Patent GB-593499-A (GB)
Title: New pyrimidine compounds
IPC: C07D403/12
Filed: 1945-10-09
Abstract: Pyrimidine compounds, useful as chemotherapeutic agents, and of the general formula <FORM:0593499/IV/1> wherein X and Y, which are not necessarily alike, each represent hydrogen or a hydrocarbon radical or jointly represent a divalent aliphatic hydrocarbon radical which forms with the 5- and 6-carbon atoms an alicyclic ring, R11 represents hydrogen or an alkyl or substituted alkyl (e.g. alkoxyalkyl or dialkylaminoalkyl) group, A represents an aliphatic, alicyclic or aliphatic-carbocyclic linking group which may be substituted by hydrocarbon radicals or hydroxy, alkoxy or dialkylaminoalkyl groups and, 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 such as alkylamino, dialkylamino or piperidino or other strongly basic nitrogen-containing heterocyclic group, and wherein the Bz ring of the benziminazolyl group may be unsubstituted or may bear one or more non-acidic substituents, e.g. hydrocarbon radicals (which themselves may bear substituents and which may be attached to the Bz ring directly or indirectly, e.g. through an oxygen, sulphur or nitrogen atom, or may be fused thereto as in the case of a naphthiminazolyl radical), halogen atoms or nitro or cyano groups, are manufactured by the interaction of a diamine NHR11-A-NRR1 with an appropriate 2-benziminazolyl-(21)-aminopyrimidine bearing in the 5- and 6-positions the atoms or groups Y and X respectively and in the 4-position a labile substituent such as a halogen atom or a hydrocarbon radical attached by an ether or thioether linkage, e.g. an alkoxy, aryloxy or alkylmercapto group.  The reaction may be effected by heating the reactants together, optionally in the presence of a solvent or diluent.  One or other of the reactants may be in the form of a salt, e.g. hydrochloride or acetate, and an acid-binding agent, e.g. sodium hydroxide, may be present if desired. When R1 in the general formula above represents hydrogen, the diamine may be replaced by its acyl derivative, the acyl group being subsequently removed by hydrolysis.  A further modification consists in introducing the basic substituent-NR11-A-NRR1 in stages by reacting the benziminazolylamino-pyrimidine compound, carrying a labile substituent in the 4-position, with an amino compound NHR11-A1-B, wherein A1 represents the whole or a part of the linking group A and B represents a reactive group which is then converted, directly or indirectly, by methods involving reaction with ammonia or a compound containing an amino group, into the group NRR1 or into a group A11-NRR1 such that A and A11 together constitute the linking group A.  Thus, B may represent a hydroxy group or a derivative thereof which is, or is readily convertible to, a reactive ester thereof, e.g. a halide, this then being brought into reaction with an amine NHRR1 or an amino-, hydroxy-or mercapto-substituted amine NH2-A111-NRR1, HO-A111-NRR1 or HS-A111-NRR1 (or an alkali metal derivative of the hydroxy or mercapto compound) such that A1-NH-A111, A1-O-A111 or A1-S-A111 constitutes the linking group A.  The terminal amino group, when unsubstituted, may be subsequently modified, e.g. by alkylation, conversion into a heterocyclic group such as piperidino or by bringing it into reaction with a halogen-substituted amine Hal-A111-NRR1 so as to extend the linking group A to A-NH-A111. In examples, the following compounds are prepared by heating the appropriate 2-benziminazolyl-(21)-amino-4-chloro-6-methylpyrimidine (or its hydrochloride) with the appropriate diamine in the presence of potassium iodide: 4-b -diethylaminoethylamino-2-benziminazolyl-(21) -amino-6-methylpyrimidine and its 51-(61)-chloro- and -methyl-derivatives; 4-g -diethyl-, -dimethyl- and -dibutyl-aminopropylamino-, 4 - g  - (N - methyl - N - isopropylamino) - propyl - amino-, 4-b -piperidinoethylamino- and 4-g -(b 1-diethylaminoethoxy) - propylamino - 2 - (51 - (61) - chlorobenziminazolyl - (21) - amino) - 6 - methyl - pyrimidine; 4-g -diethyl- and -dibutyl-amino-propylamino-2-(51-(61) -methoxybenziminazolyl-(21)-amino)-6-methylpyrimidine; 4-b -diethylaminoethylamino-2-(naphtho-111 : 211 : 41 : 51-iminazolyl - (21) - amino) - 6 - methylpyrimidine; 4-g -diethylaminopropylamino - 2 - (51 - methyl - benziminazolyl - (21) - amino) - 6 - methylpyrimidine; and 4 - g  - dibutylaminopropylamino - 2 - benziminazolyl-(21)-amino-6-methylpyrimidine.  4 - Halogeno - 2 - benziminazolyl - (21) - amino - pyrimidines are obtainable by the action of phosphorus pentahalides or oxyhalides on the corresponding 4-hydroxy-compounds, themselves obtainable by interaction of the corresponding 2 - cyanamino - 4 - hydroxypyrimidines with an o-phenylenediamine or by interaction of the corresponding benziminazolylguanidines with an appropriate formylacetic ester. 2-Benziminazolyl-(21)-aminopyrimidines containing ether or thioether groups in the 4-position are obtainable by treating the 4-halogen-derivatives with appropriate hydroxy or mercapto compounds or with their alkali metal derivatives.