Patent GB-592928-A (GB)
Title: New pyrimidine compounds
Filed: 1943-06-11
Abstract: Pyrimidine compounds, useful as chemotherapeutic agents, of the general formula <FORM:0592928/IV/1> wherein X represents hydrogen or a hydrocarbon radical, Y represents hydrogen or a neutral substituent such as a hydrocarbon radical, a halogen atom or an alkoxy, aryloxy, alkylmercapto or cyano group, and also X and Y may be joined together to form an alkylene chain, and of G and G1 one represents an arylamino group optionally bearing one or more non-acidic substituents such as halogen atoms, nitro, cyano or esterified carboxyl groups or hydrocarbon radicals (which themselves may bear substituents and which may be attached to the arylamino group directly or through an oxygen nitrogen or sulphur atom or through a sulphonyl or boxyl group), and the other represents a group of the form NR11-A-NRR1 wherein R11 represents hydrogen or an alkyl or simply substituted alkyl group, A represents an aliphatic, alicyclic or aliphatic-carbocyclic group which may be substituted and which, when wholly or partly an aliphatic chain, may be interrupted by oxygen, sulphur or nitrogen atoms, and -NRR1 represents a strongly basic amino or substituted amino group, are made by the interaction of a diamine NHR11-A-NRR1 with an appropriate 2- or 4-arylaminopyrimidine bearing groups Y and X in the 5- and 6-positions respectively and a labile group, such as a halogen atom or a hydrocarbon radical which is attached by means of an ether or thioether linkage, in the 4- or 2-position. Alternatively, such a pyrimidine derivative is reacted with an amino compound of the form NHR11-A1-B, wherein A1 represents either the whole or part of the group A above and B represents a reactive group which is then converted directly or indirectly, by methods involving the step of reaction with ammonia or a compound containing an amino group, into the amino group NRR1 or into a group A11-NRR1 such that A1 and A11 together constitute the group A above. Thus, the group B may be a hydroxy group or a derivative thereof which is, or is readily convertible to, a reactive ester thereof, which is then reacted with an amine, an amino-substituted amine or a hydroxy- or mercapto-substituted amine.  Alternatively, diamine is replaced by its acyl derivative NHR11-A1-NH- acyl and the acyl group is subsequently hydrolysed off.  The terminal amino group when unsubstituted may be further modified, as by alkylation, by conversion to a heterocyclic group such as piperidino or by bringing it into reaction with a halogeno-substituted amine, halogen -A111-NRR1 so as to extend the linking group A to A-NH-A111.  The reactions are effected by heating the reagents together, optionally in the presence of a solvent or diluent.  Either of the reagents may be used in the form of a salt (e.g. hydrochloride or acetate), and, if desired, an acid-binding agent such as sodium hydroxide may be present.  In the examples, pyrimidine derivatives of the above general formula are made by the above process, a large number of starting materials being specified.  The products form salts with acids such as picric acid, hydrogen halides, sulphuric, phosphoric, acetic, lactic, tartaric, methanesulphonic, methylene-bis-2.3-hydroxynaphthoic and methylene-bis-salicylic acids. The 2 - chloro - 4 - arylamino isomers of the pyrimidine derivatives used in the examples may be employed, and also the corresponding 4-arylamino-2-bromo-, 2-phenoxy-, 2-ethoxy, 2-methylmercapto, 2 - ethylmercapto and 2-phenylmercapto-compounds and their isomers in which the 2- and 4-substituents are transposed.  Specifications 592,933, 592,934, 592,935, 592,936, 592,937, 592,938, 592,940 and 4900/39, as open to inspection under Sect. 91, are referred to. Samples have been furnished under Sect. 2(5) of the following compounds: the 2-b -diethylaminoethylamino-, -g -piperidinopropylamino-, -g  - dimethylaminopropylamino-, -d  - diethylaminobutylamino-, -d -diethylamino-a -methylbutylamino-, -g -(N-methyl-N-isopropylamino)-propylamino-, -g  - dibutylaminopropylamino-, d -dimethylaminobutylamino-, -g -monobutylaminopropylamino- and -d -dibutylaminobutylamino - derivatives of 4 - p - chloroanilino - 6 - methylpyrimidinedihydrochloride; 2-b -diethylaminoethylamino - 4 - p - methyl- or -methoxyanilino - 6 - methylpyrimidine dihydrochloride; 2 - g  - dibutylaminopropylamino - 4 - p - chloroanilino - 5 : 6 - dimethylpyrimidine dihydrochloride; 2-g -diethylaminopropylamino - 4 - p - chloroanilino - 5 : 6 - dimethylpyrimidine; the 2-g  - diethylaminopropylamino-, -g -(N - methyl - N - isopropylamino) - propylamino-, -g -dibutylaminopropylamino-, -g -dimethylaminopropylamino- and -b -diethylaminoethylamino-derivatives of 4 - p - chloroanilino - 5 - nitro - 6 - methylpyrimidine; 2-p-chloroanilino-4-g -(N-methyl- N - isopropylamino) - propylamino - 6 - methyl - pyrimidine dihydrochloride; 2-p-chloroanilino - 4 - b  - aminoethylamino - 6 - methylpyrimidine (two samples illustrating different methods of manufacture); and 2-p-chloroanilino-4-g -dimethylaminopropylamino - 5 : 6 - trimethylene - pyrimidine.  3 - Diethylamino - 1 : 2 - dimethylpropylamine is made by reduction with sodium and butanol of the oxime of 4-diethylamino-3-methylbutan-2-one (made by the condensation of methyl ethyl ketone, formaldehyde and diethylamine followed by conversion to the oxime in the usual manner). 2-Pyrrolidinoethylamine is made by the inter-action of pyrrolidine with bromoethylphthalimide with subsequent removal of the phthalyl radical by treatment with dilute acid.  N - Methyl - N - b  - diethylaminoethylpropylene - diamine is made by condensing acrylonitrile with b -diethylaminoethyl-methylamine and reducing the product.  b -Diperidino-b -methylethylamine is made by reducing with sodium and ethanol a -piperidino-propionitrile (made by condensing piperidine with acetaldehyde-bisulphite and subsequent reaction with potassium cyanide).  Pyrimidine derivatives containing ether or thioether groups in the 2- or 4-position, used as starting materials above, are made by reacting the corresponding halogen derivatives with appropriate hydroxy or mercapto compounds or with alkali metal derivatives of such compounds.  According to the first four Provisional Specifications, the group represented by A in the above formula may also be carbocyclic.