United States Patent 0

32,736,331 United States Patent 0 CC Patented May 29, 1973 1 2 Speci?c compounds which fall with the above classes 3,736,331 of novel compounds and are particularly useful include ISOTHIOUREAS James Whyte Black, Hempstead, Graham John Durant, N-3- (4 ( 5 ) -imidazolyl) propyl-S-ethylisothiourea, Welwyn Garden City, John Colin Emmett, Kimptdn, N-3- ( 4( 5 ) -imidazolyl) propyl-S-(2-phenylethy1) isothio and Charon Robin Ganellin, Welwyn Garden City, urea, England, assignors to Smith Kline & French Labora N-3 - (4 ( 5 ) -imidazolyl) propyl-S-propargylisothiourea, and tories Limited, Welwyn Garden City, England N-4» (4 ( 5 ) -imidazolyl) butyl-S-methylisothiourea. No Drawing. Filed Oct. 14, 1970, Ser. No. 80,819 Int. Cl. C07d 49/36‘, 31/40, 91/42 Suitable starting materials which may be used for the US. Cl. 260—309 14 Claims 10 synthesis of the isothioureas of Formula I are the com pounds represented by the following Formula II: ABSTRACT OF THE DISCLOSURE FORMULA II N-(heterocyclic-alkyl)isothioureas. These compounds inhibit histamine activity. 15 {To-(0112mm,‘N This invention relates to isothiourea compounds which in which n and A have the same signi?cance as in For are pharmacologically active and to intermediates in the mula I. Of the preferred compounds wherein A is such preparation of these compounds. The compounds of the that an imidazol-4(5)-y1 ring is formed, histamine (n=2) invention normally exist as the addition salts but, for 20 is of course well known and readily available; the com convenience, reference will be made throughout this spec pound where n=3 may ‘be synthesized from 4(5)-2-chlo i?cation to the parent compounds. roethylimidazole as described in Example 1 hereinafter; It has for long been postulated that many of the physio the synthesis of the compound wherein ni=4 has [been de logically active substances within the animal body, in the scribed and the compound wherein n==5 is synthesized course of their activity, combine with certain speci?c sites 25 from e-aminocaproic acid. known as receptors. Histamine is a compound which is Reaction of amines of Formula II with an isothiocy believed to act in such a way but, since the actions of anate of the formula R3NCS wherein R3 is an alkyl group histamine fall into more than one type, it is believed that containing from one to four carbon atoms, phenyl, benzyl there is more than one type of histamine receptor. The or benzoyl leads to compounds of Formula III: type of action of histamine which is blocked by drugs FORMULA III commonly called “antihistamines” (of which mepyramine is a typical example) is believed to involve a receptor which has been designated by Ash and Schild (Brit. J. Pharmac. Chemother. 27:427, 1966) as H-l. The sub 35 stances of the present invention are distinguished. by the The compounds of Formula HI may also be formed, in fact that they act as histamine receptors other than the certain cases, from the amines of Formula II by treatment H-1 receptor. Thus they are of utility in inhibiting certain of the latter with carbon disulphide to form the dithio actions of histamine which are not inhibited by the above carbamic acid, the alkyl ester of which is then treated with mentioned “antihistamines.” 40 R3NH2. The pharmacologically active isothiourea compounds, In the case where R3 in the compounds of Formula III of this invention are represented by the following formula is benzoyl, hydrolysis leads to the corresponding com in which it is understood that the structure of the nucleus pounds wherein R3 is hydrogen, which compounds may is such that the bond between the carbon and nitrogen alternatively be formed directly from the amines of For atoms might equally well be represented as a double 45 mula II by reaction at an elevated temperature with am bond: monium or an alkali metal thiocyanate. FORMULA I The compounds of Formula III wherein R3 is hydrogen, NR2 an alkyl group containing from one to four carbon atoms, phenyl, benzyl or benzoyl form an important part of the 50 present invention. Treatment of these compounds with SR1 the compound R1Y wherein R1 has the same signi?cance in which: as in Formula I and Y is halogen or hydroxy leads to the isothioureas of Formula I. This reaction is normally n is 2 to 5; carried out on the halogen acid addition salt of the com A is a chain of 3 to 4 atoms of which 1 to 2 are nitrogen 55 pounds of Formula III and/or in the presence of a halo or 1 is sulfur in the position alpha to the carbon atom gen acid which, when Y is halogen, will conveniently be and the remainder are carbon, which chain forms an of the Formula HY. The reaction will normally be car unsaturated ring with the carbon and nitrogen atoms ried out in a suitable solvent such as an alcohol, e.g. to which it is attached; ethanol, dimethylformamide or acetone. R1 is a saturated or unsaturated alkyl group having 1 to 60 Alternatively, the compounds of Formula III may be 6 carbon atoms or (CH2)mZ where m is 1 to 3 and Z treated with an unsaturated substance such as acrylonitrile is phenyl optionally substituted by halogen, hydroxy or as described in Example 16 hereinafter to yield the cor nitro; hydroxy; di-lower alkylamino; cyano; carboxy; responding isothiourea within the scope of Formula I. phenoxy; benzhydryloxy or imidazolyl and An alternative method for the production of certain R2 is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl 65 compounds of Formula I from the amines of Formula H or benzyl or R1 and R2 together with the carbon-atoms involves treatment of the latter with an alkylthio com to which they are attached may form a thiazoline or pound for example with 2-methylmercapto-Z-thiazoline thiazolin-4-one ring I as described in Example 27 hereinafter. and pharmaceutically acceptable acid addition salts there As stated hereinabove the isothioureas of our invention of. 70 normally exist and are produced as addition salts with Most preferably A is such that it forms with the carbon acids. Such addition salts include those with hydrochloric, and nitrogen atoms shown an imidazol-4(5)-yl ring. hydrobromic, hydriodic, sulphuric, picric and maleic 3,736,331 acids and as described in a number of the examples here M.P. 118—120° C., is obtained by acidi?cation with dry inafter, the addition salt with one of these acids may hydrogen chloride in ether. readily be converted to that with another. Such conver A solution of 4(5)-(2-cyanoethyl)imidazole (61 g.) in sion may be effected by means of ion-exchange tech absolute alcohol (600 ml.) is saturated with gaseous am niques. A particularly useful method which also in many monia at --20° C. The resultant solution is hydrogenated cases elfects puri?cation to a su?icient degree to allow the over Raney nickel catalyst (approximately 4 g.) at 100 resultant solution of the addition salt to be used for phar atmospheres pressure for four hours at a temperature of macological estimations involves the formation of the 135-145 ° C. After cooling, ?ltration and treatment with picrate salt and conversion therefrom to the chloride salt. charcoal, the solution is concentrated under reduced pres As stated above, the isothioureas of Formula I have 10 sure, a?'ording 4(5) - 3-aminopropylimidazole as a low been found to have pharmacological activity in the animal melting solid. For puri?cation, the amine (61 g.) is dis body as antagonists to certain actions of histamine which solved in a solution of sodium bicarbonate (82 g.) in are not blocked by “antihistamines” such as mepyramine. water (1.6 l.) and N-carbethoxyphthalimide ‘(122 g.) For example, they have been found to inhibit selectively added over 0.5 hour. After stirring for 1.5 hours, the solid the histamine-stimulated secretion of gastric acid from 15 is collected, Washed with water and dried. Recrystalliza the lumen-perfused stomachs of rats anaesthetised with tion from aqueous ethanol yields 4(5)-(3-phthalimido~ urethane, at doses from 8 to 256 micromoles per kilogram. propyl)imidazole. A pure sample obtained by further re~ Similarly, the action of these compounds may, in many crystallization from aqueous ethanol has M.P. 160 cases, be demonstrated by their antagonism to the eifects 162° C. of histamine on other tissues which, according to the Hydrolysis with 5 N hydrochloric acid for 16 hours above-mentioned paper of Ash and Schild, are not H-l followed by removal of phthalic acid yields 4(5)-3 receptors. Examples of such tissues are perfused isolated aminopropylimidazole dihydrochloride, M.P. 156-158° C. guinea-pig heart, isolated guineaapig right atrium and (from ethanol-ether). Treatment with sodium ethoxide in isolated rat uterus. ethanol yields pure 4(5)-(3-aminopropyl)imidazolc. The compounds of Formula I may be combined with a A solution of benzoyl isothiocyanate (65.2 g.) in chlo pharmaceutically acceptable carrier to form pharmaceu roform is added slowly to a solution of 4(5)-(3-amino tical compositions. Advantageously the composition will propyl)~imidazole (50.0 g.) in chloroform (1.5 1.). The be made up in dosage unit form appropriate to the de resultant solution is heated at re?ux temperature for two sired mode of administration. The pharmaceutical carrier hours and concentrated under reduced pressure. The employed may be, for example, either a solid or liquid. 30 residue is dissolved in ethanol and added to an excess Exemplary of solid carriers are lactose, terra alba, su of distilled water which results in the precipitation of a crose, talc, gelatin, agar, pectin, acacia, magnesium stea White solid.

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