Patented Feb. 1, 1949 2,460,409 UNITED STATES PATENT of FICE 2,460,409. 2-BENZIMINAZOYL-AMINO PYRIMIDINES Frederick Robert Basford, Francis Henry. Swin den Curd, and Francis Leslie Rose, Blackley, Manchester, England, assignors to Imperial Chemical Industries Limited, a corporation of Great Britain No Drawing. Application October 4, 1946, Seria No. 701,092. In Great Britain October 9, 1945 9 Claims. (C. 260-251) 1. 2 This invention relates to the manufacture of may be used in the form of a salt, such as the new pyrimidine compounds which are useful as hydrochloride or acetate. Also, if desired, the chemotherapeutic agents and particularly as reaction may be carried out in the presence of an parasiticidal agents, especially against the para acid-binding agent such as sodium hydroxide. sites that cause malaria. . . 5 The reagents are conveniently, but not neces The said new compounds are pyrimidine deriv sarily, used in approximately stoichiometric pro portions. . If desired, a large excess of the amine atives of the formula. may be used so that it functions as a solvent or N / N-C-X diluent. O A further feature of the invention is a modified Ye-sh Ö-y process wherein the basic substituent NR'-A- N? N--NR-A-NRR NRR' is introduced by stages. Thus the benzi minazolylamino-pyrimidine compound carrying wherein X and Y, which are not necessarily alike, a labile group in the 4-position is brought into each represent hydrogenior a hydrocarbon radical reaction With an amino-compound of the form or X and Y together represent a divalent aliphatic NHR'-A'-B, where A represents either the hydrocarbon radical which forms with the 5 Whole or a part of the linking group A defined and 6-carbon atoms an alicyclic ring; wherein above and where B stands for a reactive group the benz ring of the benziminazolyl group may be which is then converted by known methods into unsubstituted or may bear one or more non 20 the group NRR- or into a group A'-NRR. Such acidic substituents such, for example, as hydro that A and A' together constitute the linking carbon radicals (which themselves may option group A. For example, the group B may be a. ally bear substituents and which may be at hydroxy group or a derivative thereof which is, tached to the benz radical directly or indirectly or is readily convertible to, a reactive ester as, for instance, through an oxygen, Sulphur or 25 thereof, such as a halide, this then being brought nitrogen atom or may be fused thereto as in the into reaction with an amine NHRR' or an amino case of a naphthiminazolyl radical), halogen. substituted amine NH2-A'-NRR' or a hy atoms or nitro or cyano groups; wherein R is droxy or mercapto-substituted amine HO hydrogen or an alkyl or simply substituted alkyl A'-NRR' or HS-A'-NRR' (or an alkali group, for example an alkoxyalkyl or dialkylami 30 metal derivative of such a hydroxy or mercapto noalkyl group; wherein A is a linking group which compound) such that A’-NH-A', A'-O-A' is aliphatic or alicyclic or aliphatic-carbocyclic . . . or A-S-A' constitutes the linking group A and may be substituted, for example, by hydro previously mentioned. Another alternative is to carbon radicals, hydroxy or alkoxy groups or bring the labile group in the 4-position of the dialkylaminoalkyl groups and where A or part of 35 benziminazolylaminopyrimidine compound into A is an aliphatic chain it may be interrupted by reaction with an acylated diamine NHR'-A'- oxygen, sulphur or nitrogen atoms; and wherein NHAc and then to hydrolyse off the acyl group. NRR' is a strongly basic amino or Substituted ... Further, if desired, the free amino group so gen amino group such as alkylamino or dialkylamino erated may be modified, as by alkylation, con or piperidino or other strongly basic nitrogen 40 version to a heterocyclic group such as piperidino containing heterocyclic group. . . or by bringing it into reaction with a halogeno We make the said compounds by a process com t; substituted amine Hal-A'-NRR' such that prising the interaction of a diamine NHR'-A- A’-NH-A''' constitutes the linking group A. NRR' with an appropriate 2-(benziminazolyl The 4-halogeno-2-benziminazolylaminopyrimi (2)-amino)- pyrimidine bearing in the 5- and 45 dine compounds used as starting materials may 6-positions the groups X and Y respectively and conveniently be made from the corresponding 4 in the 4-position a labile group such as a halogen hydroxy-2-benziminazolylaminopyrimidine COs atom or a hydrocarbon radical which is attached pounds by the action of for example, phosphorus by means of an ether or thioether linkage, for pentahalides or oxyhalides. The 4-hydroxy-2- example, an alkoxy, aryloxy or alkylmercapto 50 benziminazolylaminopyrimidines may be obtained grOllp. The reaction is conveniently brought about by by interaction of the corresponding 2-cyanamino heating the reagents together, optionally in 4-hydroxypyrimidine and an o-phenylene diamine presence of a solvent or diluent...If desired, the or by interaction of the corresponding benzimina benziminazolylaminopyrimidine or the diamine 55 zolylguanidines and an appropriate formylacetic. 2,460,409 3 4. ester. The alternative starting materials con 3-diethylaminopropylamine and 0.03 part of po taining ether or thioether groups can readily be tassium iodide are heated together at 155-165 C. made by the interaction of the 4-halogeno-deriv for 6 hours. The mixture is then dissolved in atives with appropriate hydroxy or mercapto dilute acetic acid, the Solution is filtered and the compounds or with alkali metal derivatives of filtrate is made alkaline with sodium hydroxide. Such compounds. s It is then filtered and the solid is washed with The invention is illustrated but not limited by Water and dried. It crystallises from a mixture the following examples, in which the parts are by Weight. of benzene and ligroin and has M. P. 183-184° C. Eacample 1 0 Eacample 14 2 parts of the hydrochloride of 2-(benzimina 4 parts of 4-chloro-2-benziminazolyl-(2’) - zolyl - (2) -amino)-4-chloro-6-methylpyrimidine, amino-6-methylpyrimidine, 8 parts of y-dibutyl 4 parts of 6-diethylaminoethylamine and 0.01 amino-propylamine and 0.04 part of potassium part of potassium iodide are stirred and heated iodide are heated in an oil bath at 160-170° C. for together at 150-160° C. for 6 hours. The melt 15 8 hours. The resulting reaction mixture is dis is then cooled and extracted with dilute hydro solved in a mixture of 20 parts of Water and 10 chloric acid. The extract is clarified with chair parts of hydrochloric acid, the Solution is filtered coal and then made alkaline with ammonia. A and the filtrate is made alkaline With Sodium hy white solid is precipitated. This is crude 2 droxide. The precipitated product is filtered off, (benziminazolyl- (2) -amino)-4-3-diethylamino 20 washed with water, dried and crystallised from ethylamino-6-methylpyrimidine, whose structure a mixture of benzene and ligroin, M.P. 158°C. may be represented by the following formula In the claims below, the expression "acidic sub N stituents' refers to radicals commonly recognized / N. N=C-Cs as ionizable, salt-forming, acid radicals, as typi C-NE-C2 CE -CH fied by carboxy and sulfo radicals. We claim: NY N-C-NB-C-C-N4. 1. A compound of the pyrimidine series char N Yosh, acterized by carrying a benziminazolyl-amino It is filtered off and purified by recrystallisation radical in the 2-position, said benziminazolyl from benzene When it has M. P. 198-200° C. amino radical being free of acidic substituents; Working in a similar manner but starting from and carrying the radical of a diamine in the 4 other appropriate 4-halogeno-2-benziminazolyl position, said diamine radical having the form. aminopyrimidines and appropriate diamines, the -NH-A-NRR', wherein NRR is a strongly following further compounds can be made; the basic radical selected from the group, consisting table indicates the constitution of the compounds 3 5 of primary, secondary and tertiary amine radicals and their respective melting points. and heterocyclic nitrogenous base radicals, while

Ex, No. Constitution of Compound MeltingPoint

2------2-(5-(6)-chlorobenziminazolyl-(2)-amino)-4-8-diethylaminoethylamino-6-methylpyrimidine------204-205o C.

8------2-(5-6)-chlorobenziminazolyl-(2)-amino)-4-y-diethylaminopropylamino-6-nethylpyrimidine.------193 4.-- - 2-(5-(6)-chlorobenziminazolyl-(2)-amino)-4-y-dimethylaminopropylamino-6-methylpyrimidine---- 196-197 6.------2-(5'-(6)-chlorobenziminazolyl-(2)-amino)-4-y-(N-methyl-N-isopropylamino)-propylamino-6-methylpyrinidine,5--- - 2-(5-(6)-chlorobenziminazolyl-(2-amino)-4-dibutylaminopropylamino:6-methylpyrinidine------166-6203 N N = -CH, C- ? C-NH-N-(-NH-CH, gh CHCH-N-CH, (iso). (The Cl-atom is located in one of the positions 5, 6) 8.------,7------2-(5-8)-chlorobenziminazolyl-(2)-amino)-4-3-piperidingethylamino-6-methylpyrimidine2-(5'-(6')-chlorobenziminazolyl-(2)-amino)-4-y-(6-diethylaminoethoxy)-propylamino-6-methylpyrimidine, ------. ------22362 N=-C s C-NH-gN-(-NH-CH, H CH, CH-O-CHCH-N- (C.H.),- 2-(5'-(6)-methoxybenziminazolyl- 3. -amino)-4-y-diethylaminopropylamino-6-methylpyrimidine. 164-166 - 2-(5-(6)-methoxybenziminazolyl-(2)-amino)-4-y-dibutylaminopropylamino-6-methylpyrimidine. 58-59 - 2-(5'-(6)-methylbenziminazolyl-(2)-amino)-4-6-diethylaminoethylamino-6-methylpyrinidine----- . . .210 12------2-(naphtho-1":2':4:5'-iminazolyl-(2)-amino)-4-3-diethylaminoethylamino-6-methylpyrimidine, 226

N N Na-C-CE C-NEN-C-NH-CHCH-N(CH3),

Eacample 13. A is a linking radical selected from the group 3 parts of 4-chloro-2(5'-methylbenziminazolyl consisting of aliphatic, alicyclic and aliphatic 2'-amino) -6-methylpyrimidine and 5.2 parts of 7 carbocyclic bivalent radicals. 2,460,409 6 2. As new compounds, the pyrimidine deriva wherein Ar designates an ortho-attached arylene tives of the formula radical of not more than 10 cyclic carbon atoms and whose cyclic carbon atoms carry substituents Selected from the group consisting of hydrogen, chlorine, methyl and methoxy; R and R' are lower alkyl radicals, A is an aliphatic link joining wherein Q stands for a benziminazolyl-amino the N-atom of the NH group to the N-atoms of group which is free of acidic substituents, A is the NRR' group and interposing therebetween at a linking radical selected from the group con sisting of aliphatic, allicyclic and aliphatic-carbo 0. least two carbon atoms, while X and Y represent cyclic bivalent radicals, NRR' is a strongly basic members Selected from the group consisting of radical selected from the group consisting of hydrogen and hydrocarbon radicals. primary, secondary and tertiary amine radicals 5. As new compounds, 6-methyl-4-dialkyl and heterocyclic nitrogenous base radicals, while aminoalkylamino pyrimidines bearing in the 2 X and Y represent members selected from the 5 position a 2-benziminazolyl-amino radical. group consisting of hydrogen and hydrocarbon 6. 2-6'-chlorobenziminazolyl-(2') - aminol-4- radicals, 1-dimethyl-aminopropylamino-6-methylpyrimi - 3. As new compounds, the pyrimidine deriva dine.7. 2-(6'-chlorobenziminazolyl-(2)-aminol-4- tives of the formula g-diethylaminoethylamino-6-methylpyrimidine. 20 8. 2-6'-chlorobenziminazolyl-(2)-amino-4- 6-piperidino-ethylamino-6-methylpyrimidine. 9. A process for the manufacture of compounds as defined in claim 1, which comprises reacting wherein Q stands for a benziminazolyl-amino a 4-halogeno pyrimidine compound bearing in group which is free of acidic substituents, A is 25 an aliphatic link joining the N-atom of the the 2-position a 2-benziminazolyl-amino radical, NH group to the N-atom of the NRR' group and With a diamine of the formula NH2-A-NRR, interposing therebetween at least two carbon wherein NRR' is a strongly basic radical selected atoms, NRR' is a dialkylamino group, While X from the group consisting of primary, secondary 30 and tertiary amine radicals and heterocyclic ni and Y represent members selected from the group trogenous base radicals, while A is a linking consisting of hydrogen and hydrocarbon radicals. radical Selected from the group consisting of 4. As new compounds, pyrimidine derivatives aliphatic, alicyclic and aliphatic-carbocyclic bi of the formula Valent radicals. 35 FREDERICK ROBER BASFORD. FRANCIS HENRY SWINDEN CURD. FRANCIS LESLE ROSE. No references cited