Patent GB-785142-A (GB)
Title: Manufacture of quaternary isoindoline compounds
IPC: C07D209/48
Filed: 1955-08-05
Abstract: The invention comprises isoindoline derivatives of the formula <FORM:0785142/IV (a)/1> in which n represents 1 or 2 and R, R1, R2 and R3 each represent an alkyl radical containing at most 5 carbon atoms, or R2 and R3 together with N represent a saturated heterocyclic radical containing 4 or 5 carbon atoms and A- is any anion suitable in therapeutic compounds.  Such compounds are obtained by reacting a compound of the formula <FORM:0785142/IV (a)/2> or a mono-alkyl-quaternary derivative thereof in which the alkyl group contains at most 5 carbon atoms with a quaternating agent capable of introducing an alkyl radical containing at most 5 carbon atoms so as to produce a diquaternary compound and, if desired, the anions in a compound so obtained are exchanged for other anions.  Anions which A- may represent include those from hydrochloric, hydrobromic, hydriodic, phosphoric, nitric, oxalic, acetic, citric, tartaric or aryl- or alkanesulphonic acids and the hydroxyl ion.  Exchange of the anions may be effected by treating the quaternary iodide with the silver salt of the appropriate acid, by forming the quaternary hydroxide by treatment with silver oxide and neutralization with the acid, or by use of an anion exchanger.  Quaternary iodides can be converted to chlorides by refluxing with methanolic hydrogen chloride.  The products have ganglionic blocking properties. In examples: (1) 4:5:6:7 - tetrachloro - 2 - (21 - dimethyl - aminoethyl)-isoindoline is refluxed in ethanol with methyliodide to give 4:5:6:7-tetrachloro-2 - (21 - dimethylaminoethyl) - isoindoline dimethiodide.  This is converted to the dimethochloride by treatment with silver chloride; (2) 4:5:6:7 - tetrachloro - 2 - (21 - diethylamino - ethyl) - isoindoline dimethiodide is similarly prepared.  It is converted to the dimethochloride by refluxing with methanolic hydrogen chloride or to the dimetho-tartrate by treatment with silver oxide followed by tartaric acid; (3) the dimethosulphate is prepared similarly to the dimethiodide of (2); similarly prepared are (4) 4:5:6:7 - tetrachloro - 2 - (21 - piperidino - ethyl)-isoindoline dimethiodide; (5) 4:5:6:7-tetrachloro - 2 - (31 - dimethylaminopropyl)-isoindoline dimethiodide and dichloride; (6) 4:5:6:7 - tetrachloro - 2 - (31 - diethylamino - propyl)-isoindoline dimethiodide; (7) 4:5:6:7-tetrachloro - 2 - (31 - pyrrolidinopropyl) - iso - indoline dimethiodide.  In further examples: (8) 2 - (41,51,61,71 - tetrachloro - isoindolinyl-21-ethyl)-trimethylammonium chloride (from the reaction of the base with methyl chloride in refluxing ethanol) is heated with methyl chloride and methanol in a closed vessel to give the diquaternary compound; (9) the di-iodide is prepared similarly; (10) in a process similar to (1) dimethyl formamide is used as the solvent; (13) 4:5:6:7 - tetrachloro - 2 - (21 - dimethyl - aminoethyl) - isoindoline dimethosulphate is obtained by quaternation of the base in methanol; (15) 4:5:6:7 - tetrachloro - 2 - (21 - morpholinoethyl) - isoindoline dimethiodide is preparing by quaternation of the base with methyl iodide in refluxing dimethyl formamide.  As starting materials, the 2-(di-substituted-aminoalkyl) - 4:5:6:7 - tetrachloroisoindolines can be prepared by reacting 3:4:5:6-tetrachlorophthalic anhydride with excess-di-substituted-aminoalkylamine or by reacting potassium 3:4:5:6-tetrachlorophthalimide in a solvent such as dimethyl formamide with a disubstituted-aminoalkyl halide, the 3:4:5:6-tetrachloro - N - (disubstituted aminoalkyl) - phthal - imide obtained being reduced, for example, with lithium aluminium hydride or electrolytically.  Monoquaternary compounds are obtained by effecting quaternation under mild conditions or by reacting a 4:5:6:7-tetrachloro - 2 - alkyl - isoindoline with a reactive ester of a di-substituted amino - alkanol or by reacting a reactive ester of a 4:5:6:7 - tetrachloro - 2 - hydroxy - iso - indoline with a trisubstituted amine.  2 - Alkyl - 4:5:6:7 - tetrachloro-iso-indolines are obtained by reduction of the corresponding phthalimides with lithium aluminium hydride.  A 2-hydroxyalkyl-4:5:6:7-tetrachloro-isoindoline may be prepared by reacting tetrachlorophthalic anhydride with 2-aminoethanol to form the imide, followed by reduction with lithium aluminium hydride, and may be esterified with e.g. hydrochloric acid.  By such methods there are prepared as intermediates in examples: (1) N-(21-dimethylaminoethyl) - 3:4:5:6 - tetrachlorophthalimide and 4:5:6:7 - tetrachloro - 2 - (21 - dimethyl - aminoethyl) - isoindoline; (2) N - (21 - diethyl - aminoethyl) - 3:4:5:6 - tetrachlorophthalimide and 4:5:6:7 - tetrachloro - 2 - (21 - diethyl - aminoethyl) - isoindoline; (4) 3:4:5:6-tetrachloro - N - (21 - piperidinoethyl) - phthalimide and 4:5:6:7 - tetrachloro - 2 - (21 - piperidinoethyl)-isoindoline; (5) N-(31-dimethylaminopropyl) - 3:4:5:6 - tetrachlorophthalimide and 4:5:6:7 - tetrachloro - 2 - (31 - dimethylaminopropyl) - isoindoline; (7) N - (31 - pyrrolidono - propyl - 3:4:5:6 - tetrachlorophthalimide and 4:5:6:7 - tetrachloro - 2 - (31 - pyrrolidino - propyl) - isoindoline; (15) N - (2 - morpholinoethyl) - tetrachlorophthalimide and 4:5:6:7-tetrachloro - 2 - (21 - morpholinoethyl) - iso - indoline.ALSO:A pharmaceutical preparation for oral or parenteral administration as a ganglionic blocking agent comprises a quaternary N-(substituted - aminoalkyl) - tetrachloroisoindoline of the formula <FORM:0785142/VI/1> in which n represents 1 or 2 and R, R1, R2 and R3 each represent an alkyl radical containing at most 5 carbon atoms or R2 and R3 together with N represent a saturated heterocyclic radical containing 4 or 5 carbon atoms and A-is an anion suitable in therapeutic compounds, in admixture with a carrier suitable for oral or parenteral administration. The preparations can take the form of tablets, dragees, salves, creams, solutions, suspensions or emulsions. Carriers include gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, polyalkylene glycol, petroleum jelly and cholesterol.  Auxiliary substances such as preservatives, stabilizing, wetting or emulsifying agents, salts which alter the osmatic pressure and buffer substances and other therapeutically active compounds may also be present.  In Example (14) a composition of 4 : 5 : 6 : 7 - tetrachloro - 2 - (21 - dimethylaminoethyl)-isoindoline dimethochloride with tragacanth, lactose, corn starch, talcum powder and magnesium stearate is made into tablets.