Patent GB-836738-A (GB)
Title: New heterocyclo compounds and process for manufacturing same
Filed: 1957-04-08
Abstract: The invention comprises a 3-R-cycloalkano[d]-thiazoline-2-one in which the cycloalkano portion contains 5 to 7 ring carbon atoms and R stands for hydrogen or an unsubstituted or substituted hydrocarbon radical having from 1-10 carbon atoms and salts and quaternary ammonium compounds thereof.  Specified unsubstituted hydrocarbon radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, allyl, methallyl, propargyl, cyclopentyl, cyclohexyl, cyclohexyl-cyclohexylethyl, cyclopentylpropyl, phenyl naphthyl, benzyl and phenylethyl. Substituted hydrocarbon radicals may be substituted by nitro, amino, imino, hydroxyl, etherified hydroxyl, esterified hydroxyl, oxido, carbamyl, esterified sulphonyl groups or a halogen atom. These compounds may be prepared by (1) treating a 2-halo-cycloalkanone with a salt or an ester of an N-R-thiocarbamic acid and, if desired converting the R attached to the N-atom into another radical (e.g. if R=H the thiazoline may be treated with a reactive ester such as an alkyl halide, if R=NO2 then this may be reduced to an amino group or if R=OH this group may be esterified); (2) treating a 2-thiocyano-cyclo-alkanone to form a 3-4-cycloalkano-[d]-4-thiazoline-2-one and if desired replacing the hydrogen atom attached to the N-atom by an organic radical. Suitable hydrolysing agents are aqueous mineral acids and aqueous alkaline agents; (3) treating a 2-B-cycloalkano-[d]-thiazole, in which the radical B is a substituent convertible into an oxo or hydroxyl group, e.g. an esterified or etherified hydroxyl group, a free or substituted amino group, a free or substituted imino group, or a free or substituted methylene group, to convert the group B, e.g. by hydrolysis, oxidation or diazotization, to an oxo group, and subsequently modifying the group R.  The products obtained in which R is a salt-forming group, e.g. amino, may be converted into salts by means of inorganic acids such as hydrohalic acids, perchloric, sulphuric and phosphoric acids or organic acids such as acetic, succinic, benzoic, methane sulphonic and naphthalene sulphonic acids. 3 - R - Cycloalkane - d - 4 - thiazoline - 2 - one in which R contains an amino group are converted to quaternary ammonium compounds by means of a lower alkyl halide, and the corredsponding quaternary hydroxides are obtaine therefrom by treatment with silver oxide.  Examples describe the preparation of cyclohexano - [d] - thiazoline - 2 - one, spiro - (4,5) - decano - (6,7-d1) - 41 - thiazoline - 21 - one, cyclopentano - [d] - 4 - thiazoline - 2 - one, cycloheptano - [d] - thiazoline - 2 - one, 3 - phenyl - cyclopentano - [d] - thiazoline - 2 - one, 3 - m - and - p - chlorophenyl - cyclopentano - [d] - thiazoline - 2 - one, 3 - methyl - cyclopentano - [d] - 4 - thiazoline - 2 - one, 6 - methyl and 3,6 - dimethyl - cyclohexano - [d] - 4 - thiazoline - 2 - one, 3 - methyl - cyclohexano - [d] - 4 - thiazoline - 2 - one, 3 - (21 - dimethylaminopropyl) -, 3-phenylethyl-, 3-(31-hydroxypropyl)-, 3-ethyl-, 3-allyl-, 3-[piperidino-(N)-ethyl]-, 3-(pyrrolidino-N - ethyl]-, 3 - propargyl -, 3 - (methylsulponylethyl)-, 3-(21-acetoxyethyl)-, 3-(41-nitrophenylethyl)-, and 3-[morpholino-(N)-ethyl]-cyclopentano - [d] - 4 - thiazoline - 2 - one, 3 - ethyl-, 3-allyl-, 3-diethylaminoethyl-, 3-phenylethyl-, and 3-(41-nitro-phenylethyl)-cyclohexano - [d] - thiazoline - 2 - one, 3 - methyl - cycloheptano - [d] - 4 - thiazoline - 2 - one, 3 - cyclohexanoethyl - cyclopentano - [d] - 4 - thiazoline - 2 - one, 3 - (21 - dimethylaminopropyl) - cyclohexano - [d] - 4 - thiazoline - 2 - one and salts thereof with hydrochloric, oxalic and tartaric acids, 3 - (31 - dimethylaminopropyl) - cyclopentano - [d] - thiazoline - 2 - one, 3 - (31 - dimethylaminopropyl) -, 3 - (21 - diethylaminoethyl) -, 3 - (methylsulphonylethyl) -, 3 - cyclohexanoethyl -, 3 - (21,31 - oxido - propyl) -, and 3 - (21,31 - dihydroxypropyl) - cyclohexano - [d] - 4 - thiazoline - 2 - one, 3 - (41 - acetyl - aminophenoxyethyl) - cyclopentano - [d] - thiazoline - 2-one, the hydrochloride of 3 - (41 - aminophenoxyethyl) - cyclopentano - [d] - 4 - thiazoline-2-one, 3 - hydroxymethyl - cyclopentano - [d] - 4 - thiazoline - 2 - one, the hydrochloride of 3 - (41 - aminophenylethyl) - cyclohexano - [d] - 4 - thiazoline - 2 - one, and 3 - amidino - cyclopentano - [d] - 4 - thiazoline - 2 - one hydrochloride.  N - R - Thiocarbamic acid lower alkyl ester is obtained by reacting carbon disulphide with a lower alkanol and treating the lower alkyl xanthate with an amine of the formula R-NH2, wherein R stands for H or an organic radical.  2 - Amino - cycloalkano - [d] - thiazoles are obtained by reacting a 2-chloro-cycloalkanone with thiourea and isolating the hydrochloride salt of 2-aminocycloalkano - [d] - thiazole.  2 - Chloro - cyclohexano - [d] - thiazole is obtained by treating 2-amino-cyclohexano-[d]-thiazole with sodium nitrite and treating the nitrosamine with cupric sulphate and sodium chloride.ALSO:3 - R - Cycloalkano - [d] - 4 - thiazoline - 2 - ones, wherein R stands for hydrogen or an unsubstituted or substituted hydrocarbon radical having from 1-10 carbon atoms, e.g. compounds having the formulae <FORM:0836738/VI/1> or a salt thereof are employed in pharmaceutical preparations in admixture with a pharmaceutical, organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. The preparations may take the form of tablets, dragees or solutions.  Example 18 describes a preparation containing 3-methylcyclopentano - [d] - 4 - thiazoline - 2 - one.  Among the salts specified are the salts with inorganic acids, e.g. sulphuric and phosphoric and organic acids, e.g. formic, acetic, glycolic, oxalic, citric, tartaric, cinnamic, lysine and arginine.