[1]United States Patent Office 3109810,71 3,098,071 TRIACYCLES Herbert Morton Blatter, A4iliburn, and George de Stevens, IViBow Knoll, New Providence, N.J., assignors to Ciba Corporation, a corporation of Delaware No Drawing. Filed Nov. 9, 1961, Ser. No. 151,148 6 Claims. (Cl. 260-243) The present invention refers to novel H-1,3-thiazine compounds. More especially, it relates to compounds having one of the tautomeric structures O=C C-0-R2 I 11 I-LI-U N C/ I OTT s HO-C C-0-R2 11 11 N 0 and s 0=0 C-o-R2 I RI-CH \0/ l I 0 III in which R, stands for hydrogen or an organic radical, and R2 represents an organic radical, or salts thereof, as well as processfor t-he preparation of such compounds. In view of the .@Lact that the above structures are tautomeric to one another, a single compound may be assigned any of the three possi'ole structures. Since the structure ,of Formula I appears to be thepreferred one, the compounds of this invent@ion will be named hereinafter as in the derivatives of 6H-1,3-thiazines, or, more specifically, as 4-hydroxy-5-R,-2-(R2- 0)-6H-1,3-thiazin6-one compounds. An organic radical representing the group RI, which also stands for hydrogen, may be an aliphatic radical, such as lower alkyl, having from one to ten, preferably from one to four car-bon atoms, e.g. methyl, ethyl, npropyl, isopropyl, n-butyl, isabutyl, secondary butyl and tertiary,butyl, as well as npentyl,- neopentyl, n-hexyl, isohexyl, n-heptyl, n-ortyl, 2,2,3,3-tetramethyl-butyl, 5,5- dimethyl-hexyl, n-nonyl, n-decyl and the like. Aliphatic radicals RI are also lower alkenyl, e.g. vinyl, ally-1, 2methyl-allyl, 2- butenyl and the like, or lower alkynyl, e.g. ethynyl, lpro-pynyl and the like. RI -may also be a cycloaliphatic radical, such as cycloalkyl, havin.- from three to eight, particularlyfromfive to seven, ring carbon atoms, e.g. @Gyclopropyl, cyclobutyl, cycl,opentyl, cyclohexyl, cyrloheptyl and the like, or cyclo. alkenyl havin.g -from five to eight, especially @from five to seven,,r@ing carbon atoms, e.g. 2- cyclopentenyl, 3-cyclohexenyl, 3-cycloheptenyl and the like. Other radicals representing R, are cycloaliphatic-aliphatic radica@ls, particularly cycloalkyl-alkyl, in which cycloalkyl has from three to eight, especially -from five to seven, rin-,carbon atoms, and lower alkyl has -from one to four carbon atoms, e.9. cyclopenty-l-methyl, cyclohexylmethyl, 2-cyclohexyl-ethyl, 3- cyclopentyl-propyl and the like, or cycloalkenyl4ower alkyl, in which cycloalkenyl hasfrom five to eight, especially from five to seven, ring carbon atoms, and lower alkyl has from one to four car-bon atoms, e.g. 3-cyclohexenylmethyl, 2-(3-cyclohexenji)- ethyl and the like. Patented July 16, 1963 2 Aliph,atic Oradicals representing R, may also have substituents; wer alkyl, e.g. methyl, et-hyl, npropyl, iso' propyl and the like, may be primarily attached to cycloalipliatic radicals. ifunctional groups represent substituents attached to aliphatic or cycloaliphatic radicals, whereby one or more than one of the same or of different groups may be present; functional g-roups substitute primarily lower alkyl radicals. Such functional groups are, for example, oxygen-containing groups, such as, for ex10 ample, etherified bydroxyl, particularly lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, -isopropyloxy, n@butyloxy, isobutyloxy and the like, as well as polyalkylenedioxy, e.g. polypropylenedioxy,and the like (.which groups may have from two to twenty lower alkylenedioxy portions, and 15 which may have a -free terminal hydroxy@l or an etherified terminal hydroxyl, such as a terminal lo@wer alkoxy, e.g. methoxy, ethoxy and the like, group), car@bocyclic aryloxy, such as monocyclic carbocyclic aryloxy, e.g. phenyloxy and the like, or carbocyclic aryl4ower alkyloxy, such as 20 monocyrlic carbocyclic aryl4ower alkoxy, for example, phenyl-lower all-yloxy, e.g. benzyloxy, diphenylmethoxy, (4- chlorophenyl) -phenyl-methoxy and the like, or esterifled hydroxyl, such as lower lalkoxy-earbonyloxy, e.g. mothoxycarbonyloxy, ethoxy-earbonyloxy and the like, 25 carbamyloxy, such as carhamyloxy, N-lower alkyloarbamyloxy, e.g. N-methylcarbamyloxy and the like, N,Ndilower alkyl-car-bamyloxy, e.g. N,N-dimethyl-carbamyloxy and the like, or N-carbocyclic aryl-carbamyloxy, particular@ly N-monocyclic carbocyclic aryl-carbamyloxy, 30 e.g. N-phenyl-carbamyloxy and -the Ue, or lower alkanoyloxy, e.g. acetoxy, propionyloxy and the like, lower alkanoyl, e.g. acetyl, propionyl and the like. Functional substituents of aliphatic, particularly lower alkyl, xadicalsrepresenting the groilp RI are also nitrogen35 containing groups, such as amino, groups, primarily N,N&ubstituted amino, such as N,N-di-lower alkyl-amino, in - whir-rh lower alkyl hasfrom one to four carbon atoms, e.g. N;N-dimethylamino, N-ethyl-N-methylamino, N,Ndiethylamino, N@N-di-n-propylamino, NN-diisopropyl40 amino and the lilce, N-cycloalkyl-N-lower alkylamino, in which cycIGalkyl has ifrom three to eight, preferably -from five to seven, ring car-bon atoms e.g. N-cyclopentyl-Nmethylamino, -N-cyclohexyl-N-mcib@l,amino and the like, 45 N-car-bocyciie aryl-N-lower alkyl@amino, e.g. N-methylNphenyl-amino and the like,!N-carbocyclic aryl-lower alkylNlower alkyl-amino, such as N4ower alkyl-N-phenyllower alkyl-aniino, e.g. N-benzyl-N-methyl-amino, Nmethyl-N-(2- phenylethyl)-amino and the like, or N,N50 alkylene-imino, in which alkylene has from four to six chain carbon atoms, such as, for exa@mple, lpyrrolidino, e.g. Ipyrrolidino, 2-methyl-l-pyrrolidino and the like, 1-piperidino, e.g. 1-pipendiio, 2-methyl-l-piperidino, 3methyl-l-piperidino, 4- methyl-l-piperidino, 3-hydroxy-l55 piperidino, 3-acetoxy-l-piperidino, 3-hydroxymethyllpiperidino and the like, 1-N,N@hexa-Tnethylene-imino, and the like, N,N-oxa-alkylene-imino, in which alkylene has preferably four carbon atoms, e.g. 4-morpholino and the like, N,N-thia-alkylene-imino, in which,alkylene haspref60 erably four chain carbon atoms, e.g. 4-thiamorpholino, or N,Naza-alkylene-im-ino, in -which alkylene has from four to six chain car@bon atoms, particularly I-piperazino, such as 4- lower alkyl-l-piperazino, e.g. 4-methyl-l-piperazino and the lik-el as well as piperazino, 4-(2-,hydroxyethyl)-l65 piperazino, 4-(2-acetoxyethyl)-l-piperazino, 4-(2- polyethylenedioxy-ethyl)-1-piperazino and the Eke. Sulfur-containing substituents of aliphatic, especially lower alkyll radicals representing RI are -primarily etheri70 fled mercapto groups; the latter may be represented by lovier alkyl@mercapto, e.g. me,thy1mercapto, ethylmereapto and - the like, ca@rbocyclic aryl-mercapto, e.g. phenyl-mercapto and the like, or carbocyclic aryl4ower alkyl-mer-
[2]3 capto, such as phenyl-lower alkyl-mereapto, e.g. benzylmercapto and the like. Also include-d as substituents of aliphatic, particularly, alkyl, radicals -representing RI are halogeno atoms, e.g. fluoro, chloro, bromo and the like, whereby one or more tliarl one halogen atom may be attached to one or more than one carbon atom of an alkyl radical. An organic radical RI may also be a carbocyclic aryl, primarily a monocyclic carbocyclic aryl radical, e.g. plienyl, or a bicyclic carbocyclic axyl radical, e.,-. 1- naphthyl or 2-naphthyl. These radicals may be unsubstituted or may contain one or more than one of the same or different substituents attached to any of the positions available for substitution. Substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl and the like, etherified hy&oxyl, such as lower alkoxy, e..-. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, or lower alkylenedioxy, e.g. methylenedioxy and the like, esterified hydroxyl, such as lower alkoxycarbonyloxy, ie.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, or lower alkanoyloxy, e.g. acetyloxy, n-propionyloxy and the like, etherified mereapto, particularly lower alkyl-mercapto, e.g. methylmercapto,- ethylmereapto and the like, esterified carboxyl, such as carbo-lower alkoxy, e.g. carbomethoxy, carbethoxy and the L,'ke, nitro, amino, particularly N,N-disubstituted amino, for example, N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogeno, e.g. fluoro, chloro, bromo and the like, or trifluotomethyl and the like. Also included as representing R, are carbocyclic aryllower al@iphatic radicals, primarily monocyclic carbocyclic aryl-lower alkyl, such as phenyl-lower alkyl, e.g. benzyl, diphenylmethyl, I-phenylethyl, 2-phenyletl-iyl,- 3-phenylpro@yl and the like, bicyclic carbocyclic aryl-lower all-,yl, such as naphthyl-lower alkyl, e.g. 1- naphthylmethyl, 2-naphthylmethyl and the like, monocyclic carbocyclic aryl4ower alk,nyl, such as phenyl-lower alkenyl, e.g. 2phenylethenyl and the like, or bicyclic carbocyclic aryllower alkenyl, such as naphthyl-lower alkenyl, e.g. 1-(2naphthyl)- Dthenylandthelil,,e. 'fbecarbocycl-icpordons of these radicals may be iinsubstituted or may contain silbstituents, such as, for example, those mentioned hereinbefore present as substituents of the carbocyclic aryl radicals. A heterocyclic aryl radical R, is primarily a monocyclic or a bicyclic heterocyclic aryl radical, which contains one ,or more than one sulfur, oxygen and/or nitrogen atoin as ring members. Such radicals are preferably pentacyclic or hexacyclic, and are represented, for example, b@ pyridyl, e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl and the like, pyradazinyl, e.g. 3-pyridazinyl and the like, pyrimidyl, e.g. 2pyrimidyl, 4-pyrimidyl and the like, pyrazinyl, e.g. 2-pyrazinyl, pyrryl, e.g. 2-pyrryl and the like, thienyl, e.g. 2-thienyl and the lilce, furyl, e.g. 2-furyl and the like, as well as quinolyl, e.g. 2-quinolyl and tlle like, isoqui-nolyl, e.g. 1-isoquinolyl and the like, or any other suitable heterocyclic radical. The group RI may also stand for a heterocyclic aryl-lower aliphatic hydrocarbon radical, such as a monocyclic or a bicyclic heterocyclic aryl-lower alkyl radical, partictil-.rly pyridyl-lower alkyl, e.,-. 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)-ethyl and the like, tliienyl-lower alkyl, e.,-. 2-thenyl and the like, furyl-lower alkyl, e.g. 2-furylmethyl and the like, pyridazinyl-lower alkyl, e.g. 4-pyridazinylmethyl and the like, pyrimidyl4ower alkyl, e.g. 2-pyriinidylmethyl and the like, pyrazinyl-lower alkyl, e.g. 2-pyrazinylmethyl and the like, or any other analogous heterocyclic arylaliphat,ic radical. The above-described heterocyclic aryl radicals @are unsubstituted or may contain substituents, such as lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkyl-mercapto, 3,098,071 4 geno, e.g. fluoro, chloro, bromo and the like, or any other suitable substituent. The organic group R2 iS primarily an aliphatic radical,- especially lower alkyl, having from oileto seven, preferably from one to four, carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and the like, as wcll as n-pentyl, n-haptyl and the like, as well as lower alkenyl, having from two to seven, preferably from three to five, carbon atoms, e.g. alkyl, 2-metliylalkyl, 2-butenyl 10 and the like. The group R2 may also stand for a cycloaliphatic radical, such as cycloalkyl having from tbrce to eight, pteferably from five to seven, carbon atoms, e.g. cyclopentyl, cyclohexyl and the like, or cycloalkenyl having from five to eight, preferably from five to seven, 15 carbon atoms, e.g. 2-cyclopentenyl, 3-cyclopantenyl,- 2cyclohexenyl, 3- cyclohexenyl and the like, a cycloaliphaticaliphatic radical, such as cycloalkyllower alkyl, in which cycloalkyl has from three to eight, preferably from five to seven, carbon atoms, and lower alkyl has ftom one to 20 seven, preferably from one to four, carbon atoms, e.g. cyclopentylmethyl, 2- cyclop-.ntylethyl, cyclohexylmethyl, 1-cyclohexylethyl and the like, or cycloalkenyl-lower alkyl, in which cycloalkenyl has from five to eight, preferably from five to seven, carbon atoms, and lower alkyl 2@5 has from one to seven, preferably from one to four, carbori atoms, e.g. 1- cyclohexenylmethyl, 1-(I-cyclohexenyl)ethyl, 3-cyclohexenylmethyl and the like, a carbocyclic aryl radical, such as riionocyclic or bicyclic carbocyclic aryl, e.g. phenyl, 1-naphthyl, 2-naphthyl, or these radicals 30 having substi@tuents, such as lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl aiid the like, lower alkoxy, e.g. methoxy, ethoxy, isopropyloxy, n-butyloxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, trifluoromethyl and the like, carbocyclic aryl-aliphatic rad35 ical, such as monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lower alkyl, e.g. benzyl, I-phenylethyl, 2phenylethyl, diphenylmethyl and the like, or phenyl-lower alkyl, in which phenyl has substituents, sucli as those previously mentioned, or any other suitable and ;analogous 40 radical capable of representing the group R2- Salts of the compounds of this invention are primarily pharmaceutically acceptable alikali metal and alkaline earth metal salts, e.g. sodium, potassiun-1, ma-nesium, calcium andthe like, salts. Compounds of this invention, 45 having basic an-tino groups as substituents, may form pharmaceutically acceptable acid addition salts, such as those with inorganic acids, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, with organic acids, e.g. acetic, propionic, glycolic, malonic, suecinic, 50 maleic, hydroxymaleic, dihydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, 2-phonoxybenzoic, 2-acetoxybenzoic, acid and the like, o-r with organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic,- 2-hydroxyethane S'Ifonic, p-toluene sulfonic acid and the like. The compounds of this invention have depressant effects on the central nervous system (CNS) -and can, therefore, serve as tranquilizin@ and seda@ting agents in cases of overactiveness, nervousness and agitation. Advantageously, the compounds of this invention are virtually free from 60 undesirable hypnotic side effects, they are non-addicting, and @the therapeutic ratio, i.e.,relationship between effective and toxic doses, is very favorable. Particularly outstanding CNS-depressant effects are shown by the 2-lower alkyloxy-4-hydroxy-5-R,'-6H-1,3- 65 thiazin-6-ones of the formula s O=C) C-0-R2' 11 70 N in which Rl' represents bydrogen, an aliphatic radical,- particularly lower alkyl having from one to four carbon e.g. methyl-mercapto, ethyl-mercapto and the like, halo- 7,5 atoms, as well as a cycloaliphatic radical, particularly
[3]5 cycloalkyl having from five to seven carbon . atoms, or a cycloaliphatic-aliphatic radical, particularly cycloalkyllower alkyl, in which cycloalkyl has from five to seven carbon atoms and lower alkyl has from one to four carbon atoms, and R2' is lower alkyl, and alkali metal or alkaae earth metal salts of such compounds. The compounds of this invention may be used in the form of pharmaceutical preparations, which contain the new compounds or salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there can be employed substances which do not react with the active ingredient; suit-. able carriers may be, for example, water, gelatine, lactose, starche,s, magnesium stearate, steary-I alcohol, talc, vegetable oils, benzyl alcohol, gums, propylene glycol, polyalkylene glycols or any other ingredients used for pharmaceuticalpreparations. Thelattermaybeinsolidform, e.g. capsules, tablets, dragees and the like, or in liquid form, e.g. solutions, suspensions, emulsions and the like. If desired, they may contain auxfliary substances, such as preserving, stabilizing, wefting, emulsifying agents and the like, salts for varying the osmotic pressure, -buffers, etc. They may also contain, in combination, other useful substances. The compounds of this invention may be prepared, for example, by treating a reactive derivative of a malonic acid, having the formula on 0=0 I RI-CH OH 0 11 v in which RI has the previously-given meaning, with a thionocarbamate compound having one of the tautomeric formulae Hs C-0-Rg N-El and s e O-R2 1 NH2 in which R2 has the previously-given meaning, and, if desired, replacing in a resulting compound, in which R, stands for hydr4Dgen, such hydrogen atom by an organic radical, and/or, ff desired, converting a resulting compound into a salt thereof. A reactive derivative of a malonic acid having the previously-given formula is more especially a malonic acid halide represented by the formula x O=C I RI-CH \C 1! 0 in Which,R, has.the@ previously-given meaning, and each of the groups X and X' stands for halogeno, e.g. chloro, 3,098,071 in which RI has the previously-given meaning, and each of t@he groups Ro and Ro' istands for an etherffied hydroxyl group, such as 2-tetrahydropyranyloxy, as well as lower alkoxy, e.g. methoxy, ethoxy, isopropanyloxy, tertiary 5 butyloxy and the like. A further reactive derivative Df a malonic acid is a monoester halide having the formula 0=0/ 10 RI-CH Ro' \0/ 11 0 15 in which RI, X and Ro have the previously-given meanings. The reaction is preferably carried out in the presence of an inert solvent, for exami)le, methylene chloride, chloro20 form, carbon tetrachloride, diethyl ether, benzene, or any other suitable solvent. If desired, the reaction is performed in the presence of an inorganic or organic base, such as an alkali metal salt of an organic carboxylic -acid, e.g. sodium acetate and the like, an alkali metal lower . 25 alkanolate, e.g. sodium or potassium methanolate, ethanolate, tertiary butanolate and the like, or any other suitable base, such as a tertiary amine, e.g. N,N,N-triethylamine, pyridine and the like, if necessary, while cooling or at -an elevated temperature, in a closed vessel and/or in the 30 atmosphere of an inert gas, e.g. nitrogen. The starting materials are known or may be prepared according to known methods 'Ihe compounds of the present invention may also be prepared by rin.--closing a compound having one of the 35 tautomeric formulae R@ s I 11 0=0 C-0-R2 R@- @H Nil 4,0 c and R. SH O=C @-0- Rs I it RICli N \0/ 11 50 0 in which R, and R2 have the previously-given meaning, and R,, stands for hydroxyl or etherified hydroxyl, and, if @desired, carrying out the optional steps. 55 Apart from representing hydroxyl, the group R, in the - above formulae is an etherified hydroxyl group, such as lower alkoxy, e.g. methoxy, ethoxy and the like, or another etherified hydroxyl group, e.g. 2-tetrahydropyranyloxy and the like. 60 Ring closure is achieved accordin.- to known methods, for example, by heating, preferably in an inert solvent. Ring.closure is also accomplished by treatment with a suitable reagent, such as, for example, an N,N'-di-substituted carbodiimide, e.g. N,N'-di-cyclohexyl-carbodiimide bromo and the like. Other reactive derivatives of mar,5 and the like. Other ring closing reagents are, for exIonic acids are reactive esters, such as the 2@tetrahydroampl e, inorganic acid halides, e.g. thionyl chloride, phospyranyl ester, as well as the lower -alkyl esters, e.g. methyl, p horous pentachloride and the like or inorganic or orethyl, isopropyl, tertiary butyl ester and the like. Suit. ganic bases, such as, for example, a --@ alkali metal hydroxable esters of a malonic acid have the formula i de, e.g. sodium hydroxide, potassium hydroxide and the Ro 10 li ke, an alkali metal lowe.r alkanolate, e.g. sodium or poO=C t assium methanolate, ethanolate, tertiary butanolate and I t he like, an organic amine, e.g. N,N,N-triethylamine and RI-CH Ro' the like, pyridine, or any -other equivalent reagent. Treat\C ment with the reagent is preferably carried out in the 11 75 p resence of a suitable inert solvent,,,and, if desired, while 0
[4]3,098,071 7 cooling or at an elevated temperature, in a closed vessel and/or in the atmosphe@re of nitrogen. The starting materials may be prepared according to known methods, for example, by reacting, a malonic acid halide monoester, such as a malonic acid chloride mono5 lower alkyl-ester, with a suitable metal thiocyanate compound, such as, for example, lead thiocyanate and the like, and then with a suitable hydroxylated - compound, such as a lower alkanol, e.g. ethanol and the like, or with a lower alkyl thionocarbamate, e.g. ethyl thionocarbamate 10 and the like, and, if necessary, conver-ting the ester group into a free carboxyl group by hydrolysis. ,In a resulting compound, in which the group RI stands for hydrogen, such hydrogen atom may be replaced by an organic radical, particularly an aliphatic or a substituted 1,5 aliphatic radical, according to known methods, for example, by forming a metal salt, such as an alkali metal, e.g. sodium, potassium and the like, salt of a resulting compound, in which RI is hydrogen, and reacting the salt with a reactive ester of an organic hydroxyl compound, par20 ticularly the reactive ester of an aliphatic or substituted aliphatic hydroxyl compound, especially with an organic halogeno compound, such as an aliphatic or substituted aliphatic halogeno compound. A resulting compound may be converted into an alkali 25 metal salt or an alkaline earth metal salt according to known methods, for example, by treating it or a solution thereof with a metal hydroxide or hydride, preferably used in admixture with a solvent, and evaporating the diluent. 30 The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as weR as any new interniediates. In the process of this invention such starting materials 35 are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention. The following examples are intended to illustrate the in- 4( vention and are not to be construed as being limitations thereon. Temperatures are -iven in degrees centigrade. Exa7nple 1 A solution of 6.3 g. of ethyl thionocarbamate in 75 Mi. of dry methylene chloride in added dropwise over a period 45 of three hours to a solution of 8.46 g. of malonic acid dichloride in 45 ml. of dry methylene chloride while stirring and maintaining an atmosphere of nitrogen. The reaction proceeds at room temperature, and after completing the addition, stirring is continued for an additional 50 hour. The resulting precipitate is filtered off and the desired 2-ethoxy-4-hydroxy-6H-1,3-thiazin-6-one of the formula s 55 O=c c-o-c2]-f5 N c 60 is purified by crystallizing the crude product twice from a mixture of diethyl ether and npentane using a charcoal decolorizing preparation; M.P.- 129-132'. Exaniple 2 65 To 0.95 g. of @N-(ethoxythiocarbonyl)-malonamic acid in 50 ml. of dry diethyl ether is added a solution of 1.1 g. of N,N'-dicyclohexylcarbodiimide in 10 ml. of dry di-ethyl ether. The mixture is allowed to stand for one 7o hour, the precipitate is filtered off, and the futrate is concentrated. Dry n-pentane is added, whereupon 0.15 g. of the desired 2-ethoxy-4-hydroxy-6H-1,3-thiazin-6-one precipitates; the compound melts at 129-131' and is identical with the product of Example 1. 15 8 The starting material used in the above reaction may be prepared, for example, by reacting malonic acid monotertiary butyl ester with lead thiocyanate and then with ethanol, and hydrolyzing the tertiary butyl ester group by treatment @with a small amount of hydrochloric acid. Other compounds, which are prepared according to the above methods are, for example, 2-ethoxy-4-hydroxy-5methyl-6H-1,3-thiazin-4-one, 5-ethyl-4-hydroxy-2-methoxy6H-1,3-thiazin-4-one, 4-hydroxy-5-isopropyl-2-methoxy - 6H - 1,3 - thiazin - 4 - one, 5 - cyclohexyl - 2 - ethoxy-4-hydroxy-6H-1,3-thiazin-4-one, 5-cyclopentylmethyl2- ethoxy-4-hydroxy-6H-1,3-thiazin-4-one and the like. What is
