventional means, for example, by evaporating the solvent from the reaction system, by crystallization or by silica gel chromatography.  
  The object compound of the present invention wherein both R and R are hydrogen atom (i.e. a compound of the formula CHaCN wherein R and n have the same meaning as defined above, is allowed to react with a compound of the general formula (III) wherein R has the same meaning as defined above.  
 The lower alkyl, aralkyl or aryl represented by R is I An amount of the acid employed isgenerally about 0.1 to about 20 moles per mole of the compound (III).  
 An amount of the compound.(IV) employed is generally about 1 mole to about moles per mole of the compound (111). The most desirable example of a technique for conducting this reaction is as follows.  
 Namely, hydrogen chloride-is introduced into a solu-.  
 tion of the compound (III) under cooling at about 20C to about 20C, then the compound (IV) is added to the mixture, and finally the resulting mixture is heated at about 20C to about 150C. v  
  The object compound as prepared above can be isolated by per se conventional means, for example, by evaporating the solvent from the reaction system.  
 In the method (6), the compound of the formula (III) is allowed to react with hydrogen sulfide. The reaction is preferably conducted in the presence of a suitable solvent such as alcohols (e.g. methanol, ethanol, butanol, etc.), ethyl ether, petroleum ether, benzene, chloroform, carbontetrachloride, carbondisulfide, dimethylformamide and dimethylsulfoxide. It is preferable to conduct the reaction in the presence of a basic compound such as organic amines (e.g. pyridine, picoline,  
 piperidine, diethylamine, triethylarnine, diethylaniline, morpholine, or quinoline). The above-mentioned organic amine may take a part also as a reaction solvent. The reaction temperature ranges generally from about 0C to about 80C. Practically, gaseous hydrogen sulfide is introduced into a reaction system to allow the reaction to proceed. An amount of the hydrogen sul fide to be introduced is about 1 to about 20 moles per mole of the compound (III).  
  The object compound can be recovered after per se conventional manner, for example, by evaporating the solvent from the reaction system, by crystallization or by silica gel chromatography.  
  In the method (7), the compound (III) is allowed to react with a compound of the general formula PSH RO (VI) (wherein R has the same meaning as defined before). The alkyl of R is preferably a lower alkyl up to 4 carbons (e.g. methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl, etc.), in the presence of an acid such as mineral acids (e.g. hydrochloric acid, sulfuric acid, etc.).&#39;  
  Preferable acid is hydrochloric acid, which may be introduced in the reaction system in a state of hydrogen chloride gas. An amount of the acid to be used is about 0.1 to about 20 moles per mole of the compound (111). The reaction is generally conducted without a solvent,  
 since the compound (VI) can take a part as a solvent, but, if desired, a suitable inert solvent (e.g. benzene, toluene, xylene, etc.) may be used.  
  The reaction temperature generally ranges from about lOC to about 100C. An amount of the compound (VI) employed is generally about 1 to about 3 moles, preferably around equimolar, per mole of the compound (III).  
  The object compound thus prepared can be isolated by per se conventional means, for example, by evaporating, the solvent from the reaction system or by extracting the reaction mixture with a suitable solvent, followed by evaporation of the solvent.  
  The compound (l)-(i) prepared according to the method (4), (5), (6) or (7) may be, if desired, converted to the compound (1)-(iii) by the method (3).  
  The object compound of the present invention thus prepared according to the methods described above in detail can be converted after a conventional manner to an acid addition salt or a quaternary ammonium salt which is exemplified before. The quaternary ammonium salt can also be prepared directly by using the starting compound (i.e. compound (II), (I)-(i) or (111)) in a form of the corresponding quaternary ammonium salt.  
 The pyridine thioacetamide derivative of the present I invention as well as its pharmaceutically acceptable acid salt are useful for treatment and/or prevention of duodenal ulcer and gastric diseases such as peptic ulcer, and hyperacidity. For such purposes, the object compound as well as its salt are administered per se or in a pharmaceutically acceptable form such as powder, granule, tablet, solution, and injection, together with a conventional adjuvant or carrier. Dosage of the compound as well as its salt varies depending on severity. of the disease, kind of the compound, etc. and falls within the range of about 1 to about 100 milligrams per day for an adult. The administration of the object compound or its salt can prevent or treat the disease effectively without undesirable side effect. Further, the salt of the compound is easily soluble in water, and therefore, can beprefei&#39;ably used for injection.  
  For further explanation of this invention, the following examples are given, wherein part means weight part unless otherwise specified, and the relationship between part and part by volume corresponds tothat gram and milliliter. 1  
  Ina mixture of 40 .parts by volume of pyridine and 1 1.8 parts by volume of triethylarnine is dissolved 10.4 parts of 6-methyl-2 pyridineacetonitrile, followed by introduction of hydrogen sulfide into the solution for 3 days. After the pyridine is removed by evaporation, the resultant is dissolved in chloroform. The chloroform solution is passed through a column (5.5 X 30cm) packed with silica-gel, which is then eluted with chloroform-methanol-acetic acid (:5:1 by volume). The solvent is removed from the eluate by evaporation and the residue is dissolved in ethanol. The ethanol solution is acidified with concentrated hydrochloric acid and subjected to evaporation to remove the ethanol. Twice recrystallization of the residue from ethanol gives 8 parts of 6-methyI-Z-pyridinethioacetamide hydrochloride as prisms melting at 194 to 198C (decomposition).  
 EXAMPLE 2 In a mixture of 45 parts by volume of pyridine and 17.3 parts by vvolume oftriethylamine is dissolved 17.3 parts of -ethyl-Z-pyridineacetonitrile, followed by introduction of hydrogen sulfide for 2 days. The resultant is subjected to a Silica-gel column chromatography in a similar manner to that in Example 1. The residue is dissolved in ethanol and the ethanol solution is acidified to pH 2 with concentrated hydrochloric acid, whereby crystals precipitate out. The crystals are recrystallized from ethanol to give 14.2 parts of S-ethyl- Z-pyridinethioacetamide hydrochloride as pale orange pillars melting at 220 to 222C (decomposition).  
 EXAMPLE 3 Into a solution of parts of 5-methyl-2- pyridineacetonitrile ina mixture of 50 parts by volume of pyridine and 10.6 parts by volume of triethylamine is introduced hydrogen sulfide at room temperature, followed by keeping under sealing. This series of process steps consisting of the introduction of hydrogen sulfide and keeping under sealing is repeated until the starting compound, 5-methyl-2-pyridineacetonitrile, is exhausted by the reaction. The solvent is removed from the reaction mixture, and ethanol is added to the resi due, followed by concentration.  
  The addition of ethanol and the subsequent concentration are repeated several times. To the resultant is further added ethanol to give crystals. The crystals are dissolved in ethyl acetate, followed by extraction with diluted hydrochloric acid. The aqueous layer is subjected to filtration to remove insoluble sulfur. The filtrate is alkalified with sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer is dried over anhydrous sodium sulfate and subjected to evaporation to remove the solvent. Recrystallization of the residue from ethanol gives 5-methyl-2-pyridinethioacetamide as crystals melting at 100 to 101C.  
  The crystals are dissolved in ethanol. The solution is acidified to pH 1 to 2 with concentrated hydrochloric acid and subjected to evaporation to remove the solvent. The precipitated crystals are recrystallized from a mixture of methanol and ethyl acetate to give 8.1 parts of S-methyl-2-pyridinethioacetamide hydrochloride as colorless belonites melting at 209 to 211C (decomposition).  
 EXAMPLE 4 To a mixture of 50 parts by volume of pyridine and 28 parts byvolumeof triethylamine is added 13 parts of 3-methyl-Z-pyridineacetonitrile. Hydrogen sulfide is introduced into the mixture at room temperature, followed by keeping under sealing. This series of process steps consisting of the introduction of hydrogen sulfide and the subsequent keeping under scaling is repeated until the starting compound, 3-methyl-2- pyridineacetonitrile, is exhausted by the reaction. After removing the solvent by evaporation, the reaction mixture is washed well with ethanol, dissolved in chloroform and extracted with lN-hydrochloric acid. The extract is subjected to filtration to remove insoluble sulfur, followed by concentration under reduced pressure. The colorless crystals precipitated are recrystallized twice from methanolethanol (1:1 by volume) to give 12.5 parts of 3-methyl-2-pyridinethioacetamide hydrochloride as colorless prisms melting at 214 to 216C (decomposition).  
 EXAMPLE 5 EXAMPLE 6 Into a mixed solution of 17.5 parts of 4-methoxy-2- pyridineacetonitrile, 60 parts by volume of pyridine and 17 parts by volume of triethylamine is introduced hydrogen sulfide at room temperature, followed by keeping under sealing. This series of process steps consisting of the introduction of hydrogen sulfide and the subsequent keeping under sealing is repeated until the starting compound, 4-methoxy-2-pyridineacetonitrile is exhausted by the reaction. The solvent is removed from the reaction mixture by evaporation and the residue is recrystallized twice from ethanol to give 13.7 parts of 4-methoxy-2-pyridinethioacetamide as pale brown crystals melting at 129 to 130C.  
  The crystals are dissolved in ethanol and pH of the ethanol solution is adjusted to 2 with concentrated hydrochloric acid. The ethanol solution is subjected to evaporation to remove half a volume of the ethanol,  
  and the resulting solution is decolorlized with charcoal,  
 followed by the addition of ethyl ether, whereby 13.4 parts of 4-methoxy-2-pyridinethioacetamide hydrochloride is obtained as fine crystals melting at to 166C. (decomposition).  
 EXAMPLE 7 In a mixture&#39;of 50 parts by volume of pyridine and 20 parts by volume of triethylamine is dissolved 10 parts of 2-quinolineacetonitrile. Into the solution is introduced hdyrogen sulfide, followed by keeping under sealing. This series of process steps consisting of the introduction of hydrogen sulfide and the subsequent keeping under scaling is repeated until the starting compound, 2-quinolineacetonitrile, is exhausted by the reaction.  
  The reaction mixture is subjected to evaporation to remove the solvent, and ethanol is added to the syrupy residue, followed by concentration to dryness. The addition of ethanol and the subsequent concentration are repeated several times. To thus-obtained concentrate is further added ethanol. The precipitated crystals are dissolved in diluted hydrochloric acid and the insolubles are removed by filtration. The filtrate is alkalified with potassium hydroxide, followed by the extraction with chloroform. The chloroform layer is dried over anhydrous sodium sulfate and concentrated.  
  Recrystallization of the residue from ethanol gives 2-quinolinethioacetamide as yellow crystals melting at 153 to 154C (decomposition).  
  The crystals are dissolved in diluted hydrochloric acid and the solution is concentrated. The concentrate is recrystallized from methanol containing charcoal to give 10.69 parts of 2-quinolinethioacetamide hydrochloride as pale yellow crystals melting at 216 to 217C (decomposition).  
 EXAMPLE 8 To a solution of 21.6 parts of N-methyl-6-methyl-2- pyridineacetamide in 150 parts by volume of pyridine is added 21 parts of phosphorus pentasulfide. The mixture is heated under reflux for 5 minutes, followed by evaporation to remove the pyridine. After cooling, the reddish syrupy residue is alkalified with an aqueous sodium hydroxide solution. The alkaline mixture is extracted with chloroform and the chloroform layer is treated with hydrochloric acid, followed by filtration to remove insolubles.  
  The filtrate is alkalified with sodium carbonate, followed by extraction with chloroform. The chloroform layer is dried over anhydrous potassium carbonate, treated with charcoal and concentrated to dryness. To the concentrate is added petroleum ether to give crystals. The crystals are recovered by filtration and then recrystallized from a mixture of chloroform and petroleum ether and then from ethanol to give 14.47 parts of N-methyl-6-methyl-2-pyridinethioacetamide as pale yellow crystals melting at 128 to 129C.  
  Into hot ethanol is dissolved 3.8 parts of N-methyl-6- Z-pyridinethioacetamide. To the solution is added hy- EXAMPLE 10 To a solution of 6.2 parts of N,N-dimethyl-6-methyl- 2-pyridineacetamide in 50 parts by volume of pyridine is added 5.8 parts of phosphorus pentasulfide, and the mixture is heated under reflux for 5 minutes. The resultant is treated in a similar manner to that in Example 1, whereby chloroform extract is given. The chloroform extract is subjected to silica-gel column chromatography (3.5 X 33cm) using chloroform-ethyl acetatemethanol (10:20:05 by volume) as an eluating solvent. The fractions containing the object compound are concentrated to give an oily substance, which is then dissolved in ethanol. The solution is adjusted to pH 2 and supplied with ethyl ether to precipitate crystals. Recrystallization of the crystals from a mixture of ethanol and ethyl ether gives 5.0 parts of N,N-dimethyl-6- methyl-2-pyridinethioacetamide as slightly yellowish crystals melting at 142 to 145C.  
 EXAMPLE 1 1 To a solution of 200 parts of N-methyl-2- pyridineacetamide in 1000 parts by volume of pyridine is added 145 parts of phosphorus pentasulfide and the mixture is heated under reflux for 5 minutes. Pyridine dl&#39;ochlol&#39;ic acid 50 as adjust a p to 1 t0 2, is evaporated under reduced pressure, and a concenlowed y concentratlon- The preclpltated Crystals are trated aqueous solution of sodium hydroxide is added collected by filtration and recrystallized from ethanol to the residue The mixture i Subjected to a salting out to E Parts f Y with potassium carbonate, followed by extraction with pyl&#39;ldmethloacetamlfle hydrocgllorlde shghtly y ethyl ether. The ethyl ether layer is dried over anhy- IQWISh crystals meltlng at 185 to 186 C (decomposl&#39; drous sodium sulfate and subjected to evaporation to remove ethyl ether. To the residue is added petroleum ether, whereby powder is precipitated. The powder is EXAMPLE 9 collected and dissolved in ethanol. The solution is acidified with concentrated hydrochloric acid and concen- Solutlor} Parts of q l &#39;g&#39; trated to dryness under reduced pressure. Crystallizapyndmeacetamlde Parts by Volume of Pyndme tion of the residue from ethanol gives 178.5 parts of N- adfied 1 parts of Phosphorus pentasPlfide and the methyl-2-pyridinethioacetamide hydrochloride as crysmrxture is heated under reflux for 15 minutes. The retals melting at 215C to 2200C (decomposition) sultant is treated in a similar manner to that in Example In a Similar manner 1, whereby chloroform extract 1S glven. The chloro- 4 ridinethioacetamide hydrochloride is prepared havform extract is dried and sub ected to evaporation to ing a melting point of to 181C remove the chloroform. The residue is washed with petroleum ether to give 5.25 parts of N-ethyl-6-methyl-2- EXAMPLE 12 pyridinethioacetamide as orange-red crystals melting at I a similar manner to that in Example 1 l, the follow- 73 to 74C. 45 ing compounds are prepared.  
  S Ha CH:!JR  
  Melting point (M.P.) 0r boiling point (B.P.) 0.) Compound No. HCl salt Free base 1 NHcH,oH,oH= 152154(M.P.) 2 -NHCH,CH:CH:CH; 146148(M.P.) 139-143(B.P.) (0.25 mm. Hg). 3 I( 19 B200(M.P.) (decomposition)...  
 4 01H; 154-156(M.P.) (decomposition).. 125130(B.P.) (0.2-0.3 mm. Hg).  
 5 196-196(M.P.) (decomposition)-. 97-98(M.P.).  
 171172(M.P.) (decomposition).. 149-151(B.P.) (0.6 mm. Hg).  
 192(M.P.) (decomposition) EXAMPLE 13 To a solution of 1.04 part of 6-methyl-2- pyridineacetamide in 15 parts by volume of pyridine is added 0.75 part of phosphorus pentasulfide, and the mixture is heated under reflux for 10 minutes. The pyridine is evaporated from the resultant and the residue is alkalified with an aqueous sodium hdyroxide solution. The solution is subjected to salting out with potassium carbonate, followed by extraction times with about 200 parts by volume each of ethyl ether. The ethyl ether solution is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated, and passed through a Silica-gel column (3.0 20cm, particle size of 70 to 325 mesh), which is then eluted with ethyl acetate-chloroform (1:1 by volume). The fractions containing a substance which shows Rf value of 0.34 in a thin layer chromatography (silica-gel G 2.6X7.6cm, developer ethyl acetate-chloroform=l:l by volume) are collected and concentrated to dryness. The concentrate is recrystallized from ethanol to give 0.334 part of 6-methyl-2-pyridinethioacetamide as slightly yellow needles melting at 116 to 118C.  
 EXAMPLE 14 To a solution of 1.00 part of 5-ethyl-2- pyridineacetamide in 20 parts by volume of pyridine is added 0.8 part of phosphorous pentasulfide, and the mixture is heated under reflux for 5 minutes. The pyridine is evaporated from the resultant and the residue is adjusted in its pH value to 9 by the addition of an aqueous solution of sodium hydroxide-followed by 4 times extraction with 25 parts by volume each of ethyl ether. The ethyl ether solution is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to 20 parts by volume and adjusted in its pH value to 2 by the addition of a few droplets of hydrochloric acid and is further concentrated to 10 parts by volume. After addition of 30 parts by volume of ethanol, the concentrate is further concentrated to 5 parts by volume and left standing. The precipitated crystals are recrystallized from ethanol to give 0.780 part of 5-ethyl-2- pyridinethioacetamide as slightly yellow needles melting at 208 to 209C (decomposition).  
 EXAMPLE To a solution of 0.66 part of N-methyl-4-ethoxy-2- pyridineacetamide in 15 parts by volume of pyridine is added 0.50 part of phosphorus pentasulfide, and the mixture is heated under reflux for 30 minutes. The pyridine is evaporated from the resultant under reduced pressure and the residue is alkalified by the addition of an aqueous sodium hydroxide solution, followed by extraction with ethyl ether. The ethyl ether solution is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated and left standing. The precipitated crystals are recrystallized from ethanol to give 0.3 10 part of N-methyl-4-ethoxy-2- pyridinethioacetamide as pale yellow prisms melting at 103 to 105C.  
 EXAMPLE 16 To a solution of 8.51 parts of N-phenyl-2- pyridineacetamide in 100 parts by volume of pyridine is added 5 parts of phosphorus pentasulfide. The mixture isheated under reflux for 40 minutes and concentrated. The concentrate is alkalified with an aqueous sodium hydroxide solution and subjected to salting out with the addition of potassium carbonate, followed by extraction with chloroform. The chloroform layer is dried over anhydrous potassium carbonate and filtered. The filtrate is concentrated, followed by the addition of ethyl ether. The precipitated crystals are recrystallized from ethanol to give 5.0 parts of N-phenyl-2- pyridinethioacetamide as yellow fine needles melting at l56.5 to 158C.  
 EXAMPLE 17 To a solution of 1.37 parts of 2-quinolineacetamide in 25 parts by volume of pyridine is added 0.8 part of phosphorus pentasulfide. The mixture is heated under reflux for 6 minutes and concentrated. The concentrate is alkalified with the addition of an aqueous sodium hydroxide solution and subjected to salting out with the addition of potassium carbonate, followed by extraction with ethyl ether. The ethyl ether layer is dried over anhydrous potassium carbonate, and filtered. The filtrate is concentrated and passed through a column packed with silica-gel (-325 mesh ASTM, 3.0X20cm), which is then eluted with ethyl acetatechloroform (1:1 by volume). The fractions containing a substance showing Rf value of 0.42 on a thin layer chromatograph (silica-gel G, 2.6X7.6cm, developer, ethyl acetate-chloroform=l:l by volume) are collected, decolorlized with&#39;charcoal and filtered. The filtrate is concentrated to dryness and recrystallized twice from ethanol, whereby 0.23 part of 2- quinolinethioacetamide is given as yellow prisms melting at 152 to 154C.  
 EXAMPLE 18 To a solution of 1.50 parts of N-methyl-2- quinolineacetamide in 20 parts by volume of pyridine is added 1 part of phosphorus pentasulfide. The mixture is refluxed for 5 minutes and concentrated. The concentrate is alkalified with an aqueous sodium hydroxide solution and subjected to salting out with the addition of potassium carbonate, followed by extraction with ethyl ether. The ethyl ether layer is dried over anhydrous potassium carbonate and filtered. The fil-&#39; trate is concentrated to dryness and recrystallized twice from the ethanol, whereby 0.57 part of N-methyl-2- quinolinethioacetamide is given as pale yellow needles melting at to 131C.  
 EXAMPLE 19 In a small portion of pyridine is dissolved 2.0 parts of 2-pyridineacetonitri1e and the pyridine is evaporated. The residue is dried and dissolved in 10 parts by volume of pyridine. Into the solution is introduced anhydrous methylamine under ice-cooling until the solution is saturated with the same, followed by keeping standing at room temperature for l to 1.5 hours. Hydrogen sulfide is gradually introduced into the resultant under cooling with ice-water. The resulting mixture is kept in a tight seal at room temperature for 2 days, at the end of which time pyridine is evaporated and then water and ethyl acetate are added to the residue, followed by shaking.  
  The ethyl acetate layer is extracted 4 times with ethyl acetate. The ethyl acetate extracts are combined and shaken with water and then with aqueous sodium chloride solution, followed by drying over anhydrous sodium sulfate. The resultant is subjected to evaporation to remove the solvent, and the resulting syrup is cooled, whereby crystals are given. Petroleum ether is added to the crystals and the mixture is filtered to collect the 10 (decomposition).  
  In a similar manner to the above, the following compounds are prepared.  
  Starting material Compound produced Melting point C.) CHaNH: I 128-129.  
 H CH CH i JNHCH aa a C N N CHICHICHINHI 152-154 (hydrochloride). L L H CH: CHgCN CHt-&#39; CHsCNHCHaCHgCH;  
 CzHlNH: 73-74.  
  L L n CH N CHlCN CHz N CHCNHCH CHaCHgCHzCHgNHg Mfr-148 (hydrochloride).  
  L ll CH? N OH; N CH,CNHCH|CH1CH1CH| 190-192 (hydrochloride).  
  --CH:NHI cnt -omcn on \N CH;CNHCHr- 5 \N CH;CN \N CHiCNH CHaNH: 130-131.  
 i ll N CH:CN N CHaCNHCH:  
 O C|H CHsNH: O CQHI 103-106.  
 I -CH:CN CHaQ INHCHI C H5CH NH 180 to 181 (hydrochloride).  
  N CH|CN CH:NHCHr-C|H5 EXAMPLE A mixture of 2 parts of Z-pyridinethioacetamide and 2 parts by volume of aqueous methylamine solution is boiled for 10 minutes. Potassium carbonate is added to the reaction mixture, followed by extraction with chloroform. The chloroform layer is dried over potassium carbonate and filtered. The filtrate is concentrated and the crystals are taken by filtration. The crystals are washed with ethyl ether and purified by Silica-gel column chromatography employing as a developer ethyl acetate-chloroform( lzl by volume). Recrystallization of the resulting crystals from ethanolpetroleum ether gives 0.7 part of N-methyl-2- pyridinethioacetamide as yellow prisms melting at 89C to C.  
  in a similar manner to the above, the following compounds are prepared.  
 EXAMPLE 2] acetate are added to the residue,&#39;followed by shaking well. The ethyl acetate layer is dried over anhydrous sodium sulfate and subjected to evaporation to remove S CHzlL-R the solvent. After cooling, petroleum ether is added to the residue. The precipitated crystals are recrystallized from ethanol-petroleum ether to give N-methyl-Z- pyridinethioacetamide as crystals melting at 89C to 90C.  
  Hydrochloride of the compound as obtained above is prepared by using ethanolic hydrochloric acid.  
 Melting point: 215C to 220C (decomposition).  
 EXAMPLE 22 To a mixture of L0 part of N,N-dimethyl-2- pyridineacetamide and 6 parts by volume of pyridine is added dropwise under ice-cooling 0.5 part by volume of tetrachloropyrophosphoric acid. Twenty minutes after the addition, hydrogen sulfide is introduced into the mixture for 10 minutes, followed by keeping overnight with sealing at room temperature. Pyridine is evaporated, and water, potassium carbonate and chloroform is added to the residue. The mixture is shaken well, and the chloroform layer is dried over anhydrous potassium carbonate and concentrated. The concentrate is passed through a column packed with silica-gel (3.0 X 20cm, particle size 0.05-0.2mm) and the column is eluted with acetic acid-chloroform (1:1 by volume). The eluate is concentrated and treated with ethanolic hydrochloric acid, whereby 0.45 part of N,N- dimethyl-Z-pyridinethioacetamide hydrochloride is precipitated as crystals melting at 175 to 177C.  
  In a similar manner to the above, the following compounds are prepared.  
 Rt (position) R Melting point C.)  
 CH; (6) -NHCH; 186-186 (decomposition, hydrochloride). CH (6) NHC:H5 73-74. CH; (6) NHOH1CH;CH 152-154 (decomposition, hydrochloride). CH; (6) -NHCH,CH;CH:CH; 146-148 (decomposition, hydrochloride).  
 CH; (6) 190-192 (hydrochloride).  
 NHCHr- CH; (6) /CH 142-145 (decomposition, hydrochloride).  
 CH; (6) C H 164-156 (decomposition, hydrochloride).  
  H 195-196 (decomposition, hydrochloride). 0 I (6) CH; (6) l 198-200 (decomposition, hydrochloride).  
 CH, (6) Q 171-172 (decomposition, hydrochloride).  
 CH=CHCH=CH- (5,6) -NHCH: -131.  
 H CH: -177 (hydrochloride).  
 -181 (hydrochloride).  
 K cn, -R  
 R1 (position) R oge agent Melting point 0.  
 H NHCH; Phosphorus oxychloride or phosphorus 215-22) (decomposition,hydrochloride).  
 pentachloride.  
 H NH Q Tetrachloropyrophosphoric acid 156.5-168.  
 H, (6) NH: ....do.-. 194-198 (decomposition, hydrochloride). (3H, (5) --NH; do 209-211 (decomposition, hydrochloride). 03H, (6) --NH: do 220-222 (decomposition, hydrochloride). CH3 (3) -NH: 214-216 (decomposition, hydrochloride). CH; (4) -NH: ..-..d0 200-201 (decomposition, hydrochloride). CHaO (4) NH, -----do 165-166 (decomposition, hydrochloride). CQHQO (4) NH, -.---d0-.- 103-105. CH=CHCH=CH (5,6) NH, -.do- 216-217 (decomposition, hydrochloride). CH; (6) NHCH: do 185-186 (decomposition, hydrochloride). CH; (6) -NHC2H5 -&#39;-d0 73-74. CH; (6) -NHCHzC zC a .-.d 152-154 (decomposition hydrochloride). CH; (6) NHCHiCH: H: H: .....d0 146-148 (decomposition, hydrochloride). -CH=CH-CH=CH- (6,6) -NHCH; do 130-131.  
 011; (6) 1 /CH: &#34;H.001 142-145 (decomposition, hydrochloride).  
 CH. (6) C:Hi ----.do 154-156 (decomposition, hydrochloride).  
 011 (6) ----.d0 195-196 (decomposition, hydrochloride).  
 011 (6) v 198-200 (decomposition, hydrochloride).  
 CH; (6) 171-172 (decomposition, hydrochloride).  
 H NHCHr-CuH; .-do 130m 181 mammal-me).  
  Dry hydrogen chloride is introduced into 50 parts by volume of dimethylformamide under ice-cooling until saturation, followed by the addition of 7.5 parts of thioacetamide and 6.7 parts of 6-methyl-2- pyridineacetonitrile. The mixture is heated at 90C to 100C with stirring for minutes.  
  The reaction mixture is concentrated under reduced pressure and the residue is dissolved in a small amount of water. The solution is subjected to salting out with potassium carbonate, followed by extraction with chloroform. The chloroform layer is dried over anhydrous sodium sulfate and subjected to evaporation to remove the chloroform. The residue is dissolved in a small amount of water and the solution is acidified with hydrochloric acid and cooled. The precipitated crystals are crystallized from ethanol to give 8 parts of 6- methyl-Z-pyridinethioacetamide hydrochloride as crystals melting at 194C to l98C (decomposition).  
 EXAMPLE 24 into a mixture of 9.3 parts of ethyl phosphodithioate and 6.7 parts of 6-methyl-2-pyridineacetonitrile is introduced hydrogen chloride with stirring for 30 minutes. Water is added to the reaction mixture and the separated oily layer is removed. The aqueous layer is washed with chloroform and then with ethyl ether, followed by concentrating to dryness. The concentrate is crystallized from ethanol to give 3.5 parts of 6-methyl- Z-pyridinethioacetamide hydrochloride as melting at 194C to 198C (decomposition).  
  In a similar manner to Example 22 or 23, the following compounds are prepared.  
 crystals OH; NH:  
  (decomposition, hydrochloride) CH O (4) 165-166 (decomposition, hydrochloride). C,H 0 (4) 103-105. -CH=CH-CH=CH 216-217 (decomposition).  
 EXAMPLE 25 Dry hydrogen chloride is introduced under icecooling into 8 parts by volume of dimethylformamide until saturated, followed by the addition of 0.75 part of thioacetamide and 1.3 parts of 2-cyanomethyl-lmethyl pyridinium chloride. The mixture is heated at 80C to 90C for 30 minutes with stirring, followed by concentrating under reduced pressure. The residue is recrystallized from ethanol. The crystals are dissolved in about 5 parts by volume of water and the solution is passed through a column packed with 20 parts by volume of anion ion exchange resin (chlor type) of 100 to 200 meshes, which is then eluted with about 30 parts by volume of water. The eluate and the washing are combined and concentrated under reduced pressure. The residue is recrystallized from ethanol to give 0.51 part of 2-thioacetamide-l-methyl-pyridinium chloride as crystals melting at 240C to 241C (decomposition).  
 EXAMPLE 26 To a solution of 1.5 parts of N-methyl-Z- pyridineacetamide in parts by volume of pyridine is added under ice-cooling 0.7 part of thionyl chloride. One hour after the addition, hydrogen sulfide is introduced into the mixture for 5 minutes, followed by keeping with sealing for a day. The mixture is treated in a similar manner to that in Example 22, whereby 1.1  
 parts of N-methyl-2-pyridinethioacetamide hydrochloride is given as crystals melting at 215 to 220C (decomposition).  
 EXAMPLE 27 wherein R is hydrogen, lower alkyl, lower alkoxy or halogen and R and R together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of piperazine and pyrrolidine, and pharmaceutically acceptable salts thereof.  
 2. The compound l-(6-methyl-2-pyridinethioacetyl)- pyrrolidine.