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United States Patent Office Patented Apr 3,726,878 United States Patent Office Patented Apr. 10, 1973 2 The novel pyridine thioacetamide derivatives of the 3,726,878 present invention are represented by the following general PYRONE THOACETAMIDE DERVATIVES formula: Yoshio Kanai, Osaka, Haruomi Honda, Kawanishi, Hyogo, Yasushi Sanno, Osaka, Kawani, Akira Nohara, Kyoto, and Morio Kanno, Osaka, Japan, assignors to Takeda Chemical Industries, Ltd., Osaka, Japan (Ri)n R. No Drawing. Filed July 7, 1970, Ser. No. 53,008 s'-OH,C-C-N N Claims priority, application Japan, July 8, 1969, R 44/53,946 Int, C. C0731/50 O wherein R1 is H, lower alkyl, alkoxy or halogen and n is U.S. C. 260-294.8 E 19 Claims 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 5- and 6-positions of the pyridine ABSTRACT OF THE DISCLOSURE ring, each of R2 and R3 independently is hydrogen, lower Compounds of the formula 5 alkyl, aralkyl, aryl, or where R and R3 form a hetero cyclic ring together with the adjacent nitrogen atom, with a proviso that at least one of R, R2 and Ra is other than hydrogen. S R The lower alkyl represented by R1, Ra and Rs may be 20 the same or different and is preferably one having up to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, J-CH-C-NC Ra butyl, iso-butyl, sec-butyl and tert-butyl. The alkoxy represented by R1 is preferably lower alkoxy having up to 4 carbon atoms such as methoxy, ethoxy, propoxy, wherein R1 is hydrogen, lower alkyl, lower alkoxy or 25 iso-propoxy, butoxy, iso-butoxy, sec-butoxy and tert halogen and n is an integer of 1 to 4, or wherein (R) butoxy. The radical of (R1) may be a divalent straight is a divalent straight chain hydrocarbon radical having 4 chain hydrocarbon having 4 carbon atoms, which is at carbon atoms which is attached to the 5th and 6th posi tached to the 5th and 6th positions of the pyridine ring, tions of the pyridine ring, each of R2 and R3 independent and this radical is exemplified by ly represents hydrogen, lower alkyl, aralkyl or aryl, or 30 -CH=CH-CH=CH-, -CH=CH-CH-CH R2 and R together with the nitrogen atom to which they are attached form a heterocyclic ring with a proviso that -CH-CH-CH2-CH-, etc. Namely in the above at least one of R, R and R is other than hydrogen and cases, the radical of a pharmaceutically acceptable salt thereof with acids. 35 (R)n This invention relates to a novel pyridine thioacet amide derivative useful for treatment and/or prevention SN of gastric diseases, and further relates to a method for 40 is quinolyl, dihydroquinolyl and tetrahydroquinolyl radi the production of the pyridine thioacetamide derivative. cal, respectively. The halogen represented by R1 includes The present inventors have succeeded in synthesizing chlorine, bromine, iodine and fluorine. The aralkyl rep a series of novel pyridine thioacetamide derivatives rep resented by R2 or Ra is preferably phenyl lower alkyl resented by the general formula shown below, and fur exemplified by benzyl or phenethyl. The aryl represented ther, with regard to the novel compounds, the inventors 45 by R or R3 is exemplified by phenyl and naphthyl. The have found the following fact. heterocyclic ring which is formed with R2, R3 and the Namely, the pyridine thioacetamide derivative can adjacent nitrogen atom is preferably 5 or 6 membered supress excessive secretion of gastic juice caused by and may contain additional hetero atoms and is exempli histamine, gastrine or acetylcholine, without producing fied by six membered ones such as piperazine, piperidine undesirable effect on digestive secretions in the other or 50 and morpholine, and five membered ones such as pyr gans such as pancreas, gall bladder and liver, and also rolidine. without showing uncoupling of oxidative phosphorylation The pyridine thioacetamide derivatives of the above in mytocondoria. Thus, the compound of the present in Formula form acid addition salts with suitable acids such vention can prevent or treat effectively hyperacidity, as inorganic acids (e.g., hydrochloric acid, nitric acid, peptic ulcer and duodenal ulcer without causing any un 55 phosphoric acid, oxalic acid, succinic acid, malic acid, desirable side effect by oral or parenteral administration. maleic acid, malonic acid, tartaric acid, benzoic acid, The present invention has been accomplished on the toluene sulfoni acid, methane sulfonic acid, etc.), and basis of these findings. also can form a quaternary ammonium salt such as 1 Thus, the principal object of the present invention is methyl pyridinium chloride, 1-methyl pyridinium bro to provide novel pyridine thioacetamide derivatives which 60 mide, 1-ethyl pyridinium chloride, 1-ethyl pyridinium bro are useful for treatment and/or prevention of peptic mide, 1-methyl pyridinium iodide, 1-ethyl pyridinium ulcer, duodenal ulcer or hyperacidity and show low tox iodide, etc. icity and no or only a slight side effect. Any of these salts, so far as pharmaceutically accept Another object of the present invention is to provide able, can be used for the purpose of the present invention. a method for the production of the novel pyridine thio 65 The object compound (I) of the present invention can acetamide derivatives. be produced by one of the methods as summarized below. 3,726,878 3 4. In the following, the methods of Group (A) can be applied to the production of any of the present com (6) pounds; the method of Group (B) can be applied to the ES production of the present compound (I) wherein both (R) - (R) of R and R3 are hydrogen or that wherein one of R and NN CHCN NN CHC-NE R3 is lower alkyl, aryl or aralkyl and the other is hydro gen; and the methods of Group (C) can be applied to (III) (I)-(i) the production of the present compound (I) wherein both (7) RO S of Ra and R3 are hydrogen. Group (A).-The methods applicable to the produc -sh tion of any of the present compounds. O RO (VI) (1) (R)n serra-e- (R)n (R)n / - sy-CHON sy-CH.C-NH. NN CH-5-N Ephorus 5 (III) an acid (I)-(i) (II) R compound wherein R1 and in have the same meaning as above, and R’ is alkyl, and R is lower alkyl, aryl or aralkyl. (R)n O R. The object compounds of the present invention are 20 most generally prepared according to the methods of NN CH-5-NN Group (A)(1), (2) or (3). Namely, the compound of (I) R the Formula II is allowed to react with a phosphorus (2) sulfide compound or it is at first allowed to react with a a halogenating halogenating agent and then allowed to react with hydro (R) O R. agent 25 gen sulfide, and when the resultant is a compound of NN CH-5-NN the Formula I wherein both R and R are hydrogen, the (II) R resultant may be converted to the compound of the For mula I-(ii) by reacting with a primary or secondary ES S R amine of the formula resultant -i. (R) / 2 30 C-C-N (I) R HN N R In the method (1), the phosphorus sulfide compound employable is exemplified by diphosphorus pentasulfide, tetraphosphorus trisulfide, tetraphosphorus pentasulfide and tetraphosphorus heptasulfide. Among them, diphos phorus 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.). (I)-() In this reaction, it is preferable to use a basic com 45 pound such as organic amines (e.g. ethylamine, diethyl wherein n, R, R and Ra have the same meaning as amine, triethylamine, diethylaniline, picoline, piperidine, above, and Ra and Rs have the same meaning as Ra morpholine, quinoline, pyridine, etc.). and Rs except that R and Rs are not both hydrogen As the compound can take a part also as a reaction atOS. - 50 solvent, it may be used in a large excess amount with or . Group (B).-The method applicable to the produc without other solvent. The reaction temperature generally tion of the present compound (I) wherein one of R and ranges from about 20°. C. to about 200° C. The pyridine R3 is lower alkyl, aryl or aralkyl and the other is hydro thioacetamide derivatives (I) thus produced can be re gen or that wherein both of R and R3 are hydrogen. covered from the reaction mixture after a per se con (4) NHR 55 ventional manner, for example, by evaporating the sol (V) S Went. (R) -els resultant - In the method (2), the compound (II) is at first al NN/ CHCN lowed to react with a halogenating agent. (III) The halogenating agent employable includes, for ex 60 ample, phosgene, phosphorous halides (e.g., phosphorous (R) S oxychloride, phosphorus pentachloride, phosphorus tri NN CH, -NHR, chloride and tetrachloropyrophosphoric acid), thionyl chloride and sulfuryl chloride. Among them, the phos (I)-(iii) phorus halides are preferable. wherein R, R2 and in have the same meaning as above. 65 The amount of the halogenating agent employed varies . Group (C).-The methods applicable to the produc depending on the kind of the halogenating agent and gen tion of the present compound (I) wherein both of R and erally falls within the range of about 0.1 to about 2 moles Ra are hydrogen.
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