Patent GB-743932-A (GB)
Title: Improvements in or relating to derivatives of phenthiazine
Filed: 1953-06-22
Abstract: The invention comprises new derivatives of phenthiazine having the general formula <FORM:0743932/IV(a)/1> and acid addition salts thereof, wherein R is an alkyl or alkenyl group containing up to 4 carbon atoms and Y is a chlorine atom or a methoxy or methyl group. The compounds may be prepared by treating a 3-chloro-, 3-methoxy- or 3-methyl-phenthiazine which is unsubstituted or suitably substituted in the 10-position by known methods for the introduction or formation in the 10-position of a mono-alkyl (or monoalkenyl)-aminoalkyl group. Suitable methods include the following in which R and Y are as defined above and X is a halogen atom: (a) by condensation of 3-chloro-, 3-methoxy-or 3-methyl-phenthiazine with a secondary amine of the formula X.(CH2)3.NHR.  The reaction may be carried out in the presence of a condensing agent, e.g. an alkali metal or a derivative thereof, e.g. the hydride, hydroxide, amide, or alcoholate, preferably sodamide or caustic soda; (b) by conversion of the NH2 group of a phenthiazine derivative having the grouping -(CH2)3-NH2 in the 10-position and the group Y in the 3-position into an -NHR group. The conversion may be effected by various methods, e.g. (i) by the action of a halide RX; (ii) by forming a Schiff's base by treating with an aldehyde R1CHO to form an intermediate in which the substituent grouping on the ring nitrogen is -(CH2)3-N=CH-R1 and subjecting this to reduction to form the group -(CH2)3-NH-CH2R1, R1 being hydrogen atom or an alkyl or alkenyl radical containing at most 3 carbon atoms; (iii) by condensation of the phenthiazine derivative with an aldehyde R1CHO in the presence of formic acid, R1 being as defined above except that it does not represent a hydrogen atom; (iv) by forming a Schiff's base as in (ii), quaternizing the base with a reactive ester of the formula RQ to form the grouping <FORM:0743932/IV(a)/2> where Q is the acid residue of a reactive ester, and then effecting fission between the nitrogen atom and the =CH-R1 group by hydrolysis under mild conditions, e.g. by boiling with water or aqueous alcohol to form the grouping -(CH2)3-NH-R.HQ, and converting the salt thus formed to the corresponding base, the value of R1 in this case being of no direct significance; (c) by alkylation or alkenylation of a sulphonamide of the general formula <FORM:0743932/IV(a)/3> by treatment with a halide RX and hydrolysing the product; (d) by treating a halogeno alkyl phenthiazine having the group (CH2)3X substituted on the 10 position and the group Y in the 3-position with a primary amine RNH2; (e) by reacting a phenthiazine aldehyde having the grouping (CH2)2.CHO in the 10-position and the group Y in the 3-position to form a Schiff's base in which in the N-substituent grouping is -(CH2)2-CH=N-R and reducing this to form the grouping -(CH2)3-NHR.  Examples describe the preparation of (1) 3-chloro-10-(31-methylaminopropyl) phenthiazine using method (a) above, and (2) 3-chloro-10-(31-iso-propylaminopropyl) phenthiazine using method (d) above.  It is stated that 3-chloro 10-(31-methylaminopropyl phenthiazine, 3-methyl 10-(31-methylaminopropyl) phenthiazine, 3-chloro 10-(31-ethylaminopropyl) phenthiazine, 3-methyl 10-(31-isopropylaminopropyl) phenthiazine and 3-methyl 10-(31-ethylaminopropyl) phenthiazine may be obtained in a similar manner.  The hydrochlorides of each of the above products are also referred to.  The products are stated to have therapeutic value especially as anti-shock agents.