Patent GB-690274-A (GB)
Title: Antihistaminic substances
IPC: C07D401/06
Filed: 1948-10-18
Abstract: A process for the manufacture of antihistaminic substances of the general formula <FORM:0690274/IV (b)/1> where Py represents a pyridine residue which may carry halogen, alkyl or alkoxyl as substituents, Y stands for an alkylene group having 2 or 3 carbon atoms, R represents a dialkylamino-, piperidino-, morpholino-, or iminazolino group and R1 stands for alkyl, aryl, aralkyl, cycloalkyl or a heterocyclic residue, which may carry as substituents alkyl, alkoxyl, dialkylamino, chlorine or bromine, and of salts of such compounds, comprises the hydrolysis and decarboxylation of a nitrile having the formula <FORM:0690274/IV (b)/2> by reaction with a strong acid, e.g. 80 per cent sulphuric acid. In the alkyl, alkoxy and dialkylamino groups, the alkyl group contains not more than four carbon atoms.  The preparation of the nitriles is described in Specification 666,778.  In an example, 3-phenyl-3-(21-pyridyl)-N,N-dimethylpropylamine is prepared by heating a  - phenyl - a (b  - dimethylaminoethyl)-2-pyridylacetonitrile with (a) 80 per cent sulphuric acid; (b) 48 per cent hydrobromic acid; (c) a mixture of 80 per cent sulphuric acid and 48 per cent hydrobromic acid; (d) concentrated hydrochloric acid.  In (b) the product is isolated as the picrate.  Other compounds obtainable by the above methods include 3 - phenyl - 3 - (21 - pyridyl) - N,N - diethylpropylamine; 3 - (21 - pyridyl) - N,N - dimethylbutylamine substituted at the 4-position by phenyl, 211-thienyl, or p-bromophenyl radicals; 4-phenyl-4-(21-pyridyl)-2-(dimethylamino) - butane; 4 - phenyl - 4 - (21 - pyridyl) - N,N - dimethylbutylamine; 3 - cyclohexyl - 4 - (21 - pyridyl) - N,N - dimethylbutylamine; 3 - (21 - pyridyl) - N,N - dimethylpropylamine substituted at the 3-position by 211-thienyl, p-methylphenyl, p-methoxyphenyl, p-isopropylphenyl, p-bromophenyl, phenyl, cyclohexyl or 511 - bromo - 211 - thienyl radicals; 3 - phenyl - 3 - (61 - methyl - 21 - pyridyl) - N,N - dimethylpropylamine. Salts mentioned are of hydrochloric, hydrobromic, sulphuric, phosphoric, salicylic, tartaric, maleic, succinic and lauric acids.  The monohydrochloride, mono-hydrogen oxalate, mono-hydrogen succinate, and mono-hydrogen maleate of the product of the example are described.  The compounds may be administered as tablets, creams, or injectible solutions.  As open to inspection under Sect. 91, the Specification comprises compounds of the above general formula in which Y is an alkylene group of from 1 to 5 carbon atoms.  Instead of strong acids, alkali metal amides or organometallic compounds may be employed for reaction with the nitriles.  Additional examples describe carrying out the process of (1) above using in place of acid (d) sodamide, (e) lithium ethyl, (f) ethyl magnesium bromide; (2) the preparation of a -(2-pyridyl)-b -(2-imidazolinyl) ethylbenzene by reacting a -phenyl-a -(2-pyridyl)-b -2-(imidazolinyl) propionitrile with 80 per cent sulphuric acid; (3) the preparation of b -(2-pyridyl)-g -(2-imidazolinyl) propylbenzene from b  - phenyl - a  - (2 - pyridyl) - a  - (2 - imidazolinyl) propionitrile.  There are also mentioned as obtainable by the procedure of example (1), derivatives of 3-(2-pyridyl)-N,N-dimethylpropylamine substituted at the 3-position by an o- or p-chlorophenyl-, 2-pyridyl-, 2-thiazyl, 2-furyl-, or 2-pyrimidyl radical; and 3-(2-thiazyl) - 3 - (2 - pyridyl) - N,N - diethylpropylamine.  For use in examples (2) and (3), a -phenyl-a -(2 - pyridyl) - b  - (2 - imidazolinyl) propionitrile is prepared by condensing phenylacetonitrile and 2-(chloromethyl) imidazoline in the presence of sodamide, and b -phenyl-a -(2-pyridyl)-a -(2-imidazolinylmethyl) propionitrile is obtained by condensing b -phenylpropionitrile with 2-bromopyridine and 2-(chloromethyl) imidazoline.  This subject-matter does not appear in the Specification as accepted.ALSO:Antihistaminic preparations comprise compounds of the general formula <FORM:0690274/VI/1> where Py represents a pyridine residue which may carry halogen, alkyl or alkoxyl as substituents, Y is an alkylene group of 2 or 3 carbon atoms, R is a dialkylamino-, piperidino-, morpholino-, or iminazolino group, and R1 is alkyl, aryl, aralkyl, cycloalkyl or a heterocyclic residue, which may carry as substituents alkyl, aryl, alkoxyl, dialkylamino, chlorine or bromine, and salts of such compounds. Salts mentioned are the hydrochloride, hydrobromide, sulphate, phosphate, salicylate, tartrate, maleate, succinate, citrate, lactate and oxalate, some being the monohydrogen salts.  The compounds may be used as tablets, creams or as aqueous solutions, the latter being preferably of the salts in admixture with sodium carbonate and boric acid.  The preparation of such substances is described (see Group IV (b)).  Products of the above formula mentioned are 3-phenyl-3-(21-pyridyl)-N,N-dimethyl- or diethyl-propylamine; 3-(21-pyridyl)-N,N-dimethylbutylamine substituted at the 4-position by phenyl, 211-thienyl or p-bromophenyl radicals; 4-phenyl-4-(21-pyridyl)-2-(dimethylamino)-butane; 4-phenyl-4-(21-pyridyl)-N,N-dimethylbutylamine; 3-cyclohexyl-4-(21-pyridyl)-N,N-dimethylbutylamine; 3-(21-pyridyl)-N,N-dimethylpropylamine substituted at the 3- position by 211-thienyl, p-methylphenyl, p-methoxyphenyl, p-isopropylphenyl, p-bromphenyl, phenyl, cyclohexyl or 511-bromo-211-thienyl radicals; 3-phenyl-3-(61methyl-21-pyridyl)-N, N-dimethyl-propylamine. Specification 666,778 is referred to.  The Specification as open to inspection under Sect. 91, comprises compounds of the above formula in which Y is an alkylene group of from 1 to 5 carbon atoms. Mentioned are a -(2-pyridyl)-b -(2-imidazolinyl) ethylbenzene; b -(2-pyridyl)-g -(2-imidazolinyl) propylbenzene; 3-(2-pyridyl)-N,N-dimethylpropylamines substituted at the 3-position by an o- or p-chlorophenyl-, 2-pyridyl-, 2-thiazyl, 2-furyl-, or 2-pyrimidyl radical; and 3-(2-thiazyl)-3-2-(pyridyl)-N,N-diethyl propylamine.  This subject-matter does not appear in the Specification as accepted.