PYRIMIDONE COMPOUNDS, THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Novel pyrimidones of the formula I and salts thereof are gastric acid secretion inhibitors and some have other medical utility: wherein R₁ represents a hydrogen atom, a C₁ to C₁₀ alkyl group, a C₁ to C₅ alkenyl group, a C₁ to C₅ alkinyl group, a phenyl group, a cycloalkylmethyl group, an unsubstituted or substituted aralkyl group, or the group wherein A represents a C₁ to C₅ alkylene group and R₃ and R₄ are the same or different C₁ to C₅ alkyl groups or combine to form with the adjacent nitrogen atom a piperidine or pyrrolidine ring; R₂ represents a hydrogen atom, a C₁ to C₅ alkyl group or a tri­ fluoromethyl group: Y represents a heterocyclic group of the formula: wherein R represents a hydrogen atom or a C₁ to C₅ alkyl group: B represents an oxygen atom or a sulfur atom; m repre­ sents zero or an integer of 1 to 3; and n represents an integer of 1 to 3. Methods and novel intermediates for their preparation are disclosed, as well as medicaments containing them and medical treatments using them.

Description: PYRIMIDONE COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM The present invention relates to pyrimidone compounds useful in general as gastric acid secretion inhibitors, their preparation and intermediates therefor, and medical compositions containing them. Some compounds of this invention are also useful as anti-inflammatory agents or medicaments for treating disease of the cardiovascular system or disease of the stomach. Known pyrimidone compounds include those of the formula EMI1.1 which exhibit prolonged gastric acid secretion inhibiting activity (published Japanese Patent Application No: 55-115883); and those of the formula: EMI1.2 where E is or EMI1.3 and X is -CH2-heterocyclic-, which have the characteristic of a dimethylaminomethyl group at the 5-position. Other pyrimidone derivatives are disclosed in published Japanese patent applications Nos. 54-115385 and 55-500898. According to this invention there are provided pyrimidone compounds of general formula I EMI2.1 wherein R1 represents a hydrogen atom, an alkyl group, a lower alkenyl group, a lower alkinyl group, a phenyl group, a cycloalkylmethyl group, an unsubstituted or substituted aralkyl group, or the group EMI2.2 wherein A represents a lower alkylene group and R3 and R4 are the same or different lower alkyl groups or combine to form with the adjacent nitrogen atom a piperidine or pyrrolidine ring; R2 represents a hydrogen atom, a lower alkyl group or a trifluoromethyl group; Y represents a heterocyclic group of the formula EMI2.3 wherein R represents a hydrogen atom or a lower alkyl group; B represents an oxygen atom or a sulfur atom; m represents zero or an integer of 1 to 3; and n represents an integer of 1 to 3; and the pharmacologically acceptable salts thereof. The invention also provides processes and intermediates or starting compounds for preparing compounds of general formulas, methods of treatment by administering effective amounts of formula I compounds, and pharmaceutical compositions containing effective amounts of formula I compounds and pharmaceutically acceptable carrier(s) and/or diluent(s). Te term "lower" in the above definition means a straight or branched carbon chain having 1 to 5 carbon atoms. For example, as lower alkyl groups, there are methyl, ethyl, propyl, isopropyl , butyl, isobutyl, sec-butyl, tert-butyl, and pentyl groups etc, as lower alkenyl groups there are vinyl and allyl groups etc; as lower alkinyl groups there are ethinyl, 2-propinyl, 3-butinyl, 2-butinyl, l-butinyl, l-methyl2-propinyl, and pentinyl groups etc.; and as lower alkylene groups there are methylene, ethylene methylmethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, and pentamethylene groups etc. The alkyl group in the definition of R1 is a straight or branched alkyl group having 1 to 10 carbon atoms. For example, as the alkyl group, there are, in addition to the above listed lower alkyl groups, n-hexyl, isohexyl, l-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,2,2-trimethylpropyl, l-ethyl-2-methylpropyl, l-ethyl-l-metbylprQpyl, n-heptyl, 1-methylhexyl, 2-methyl hexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,3 dimethylpentyl, 1,4,dimethylpentyl, . 2,2-dimethylpentyl, 2,3-dimethylpnentyl, 2,4-dimethylpentyl, 1 ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, l-ethyl-l-methylbutyl, .l-ethyl-2-methylbutyl , l-ethyl 3-methylbutyl, 2-ethyl-1-methylbutyl, 2-ethyl-2-methylbutyl, 1,1,2-trimethylbutyl, 1,2,2-trimethylbutyl, 112,3-trimethylbutyl, 1-propylbutyl, n-octyl, - 6-methylheptyl, n-nonyl, 7-methyloctyl, n-desyl, and 8-methylnonyl groups, etc. WhenR1 is an aralky group, the aryl portion may for example be a phenyl or naphthyl group, a: 5 or 6 membered heterocyclic group containing nitrogen atom(s) such as a pyridyl, pyrazolyl orimidazolyl group etc., or other unsaturated heterocyclic group containing nitrogen atom(s) such as a benzimidazolyl, indazolyl or quinolyl group etc, Such aryl groups may have one or more substituents such as lower alkyl halogen, lower alkoxy, lower alkylenediosy, phenyl etc. As such halogens there are fluorine, chlorine, bromine etc.: as such. alkoxy groups, there are for example methoxy, ethoxy, propoxy and butoxy groups etc.; and assuch lower alkylenedioxy groups there are for example methylenedioxy and ethylenedioxy groups etc. A- the above aryl group, there are particularly listed naphthyl, pyridyl, benzimidazolyl, and phenyl optionally substituted by one or more substituent(s) selected from halogens and tert-butyl, methylenedioxy and phenyl groups. As cycloalky groups herein there are for example cyclohexyl and cyclopentyl groups etc. Typical compounds of this invention are as follows: 5-(p-tert-butylbenzyl)-2-[2-[[[2-[(diaminomethylene)amino]4-thiazolyl]methyl]thio]ethyl]-6-methyl-4(1H)-pyrimidone; 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-n-butyl-6-methyl-4(1H)-pyrimidone; 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-n-pentyl-4(1H)-pyrimidone; 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-(1-naphthylmethyl)-4(1H)-pyrimidone; 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-(3-dimethylaminopropyl)-6-methyl-4(1H)-pyrimidone; 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-(3-diethylaminopropyl)-6-methyl-4(1H)pyrimidone; 5-[(1,3-benzodioxole-5-yl)methyl]-2-[2-[5-(dimethylaminomethyl)furfurylthio]ethyl]-6-methyl-4(1H)-pyrimidone; and 5-(p-tert-butylbenzyl)-6-methyl-2-[3-(m-piperidinomethylphenoxy)propyl]-4(1H)-pyrimidone. The compounds of formula I can form acid addition salts, with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, etc., and with organic acids such as maleic acid, fumaric acid, and picric acid, etc. Furthermore, there also exist tautomers of the compounds of formula I at the lH- and 3H-positions, and there exist occasionally hydroxy-tautomers in a small proportion. The invention includes such salts and tautomers. -The compounds of formula I and their acid addition salts have histamine H2-receptor blocking activity, and are useful as gastric acid secretion inhibitors; some additionally have histamine H1-receptor blocking activity and are useful also as anti-inflammatory agents and as medicaments acting on the cardio-vascular system. Further, some compounds of this invention have cytoprotective action, and such compounds are useful as medicaments, for treating various diseases of the stomach. For many of the compounds of this invention, their activities, such as histamine H2-receptor blocking activity and/or histamine H1-receptor blocking activity, are prolonged, lasting for a long period of time. The compounds of this invention can be administered orally or parenterally, as the free bases or pharmacologically acceptable salts thereof. They are generally used as medical or pharmaceutical compositions with suitable carriers or diluents. The rate of administration is usually 100 to 800 mg per day for adults in 1 to 4 doses. It has been shown by Shay rat 4 hr method (Shay et al., Gastroenterology, 5, pages 43 - 61, 1945) and other animal experiment methods that compounds of this invention inhibit gastric acid secretion at administered doses below 10 - 50 mg/kg and have histamine H2-recCptor blocking activity; that some of the compounds also have histamine H1-receptor blocking activity; and that some also have cytoprotective action. Some relevant data is shown in the following Table Table EMI8.1 <tb> Compound <SEP> lI2-blocking <SEP> -Acid <SEP> Inhibition <tb> <SEP> activity <SEP> Shay(4hr.) <tb> <SEP> Eel)50 <SEP> (mg./kg.) <tb> <SEP> (Doe) <tb> <SEP> iiyy <tb> <SEP> L <SEP> 3 <tb> <SEP> H <tb> <SEP> R=uthyl <SEP> 3.7x1017 <tb> <SEP> Pethy1 <SEP> 1.4xlo <SEP> 7 <SEP> 90%(0.hmg) <tb> <SEP> Propyl <SEP> 1.7xlO <SEP> 7 <SEP> 60%C0.iug) <tb> <SEP> R=CRECCH2- <SEP> 1.8xlO <SEP> 7 <SEP> 95%(0.lmg) <tb> <SEP> R=butyl* <SEP> 1.5x10-7 <SEP> 70Z(0 <SEP> Mmg) <tb> <SEP> R=amyl* <SEP> 0.9xlO <SEP> 7 <SEP> 95%(0.Mmg) <tb> <SEP> R=iso-anyl* <SEP> 3xlO <SEP> 7 <SEP> + <tb> <SEP> p-tert-butx71 <tb> <SEP> benzyl <SEP> 2.7x107 <tb> <SEP> R= <tb> <SEP> diinethyliiiino <tb> <SEP> propyl <SEP> 3.4x10-7 <tb> <SEP> R= <tb> <SEP> diethylamino <tb> <SEP> propyl <SEP> 5x10 <SEP> 83%(3rug) <tb> <SEP> A)·; ;CH3 <tb> <SEP> N <SEP> S <SEP> - <SEP> <SEP> S <SEP> < <SEP> 7.7xlO <SEP> 7 <tb> MeLI-\v <SEP> N <SEP> CH3 <tb> <SEP> * <SEP> These <SEP> compounds <tb> <SEP> N <SEP> 3 <tb> <SEP> also <SEP> have <tb> <SEP> cytoprotective <tb> <SEP> -R=tert-butylbenzyl <SEP> 5xlO <SEP> 7 <SEP> action. <tb> <SEP> R=H <SEP> 4.9xlO <tb> Most at least of the compounds of tis invention wherein R1 is an alkyl group having 4 to 9 carbon atoms possess not only. histamine H2-receptor blocking activity but also cytoprotective action, and may therefor be useful as medicaments for treating various stomach diseases. Compounds of this invention can be produced by various processes, some of which are shown below Process I. EMI9.1 (wherein R represents a lower alkyl group) .5 This process is a condensation cyclization reaction between the amidine compound of formula (II) and the acylacetic acid derivative of formula (III). The reaction is usually performed in a solvent at room temperature or under heating. As trie solvent, there is preferably used alcohol (e.g. methanol, ethanol, isopropanol, etc), dimethylformamide, dimethylsulfoxide, methylcellosolve, ethylcellosolve, diglyme, etc. If necessary, a basic material may be present, suitable base materials including alkali metal (e.g. sodium or potassium) alcoholate, sodium hydroxide etc. The starting materials ( and (III) may be used in equival molar amounts, or some excess of either may be used. Process II EMI10.1 (wherein R6 and R7 are the same or different alkyl groups). This process is a condensation cyclization reaction between the imidate compound of formula IV and the 3-aminoacrylic acid ester derivative of formula V. The reaction can be performed substantially as for Process I - i.e. using the same organic solvents and if necessary the same basic materials and reacting with heating or under reflux. The compounds of this invention thus prepared can be separated as the free base or an acid addition salt thereof, and further can be purified by standard procedures such as column chromatography, recrystallization, etc. The starting materials of formula II and IV can be obtained as disclosed in published Japanese patent applications Nos.55-115860, 55-115877 and 55-118476. Some of the starting materials of formula II and III are novel, and can be produced as described in the Reference Examples 1 to44 below. Compounds of formula I and salts thereof, amd their preparation, are illustrated by Examples 1 to 64. In the Examples and Reference Examples, mp., Anal., NMR and Mass. are abbreviations for melting point, elementary analysis values, nuclear magnetic resonance spectrum and mass spectrum, respectively. Reference Example 1 Ethyl &alpha;-(3-pyridylmethyl)acetoacetate EMI12.1 Under nitrogen, 8.4 g of metallic sodium was dissolved in 500 ml of anhydrous ethanol, and after adding 23.8 g of ethyl acetoacetate thereto and stirring the solution at room temperature for 1 hour, 30 g of 3-chloromethylpyridine hydrochloride was added to the solution followed by heating mildly for 20 hours. After filtering away the salt formed, the solvent was distilled off under reduced pressure, and the residue formed was purified by column chromatography using chloroform - ethyl acetate as the developing solvent to provide 120 g of the oily product. NMR (in CDCl3) #(ppm); 1.18 (t, 3H) 2.20 (s, 3H) 3.1 3 (d, 2 H ) 3.7 8 ( t, 1 H) 4.13 (q, 2H) 7.04#7.60 (m, 2H) 8.40 (m, 2H) Mass. (m/z) 221 (M+) Reference Examples 2 - 18 By following the same procedure as in Reference Example 1, the following compounds were obtained: Reference Example 2 EMI13.1 ethyl &alpha;-(1-naphthyl- methyl)acetoacetate NMR (in CDCl3) #(ppm) ; 1.16 ( t, 3 H) 2.1 5 ( s, 3 H) ) 3.6 4 ( d, 2 H) 3.9 5 ( t, 1 H) 4.13 ( q, 2 H) 7.2#8.2 (m, 7H) Mass (m/z) 270 (M+), 227, 181 Reference Example 3 EMI13.2 ethyl &alpha;-(3-pyrazolyl- methyl)acetoacetate NMR (in CDCl3) #(ppm); 1.24 (t, 3H) 2.24 (s, 3H) 3.24 (d, 2H) 3.94 (t, 1H) 4.19 (q, 2H) 6.10 (d, 1H) 7.50 (d, 1H) Mass (m/z) 210 (M+), 167 Reference Example 4 EMI14.1 ethyl &alpha;-(2-benzimidazolylmethyl) acetoacetate Mass (m/z) 260 (M+), 217 Reference Example 5 NMR (CDCl3) EMI14.2 ethyl i-(2-N,N-dimethyl- aminoethyl)acetoacetate (ppm); 1.28 (t, 3H) 2.08 (q, 2H) 2.1#2.4 (11H) 3.58 (t, 1H) 4.20 (q, 2H) Mass (m/z) 201 (M+), 156 Reference Example 6 NMR (CDCl3) #(ppm); 1.28 (t, 3H) EMI14.3 ethyl &alpha;-(3-N,N-dimethyl- ami;nopropyl) acetoacetate 1.4#1.6 (m, 2H) 1.7#2.0 (m, 2H) 2.1#2.5 (11H) 3.44 (t, 1H) 4.19 (q, 2H) Mass (m/z) 215 (M+), 170 Reference Example 7 NMR (CDCl3 EMI15.1 ethyl &alpha;-(p-tert-butyl- benzyl)acetoacetate (ppm) ; 1.18 (t, 3H) 1.27 (s, 9H) 2.17 (s, 3H) 3.11 (d, 2H) 3.75 (t, 1H) 4.14 (q, 2H) 7.08 (d, 2H) 7.28 (d, 2H) 7.00#7.36 (m, 4H) IR (neat) #:1735, 1710cm-1 Mass (m/z) 276(M+), 261(M+-15) 233(M+-43) Reference Example 8 NMR(CDCl3) EMI15.2 ethyl &alpha;-(2-quinolylmethyl)- acetoacetate #(ppm); 1.26(t, 3H) 2.45 (s, 3H) 3.50#3.67 (m, 2H) 4.20 (q, 2H) 4.54 (t; 1H) 7.20#8.08 (m, 6H) IR(neat) #; 1760, 1705cm Reference Example 9 Mass(m/z) 271 (M+), 256 (M+-15) 228 (M+-43) ethyl &alpha;-(p-chloro- benzyl)acetoacetate NMR(CDCl3) EMI16.1 #(ppm); 1.18(t, 3H) 2.17 (a, 3H) 3.08 (d, 2H) 3.70 (t, 1H) 4.10 (q, 2H) 6.90#7.45 (m, 4H) IR(neat) #; 1735, 1710 cm-1 Mass(m/z) 254(M+), 211(M+-43) Reference Example 10 NMR(CDCl3) EMI16.2 ethyl &alpha;-[(b-chloro-1,3- benzodioxole-5-yl)methyl]acetoacetate #(ppm); 1.20(t, 3H) 2.18(s, 3H) 2.94#3.35(m, 2H) 3.60#3,87(m, 1H) 4.10(q, 2H) 5.83(s, "H) 6.54#6.81(m, 2H) IR(neat) #; 1735, 1710 cm-1 Reference Example 11 EMI17.1 ethyl &alpha;-[(1,3-benzo- dioxole-5-yl)methyl) - acetoacetate NMR(CDCl3) #(ppm); 1.20 (t, 3H) 2.16 (s, 3H) 3.05 (d, 2H) 3.68 (t, 1H) 4.10 (q, 2H) 5.82 (s, 2H) 6.58 (s, 3H) IR(neat) #; 1730, 1710cm-1 Mass(m/z) 264(M+), 191(M+-73) Reference Example 12 EMI17.2 ethyl &alpha;-(p-fluoro- benzyl)acetoacetate Mass(m/z) 234(M+) IR(neat)#; 1700cm-1 NMR(CDCl3) #(ppm); 1.22(t, 3H) 2.18(s, 3H) 2.30(s, 3H) 3.16(d, 2H) 3.70(dt, 1H) 4.14(q, 2H) 7.04(s, 4H) Reference Example 13 EMI18.1 ethyl phenethyl- acetoacetate Mass(m/z) 235(M+1) NMR(CDCl3) #(ppm); 1.25(t, 3H) 2.10#2.75(m, 4H) 2.20 (s, 3H) 3.35 (t, 1H) 4.20 (q, 2H) 7.15 (s, 5H) Reference Example 14 EMI18.2 ethyl &alpha;-[(3,4,5-tri- methoxy)benzyl]acetoacetate Mass (m/z-) 310(M+) NMR(CDCl3) #(ppm); 1.22(t, 3H) 2.20(s, 3H) 3.12(d, 2H) 3.6#3.95(m, 10H) 4.18(q, 2H) 6.40(s, 2H) Reference Example 15 EMI18.3 ethyl &alpha;-[(p-phenyl)- benzyl]acetoacetate Mass(m/z)224(M+-COOEt+1) IR(neat)#; 1710cm-1 NMR(CDCl3) #(ppm); 1.22 (t, 3H) 2.20 (s, 3H) 3.20 (d, 2H) 3.78 (dt, 1H) 4.18 (q, 2H) 7.10#7.65 (m, 9H) Reference Example 16 EMI19.1 ethyl &alpha; ;-(p-methyl- benzyl)acetoacetate Mass (m/z) 234 (M+) IR(neat) #; 1700cm-1 NMR(CDCl3) #(ppm); 1.22 (t, 3H) 2.18 (s, 3H) 2.30 (s, 3H) 3.16 (d, 2H) 3.70 (dt, 1H) 4.14 (q, 2H) 7.04 (s, 4H) Reference Example 17 EMI19.2 ethyl &alpha;-n-hexyl- acetoacetate. Mass (m/z) 214 (M+) NMR(CDCl3) #(ppm); 0.80#2.00 (m, 16H) 2.20 (s, 3H) 3.35 (t, 1H) 4.15 (q, 2H) Reference Example 18 EMI19.3 ethyl &alpha;-n-octyl- acetoacetate Mass(m/z) 242(M+) NMR(CDCl3) #(ppm); 0.80#2.05 (m, 16H) 2.20 (s, 3H) 3.35 (t, 1H) 4.20 (q, 2H) Reference Example 19 Ethyl formacetate EMI20.1 Under nitrogen, 0.23 g of chipped metallic sodium was dissolved in 10 ml of dry ether; while stirring vigorously, a solution of 0.88 g of ethyl acetate and 0.81 g of ethyl formate in 5 ml of dry ether was added dropwise to the mixture maintained at a temperature below -lO0C for 3 hours, and the stirring was continued for 2 hours under these conditions. Thereafter, the mixture was stirred at room temperature for 1 day, and the solvent was distilled off under reduced pressure to provide the unpurified oily product. Reference Example 20 By following the same procedure as in Reference Example 19, the following compounds were obtained. EMI20.2 ethyl &alpha;-phenyl- ethyl &alpha;-n-butyl- ethyl &alpha;-n-pentyl formacetate formacetate formacetate Reference Examples 21 - 30. By following the same procedure as in Reference Example 1, the following compounds were obtained: Reference Example 21 EMI21.1 ethyl &alpha;-(3-diethyl- aminopropyl ) acetoacetate b.p. 110#114 C/1.8 mmHg Mass (m/z) 243 (M+) 198 (M+-45) Reference Example 22 EMI21.2 ethyl &alpha;-(2-piperidino- ethyl)acetoaceate b.p. 125#130 C/2.0mmHg Mass (m/z) 241 (M+) 196 (M+-45) Reference Example 23 EMI21.3 b.p. 1100C/2SmmHg Mass (m/z) 159 (M++1) ethyl &alpha;-ethylacetoacetate Reference Example 24 EMI22.1 b.p. 125#130 C/25 mmHg Mass(m/z) 173 (M++1) ethyl &alpha; ;-propyl- acetoacetate Reference Example 25 EMI22.2 b.p. 135#140 C/25 mmHg) Mass (m/z) 169 (M++1) ethyl &alpha;-(2-propinyl)- acetoacetate Reference Example 26 EMI22.3 ethyl &alpha;-n-cyclohexyl- methylacetoacetate Mass (m/z) 227 (M++1) NMR(CDCI3 ) ä(ppm); 0.8#1.90 (m, 13H) 1.25 (t, 3H) 2.30 (s, 3H) 3.45 (t, 1H) 4.15 (q, 2H) Reference Example 27 EMI22.4 ethyl &alpha;-n-butylaceto- acetate Mass (m/z) 187 (M++1) NMR(CDCl3) #(ppm); 0.75#2.05 (m, 9H) 1.25 (t, 3H) 3.3 5( t, 1 1H) 4.15 (q, 2H) Reference Example 28 EMI23.1 ethyl &alpha;-n-pentyl- acetoacetate Mass(m/z) 201(M++1) NMR(CDCl3) #(ppm); ; 0.70#2.05 (m, 1H) 1.25 (t, 3H) 3.35 (t, 1H) 4.15 (q, 2H) Reference Example 29 EMI23.2 ethyl &alpha;-[(3-methyl)- butyl]acetoacetate Mass(m/z) 201(M++1) NMR(CDCl3) #(ppm); 0.90 (d, 6H) 1.05#2.05 (m, 5H) 1.25 (t, 3H) 3.30 (t, 1H) 4.15 (q, 2H) Reference Example 30 EMI23.3 b.p 7 5 - 7 8 C/0.4mmHg Mass(m/z) 229(M+) ethyl &alpha;-[3-(N,N-dimethyl- amino)-2-methylpropyl]acetoacetate Reference Example 31 EMI24.1 8.75 g of 3-[[[2-(8-methylisothioureido)thiazole-4-yl]methyl]thio] propionitrile hydroiodide and 12.9 g of n-propylaminewere dissolved in 200 ml of ethanol, and the solution was refluxed under heating for 48 hours. The solvent was distilled away, and the residue formed was purified by column chromatography using a mixture of chloroform and methanol as the developing solvent to provide 6.0 g of 3-(2-n-propylguanidinothiazol-4 ylmethylthio) prop jonitrile NMR(CDCl3) #(ppm); 1.03 (t, 3H) 1.68 (m, 2H) 2.4-2.9 (m, 4H) 3.20 (t, 2H) 3.72 (s, 2H) 6.44 (s, 1H) Mass(m/z) 283(M+) EMI25.1 6.0 g of the'nitrile compound obtained as in (1) above was dissolved in 100 ml of dry chloroform and after adding 20 ml of dry ethanol thereto and cooling the solution below 100C and passing therethrough dry hydrogen chloride gas for 3 hours, the solution was allowed to stand at 0-40C for 48 hours. Then, the solvents were distilled off and the residue was poured into a cooled aqueous solution of potassium carbonate for alkalifying, and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to provide 6.0 g,of the oily product. EMI25.2 A mixture of 6.0 g of the imidate compound obtained as at (2) above @ and 1.0 g of ammonium chloride in 70 ml of methanol was stirred at room temperature for 1 hour, and the solvent was-distilled off under reduced pressure. The residue wastreatèd with hydrochloric acid in ethanol, and was recrystallized with acetonitrile - ethanol to provide 5.8 g of the. amidine hydrochloride having a melting point of 133 - 184.50 C. Reference Example 32 4-(m-piperidinomethylphenoxy)butaneamidine hydrochloride EMI26.1 To 200 ml of dry chloroform were added 20.0 g (77.4 ml) of 4-(m-piperidinomethylphenoxy)butanenitrile and 15.7 ml (387 mmol) of dry methanol, and the. solution obtained was cooled by 8 icewater bath. zsugh the solution was passed hydrogen chloride gas at- 10 0C. After confirming the disappearance of the starting material in 8 hours, the reaction was stopped, and the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, and the solution was added to saturated aqueous potassium carbonate solution and stirred. The organic solvent layer was separated, and the aqueous layer was extracted with chlorform. The organic layer and the chloroform solutiQn-were combined, and the combined solution was dried over anhydrous magnesium sulfate. The solvent was distilled away to provide oily crude methyL 4-(m-piperidinom2thyl- phenoxy)butaneimidate (21.1 g). The product was dissolved in 400 ml of dry methanol, and 3.5 ,g (65.4 mmol) of ammonium chloride was added to the obtained solution at room temperature. The solution became homogeneous in 10 minutes, and completion of the reaction was checked by thin layer chromatography. The imidate disappeared after stirring the solution for 3 hours (checked by chromatography). A small amount of precipitate and was filtered away lithe solution was concentrated to precipitate crystals. The precipitated crystals were collected by filtraticn to provide 12.3 g of colourless needle crystals. The filtrate was concentrated to dryness. By re crystallization from ethyl acetate-ethanol, 5.6 g of product was obtained (18.0 mmol, 23%). m.p. 151.0 - 152.0 Oe(ethanol-et'hyl acetate) Mass. (m/e) 275(M+-HCl) Elemental analysis for C16H25N30 HC1 C H N C1 Calculated 61.62 8.40 13.47 11.37 Found 61.47 8.51 13.52 11.41 Reference Example 33 Ethyl &alpha;-(3-pyridylmethyl)acetoacetate EMI27.1 In 500 ml of anhydrous ethanol was dissolved 8.4 g of metallic sodium and after adding thereto 23.8 g of acetoacetate, the mixture was stirred for 1 hour at room temperature. Then, 30 g of 3-chloromethylpyridine hydrochloride was added to the mixture, and the mixture obtained was refluxed under mild heating. The salt formed was filtered away and the solventw as then distilled off under reduced pressure. The residue was purified by column chromatography using chloroform - ethyl acetate as a develop- ing solvent to provide 12.0 g of oily product. NMR(CDCl3) #(ppm) ; 1.1 8 ( 3 H, t ) 2.20 (3H, s) .3.1 3 ( 2H, d ) 3.7 8 (1H, t) 4.13 7.04#7.60 8.40 Mass(m/z) 221(M+) Reference Examples 34-38 By following the same procedure in Reference EXample 33, the following compounds were obtained: Reference Example 34 EMI28.1 ethyl 4 (l-n,aphythyl- methyl)acetoacetate NMR(CDCl3) #(ppm); 1.16 (3 H, t ) 2.15 (3H, s) 3.64 (2H, d) 3.95 (1 H, t ) 4.13 C2H, q) 7.2#8.2(7H, m) Mass(m/e) 270(M+), 227, 181 Reference Example 35 EMI29.1 ethyl &alpha;-(2-benzimidazolyl- methyl) acetoacetate Mass(m/e)260(M+) , 217 Reference Example 36 EMI29.2 ethyl &alpha;-(p-tert-butylbenzyl)- acetoacetate NMR(CDCl3#) #(ppm); 1.18 (t, 3H) 1.27 (s, 9H) 2.17 (s, 3H) 3.11 (d, 2H) 3.75 (t, 1H) 4.14 (q, 2H) 7.08 (d, 2H) 7.28 (d, 2H) 7.00#7.36 (m, 4H) IR(neat) #; 1735, 1710cm-1 Mass(m/z) 276(M+), 261 (M+-15) 233(M+-43) Reference Example 37 EMI30.1 ethyl o(- (6-chloro-1,3-- benzodioxole-5-yl)methyl acetoacetate NMR(CDCl3) 8(ppm) ;1.20 (t, 3H) 2.18 (s, 311) 2.94 (m, "H) 3.60#3.87 (m, 1H) 4.10 (q, 2H) 4.10 (q, 2H) 5.83 (s, 2H) 6.54#6.81 (m, 2H) IR(neat) #; 1735, 1710 cm-1 Mass(m/s) 298 (M+), 255(M+-43) Reference Example 38 EMI30.2 ethyl &alpha;-(p-phenylbenzyl)- acetoacetate NMR(CDCl3) #(ppm); 1.22 (t, 3H) 2.20 (s, 3H) 3.20 (d, 2H) 3.78 (dt, 1H) 4.18 (q, 2H) 7.10#7.65 (m, 9H) IR(neat) #; 1710cm-1 Mass(m/e) 224 (M+-COOC2H5+1) Example 1 EMI31.1 0.916 g of sodium methoxide (MjeONa) was dissolved in 10 ml of methanol, and to the solution formed was added a solution of 5 g of 3-[[[2-[(diaminomethylene)amino]4-thiazoly]methyl]- thiorpropionamidine hydrochloride in 50 ml of methanol followed by stirrring, and after adding 2.2 g of ethyl acetoacetate and stirring the mixture at room temperature for 20 hours, the salt formed was filtered away and the solvents were distilled off under reduced pressure. The residue was purified by column chromatography using chloroform - methanol as the developing solvent, and was recrystallized from ethanol to provide 2 [2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl] -6-methyl-4-(lH)-pyrimidone (1.3 g) having a. melting point of 176 -- 1770C. Anal, (C12H16N5OS2) C H N CAlc. (%) 44.43 4.97 25.90 Found (%) 44.39 4.97 25.86 Examples 2 - 38 By following the same procedure as in Example 1, the - following compounds were obtained Example 2 EMI32.1 2-[2-[[[2-[ (diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5,6-dimethyl-4(1H)-pyrimidone m.p. 199#200 C Anal. (C13H18N6OS2) EMI32.2 <tb> <SEP> C <SEP> H <SEP> N <tb> <SEP> Calc. <SEP> 46.14 <SEP> 5.36 <SEP> 6 <SEP> 24.83 <tb> 46.13 <SEP> 535 <SEP> 24.62 <tb> Example 3 5-benzyl-2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl] EMI33.1 m.p. 149#150 C Anal. (C19H22N9OS2) C H N Calc. ;(%) 55.05 5.35 20.27 Found (%) 55.01 5.39 19.79 Example 4 EMI33.2 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio] ethyl]-6-methyl-5-(1-naphthylmethyl)-4(1H)-pyrimidone dihydrochloride m.p. 202#207 C Anal. (C23H25N6OS2Cl2) C H N Calc. (9) 51.39 4.88 15.63 Found (%) 51.45 4.78 15.67 Example 5 EMI34.1 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-(3-pyridylmethyl)-4(1H)-pyrimidone trihydrochloride m.p. 184#186 C Anal. (C18H24N7Os2Cl3) - C H N Cal 41.19 4.61 18.68 Found 41.28 4.65. 18.62 Example 6 EMI34.2 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio] ethyl]-6-methyl-5-(3-pyridylmethyl)-4(1H)-pyrimidone m.p. 209#211 C Anal. (C16H20N8OS2) C H N Calc. (%) 47.51 4.98 27.70 Found (so) 47.13 4.95 27.48 Example 7 EMI35.1 5-(2-benzimidazolylmethyl)-2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-(3-pyrimidone trihydrochloride m.p. 226 # 229 t Anal. (C20H25N8OS2Cl3) C H N Calc. (%) 42.60 4.47 19.87 Found (%) 42.69 4.55 19.65 Example 8 EMI35.2 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-(2-dimethylaminoethyl)-6-methyl-4(1H)-pyrimidone trihydrochloride m.p. 164#167 C Anal. (C16H23N7OS2Cl3) C H N Calc. (%) 38.06 5.59 19.42 Found (%) 38.16 5.59 19.17 Example 9 EMI36.1 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio] ethyl]-5-(3-dimethylaminopropyl)-6-methyl-4(1H)-pyrimidone tri-hydrochloride m.p. 175#177 C Anal. (C17H30N7OS2Cl3#1/2H2O) C H N. Calc. (%) 38.67 5.92 18.57 Found (%) 38.38 5.90 18.46 Example 10 EMI36.2 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-(2-quinolylmethyl)-4(1H)-pyrimidone m.p. 218#220 C Anal. (C22H23N7OS2) C H N S Calt. (%) 56.75 4.98 21.06 13.77 Found (%) 56.66 5.00 20.84 13.94 Example 11 EMI37.1 5-(p-tert-butylbenzyl)-2-[2-[[[2-[(diaminomethylene)amino] 4-thiazolyl]methyl]thio]ethyl]-6-methyl-4(1H)-pyrimidone dihydrochloride m.p. 190.5#193.0C Anal. (C23H32N6Os2Cl2) C H N Calc - (S) 50.82 5.93 15.46 Found (%) 50.51 5.81 15.38 Example 12 EMI37.2 5-(p-chlorobenzyl)-2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-4(1H)-pyrimidone dihydrochloride m.p. 194.5#198.0 C Anal. (C19H23N6OS2Cl3) C H N Calc. (%) 43.73 4.44 16.10 Found (%) 43.50 4.16 15.90 Example 13 EMI38.1 5-[(6-chloro-1,3-benzodioxole-5-yl)methyl])-2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl4(1H)-pyrimidone m.p. 201.5#202.5 C Anal. (C20H21ClN6O3S2 C H N Calc. (%) 48.73 4.29 17.05 Found (%) 48.65 4.30 17.08 Example 14 EMI38.2 5-[(1,3-benzodioxole-5-yl)methyl])-2-[2-[[[2-[(diaminomethylene) amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-4(1H)-pyrimidone m.p. 148.5#150.5 C Anal. (C19H22N6O3S2) C H N Calc. (%) 52.39 4.84- 18.33 Found (%) 52.36 4.63 18.31 Example 15 EMI39.1 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-(p-fluorobenzyl)-6-methyl-4(1H)-pyrimidone m.p. 139#141 C (recrystallized from ethanol ethylacetoacetate) Mass. (m/z) 432(M+) Anal. (c19H21N6OS2F) C H N S Calc. (%) 52.76 4.89 19.43 14.82 Found (%) 52.52 5.02 19.20 14.79 Example 16 EMI39.2 amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-phenethyl 4(1H)-pyrimidone di-hydrochloride m.p. 205#208 C (methanol) Mass, (m/z) 428(M+) Anal. (C20H24N6OS2#2HCl) C H N S Cl Calc. (%) 4790 5.23 16.70 12.79 14.14 Found (%) 47.73 5.20 16.86 12.97 13.99 Example 17 EMI40.1 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl] thio]ethyl]-5-(3-diethylaminopropyl)-6-methyl-4(1H)- pyrimidone tri-hydrochloride m.p. 179#181 C (ethanol) Anal. (C19H34N7OS2Cl3) C H N S Cl Calc. (%) 41.72 5.26 17.92 11.72 19.2 Calc. (%) 41.72 6.26 17.92 11.72 19.44 Found (%) 41.68 6.47 17.82 11.63 19.41 Example 18 EMI40.2 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-(p-phenylbenzyl)-4(1H)-pyrimidone m.p. 129.0#130.5 C (methanol) Mass (m/z) 491 (M++1 ) Anal. (C25H25N6OS2) C H N S Calc. (%) 61.20 5.34 17.13 13.07 Found (%) 61.17 5.20 17.12 13.00 Example 19 EMI41.1 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-4(1H)pyrimidone di-hydrochloride m.p. 182#185 C (methanol-chloroform) Mass (m/z ) 310 (M+) Anal. (C11H14N6Os2 - 2HCl#1/2H2O) C H N S Cl Calc. (%) 33.68 4.37 21.42 1,6.34 18.07 Found (%) 33.69 4.32 21.37 16.50 18.10 Example 20 EMI41.2 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-trifluoromethyl-4(1H)-pyrimidone hydrochloride m.p. 210#213 C (methanol) Mass. (m/z) 378 (M+) Anal. (C12H13N6OS2F3#HCl) C H N S Cl Calc. (%) 34.74 3.40 20.26 15.46 8.55 Found (%) 34.64 3.17 20.13 15.53 8.76 Example 21 EMI42.1 m.p. 175#179 C (methanol) 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl) -5-phenyl-4(1H) -pyrimidone di-hydrochloride Mass. (m/z) 386(M+) Anal. (C17H18N6OS2 . 2HCl . H2O) C H N S Calc. (%) 42.77 4.64 17.60 13.43 Found (%) 42.78 4.36 17.57 13.11 Example 22 EMI42.2 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-(p-methylbenzyl)-4(1H)-pyrimidone m.p. 133#135 C (ethanol) (2 # HCl salt m.p.177#181 C (ethanol)) Mass. (m/z) 428 (M.+.) Anal. (C20H24N6OS2 # 2HCl # H2O) C H N S Cl Calc. (%) 46.24 5.43 16.18 12.34 13.65 Found (%) 46.44 5.13 16.30 12.58 13.64 Example 23 EMI43.1 thiazolyl]methyl]thio]ethyl]-5-(3,4,5trimethoxybenzyl)-6-methyl-4(1H)-pyrimidone dihydrochloride m.p. 168#171 C (methanol-ether) Mass (m/z) 504 (M+) Anal. (C22H28N6O4S2 # 2HCl) C II N S Cl Calc. (%) 47.75 5.24 14.55 11.10 12.28 Found (%) 45.46 5.29 14.70 10.94 12.42 Example 24 EMI43.2 2-[2-[[[2-[(diaminothylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-n-hexyl-6-methyl-4(1H)-pyrimidone di-hydrochloride m.p. 166#169 C (ethanol-ethyl acetate) Mass (m/z) 408 (M+) Anal C C18 H28 N6 OS2 2HC1) C H N S Cl Calc. - (%) 44.90 6.28 17.45 13.32 14.73 Found (%) 44.80 6.29 17.47 13.51 14.64 Example 25 EMI44.1 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-n-octyl-4(1H)-pyrimidone di-hydrochloride m.p. 165#169 C (ethanol-ethylacetate) Mass (m/z) 436 (M+) Anal. (C20H32N6OS2 # 2HCl) C H N S Cl Calc. (%) 47.14 6.73 16.49 12.58 13.92 Found (S) 46.89 6.87 16.40 12.60 13.79 Example 26 EMI44.2 m.p. 156#159 C (ethanol) #3HCl Anal. (C19H32N7OS2Cl2 # 1/2 H2O) C H N Calc. (%) 41.19 5.00 17.70 Found (%) 41.04 6.15 17.80 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-(2-piperidinoethyl-4(1H)-pyrimidone tri-hydrochloride Example 27 EMI45.1 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-ethyl-6-methyl-4(1H)-pyrimidone m.p. 182#183 C (ethanol-ethylacetate) Anal. (C14H20N6OS2). C H N Calc. (%) 47.71 5.72 23.84 Found (%) 47.54 5.62 23.83 Example 28 EMI45.2 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-propyl-4(1H)-pyrimidone m.p. 218#219 C (ethanol-ethylacetate) Anal. (C15H22N6OS2). C H N Calc. (%) 49.16 6.05 22.93 Found (%) 48.86 6.06 23.00 Example 29 EMI46.1 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-(2-propinyl)-4(1H)-pyrimidone m.p. 208#210 C (ethanol-ethylacetate) Anal. (C15H18N6OS2 # 1/2H2O). C H N Calc. (%) 48.50 5.16 22.62 Found (7O) 48.65 4.94 22.46 Example 30 EMI46.2 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-n-butyl-6-methyl-4(1H)-pyrimidone di-hydrochloride m.p. 163#165 C (ethanol-ethylacetate) Mass, (m/z ) 380 (M+) Anal. (C16H24N6OS2 # 2HCl # 1/2 H2O). C H N S Cl Calc. (%) 41.56 5.88 18.17 13.87 15.33 Found (%) 41.77 5.91 18.34 13.96 15.36 Example 31 EMI47.1 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-n-pentyl-4(1H)-pyrimidone di-hydrochloride m.p. 149#151 C (ethanol-ethylacetate) Mass. (m/z) 394 (M+) Anal. (C17H26N6OS2 # 2HCl # 1/2H2O) C H N S Cacl. (%) 42.85 6.13 17.64 13.46 Found (%) 42.82 6.09 17.60 13.19 Example 32 EMI47.2 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-(3-methybutyl)-4(1H)-pyrimidone di-hydrochloride m.p. 179#180.5 C (ethanol-ethylacetate) Mass. (m/z) 394 (M+) Anal. (C17H26N6OS2 # 2HCl # 1/2H2O) C H N S Cl Calc. (%) 42.85 6.13 17.64 13.46 14.88 Found (%) 43.06 5.89 18.01 13.62 15.03 Example 33 EMI48.1 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-cyclohexylmethyl-6-methyl-4(1H)-pyrimidone di-hydrochloride m.p. 191#193 C (methanol- iso-propanol) Mass (m/z) 420 (M+) Anal, (C19 H28 N5 2 2HC1) C H N S Cl Calc. (%) 46.24 6.13 17.03 12.99 14.37 Found (%) 46.11 6.32 17.09 12.79 14.23 Example 34 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio] ethyl]-6-methyl-5-(2-methyl-3-dimethylaminopropyl)-4(1H) pyrimidone tri-hydrochloride EMI48.2 m.p. 194#198 C Anal. (C18H32N7OS2Cl3) C H N S Ci Calc. (%) 40.56 6.05 18.40 12.03 19.96 Found (%) 40.57 6.27 18.56 12.02 19.93 Example 35 EMI49.1 5-n-butyl-2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl] methyl]thio]ethyl]-4(1H)-pyrimidone di-hydrochloride m.p. 163#165 C Anal. (C15H24N6OS2Cl2 # H2O) C H N S Cl Calc. (%) 39.39 5.73 18.37 14.02 15.50 Found (%) 39.70 - 5.89 18.50 14.34 15.89 Example 36 EMI49.2 2-[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio] ethyl)-5-n-pentyl-4( IH)-pyrimidone di-hydrochloride m.p. 162#164 C Anal. (C16H26N6OS2Cl2 # H2O) C H N S Cl Calc. (%) 40.76 5.99 17.83 13.60 15.04 Found (%) 40.57 5.94 17.70 13.75 14.74 Example 37 EMI50.1 5-n-butyl-6-methyl-2-[2-[[[2-[(N-n-propyl)diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-4(1H)-pyrimidone di-hydro chloride m.p. 163#165 C Anal. (C19H32N6OS2Cl2) C H N S Cl Calc. (%) 46.05 6.51 16.96 12.94 14.31 Found (%) 45.89 6.76 16.94 13.04 14.10 Mass. (m/z) 422(M+), 230 Example 38 EMI50.2 5-(3-diethylaminopropyl)-6-methyl-2-[2-[[[2n-propyl)diaminomethylene)amino]-4-thiazolyl]methyl]thio]- ethyl]4 (1H) -pyrimidone trihydrochloride m.p. 184#187 C Anal. (C22H40N7OS2Cl3) C H N- S Cl Calc. (%) 44.86 6.84 16.64 10.88 18.06 Found (%) 44.85 7.13 16.62 10.97 18.07 Mass. (m/z) 479 (M+) Example 39 6-Methyl-2-methyl-3-(m-piperidinomethylphenoxy)propyl4(1H)-pyrimidone EMI51.1 To 30 ml of dry ethanol was added metallic sodium under cooling. To the resulting solution was added gradually a solution of 3.5 g of 4-(m-piperidinomethylphenoxy)butaneamidine hydrochloride in 10 ml of dry methanol under cooling, followed by stirring for 10 minutes. Then, to the solution was added gradually a solution of 1.28 ml of ethyl acetoacetate in 10 ml of dry ethanol under cooling. After stirring for 24 hours at room tepperature, the resulting salt was filtered and the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography using chloroform - methanol as a devloping solvent, and was recrystallized from iso-propanol to provide 2.04 g of product. m.p. 120#121 C (iso-propanol) Mass, 341(M+) Anal. ( C20H2?N302) C(%) H(%) N(%) Calç, 70.35 7.97 1 2.3 1 Found 7 0.6 2 7.9 2 1 2.4 5 Examples 40-47 By following the same procedure as in Example 39, the following compounds were obtained: : Example 40 EMI52.1 6-trifluoromethyl-2-[3-(m-piperidinomethylphenoxy) propyl]-4(1H)-pyrimidone di-hydrochloride m.p. 119#124 C Mass. (m/e) 395 (M+-2HCl) Anal. (C26H24N3O2F3 # 2HCl) C (%) H (%) N (%) Cl (%) Calc. 51.29 5.60 8.97 15.14 Found 51.15 5.62 8.95 14.80 Example 41 5,6-dimethyl-2-[3-(m-piperidinomethylphenoxy)propyl]4(1H)-pyrimidone di-hydrochloride EMI53.1 m. p. 192#195 C (ethanol - ethyl acetate) Mass. (m/e) 355 (M+-2HCl) Anal. (C21H29N3O2 # 2HCl) C (So) H (%) N N C (%) Calc. 58.88 7.29 9.81 16.55 Found 58.56 7.27 9.69 16.38 Example 42 6-methyl-5- (p-phenylbenzyl)-2-(3- (m-piperidinomethyl- phenoxy)propyl]-4(1H)-pyrimidone di-hydrochloride EMI54.1 m.p. 193#196 C (ethanol) Mass. (m/e) 507 (M+-2HCl) Anal ( C33H37N302 2HCf ) C (%) H (%) N(%) Cl (%) Calc. 68.27 6.77 -7.24 12.51 Found 67.97 6.76 7.21 12.38 Example 43 6-methyl-5-(1-naphthylmethyl)-2-[3-(m-piperidinomethylphenoxy)propyl]-4(1H)-pyrimidone di-hydrochloride EMI55.1 m.p. 176#178 C (ethanol) Mass. (m/e) 481 (M+-2HCl) Anal. (C31H35N3O2 # 2HCl) C (%) H (%) N (74 C e Calc. 67.14 6.72 7.58 12.79 Found 6 6.9 0 6.7 6 7.3 7 1 2.3 6 Example 44 5-[(6-chloro-1,3-benzodioxole-5-yl)methyl]-6-methyl-2 [3-(m-piperidinomethylphenoxy)propyl]-4(1H)-pyrimidone EMI55.2 m.p. 141#142 C (methanol) Mass. (m/e) 509 (M+-1) Anal. (C28H32N3O4 Cl') C (%) H (%) N (%) Cl (%) Calc. 65.94 6.32 8.24 6.95 Found 65.95 6.37 8.32 7.28 Example 45 EMI56.1 6-methyl-2-[3-(m-piperidinomethylphenoxy)propyl]-4(1H)pyrimidone m.p. 122#123 C (ethanol-ether-chloroform) Mass. (m/e) 432 (M+) Anal. (C26H32N4O2)# C (%) H (%) N (%) Calc. 72.19 7.46 12.95 Found 72.26 7.31 12.97 Example 46 5-(2-benzimidazolylmethyl)-6-methyl-2-[3-(m-piperidino- methylphenoxy)propyl]-4(1H)-pyrimidone EMI56.2 In. P. 208#209 C (methanol-ethanol) Mass. (m/e) 471 (M+) Anal. (C28H33N5O2). C (%) H (%) N (%) Calc. 7 1.3 1 7.0 5 1 4.8 5 Found 71.04 7.01 14.74 Example 47 5-(p-tert-butylbenzyl)-6-methyl-2-(3-(m-piperidinomethyl- phenoxy)propyl]-4(1H)-pyrimidone di-hydrochloride EMI57.1 m. p. 189#193 C (:ethanol- ethylacetate) Mass. (m/e) 487 (M+-2HCl) Anal. (C33H41N3O2 # 2HCl) C (%) H (%) N (%) Cl (%) Cale 6 6.4 2 7.7 3 7.5 0 1 2.6 5 Found 6 6.2 6 7.7 4 7.5 0 1 2.7 7 Reference Example 39 3- Es- (dimethylaminomethyl) furfurylthiomethy) Propionainidine di hydrochloride EMI58.1 34 g of ethyl 3- 5-(dimethylaminomethyl)furfurylthiomethyl propionimidate was dissolved in 250 ml of dry methanol, and after adding 6 g of ammonium chloride and stirring the' mixture at room temperature for 1 hour,an ethanol solution containing hydrochloric acid was added to the mixture to produce a dihydrochloride, and the solvent was distilled off. The residue was recrystallized from a mixture of isopropanol and ethyl acetate to provide 3- 5-(dimethylaminomethyl)furfurylthiomethyl propionamidine di-hydrochloride (31 g) having a melting point of 134 - 136 C. Reference Example 40 Ethyl &alpha;-(3-pyridylmethyl)acetoacctata EMI58.2 Under nitrogen, 8.4 g of metallic sodium was dissolved in 500 ml of anhydrous ethanol, and after adding 23.8 g of ethyl acetoacetate and stirring the mixture at room temperature for 1 hour, 30 g of 3-chloromethylpyridine hydrochloride was added to the mixture followed by ref fluxing under mild heating. Salt formed was filtered away, and the solvent was distilled away. The residue obtained was purified by column chromato- graphy using chloroform - ethylacetate as a developing solvent to provide 12.0 g of oil product. NMR (CDCl3) #(ppm); 1.18 (3H,t) 2.20 (3H,s) 3.13 (2E,d) 3.78 (1H,t) 4.13 (2H,q) 7.04#7.60 (2H,m) 8.40 (2H,m) Mass (m/e) 221(M+) Reference Examples 41 - 44 By following the same procedure as in Reference Example 40, the following compounds were obtained: Reference Example 41 EMI59.1 ethyl &alpha;-(1-naphthyl-methyl)- acetoacetate NMR (CDCl3) #(ppm); 1.16 (3H,t) 2.15 (3H,s) 3.64 (2H,d) 3.95 (1H,t) 4.13 (2H,q) 7.2#8.2 (7H,m) Mass(m/e)270(M+),227,181 Reference Example 42 EMI59.2 ethyl &alpha;-(2-benzimidazolyl- methyl)acetoacetate Reference Example 43 ethyl &alpha;-(p-tert-butylbenzyl)acetoacetate EMI60.1 NMR (CDCl3) #(ppm); 1.18(t,3H) 1.27(z,9H) 2.17(s,3H) 3.11(d,2H) 3.75(t,1H) 4.14(q,2H) 7.08(d,2H) 7.28(d,2H) 7.00#7.36(m,4H) IR(neat) # ; 1735, 1710cm-1 Mass(m/e). 276(M+),261(M+-15) 233(M+-43) Reference Example 44 EMI60.2 ethyl &alpha;-[(6-chloro-1,3-benzodioxole-5-yl)- methyl]ace NMR(CDCl3) #(ppm);1.20(t,3H) 2.18(s,3H) 2.94#3.35(m,2H) 3.60#3.87(m,1H) 4.10(q,2H) 5.83(s,2H) 6.54#6.81(m,2H) IR(neat) #;1735,1710cm-1 Mass(m/e) 298(M+),255(M+-43) Example 48 EMI61.1 To 30 ml of ethanol containing 0.44 g of metallic sodium was added 3.0 g of 3-[5-(dimethylaminomethyl)furfurylthio] propionamidine di-hydrochloride followed by stirring for 10 minutes, and to the solution was added 1.24 g of ethyl aceto acetate followed by stirring for 20 hours at room temperature. The-solvent was distilled off under reduced pressure, The residue was purified by column chromatography using chlordform - methanol mixture as a developing solvent. After converting the product to the hydrochloride with ethanol containing hydrochloric acid, the product was recrystallized from ethanol to provide 2- 2- 5- (dimethylaninomethyl)furfurylthlo ethyl -6-methyl- (1H)-pyrimidone di-hydrochloride (1.7 g). m.p. 163#165 C (ethanol) Anal (C15H23N3O2S#Cl2) C(%) H(%) N(%) Calc. 47.37 6.10 11.05 Found 47.14 5.91 10.98 Examples 49 - 54 By following the same procedure as in Example 48, the following ,compounds were obtained' Example 49 2-[2-[[5-(dimethylaminomethyl)furfurylthio]ethyl]-5,6 dimethyl-4(1H)-pyrimidone di-hydrochloride EMI62.1 m.p. 172#177 C (ethanol - ethyl actoacetate) Anal. (C18H26N3O2SCl2) C (%) H(%) N (%) Calc. 48.73 6.39 10.66 Found 48.44 6.27 10.49 Example 50 EMI62.2 5-(p-tert-butylbenzyl)-2-[2-[5-(dimethylaminomethyl)furfurylthio]ethyl]-6-methyl-4(1H)-pyrimidone di-hydrochloride m.p. 171#175 C (ethanol) Anal. (C26H37N3O2SCl2) C (%) H (%) N (%) Calc. 59.31 7.08 7.98 Found 59.12 7.14 7.94 Example 51 EMI63.1 5-[(6-chloro-1,3-benzodioxole-5-yl)methyl]-2-[2-[5-(dimethylaminomethyl)furfurylthio]ethyl-6-methyl-4(1H)-pyrimidone di-hydrochloride m.p. 158#162 C (ethanol) Anal. (C23H28N3O4 S Cl3) C(%) H(%) Calc. 50.33 5.14 7.66 Found 50.27 5.07 Example 52 EMI63.2 2-[2-[5-(dimethylaminomethyl)furfurylthio]ethyl-6-methyl5-(1-naphthylmethyl)-4(1H)-pyrimidone di-hydrochloride m.p. 178#181 C (ethanol) Anal. (C26H31N3O2SCl2 # 1/2H2O) C(%) H(%) N(%) Calc 58.97 6.09 794 Found 59.15 5.97 794 Example 53 EMI64.1 2-[2-[5-(dimethylaminomethyl)furfurylthio]ethyl-6-methyl 5-(3-pyridylmethyl)-4(1H)-pyrimidone trihydrochloride nip 1.64# 1660C (methanol) Anal. (C21H29N4O2SCl2) C(%) H(%) N(%) Calc. 49.66 5.75 11. Q3 Found 49.26 5.83 10.78 Example 54 EMI64.2 5-(2-benzimidazolylmethyl)-2-[2-[5-dimethylaminomethyl)furfurylthio]ethyl]-6-methyl-4(1H)-pyrimidone tri-hydrochloride m.p. 185#189 C (ethanol) Anal ( C23 H30 N5 02 S Cl3) ) C(%) H(%) N(%) Calc. 50: :51 5.53 12.80 Found 50.22 5.56 12.64 EMI65.1 mp. 150-155 C Mass. (m/z) 350(M++1), 304(M+-45) Example 56 EMI65.2 mp. 158 Mass. (m/z) 364(M +1), 318(M.-45) Anal. (C19H31N3 C H N S Cl Cal. (%) 52.29 7.16 9.63 7.35 16.25 Found (%) 52.03 7.45 9.64 7.29 16.22 Example 57 EMI65.3 mp. 153 - 165 C Mass.(m/z) 378(M++1), 332(M+-45) Anal. (C20H33N3O2SCl2) C H N S Cl Calc.(%) 53.33 7.38 9.33 7.12 15.74 Found (%) 53.28 7.56 9.38 7.26 15.57 Example 58 EMI66.1 mp. 98 - 98.5 C Mass. (m/z) 346(M++1), 300(M+-45) Anal. (C18H23N3O2S) C H N S Calc.(%) 62.58 6.71 12.16 9.28 Found(%) 62.67 6.43 12.20 9.25 By following the same procedure as in Example 39, the following compounds were obtained Example 59 EMI66.2 ,mp. 80 - 82 C Mass(m/z) 412(M++1) Anal.(C25H37N3O2) C H N Calc. (%) 72.96 9.06 10.21 Found (%) 72.75 9.08 10.16 Example 60 EMI67.1 mp. 128 - 1300C Mass. (m/z) 454(M+), 425(M+-29) By following the same procedure as in Example 1, the following compounds were obtained. Example 61 6-Methyl-2-[2-[[[2-[[(n-propyl)diaminomethylene]amino]4-thiazolyl]methyl]thio]ethyl]-4(1H)-pyrimidone di-hydrochloride EMI68.1 Mass(m/z) 366(M+) mp. 165.5 - 168 C (ethanol-ethyl acetate) Anal. (C15H22N6OS2 2HC1 l/2H2) C H N S Cl Calc.(%) 40.18 5.62 18.74 14.30 15.81 Found(%) 40.45 5.34 19.00 14.71 15.94 Example 62 5-Ethyl-6-methyl-2-[2-[[[2-[[(n-propyl)diaminomethylene]amino]-4-thiazolyl]methyl]thio]ethyl]-4(1H)-pyrimidone dihydrochloride EMI68.2 mp. 155 - 157 C (ethanol-ethyl acetate) Mass.(m/z) 394(M+) Anal. (C17H26N6OS2#2HCl) C H N S Calc.(%) 43.68 6.04 17.98 13.72 Found.(%) 43.50 6.05 18.01 13.68 Example 63 5-n-Hexyl-6-methyl-2-[2-[[[2-[[(n-propyl)diaminomethylene]amino]-4-thiazolyl]methyl]thio]ethyl]-4(1H)-pyrimidone di-hydrochloride EMI69.1 mp. 148 - 150 C (ethanol-ethyl acetate) Mass.(m/z) 450(M+) Anal. (C21H34N6OS2#2HCl) C H N S Cl Calc.(%) 48.17 6.93 16.05 12.25 13.54 Found (%) 47.98 6.71 16.09 12.12 13.64 Example 64 5-Benzyl-6-methyl-2-[2-[[[2-[[(n-propyl)diaminomethylene]amino]-4-thiazolyl]methyl]thio]ethyl]-4(1H)-pyrimidone dihydrochloride EMI69.2 mp. 162 - -1650C (ethanol - ethyl acetate) Mass. (m/z) 456(M+) Anal. (C22H28N6OS2#2HCl) C H N S Cl Calc.() 49.90 5.71 15.87 .12.11 13.39 Found (%) 49.71 5.51 15.69 11.87 13.52

Claims: CLAI: MS 1. A compound of the formula I EMI70.1 wherein R1 represents a hydrogen atom, a C1 to C10 alkyl group, a S to C5 alkenyl group, a C1 to C5 alkinyl group, a phenyl group, a cycloalkylmethyl group, an unsubstituted or substituted aralkyl group, or the group EMI70.2 wherein A represents a C1 to C5 alkylene group and R3 and R4 are the same or different Cl to C5alkyl groups or combine to form - with the adjacent nitrogen atom a piperidine or pyrrolidine ring; R2 represents a hydrogen atom, a Clto C5 5 alkyl group or a trifluoromethyl group; Y represents a heterocyclic group of the formula EMI70.3 wherein R represents a hydrogen atom or a C1 to C5 alkyl - group;. B represents an oxygen atom or a sulfur atom; m represents zero or an integer of 1 to 3; and n represents an integer of 1 to 3; or a pharmacologically acceptable salt. 2. A compound according to claim 1 wherein R1 is an aralkyl group in which the aryl portion is optionally substituted by at least one substituent selected from C1 to C alkyl groups, C1 to C5 alkoxy groups, halogens S and C1 to C5 alkylenedioxy and phenyl groups. 3. A compound according to- claim 1 wherein A is a C1 to C5 alkylene group. 4. A compound according to claim 1 wherein B is oxygen and m is zero. 5. A compound according to claim 1 wherein B is sulfur and m and n are the same or different integers of 1 to 3. 6. A compound according to claim 1 wherein Y is EMI71.1 B is sulfur, and m and n are the same or different integers of 1 to 3. 7. A compound according to claim 6 wherein R is a C1 to C3 alkyl group. 8. > A compound according to claim 1 wherein Y is EMI71.2 and m and n are the same or different integers of l.to 3. 9. A compound according to claim 8 wherein m is 1 and n is 2 and R1 is an aralkyl group selected from naphthylmethyl, pyridylmethyl, benzimidazolylmethyl and phenylmethyl groups which are optionally substituted on the aryl ring by at least one substituent selected from halogens and tert-butyl,methylenedioxy and phenyl groups. 10. A compound according to claim 1 wherein Y is EMI72.1 B is oxygen, and m is zero. 11. A compound according to claim 10 wherein n is 3 and R1 is dn aralkyl group selected from naphthylmethyl, pyridylmethyl, benzimidazolylmethyl and phenylmethyl groups which are optionally substituted on the aryl ring by at least one substituent selected from halogens and tert-butyl, methylenedioxy and phenyl groups. 12. A compound according to claim 1 wherein R1 is a C4 to C9 alkyl group. 13. One or more of the compounds 5-(p-tert-butylbenzyl)-2-[2-[[[2-(diaminomethylene)amino]4-thiazolyl]methyl]thio]ethyl]-6-methyl-4(1H)-pyrimidone; 2-[2-[[[2-(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-n-butyl-6-methyl-4(1H)-pyrimidone; 2-[2-[[[2-(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-n-pentyl-4(1H)-pyrimidone; 2-[2-[[[2-(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-6-methyl-5-(1-naphthylmethyl)-4(1H)-pyrimidone; 2-[2-[[[2-(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-(3-dimethylaminopropyl)-6-methyl-4(1H)-pyrimidone; 2-[2-[[[2-(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]-5-(3-diethylaminopropyl)-6-methyl-4(1H)pyrimidone; 5-[(1,3-benzodioxole-5-yl)methyl]-2-[2-[5-(dimethylamino methyl)furfurylthio)ethyl) -6-methyl-4(1H) -pyrimidone; and 5-(p-tert-butylbenzyl)-6-methyl-2-[3-(m-piperidinomethylphenoxy)propyl]-4(1H)-pyrimidone. 14. A pharmaceutical composition containing a compound according to any preceding claim and excipient. 15. A process for preparing a compound according to claim 1 which comprises reacting a compound of the formula EMI74.1 with a compound of the formula EMI74.2 wherein Y, B, m, n, R1 and R2 are as defined in claim 1, is a C1 to C5 alkyl group, R7 is a C1 to C5 alkyl group, and Z is NH3 or OH6 wherein R6 is a C1 to C5 alkyl group. 16. A process according to claim 15 which comprises reacting a compound of the formula: EMI74.3 wherein Y, B, m and n are as defined in claim 15 with a compound of the formula EMI74.4 wherein R11 R2 and R5 are as defined in claim 15. 17. A process according to claim 15 which comprises reacting a compound of the formula EMI75.1 wherein Y, B, R6, m and n are as defined in claim 15 with a compound of the formula : EMI75.2 wherein R1, R2, and R7 are as defined in claim 15. 18. A novel compound of formula II or III herein.

Inventors: OHTA, MITSUAKI, TAKAGI, TOKUICHI, YANAGISAWA, ISAO
Applicants: YAMANOUCHI PHARMACEUTICAL CO. LTD.
Application year: 1983
Main classification: C07D239
IPC codes: C07D277, C07D405, C07D239, C07D417, C07D317, C07D231, C07D295, C07D213, C07D401, C07D403, C07D235, C07D215