NOVEL BIOLOGICALLY ACTIVE EBURNAMENINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME

Abstract: The invention relates to novel eburnamenine derivatives of formula (I) wherein R<1> and R<2> as well as R<3> and R<4>, independently from each other, stand for hydrogen, C2-6alkyl group, C2-6alkenyl group; or a C3-10alicyclic group involving 1 to 3 rings, and this latter group may be substituted by a C1-6alkyl or C2-6alkenyl group; or R<1> and R<2> and/or R<3> and R<4>, together with the adjacent nitrogen atom and optionally with an additional oxygen or nitrogen atom, form a 4- to 6-membered, saturated or unsaturated cyclic group which may be substituted by a C1-6alkyl or C2-6alkenyl group; two of X, Y and Z are nitrogen whereas the third of them means a methine group; n is 1 or 2; W means oxygen or two hydrogen atoms; and the wavy line means alpha -/ alpha -, alpha -/ beta - or beta -/ alpha - steric position, as well as their acid addition salts and solvates. The invention further relates to pharmaceutical compositions containing the above compounds as well as a process for preparing the compounds of formula (I). The compounds of formula (I) possess antioxidant effect and therefore, they are useful for inhibiting the peroxidation of lipids occurring in mammals (including human).

Description: NOVEL BIOLOGICALLY ACTIVE EBURNAMENINE DERIVATIVES, PHARM CEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS F PREPARING SAME The invention relates to novel biologically acti eburnamenine derivatives of the general formula wherein R 1 and R 2 as well as R 3 and R 4 , independently from ea other, stand for hydrogen, C2_6alkyl group, C2— al enyl group; or a C3_*-Loalicyclic group involving 1 3 rings, and this latter group may be substituted by Cι_ al yl or C2_gal enyl group; or R 1 and R 2 and/or R 3 and R 4 , together with the adjace nitrogen atom and optionally with an additional oxyg or nitrogen atom, form a 4— to 6—membered, saturat or unsaturated cyclic group which may be substitut A 4869-67 MR by a C* ] __6alkyl or C2— alkenyl group; two of X, Y and Z are nitrogen whereas the third of th means a methine group; n is 1 or 2; W means oxygen or two hydrogen atoms; and the wavy line means — /a—, a—/β— or β— / — steric position, as well as their acid additions salts, solvates and pharm ceutical compositions containing these compounds. Furthe more, the invention relates to a process for the preparati of the above compounds and to a method for inhibiting t peroxidation of lipids in mammals. In the forthcoming formulae the eburnamenin-14-yl gro will hereinafter be abbreviated "EBU"; thus any reference the meaning of the wavy line relates to said line bei present in the partial formula "EBU". C 2 H 5 The compounds of the formula (I) according to the inve tion are new and possess a significant antioxidant (lip peroxidation-inhibiting) effect. Thus, they are therape tically useful. There are a high number of pathologic processes known the case of which extremely reactive free oxygen radica (O2"") are accumulated. The formation of these free radica leads to the oxidation of unsaturated fatty acids (lip peroxidation) which are important components of the ce membranes. This is a less specific, cell-destroying proces altering or damaging the biomoleculeε. In this proces functions of various levels of cells, organs or the who organism may suffer injuries. Free radical reactions likely play a causal role in t pathogenesis of ischae ia-induced injuries such as ischaem intestinal diseases, myocardial ischaemia, haemorrhag shock, cerebrovascular function disturbances accompanied ischaemia and renal ischaemia [R. J. Korthuis et al "Physiology of Oxygen Radicals", Chapter 17, pages 217-2 (1986) ] . Due to their lipid peroxidation-inhibiting effect, ant oxidative compounds assure a protection against injuri induced by free radicals under ischaemic, hypoxic cond tions. Thus, antioxidants as antiischaemic and antihypox compounds can be used for the treatment of such clinic pictures. It can be considered to be proven that free radic reactions play a partial role in the development of sympto of diseases of the connective tissues and a prima aetiological role in rheumatoid arthritis [J. Lunec et al "Cellular Antioxidant Defence Mechanisms", Chapter 3_3_, pag 143-159 (1988) (CRC Press Inc., Boca Raton, Florida, 1988) There are several hepatotoxic substances known, t liver-damaging effect of which is presumably a consequen of pathologic free radical reactions. Thus, antioxidati compounds may provide a protection against acute and chron diseases of the liver [J. Feher and A. Vereckei: " Importance of Free Radical Reactions in the Medicine" ( Hungarian) , pages 99-104 (Editory Medicina, Budapes 1985) ] . It has essentially been proven that free radical re tions play a role in several haematologic clinical pictu such as the sickle-cell anaemia and beta-thalassaemia (Me terranean anaemia) . Due to the diminished defense ability, the O2 therapy phototherapy, respectively, may further increase the risk oxidative injuries in the cases of newburn or premat infants. The use of some antioxidants proved to be favo able in the treatment of such clinical pictures. Lipid peroxidation occurring as a consequence injuries is a secondary process. Some cells are immediate destroyed by the injury, which then extends also to t surrounding cells in the next following hours. This is al caused by free oxygen radicals which attack the lipid lay of the cell membrane and can eventually lead to cell dea by injuring the membrane and releasing hydrogen peroxid Lipid peroxidation-inhibiting compounds are capable to pr vent this secondary process. Thus, they can be used f stopping degenerative processes occurring as a consequen of cephalic and spinal injuries. Compounds having such effect can be utilized also in the treatment of Alzheimer disease, muscular dystrophy and the like. The importance of lipid peroxidation-inhibiting co pounds is supported also by the great number of the mo recent literature data, patent applications and scientif publications. In the published PCT patent application No. WO 87/0170 mainly the preparation of a inosteroids is described, whe an a ino group is bound to the terminal carbon atom of t Ci7 side chain. Double bond(s) is (are) present in pos tion(s) 4 or 1,4 of ring A of the steroid skeleton where an oxo or hydroxyl group in position 3, an - or β—alk group or halogen in position 6, mainly an a— ydroxyl gro in position 11, an a— or β—methyl group in position 16 and double bond in position 9(11) are present. The ring A of t steroid skeleton may be saturated or aromatic, too. A f 21—aminosteroids are also described, wherein the double bo takes place in position -17(20) . In most cases, the disubst tuted pyri idine, triazine or pyridine cycle is connect through a piperazinyl group to position 21 of the compoun according to this publication. Among the compounds publish 16α—methyl—21—{4—[2 , 4-bis (pyrrolidino)—6—pyrimidinyl]—l—pi perazinyl}—pregna—1,4,9 (ll)-triene—3 ,20—dione methanesulfo ate (tirilazad mesylate) is in the second stage of clinic trials at present. Similarly, the synthesis of lipid peroxidation-inhibit ing compounds containing a steroid skeleton is described i the published PCT patent application No. WO 87/07895, wher mainly the preparation of steroid amino esters and corticoi amino esters, especially 17—a ino esters, 11, 17-bis (amino esters, 3, 17—bis(amino) esters, 11—amino esters and 3—amin esters is discussed. According to this patent applicatio the above derivatives can be used for inhibiting the lipi peroxidation occurring as a consequence of spinal, cephali and other injuries. The structure of amino substituents i similar to that described in the preceding publication. The preparation of novel amino—9, 10-secosteroids i described in the published PCT patent application No. W 88/07527. The amino substituent is connected to the termina carbon atom of the C17 side chain of the secosteroid. Th amino substituents are the same as those described in th preceding publications. The synthesis of lipid peroxidation-inhibiting compound is described also in the published European patent applica tions Nos. 0,389,368, 0,389,369 and 0,389,370 as follows. The preparation of corticoid-type 21-aminosteroids i disclosed in the application No. 0,389,368. For example, 4—[2, 5—bis(diethylamino)—6—pyridinyl]piperazinyl group ma be bound to the C21 carbon atoms. The steroid skeleton con tains one or two double bond(s) in the ring A, whereas th substituents being characteristic of the corticoids may b present in positions 6, 9, 11, 16 and 17. A double bond ma be present in position 9(11), too. The synthesis of amine derivatives of 3—oxo—19—norste roids is described in the patent application No. 0,389,37 wherein 17β-hydroxy-llβ-(4-dimethylaminopheny1)-17α-{3-[4-(2 , 6-bis- (pyrrolidino)—4—pyrimidinyl)—1—piperazinyl]—1—propynyl}- —estra—4, 9—dien—3—one, l7β-hydroxy—llβ-(4— imethyla inophenyl)—l7α-{3—[4—(5, 6—bis- (diethylamino)— 2—pyridy1)—1—piperazinyl]—l—propynyl}—estra- —4 , 9-dien— 3-one, 17β-hydroxy-llβ-(4-dimethylaminopheny1)—17α—{3—[4-(3 , 6-bis (diethylamino)-2-pyridyl)-l-piperazinyl]—l-propynyl}—estra —4, 9—dien—3—one, 17β-hydroxy-llβ-(4—dimethylaminophenyl)-17α-{3—[4-[2, 6—bis (1—pyrrolidinyl)—4—pyri idiny1]—1-piperaziny1]—1—propeny1} —estra—4, 9—dien—3—one and 17β-hydroxy-llβ-(4—dimethylaminophenyl)-17 -{3-[4-[2, 6-bis (pyrrolidino)—4—pyrimidiny1)—1—piperaziny1]—1—propy1}—estr —4, 9—dien—3—one are named as compounds prepared. In the patent application No. 0,389,369 the synthesis aminosteroid derivatives containing androstane skeleton described, which similarly possess a lipid peroxidatio inhibiting effect. Such compounds are e.g. llβ, 17β—dihyd oxy-17α—{3—[4—[2, 6—bis(pyrrolidino)—4—pyrimidinyl)—1—piper zinyl]—1—propynyl}—androsta—4, 6—dien—3—one, llβ, I7β—dihyd oxy-6-methy1—17 —{3—[4—[2, 6—bis(pyrrolidino)—4—pyrimidiny1 —1—piperaziny1]—1— ropynyl}—andostra-1, 4 , 6—trien—3—one, llβ, 17β-dihydroxy-6-methyl-17α-{3-[4-[5, 6-bis (diethylamino —2—pyridyl]-1—piperaziny1]-l-propynyl}—andostra—1,4, 6—trie -3-one and llβ, 17β-dihydroxy-6-methyl-17 -{3-[4-[3 , 6-bis (d ethylamino)—2—pyridyl]—1—piperaziny1]—1—propynyl}—andostra —1,4, 6—trien—3—one. In the published European patent application N 0,156,643 mainly the preparation of water-soluble cortic steroid derivatives is reported, the main characteristic which is that a hydroxyl group or an esterified hydro group stands in α—position or a double bond is present position 9(11). From the compounds discussed, sodium [17 —hydroxy—llα—(2, 2—dimethylpropylcarbonyloxy)—pregna—1, 4- —dien-3 ,20—dion—21—yl] succinate is considered to be most active lipid peroxidation-inhibiting compound. In the published PCT application No. WO 91/11453 b ("amino")pyrimidinyl-piperazinyl derivatives containing oxygen function in position 5 are disclosed, in the case which a steroid molecule or a 3,4—dihydro—6—hydroxy—2 , 5, 7, -tetramethyl-2H-l-benzopyran-2-ylmethyl group or a deriva tive thereof may be connected to the nitrogen atom in posi tion 1 of the piperazine moiety. Alky1—substituted 5-hydr oxypyrimidine derivatives are also described in this paten application. Logically, the research on the field of lipid peroxida tion-inhibiting compounds has been extended also to th investigation of amine derivatives containing no steroi skeleton. Thus, e.g. in the published PCT patent applicatio No. WO 88/08424 the preparation of novel aromatic and ali phatic bicyclic amine, cycloalkylamine, quinone-amine, amin ether and bicyclic amino ether derivatives are described which may be useful for the healing of cephalic and spina injuries. Of the derivatives described 2—{ [4—[2 , 6—bis (pyrro lidino)—4—pyrimidinyl]—1—piperazinyl]—methyl}—3 ,4—dihydro- —2,5,7, 8—tetra ethyl—2H—1—benzopyran—6—ol dihydrochloride has been subjected to detailed investigations. The present invention is aimed at developing new co pounds showing a higher biological effectivity and/or low toxicity, in comparison to those known in the art becaus the properties mentioned result in a more preferable thera peutical utilization than that achieved by the known drugs. Surprisingly, it has been found that eburnameni derivatives of the formula (I) possess the aimed excelle lipid peroxidation-inhibiting effect. The novel eburnamenine derivatives of the formula (I can be prepared by a) reacting an eburnameninecarbonyl chloride of the fo mula (V) or the hydrochloride thereof with a piperazine derivative the formula (X) , HN N H (CH 2-,)'n reacting the obtained 1—(eburnameninecarbonyl)piperazin of the formula with 2,4,6—trichloropyrimidine, separating the thus obtained isomeric mixture containin 1—eburnameninecarbonyl—4—(4,6-dichloropyrimidin—2—yl)pipera zine of the formula and 1— eburnameninecarbonyl— 4— ( 2 , 4-dichloropyrimidin— 6— yl) pi perazine of the formula EBU- to the individual isomers , then reacting about 1 mole of 1— eburnameninecarbonyl— 4— ( 4 , 6 —dichloropyrimidin—2—yl)piperazine of the formula (Ili with about 2 moles of an amine of the formula HNR***-R 2 in o or two step(s) to obtain eburnamenine derivatives of t formula (I), wherein R 1 and R 2 are the same as R 3 and R 4 , and Z means nitrogen, Y is a methine group, and n as well the wavy line are as defined above; or reacting about 1 mole of 1—eburnameninecarbonyl—4—(4 , —dichloropyrimidin—2—yl)piperazine of the formula (Ili with about 1 mole of an amine of the formula HNR 1 R 2 , then reacting the obtained 1—eburnameninecarbonyl—4—(4-amin —6—chloropyrimidin-2—yl)piperazine of the formula with an amine of the formula HNR 3 R 4 to give eburnameni derivatives of the formula (I) , wherein R 1 and R 2 are di ferent from R 3 and R 4 , X and Z mean nitrogen, Y is a methi group, and n as well as the wavy line are as defined abov or reacting about 1 mole of 1—eburnameninecarbonyl—4- (2 , dichloropyrimidin—6—yl)piperazine of the formula (Illb) wi about 2 moles of an amine of the formula HNR-^R 2 in one two step(s) to obtain eburnamenine derivatives of t formula (I) wherein R 1 and R 2 are the same as R 3 and R 4 , and Y mean nitrogen, Z is a methine group, and n as well the wavy line are as defined above; or reacting about 1 mole of 1—eburnameninecarbonyl—4—(2 , —dichloropyrimidine—6-yl)piperazine of the formula (Ill with about 1 mole of an amine of the formula HNR-^R 2 , then separating ' the obtained isomeric mixture containing —eburnameninecarbonyl—4—(2-amino—4—chloropyrimidin—6—yl)pi perazine of the formula and 1—eburnameninecarbony1-4-(4-amino—2—chloropyrimidin -yl)piperazine of the formula to the individual iεomers and reacting about 1 mole ther with about 1 mole of an amine of the formula HNR 3 R , wher R 3 and R 4 are different from R 1 and R 2 , to give eburnamen derivatives of the formula (I) , wherein R 1 and R 2 different from R 3 and R 4 , X and Y mean nitrogen, Z i methine group, or Z and Y mean nitrogen and X is a meth group, and n as well as the wavy line are as defined abo or al) reacting a 1—(eburnameninecarbonyl)piperazine of formula (IV) , wherein n and the wavy line are as defi above, with 2,4, 6—trichloropyrimidine, separating the isomeric mixture containing 1—eburna ninecarbony1-4-(4, 6-dichloropyrimidine-2-yl)piperazine the formula (Ilia) and 1—eburnameninecarbonyl—4—(2 , 4—dich ropyrimidin—6—yl)piperazine of the formula (Illb) , wherei and the wavy line are as defined above, to the individ isomers, then reacting 1* mole of the obtained 1—eburnameninecarbon —4—(4, 6—dichloropyrimidin-2-yl)piperazine of the form (Ilia) with 2 moles of an amine of the formula HNR-^ wherein R 1 and R 2 are the same as R 3 and R 4 , in one or t step(s) , to give eburnamenine derivatives of the formu (I), wherein R 1 and R 2 are the same as R 3 and R , X and mean nitrogen, Y is a methine group, and as well as the wa line are as defined above; or reacting 1 mole of 1—eburnameninecarbonyl—4—(4 , 6—dichl ropyrimidin—2—yl)piperazine of the formula (Ilia) with more of an amine of the formula HNR 1 R 2 , wherein R 1 and are different from R 3 and R 4 , to obtain eburnamenine deriv tives of the formula (I) , wherein R***- and R 2 are differe from R 3 and R 4 , X and Z mean nitrogen, Y is a methine grou and n as well as the wavy line are as defined above, then reacting the obtained 1-eburnameninecarbonyl—4—(4—a in —6-chloropyrimidin—2—yl)piperazine of the formula (Ha) wherein R 1 , R 2 , n and the wavy line are as defined abov with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 a different from R 1 and R 2 , to obtain eburnamenine derivativ of the formula (I) , wherein R 1 and R 2 are different from and R 4 , X and Z mean nitrogen, Y is a methine group and n well as the wavy line are as defined above; or reacting 1 mole of 1-eburnameninecarbonyl—4—(2,4-dichl ropyrimidin—6—yl)piperazine of the formula (Illb) with moles of an amine of the formula HNR-^-R 2 , wherein R 1 and are the same as R 3 and R 4 , in one or two step(s), to gi eburnamenine derivatives of the formula (I) , wherein R 1 a R 2 are the same as R 3 and R 4 , X and Y mean nitrogen, Z is methine group, and n as well as the wavy line are as defin above; or reacting 1 mole of l-eburnameninecarbonyl-4—(2 , 4-dichl ropyrimidine—6—yl)piperazine of the formula (Illb) with mole of an amine of the formula HNR----R 2 , wherein R 1 and are different from R 3 and R , then separating the iso eric mixture containing 1—eburnam ninecarbonyl—4—(2—amino-4—chloropyrimidin—6-yl) piperazine the formula (Ilba) and 1—eburnameninecarbonyl—4—(4—amino— —chloropyrimidin—6—yl)piperazine of the formula (Ilbb wherein R 1 , R 2 , n and the wavy line are as defined above, the individual isomers and reacting 1 mole thereof with mole of an amine of the formula HNR 3 R 4 , wherein R 3 and are different from R 1 and R 2 , to give eburnamenine deriv tives of the formula (I) , wherein R 1 and R 2 are differe from R 3 and R 4 , X and Y mean nitrogen and Z is a methi group or Z and X mean nitrogen and X is a methine group, a n as well as the wavy line are as defined above; or a2a) reacting about 1 mole of 1-eburnameninecarbonyl— —(4,6—dichloropyrimidin—2—yl) iperazine of the formu (Ilia) , wherein n and the wavy line are as defined abov with about 2 moles of an amine of the formula HNR-^-R wherein R 1 and R 2 are the same as R 3 and R 4 , in one or t step(s) to obtain eburnamenine derivatives of the formu (I), wherein R 1 and R 2 are the same as R 3 and R 4 , X and mean nitrogen, Y is a methine group, and n and the wavy li are as defined above; or a2b) reacting about 1 mole of 1—eburnameninecarbonyl— —(4, 6—dichloropyrimidin—2—yl)piperazine of the formu (Ilia) , wherein n and the wavy line are as defined abov with about 1 mole of an amine of the formula HNR 1 R 2 , where R 1 and R 2 are different from R 3 and R 4 , then reacting the obtained l—eburnameninecarbonyl—4—(4-amin —6—chloropyrimidin—2—yl)piperazine of the formula (Ha) wherein R 1 , R 2 , n and the wavy line are as defined abov with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 a different from R 1 and R 2 , to obtain eburnamenine derivativ of the formula (I) , wherein R 1 and R 2 are different from and R 4 , X and Z mean nitrogen, Y is a methine group and n well as the wavy line are as defined above; or a2c) reacting about 1 mole of 1—eburnameninecarbonyl— —(2,4—dichloropyrimidin—6—yl)piperazine of the formu (Illb) , wherein n and the wavy line are as defined abov with about 2 moles of an amine of the formula HNR***-R wherein R 1 and R 2 are the same as R 3 and R 4 , in one or t step(s) , to obtain eburnamenine derivatives of the formu (I), wherein R 1 and R 2 are the same as R 3 and R 4 , X and mean nitrogen, Z is a methine group, n and the wavy line ar as defined above; or a2d) reacting about 1 mole of 1—eburnameninecarbonyl—4 —(2,4—dichloropyrimidin—6— l)piperazine of the formul (Illb) , wherein n and the wavy line are as defined above with about 1 mole of an amine of the formula HNR 1 R 2 , wherei R 1 and R 2 are different from R 3 and R 4 , then separating the obtained isomeric mixture containing 1 —eburnameninecarbonyl—4—(2—amino—4—chloropyrimidin—6-yl)pi¬ perazine of the formula (Ilba) and 1—eburnameninecarbonyl—4 -(4-amino-2-chloropyrimidin-6-yl)piperazine of the formul (Ilbb) , wherein R 1 , R 2 , n and the wavy line are as define above, to the individual isomers and then reacting about mole thereof with about 1 mole of an amine of the formul HNR 3 R 4 , wherein R 3 and R 4 are different from R 1 and R 2 , t give eburnamenine derivatives of the formula (I) , wherein R and R 2 are different from R 3 and R 4 , X and Y mean nitroge and Z is a methine group or Z and Y mean nitrogen and X is methine group, n and the wavy line are as defined above; or a3a) reacting a 1—eburnameninecarbonyl—4—(4—amino—6 —chloropyrimidin—2—yl)piperazine of the formula (Ha) wherein R 1 , R 2 , n and the wavy line are as defined above with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 ar as defined above, to obtain eburnamenine derivatives of th formula (I) , wherein X and Z mean nitrogen, Y is a methin group, R 1 , R 2 , R 3 , R 4 , n and the wavy line are as define above; or a3b) reacting a 1—eburnameninecarbonyl—4—(2—amino—4 —chloropyrimidine-6-yl)piperazine of the formula (Ilba) wherein R 1 , R 2 , n and the wavy line are as defined above with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 ar as defined above, to obtain eburnamenine derivatives of th formula (I) , wherein X and Y mean nitrogen, Z is a methin group, R 1 , R 2 , R 3 , R 4 , n and the wavy line are as define above; or a3c) reacting a 1—eburnameninecarbonyl—4—(4— mino—2 —chloropyrimidin—6—yl)piperazine of the formula (Ilbb) wherein R 1 , R 2 , n and the wavy line are as defined above with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 ar as defined above, to give eburnamenine derivatives of th formula (I) , wherein Z and Y mean nitrogen, X is a methin group, R 1 , R 2 , R 3 , R 4 , n and the wavy line are as define above; or ba) reacting a 1—(eburnameninecarbonyl)piperazine of th formula (IV) with a 2—amino—4,6—dichloropyrimidine of th formula then reacting the obtained 1—eburnameninecarbonyl—4—(2-a in —4—chloropyrimidin—6—yl)piperazine of the formula (Ilb with an amine of the formula HNR 3 R 4 ; or bb) reacting a 1—(eburnameninecarbonyl)piperazine of t formula (IV) with a 4—amino—2, 6—dichloropyrimidine of t formula « then separating ' the obtained isomeric mixture containing —eburnameninecarbonyl—4—(4-amino—6—chloropyrimidine-2—yl)p perazine of the formula (Ha) and l—eburnameninecarbonyl- —(4—amino—2—chloropyrimidin—6—yl)piperazine of the formu (Ilbb) to the individual isomers and reacting about 1 mo thereof with about 1 mole of an amine of the formula HNR 3 R or ca) reacting a 1—(eburnameninecarbonyl)piperazine of t formula (IV) with a 4, 6-diamino—2-chloropyrimidine of t formula or cb) reacting a 1—(eburnameninecarbonyl)piperazine of t formula (IV) with a 2,4—diamino—6—chloropyrimidine of t formula or da) reacting an eburnameninecarbonyl chloride of t formula (V) or a hydrochloride salt thereof with a 4-( amino—6—chloropyrimidin-2—yl)piperazine of the formula (Villa) then reacting the obtained 1—eburnameninecarbonyl—4—(4—amin —6—chloropyrimidin—2—yl)piperazine of the formula (Ha) wi an amine of the formula HNR 3 R 4 ; or db) reacting an eburnameninecarbonyl chloride of t formula (V) or a hydrochloride salt thereof with a 4—( —amino—2—chloropyrimidin—6—yl)piperazine of the formula (VHIbb then reacting the obtained 1-eburnameninecarbonyl—4—(4—amin —2—chloropyrimidin—6—yl)piperazine of the formula (Ilb with an amine of the formula HNR 3 R 4 ; or dc) reacting an eburnameninecarbonyl chloride of t formula (V) or a hydrochloride salt thereof with a 4-( —amino—4—chloropyrimidin—6—yl)piperazine of the formula (VHIba) then reacting the obtained 1—eburnameninecarbonyl—4—(2—amin —4—chloropyrimidin—6—yl)piperazine of the formula (Ilb with an amine of the formula HNR 3 R 4 ; or e) reacting an eburnameninecarbonyl chloride of the fo mula (V) or a hydrochloride salt thereof with a 4—(diamin pyrimidinyl)piperazine of the formula and, if desired, reducing a thus obtained eburnamenin derivative of the formula (I) containing an oxo group as W and/or converting an eburnamenine derivative of the formul (I) obtained as the free base to an acid addition salt b reacting the free base with an acid, and/or liberating th free base from an obtained salt of an eburnamenine deriva tive of the formula (I) and/or transforming an obtaine eburnamenine derivative of the formula (I) to a solvat thereof. The reaction of an eburnameninecarbonyl chloride or it hydrochloride salt of the formula (V) with a piperazin derivative of the formula (X) is suitably carried out dissolving about 16 moles of piperazine derivative (calcu lated for 1 mole of "acyl chloride") in methylene chlori and dropwise adding the solution of the "acyl chloride" t the above solution at —50°C. After the dropwise addition th cooling of the reaction mixture is stopped, the reacti mixture is allowed to warm to room temperature, saturat sodium hydrogen carbonate solution is added and then t mixture is stirred for 10 minutes. After separating t organic phase is thoroughly washed with water, dried a subjected to chromatography on a silica gel column, then t product obtained is purified by recrystallization. The reaction of a 1—(eburnamenine—14—carbonyl)piperazi of the formula (IV) with 2,4 , 6—trichloropyrimidine is pr ferably carried out by dissolving the piperazine derivati in tetrahydrofuran and then dropwise adding at 0°C 2,4, —trichloropyrimidine, diluted with tetrahydrofuran, theret The reaction mixture is stirred at room temperature for hours, then evaporated to dryness. After distributing t evaporation residue between chloroform and aqueous sodiu hydroxyde solution the organic phase is washed with water dried and evaporated. The residue is subjected to chromato graphy on a silica gel column in order to separate the iso mers of the formulae (Ilia) and (Illb) . The reaction of the isomeric 1—(eburnamenine—14—carbo nyl)—4—(dichloropyrimidinyl)piperazine derivatives of th formula (Ilia) and (Illb) , respectively, with amines of th formula HNR^ 2 , e.g. pyrrolidine, 1—a inoadamantane, 1—ami no—1, 1—dimethylethane, 1—amino—2,2—dimethylpropane, cyclo pentylamine or the like is carried out at a temperatur depending on the reactivity of the amine. This reaction i performed e.g. with pyrrolidine below 10°C whereas a tem perature of at least 80 to 100°C is used in the reactio with 1—aminoadamantane. After evaporation the residue i distributed between a halogenated solvent, preferabl chloroform, and aqueous sodium hydroxide solution. Afte separation the organic phase is washed with water, dried an evaporated. The thus obtained 1—(eburnamenine—14—carbonyl) —4—(aminochloropyrimidinyl)piperazine isomers are separate on a silica gel column and purified by recrystallization. The 1—(eburnamenine—14—carbonyl)—4—(aminochloropyrimidi nyl)piperazine isomers of formulae (Ha), (Ilba) and (Ilbb) respectively, are reacted with an amine of the formul HNR 3 R 4 , which is identical to or different from the amin used in the preceding step. This reaction is carried out a a temperature and for a time depending on the reactivity o the amines. For example, in the case of pyrrolidine, boilin for about 5 hours is required. After completion of the reac tion, the excess amine is removed by distillation and th residue is distributed between chloroform and aqueous sodiu hydroxide solution. After separation the organic phase i washed with water, dried and evaporated. The obtained com pounds of the formula (I) can be recrystallized e.g. fro acetonitrile. Alternatively, according to the invention the isomeri 1—(eburnamenine—14—carbonyl)—4—(dichloropyrimidinyl)pipera- zines of the formula (Ilia) or (Illb) , respectively, may b reacted with the amines of the formula HNR-**-R 2 or HNR 3 R , respectively, in a single step. Suitably, the eburnamenin derivatives are suspended or dissolved in the primary o secondary amine used as reactant and the mixture is reacte at the boiling temperature. This reaction can be performe e.g. with pyrrolidine by boiling for 5 hours. After th reaction has become complete, the excess amine, e.g. pyrro lidine, is distilled off and the residue is purified a described above. If 1—(eburnamenine—14—carbonyl)—4—(dichloropyrimidinyl) piperazine cannot be dissolved in the amine of the formul HNR^ 2 or HNR 3 R 4 at the boiling point thereof, a solven having a higher boiling point, e.g. n—butanol, is used a solubilizing agent. Alternatively, a 1—(eburnamenine—14—carbonyl)piperazin of the formula (IV) can be reacted with an aminodichloro pyrimidine of the formula (Via) or (VIb) , respectively, an then the obtained 1—(eburnamenine—14—carbonyl)—4—(aminochlo ropyrimidiny1)piperazine of the formula (Ha) , (Ilba) o (Ilbb) , respectively, can be reacted with an amine of th formula HNR 3 R 4 . This process is conveniently carried out b dissolving the l-(eburnamenine—14—carbonyl)piperazin derivative of the formula (IV) as well as the aminodichloro pyri idine of the formula (Via) or (VIb) , respectively, e.g in acetonitrile, then boiling the reaction mixture in th presence of potassium carbonate for about 40 hours whil vigorously stirring. After termination of the reaction an evaporating the solvent the residue is distributed betwee chloroform and water. After separating the organic phase i washed with water, dried and evaporated. The residue i purified by recrystallization. The thus obtained 1—(eburna menine—14-carbonyl)—4—(aminochloropyrimidiny1)piperazine derivatives of the formula (Ha) , (Ilba) or (Ilbb) , respect ively, are reacted with the amines of the formula HNR 3 R under the reaction conditions described above. Alternatively, a 1—(eburnamenine—14—carbonyl)piperazine of the formula (IV) may be reacted with a diaminochloropyri- midine of the formula (Vila) or (VHb) , respectively. This reaction is suitably carried out by dissolving the 1—(ebur¬ namenine—14—carbonyl)piperazine derivative and a diamino- chloropyrimidine, e.g. 4—chloro—2 , 6—bis(pyrrolidino)pyrimi- dine, in N—ethylmorpholine, boiling the reaction mixture under nitrogen for 40 hours and then evaporating under environmental pressure. From the residue the traces of N- —ethylmorpholine are removed by adding water and distilling off the water. After distributing the residue between chloroform and water, the organic phase is separated, washed with water, dried and evaporated. The residue is purified by chromatography. Alternatively, an eburnamenine—14—carbonyl chloride of formula (V) or the hydrochloride salt thereof is reacted with an l—(aminochloropyrimidiny1)piperazine derivative of the formula (Villa) , (VHIba) or (VHIbb) , respectively, and thereafter, the obtained 1—(eburnamenine—14—carbonyl)—4- —(aminochloropyrimidiny1)piperazine of the formula (Ha) , (Ha) , (Ilba) or (Ilbb), respectively, is reacted e.g. with an amine of the formula HNR 3 R . This latter process is suitably accomplished, for example, as follows. A solution of the 1—(aminochloropyrimi- dinyl)piperazine of the formula (Villa) , (VHIba) or (VHIbb) , respectively, in methylene chloride and then potassium carbonate are added to the hydrochloride of ebur¬ namenine—14—carbonyl chloride of formula (V) at a tempera- ture of —15°C in small portions. Subsequently, the coolin of the reaction mixture is stopped, its temperature is allowed to warm to room temperature and then water is added. After stirring for about 10 minutes and then separating the phases, the organic solution is washed with water, the sol- vent is distilled off and the residue is purified by recrys tallization. The obtained 1—(eburnamenine—14—carbonyl)—4 —(aminochloropyrimidiny1)piperazine of the formula (Ha) (Ilba) or (Ilbb) , respectively, is then reacted with amine of the formula HNR 3 R 4 as described above. The present invention relates also to a process compri ing the reaction of an eburnamenine—14—carbonyl chloride the formula (V) or the hydrochloride thereof with a bi (amino)—(1—piperazinyl)pyrimidine derivative of the formu (IX) . According to this process, to a solution containi the bis(amino)—(1—piperazinyl)pyrimidine derivative of t formula (IX) used as reactant in a halogenated solvent, e. methylene chloride, the hydrochloride of eburnamenine—1 —carbonyl chloride of the formula (V) and then potassi carbonate are added in small portions at a temperature —15°C. Subsequently, the cooling of the reaction mixture ceased, it is allowed to warm to room temperature and wat is added. After stirring for about 10 minutes the phases a separated, the organic layer is washed with water and aft evaporating the solvent the evaporation residue is purifi by recrystallization. if desired, the eburnamenine derivatives of the formu (I) , obtained in the preceding processes and containing ox gen as W, can be reduced to eburnamenine derivatives of t formula (I) containing two hydrogen atoms as W; and/or eburnamenine derivative of the formula (I) obtained in t form of the free base can be transformed to an acid additi salt by reacting it with an appropriate acid; and/or t free base can be liberated from an eburnamenine derivati of the formula (I) obtained in the form of a salt. The reaction is suitably carried by dissolving t derivative of the formula (I) containing oxygen as W anhydrous tetrahydrofuran and adding it dropwise to a sol tion of lithium aluminum hydride in tetrahydrofuran und an inert gas, e.g. argon, then boiling the reaction mixtu for about 3 hours. After the reaction has become comple [according to thin layer chromatography (TLC) analysis] , t excess of lithium aluminum hydride as well as the compl formed is decomposed by adding water and aqueous sodi hydroxide solution. The aluminum hydroxide and lithium hyd oxide precipitate is filtered off, washed thoroughly wi tetrahydrofuran and after evaporating tetrahydrofuran fr the filtrate combined with the washings the residue is pur fied on a silica gel column by chromatography. Acid addition salts of the compounds of the formula ( are formed in a usual manner, e.g. by dissolving any of t compounds of the formula (I) in anhydrous ethanol and addi about 1 or 2 molar equivalent(s) of an acid, e. ethanesulfonic acid or ethanesulfonic acid, to the abo solution. When the salt does not precipitate, ether is add to the alcoholic solution and after compacting the precip tated product is filtered off, dried and, if desired, pur fied by dissolving and precipitation, or the precipitat product is transformed to the corresponding free base. In this description and in the claims C 2 —galkyl a alkenyl groups are meant to be straight or, preferabl branched chain C 2 — Q groups which are saturated or conta one or more carbon-carbon double bond(s) . Such C 2 —galkyl a alkenyl groups are exemplified by the ethyl, vinyl, n-pr pyl, isopropyl, 1—propen—1—yl, 1—propen—2—yl, 1—propen—3—y n—butyl, sec-butyl and tert-butyl and butenyl group as we as the various pentyl, pentenyl, hexyl and hexenyl groups. C 3 _*-Locycloalkyl groups containing 1 to 3 rings a unsubεtituted by C _ 3 alkyl group, are e.g. cyclobuty cyclopentyl, cyclohexyl, cycloheptyl as well as adamant groups. These groups may be unsubstituted or may bear o ore more methyl, ethyl or propyl group(s) and subst tuent(s). When R 1 and R 2 and/or R 3 and R 4 together with the adj cent nitrogen atom and optionally with a further oxygen nitrogen atom form a saturated or unsaturated cyclic gro containing 4 to 6 carbon atoms, optionally substituted Cι_ 4 alkyl or alkenyl group, these cyclic groups may prefe ably be a pyrrolidino, piperidino, azepino, morpholino, 4, —ethylenedioxy—1—piperidinyl or 2 ,2, 6, 6—tetramethyl—1—pipe ridinyl group. The various compounds of formulae (VI) , (VII) , (VIII) and (IX) used for the preparation of the compounds of th formula (I) or their intermediates, respectively, can b prepared as follows. For the preparation of various monoamino—dichloropyrimi dine derivatives of the formula (VI) 2 ,4, 6—trichloropyrimi dine is used as starting material, and it is reacted in a ether-type solvent, e.g. tetrahydrofuran, with a primary o secondary amine at a temperature between —20°C and 40°C, depending on the reactivity of the amine, for a period o about 30 minutes to several hours. In the case of th sterically hindered 2,2,4,4—tetramethylpiperidine (which ca be used as solvent, too) , the completion of the reactio lasts for about 50 hours at the boiling point of the reac tion mixture. After completion of the reaction the solven or the reactant (used as a solvent, too) is evaporated, th residue is dissolved in a halogenated solvent, preferabl chloroform, and extracted first with aqueous sodiu hydroxide solution, then water. After separating the organi phase is dried, the solvent is evaporated and the 4,6—di chloro—2—aminopyrimidine of the formula (Via) is separate from the 2, 6—dichloro—4—aminopyrimidine derivative of th formula (VIb) on a silica gel column by chro atography. Thereafter, the individual isomers are further purified b recrystallization. The bis(amino)—chloropyrimidine derivatives of the for mula (Vila) and (VHb) , respectively, are prepared by react ing the corresponding monoamino—dichloropyrimidine deriva tives of the formula (VI) with an amine of the formul HNR 1 R 2 or HNR 3 R 4 , respectively. Similarly to the preparatio of compounds of the formula (VI) , the reaction condition are above all determined by the reactivity of the amine o of the formula HNR-'-R 2 or HNR 3 R 4 used. Thus, on using pyrro lidine as amine component, the reaction proceeds at roo temperature; whereas the reaction with 1—amino—1, 1—dimethy ethane requires heating at 130°C for about 15 hours. T interaction with 1—amino—2, 2—dimethylpropane can be acco plished under milder conditions: it becomes complete boiling in isopropanol for about 20 hours. If as amine co ponent the bulky 1—aminoadamantane is used, it reacts boiling in n—butanol for about 75 hours. The reaction mi tures obtained are worked up as described for the prepar tion of compounds of the formula (VI) . For preparing the various piperazinyl pyrimidine deriv tives of the formula (VIII) the corresponding bis (amino —chloropyri idine derivatives of the formula (VII) a employed as starting substances. After being dissolved in tertiary amine, preferably N—ethylmorpholine, the bi (amino)—chloropyrimidine derivatives of the formula (VI are boiled with an excess of a piperazine of the formula ( under nitrogen for about 25 hours. After termination of t reaction N—ethylmorpholine used as solvent and a major pa of the piperazine are distilled off, water is added to t residue and distilled off again. After dissolving in chlor form, the residue is washed with aqueous sodium hydroxy solution, then with water. After separation the organ phase is dried and chloroform is evaporated. The residue purified by chromatography on a silica gel column a optionally the product obtained is recrystallized. For the preparation of bis(amino)—(1—piperazinyl) pyrim dine derivatives of the formula (IX) e.g. the bis(amino —chloropyrimidine derivatives of the formula (VII) may used as starting substances. Suitably, the compounds of t formula (VII) are reacted with an about 5—fold excess of piperazine of formula (X) by boiling the reactants ethanol for about 1 hour. After termination of the reacti ethanol is evaporated, the residue is dissolved in chlor form, washed with aqueous sodium hydroxide solution and th with water. After separation the organic phase is dried a the solvent is evaporated. The residue is purified recryεtallization. Eburnameninecarbonyl chlorides of the formula (V) an their hydrochloride salts used as starting substances in th proceεs of invention are known from the Hungarian paten specification No. 187,733. The pharmacological effect of the eburnamenine deriva tives of the formula (I) was studied as described herein after. The antioxidative effect was investigated in an enzy atically-induced lipid peroxidation (NADPH-induced lipi peroxidation) test as well as in a non-enzymatically induce lipid peroxidation (Fe 2+ -induced lipid peroxidation) test. The antioxidative effect was inveεtigated on microsome prepared from rat brain [J. Neurochem. 1_, pages 422-42 (1981)] and on rat brain ho ogenate [J. Biol Chem. 262 pages 10438-10440 (1987)]. Inhibition of the NADPH-induced lipid peroxidation i brain microsomes Male Hannover-Wistar rats with a body weight of 150-25 g were used for the preparation of microsomeε. After decapi tation, the whole brain of the rat waε removed and homogen ized in a 10-fold volume of ice-cold 0.25 M εaccharoεe solu tion. The homogenate was centrifuged in a Hitachi CR 26 equipment at 15000 x g at 4°C for 10 minuteε, then th εupernatant was collected and centrifuged in a Hitac SCP85H equipment at 78000 x g at 4°C for 60 minutes. Afte suspending the precipitate in 0.15 M potassium chlorid solution, the protein content of the obtained solution wa determined and then adjusted to 10 mg/ml concentration. T microsome thus obtained was frozen in a dry ice-acetone mi ture and εtored at —70°C until uεe. The component of the incubation mixtures were: 50 triε(hydroxy ethyl) aminomethane hydrochloride (pH 6.8) , 0. mM ferric chloride, 1 mM potaεεium dihydrogen phosphate, 0. mM adenosine—5'—diphosphate, 0.2 mg of microsomes as well the compound to be tested. The incubation was carried o with a final volume of 1 ml and an incubation time of 2 - 26 - minutes at a temperature of 37°C. The lipid peroxidation w induced by adding 0.4 mM NADPH (nicotine adenine dinucle tide phosphate, reduced form) . (The blank samples did n contain NADPH.) The reaction was stopped by adding 0.375 of a stopping solution containing trichloroacetic acid 40% and 5 M hydrochloric acid in a 2:1 ratio. The formati of malondialdehyde was determined by using thiobarbitur acid. After stopping the reaction, 1 ml of 1% thiobarbitur acid solution each was added to the samples, which were th placed in a water bath of about 100°C for 10 minutes. Su sequently, the samples were centrifuged at 2000 x g in Janetzki K70 equipment at 4°C for 10 minutes. The absorban value of the coloured supernatant was measured at 535 nm a Hitachi 150-20 spectrophotometer. Malondialdehyde bis(d ethylacetal) was used as reference compound. Effect on the Fe -±-induced lipid peroxidation in bra homogenate After decapitating Hannover-Wiεtar rats weighing 150-2 g each, the whole brain was homogenized in 9 volumes of ic cold Krebs-Ringer's buffer [containing 15mM 4- (2-hydrox ethyl)—1—(piperazinylethanesulfonic acid (abbreviate HEPES, pH 7.4), 140 mM sodium chloride, 3.6 mM potassi chloride, 1.5 M calcium chloride, 0.7 mM magnesium chlo ide, 1.4 mM potassium dihydrogen phosphate and 10 mM gl cose] . Then, the protein content of the solution was dete mined and adjusted to 10 mg/ml concentration. After adding the inhibitory agent to be tested in volume of 5 ml to 200 μl of the homogenate, the incubati mixture was incubated at 37°C for 20 minutes. The Fe 2 induced lipid peroxidation was accomplished by adding 5μl 8 mM ferrous diammonium disulfate [Fe(NH4) 2 (SO4) 2] solutio After passing of the incubation time, the reaction w εtopped by adding 1 ml of a stopping solution containing 0 M hydrogen chloride in trichloroacetic acid solution 12.5%, then the samples were centrifuged at 2000 x g in Janetzki equipment at 4°C for 10 minutes. - 27 To 0.5 ml portion of the supernatant, 1 ml of 1% thio barbituric acid solution was added, then the samples wer placed in a water bath of 100°C for 20 minutes. The colou intensity developed was determined at 535 nm with the aid o a Hitachi 150-20 spectrophotometer by using malondialdehyd bis(diethylacetal) as reference compound. The IC50 values of the compounds were determined on t basis of the concentration/effect correlations thereof a are indicated in Table I. Table I Lipid peroxidation-inhibiting effect Compound Inhibition of the Inhibition of t No. NADPH-induced lipid Fe 2+ -induced peroxidation lipid peroxidati IC 50 (μM) IC 50 (μM) 124.0 112.0 11.4 10.3 10.5 51.0 33.2 135.0 Signs and abbreviation used in Table I: N.I.: no inhibition 1: 1—[ (3 , 16α)—eburnamenine—14—carbonyl]—4—[2, 6—bis (pyr rolidino)—4—pyrimidinyl]piperazine 2: l—{ [ ( 3a , 16α)—eburnamenine-14-yl]methyl}—4—[2 , 6—bis- (pyrrolidino)—4-pyrimidinyl]piperazine trihydrobromi 3 : 1—[ (16 )—eburnamenine—14—carbonyl]—4—[2, 6—bis (pyr¬ rolidino)—4—pyrimidinyl]piperazine 4 : 1—[ (3α)—eburnamenine—14—carbonyl]—4—[2, 6—bis (pyr¬ rolidino)—4—pyrimidinyl]piperazine Ellagic acid: 4,4 ' , 5, 5 ' ,6, 6 '-hexahydrodiphenic acid 2 , 6 ' : 2 ' , 6—dilactone Silymarin: 2-[trans—2—(4-hydroxy-3-methoxypheny1)-3-hydroxy methyl—1,4—benzodioxan—6—yl]—3 , 5,7—trihydroxychroman- —4—one Tirilazad mesylate: 16α-methyl—21—{4—[2,4—bis (pyrrolidino) - —6—pyrimidiny1]—1—piperazinyl}—pregna—1,4,9 (11)—trien —3,20—dione methaneεulfonate (a compound of the pub- liεhed PCT patent application No. WO 87/01706) . Baεed on the data of Table I it can be εeen that each o the compounds prepared in the various Examples exerts a ver strong antioxidant (lipid peroxidation-inhibiting) action. According to the date of Table I the inhibitory effec of the compounds tested on the NADPH-induced (enzymaticall induced) lipid peroxidation is much stronger than that o the reference compounds. It is likely that the compound exert their antioxidant effect through the NADPH-cytochrom reductase involved in the reaction. The inhibitory effect o compounds 3 and 4 on the Fe 2+ -induced (non-enzymaticall induced) lipid peroxidation reaches the antioxidant activit of the therapeutically used DL-α—tocopherol; whereas the inhibit this process more effectively than the hepatopro tective sily arin or the anticancerogenic ellagic acid. I addition, the antioxidant activity of the compounds 1 and reaches and even exceeds to some extent the lipid peroxida tion-inhibiting effect of tirilazad mesylate being unde clinical trials at present. The novel eburnamenine derivatives of the formula (I are employed for pharmacological purposes alone or in th form of their salts, suitably in formulations commonly use in the therapy. These formulations may be solid, liquid o se isolid; filling, diluting, stabilizing, pH- and osmoti pressure-influencing, flavouring, savouring as well as for mulation-promoting or formulation-providing additives an auxiliaries commonly used for such preparationε can be uεe for their preparation. The εolid pharmaceutical compositions may be e.g. tab¬ lets, dragees, capεuleε, cachets (cachet power compositions) or powder a pouls useful for the preparation of injections. Liquid compositions are the injectable and infusable compo- sitions, fluid medicineε, packing fluidε and drops. Oint¬ ments, balsams, creams, mixtures to be εhaken and suppo¬ sitories are semiεolid compoεitions. The pharmaceutical composition iε administered to the patient in an amount containing the dose of the active agent required to achieve the desired effect. This dose depends on the grade of the disease, the severity of the pathological condition to be influenced, the weight of the patient, sen¬ sitivity of the patient against the active agent, route of the administration and number of daily treatments. The dose of active agent to be used can safely be determined by the physician skilled in the art in the knowledge of the patient to be treated. For the sake of a εimple administration it is suitable if the pharmaceutical compositionε comprise dosage unitε containing the amount of the active agent to be adminis¬ tered once, or a few multiples or a half, third or fourth part thereof. Such dosage units are e.g. tablets which can be provided with grooves promoting the halving or quartering of the tablet to obtain the required amount of the active agent. The tabletε can be coated by a layer inεoluble in acidic media in order to assure the release of the active agent content after leaving the stomach. In this way, the tablets become enteric-coated. A similar effect can be achieved alεo by encapsulating the active agent. The pharmaceutical compositions containing the active agent according to the invention uεually contain 1 to 100 mg of active agent in one doεage unit. Of course, it is also possible that, in some compositionε, the amount of the active agent exceeds the upper or lower limits defined above. - 30 - The invention also relates to a method for inhibit the peroxidation of lipids occurring in the organism. T method comprises administering a therapeutically effect amount of an active agent of the formula (I) or a phar ceutically acceptable acid addition salt or solvate ther to the patient. The invention is illuεtrated in detail by the aid of following non-limiting Exampleε. Example 1 Preparation of 1—[ (3α, 16α)—eburnamenine—14—carbonyl]pi razine A solution containing 20.0 g (53 moleε) of (3α,l6 —eburnamenine—14—carbonyl chloride hydrochloride in 200 of methylene chloride iε dropwise added at —50°C to 66. (796 mmoles) of piperazine dissolved in 300 ml of methyl chloride. Thereafter, the cooling of the reaction mixture stopped, the mixture is allowed to warm to room temperat and 100 ml of saturated sodium hydrogen carbonate solut are added, the mixture is stirred for 10 minutes and t settled. After separation the organic phase is twice was with 150 ml of water each, then dried and evaporated. residue is purified by chromatography on a silica column. The elution is carried out by using a mixture chloroform/methanol (98:2—>80:20) . The product obtained recrystallized to give the title compound in a yield 15.82 g (78.8%) m.p. : 185-198°C. Example 2 Preparation of 1—[ (3a:,16a)—eburnamenine—14—carbonyl]—4—(4 —dichloro—2—pyrimidinyl)piperazine and 1—[ (3α, 16α)—eburna nine—14—carbonyl]—4—(2, 6—dichloro—4—pyrimidinyl)piperazin 0.56 ml (4.87 mmoles) of 2,4, 6-trichloropyrimid diluted with 20 ml of tetrahydrofuran is dropwise added t solution of 2.0 g (5.12 mmoles) of 1—[ (3α, 16α)—eburnameni -14-carbonyl]piperazine in 50 ml of tetrahydrofuran at 0 After stirring at room temperature for 12 hours the react mixture is evaporated to dryness. The residue is distribu between 100 ml of chloroform and 25 ml of 5% sodium hydr¬ oxide solution. After separation the organic phase is dried, evaporated and the evaporation residue is subjected to chro- matography on silica gel column. By using a chloro- form/methanol mixture (100:0—>99:1) as eluent, the less polar 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—(4, 6—dichloro- —2—pyrimidinyl)piperazine is first obtained in a yield of 0.325 g (12.7%), m.p. : 100-107°C (after recrystallization from ether) . By further elution the more polar 1—[(3α,16α)- —eburnamenine—14—carbonyl]—4—(2,4—dichloro—6—pyrimidinyl) - piperazine is obtained in a yield of 2.26 g (88.3%) , m.p.: 165-175°C (after recrystallization from ether) . Example 3 Preparation of 4,6—dichloro—2—pyrrolidinopyri idine and 2,4- —dichloro—6—pyrrolidinopyrimidine 23.7 ml (286.6 mmoles) of pyrrolidine are dropwiεe added at a temperature of —20°C to the mixture of 25.0 g (136.3 mmoles) of 2,4, 6—trichloropyrimidine and 200 ml of tetrahyd¬ rofuran during about 30 minutes. Subsequently, the cooling is εtopped, the mixture iε εtirred for additional 30 minuteε and then evaporated. The residue is diεtributed between 500 ml of chloroform and 50 ml of 10% εodium hydroxide solution. After separation the organic phase is washed 4 times with 150 ml of water each, then dried and evaporated. The residue is subjected to chromatography on a silica gel column. By using a hexane/ethyl acetate mixture of 19:1 ratio as eluent 4, 6—dichloro—2—pyrrolidinopyrimidine is obtained which is recrystallized from hexane to give 7.51 g (25.27%) of product, m.p. :95-98°C. 1 H-NMR (60 MHz, CDC1 3 ) δ ppm: 6.51 (s, 1H, 5-H) By further elution a more polar product iε obtained which iε recrystallized from hexane to give 2, 4—dichloro—6- —pyrrolidinopyrimidine in a yield of 20.22 g (68.03%) , m.p.: 100.5-103.5°C. -T-H-NMR (60 MHz, CDCl 3 ) δ ppm: 6.18 (s, 1H, 5-H) Example 4 Preparation of 4—chloro—6—(1—piperazinyl)—2—pyrrolidinopyri midine A εolution of 2.0 g (9.17 mmoles) of 4, 6—dichloro— 2—pyr rolidinopyrimidine and 3.95 g (45.9 mmoles) of piperazine i ethanol is boiled under reflux for 1 hour and the evaporated. The evaporation reεidue iε diεtributed betwee 100 ml of chloroform and 100 ml of 1% sodium hydroxide solu tion. After separation the organic phase is twice washe with 50 ml of water each, then dried and evaporated. Afte recrystallizing the residue from hexane, the title produc is obtained in a yield of 2.25 g (91.6%), m.p. 89-100°C. Example 5 Preparation of 4—chloro—2—(1—piperazinyl)—6—pyrrolidinopyri idine A solution containing 2.0 g (9.17 mmoles) of 2, 4—dichlo ro—6—pyrrolidinopyrimidine and 3.95 (45.9 moleε) of pipera zine in ethanol is boiled under reflux for 1 hour and the evaporated. The evaporation residue is distributed betwe 100 ml of chloroform and 100 ml of 1% sodium hydroxi solution. After separation the organic phase is washed twi with 50 ml of water each, then dried and evaporated. T evaporation reεidue iε subjected to chromatography on silica gel column. By using a 9:1 mixture of chlor form/methanol as eluent and recrystallizing the obtain product from hexane, the title compound is obtained in yield of 1.66 g (67.6%) , m.p.: 77-92°C. Example 6 Preparation of 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—(4 -chloro-2-pyrrolidino-6-pyrimidinyl)piperazine and l- —[ (3α, 16α)—eburnamenine—14—carbonyl]—4—(2—chloro—4—pyrroli dino—6—pyrimidinyl) iperazine After adding 2.00 g (3.81 mmoleε) of 1—[ (3α, 16α)—eburn menine—14-carbonyl]-4-(2,4-dichloro-6-pyrimidinyl)piperazi in small portions to 20 ml of pyrrolidine at a temperatu below 10°C, the reaction mixture is stirred at room temper ture for 1 hour, then evaporated. After distributing th evaporation residue between 40 ml of chloroform and 10 ml o 1% sodium hydroxide solution the organic phase is separated, dried and evaporated. The evaporation residue is subjecte to chromatography on a silica gel column. By using a 99: mixture of chloroform and methanol the less polar 1 —[ (3α, 16α)—eburnamenine—14—carbonyl]—4—(4—chloro—2—pyrroli¬ dino—6—pyrimidinyl)piperazine is first eluted from th column, which is recrystallized from a mixture of ether an hexane to give a yield of 2.01 g (88.2%) , m.p.: 210-220°C By further elution the more polar 1—[ (3α, 16α)—eburnamenine —14—carbonyl]—4—( 2—chloro—4-pyrrolidino—6—pyrimidiny1)pipe¬ razine iε obtained which is similarly recrystallized from mixture of ether and hexane to give a yield of 0.13 (5.7%), m.p.: 169-200°C. Example 7 Preparation of 1—[ ( 3a ,16α)—eburnamenine—14—carbonyl]—4—(4 —chloro—6—pyrrolidino—2—pyrimidinyl)piperazine 2.0 g (3.81 mmoles) of 1—[ (3α, 16α)—eburnamenine—14—car bonyl]—4—(4, 6—dichloro—2—pyrimidinyl)piperazine are added i small portions to 20 ml of pyrrolidine at a temperatur below 10°C, then the reaction mixture is stirred at roo temperature for 1 hour and evaporated. The evaporatio residue is distributed between 40 ml of chloroform and 10 m of 10% sodium hydroxide solution. After separation th organic phase is dried and evaporated. The product obtaine is recrystallized from a mixture of ether and hexane to giv 2.10 g (92.2%) of the title compound, m.p.: 176-181°C. Example 8 Preparation of 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—(4 —chloro—2—pyrrolidino—6—pyrimidinyl)piperazine 5.0 g (12.8 mmoles) of 1—[ (3α, 16α)—eburnamenine—14—car bonyl]piperazine and 2.5 g (11.5 mmoles) of 4 , 6—dichloro—2 —pyrrolidinopyrimidine are disεoived in 100 ml of aceto nitrile and, after adding 5.0 g of potassium carbonate, th reaction mixture is boiled under reflux for 40 hours, the evaporated. The evaporation residue is distributed betwe 100 ml of chloroform and 40 ml of water. After separati the organic phase iε dried and evaporated. The produ obtained is recryεtallized from a mixture of ether a hexane to give 5.87 g (85.3%) of the title compound, m.p 210-220°C. Example 9 Preparation of 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—( —chloro—6—pyrrolidino—2—pyrimidinyl)piperazine and 1- —[ (3α, 16α)—eburnamenine—14—carbonyl]—4—(2—chloro—4—pyrroli dino—6—pyrimidinyl) iperazine After diεsolving 5.0 g (12.8 mmoles) of 1—[ (3α, 16α —eburnamenine—14—carbonyl]piperazine and 2.5 g (11.5 mmole of 2,4—dichloro—6—pyrrolidinopyrimidine in 100 ml of acet nitrile and adding 5.0 g of potassium carbonate, the rea tion mixture is boiled under reflux for 40 hours, then ev porated. The residue is distributed between 100 ml of chl roform and 40 ml of water. The organic phase is εeparate dried and evaporated. The evaporation residue is subject to chro atography on a silica gel column. By using a 99 mixture of chloroform and methanol as eluent, the less pol 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—(4—chloro—6—pyrrol dino-2—pyrimidinyl)piperazine is first eluted from t column, which is recrystallized from a mixture of ether a hexane to give a yield of 5.16 g (75.2%) , m.p.: 176-181° By further elution the more polar 1—[ (3α, 16α)—eburnamenin —14—carbonyl]—4—(2—chloro-4—pyrrolidino—6—pyrimidiny1)pipe razine is eluted, which is similarly recrystallized from mixture of ether and hexane to give a yield of 0.475 (6.92%), m.p.: 169-200°C. Example 10 Preparation of 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—( -chloro-2—pyrrolidino-6-pyrimidinyl)piperazine To a solution containing 2.0 g (7.47 mmoles) of fres prepared 4—chloro—6—(1—piperazinyl)—2—pyrrolidinopyrimid in 20 m of methylene chloride, 2.96 g (7.84 mmoles) (3α, 16α)—eburnamenine—14—carbonyl chloride hydrochloride a 1.08 g of potasεium carbonate are added in small portions —15°C. Thereafter, the cooling of the reaction mixture stopped, the mixture is allowed to warm to room temperatu and then 10 ml of water are added. After stirring for minuteε and εettling, the phaεes are separated, then t organic phase is washed with water twice, dried and evap rated. After recrystallizing the evaporation residue from mixture of ether and hexane, the title compound is obtain in a yield of 4.03 g (90.3%), m.p.: 210-220°C. Example 11 Preparation of 1—[ (3α, 16a)—eburnamenine—14—carbonyl]—4—( —chloro—6—pyrrolidino—2—pyrimidinyl)piperazine Freshly prepared 4-chloro-6-(l-piperazinyl)-2-pyrrolid nopyrimidine is reacted with (3α, 16α)—eburnamenine—14—carb nyl chloride hydrochloride as described in Example 10 obtain the title compound in a yield of 88.1%, m.p.: 17 181°C. Example 12 Preparation of 4—chloro—2, 6—bis(pyrrolidino)pyrimidine a 2—chloro—4 , 6—bis(pyrrolidino)pyrimidine 10 g of 2,4—dichloro—6—pyrrolidinopyrimidine are add in small portions to 40 ml of pyrrolidine at a temperatu below 10°C while stirring. After addition the reaction mi ture is stirred at room temperature for 1 hour, th evaporated. After distributing the residue between 150 ml chloroform and 30 ml of 10% sodium hydroxide solution, t organic phase is separated, washed 4 times with 50 ml water each, then dried and evaporated. The evaporati residue iε subjected to chromatography on a εilica g column. By uεing a 19:1 mixture of hexane and ethyl aceta as eluent and recrystallizing the product from hexane, 11. g (83.74%) of 4—chloro—2, 6—bis(pirrolidino)pyrimidine a obtained, m.p. :78-81°C. -T-H-NMR (60 MHz, CDC1 3 ) δ ppm: 5.67 (s, 1H, 5-H) By further elution a with 9:1 mixture the more polar —chloro—4, 6—bis(pyrrolidino)pyrimidine is obtained, which i recrystallized from hexane to give a yield of 1.38 (10.46%) , m.p.: 92-94°C. 1 H-NMR (60 MHz, CDCl 3 ) δ ppm: 4.91 (s, 1H, 5-H) Example 13 Preparation of 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—(2 , 4 bi (pyrrolidino)—6—pyrimidinyl]piperazine A εolution of 1.00 g of 1—[ (3α, 16α)—eburnamenine—14—car bony1]—4—(4—chloro—2—pyrrolidino—6—pyrimidiny1)piperazine i 10 ml of pyrrolidine iε boiled under reflux for 5 hours, then evaporated. The evaporation residue is distributed bet ween 20 ml of chloroform and 5 ml of 10% sodium hydroxid solution. After εeparation the organic phaεe is washed twic with water, then dried and evaporated. The evaporatio residue is recrystallized from acetonitrile to give th title compound in a yield of 0.93 g (91.7%), m.p. 267-269°C, [α] D 21= -50.9° (c=2, 1 M HCl) . Example 14 Preparation of l—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—(2, 6 —bis(pyrrolidino)—4—pyrimidinyl)piperazine By using 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—(2 —chloro—6—pyrrolidino—4—pyrimidinyl)piperazine as startin material, the process described in Example 13 is followe to obtain the title compound in a yield of 89.6%, m.p.: 267 269°C. Example 15 Preparation of 1—[ (3α, I6α)—eburnamenine—14—carbonyl]—4—(2, 6 —bis(pyrrolidino)—4—pyrimidinyl)piperazine A solution containing 2.0 g (5.12 mmoles) of 1 —[ (3α, 16α)—eburnamenine—14—carbonyl]piperazine and 3.88 (15.36 mmoles) of 4-chloro-2, 6-bis(pyrrolidino)pyrimidine i 30 ml of N-ethylmorpholine is refluxed under nitrogen for 4 hourε, then the reaction mixture is evaporated unde environmental pressure. Thereafter, 30 ml of water are adde and water is distilled off until the temperature of th vapour reaches 100°C. After cooling down the residue i - 37 - distributed between 50 ml of chloroform and 10 ml of 1 sodium hydroxide solution. After separation the organ phase is dried and evaporated. The evaporation residue purified by chromatography on a εilica gel column. By usi a mixture of chloroform and methanol (99:1—>95:5) as elue and recrystallizing the obtained product from ethanol, t title compound is obtained in a yield of 2.84 g (91,3%) m.p.: 267-269°C. Example 16 Preparation of 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—[2 , —bis(pyrrolidino)—4—pyrimidinyl] iperazine 1—[ (3α, 16α)—eburnamenine—14-carbonyl]—4—(2,4—dichloro— —pyrimidinyl)piperazine iε reacted with pyrrolidine described in Example 13 to give the title compound in yield of 89.3%, m.p.: 267-269°C. Example 17 Preparation of 2—(1—piperazinyl)—4, 6—bis(pyrrolidino)pyrim dine A mixture of 10.0 g (34.7 mmoles) of 2—chloro—2, 6—bi (pyrrolidino)pyrimidine, 11.95 g (138.8 mmoleε) of piper zine and 150 ml of N—ethylmorpholine is boiled under refl under nitrogen for 25 hours, then the solvent and exce piperazine are distilled off under environmental pressur After adding 100 ml of water to the residue, water distilled off until the head temperature reaches 100° After cooling down, the residue is distributed between 2 ml of chloroform and 30 ml of 10% sodium hydroxide solutio After εeparation the organic phaεe iε washed 4 times with ml of water each, then dried and evaporated. The evaporati residue is purified by chromatography on a εilica g column. By uεing a 9:1 mixture of chloroform and methanol eluent and recrystallizing the product from hexane, t title compound is obtained in a yield of 8.54 g (81.4% m.p.: 152-160°C. 1H-NMR (60 MHz, CDC1 3 ) δ ppm: 4.83 (s, 1H, 5-H) Example 18 Preparation of 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4- —[ (4,6—bis(pyrrolidino)—2—pyrimidinyl]piperazine 1—[ (3α, 16 )—eburnamenine—14-carbony1]—4—(4—chloro—6—py rolidino—2—pyrimidinyl)piperazine is reacted with pyrrol dine as described in Example 13 to give the title compou in a yield of 90.2%, m.p.: 275-278°C. Example 19 Preparation of 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—[4, —bis(pyrrolidino)—2—pyrimidinyl]piperazine 1—[ (3α,16α)—eburnamenine—14—carbonyl]piperazine is reacted with 2—chloro-4, 6—bis(pyrrolidino)pyrimidine described in Example 15 to obtain the title compound in yield of 89.5%, m.p.: 274-277°C. Example 20 Preparation of 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—[4 , biε(pyrrolidino)— 2—pyrimidinyl]piperazine Firεt 1.31 g (3.47 mmoleε) of (3α, ' 16α)—eburnamenine—1 —carbonyl chloride hydrochloride and then 0.48 g potasεium carbonate are added in small portions to a sol tion of 1.0 g (3.31 mmoleε) of 2—(1—piperazinyl)—4 , 6—bi (pyrrolidino)pyrimidine in 10 ml of methylene chloride —15°C. Then the cooling of the reaction mixture is stopp the temperature of the mixture iε allowed to reach room t perature and 5 ml of water are added. After stirring for minuteε and settling, the phases are separated, the orga phase is washed twice with water, then dried and evaporat The evaporation residue is recrystallized from acetonitril The product obtained is dried and recrystallized f ethanol to give the title compound in a yield of 1.81 (90.3%) , m.p.: 275-278°C. Example 21 Preparation of 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4—[4, —biε (pyrrolidino)—2—pyrimidinyl]piperazine i—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—(4, 6—dichloro —pyrimidinyl)piperazine iε brought into reaction with pyr lidine aε deεcribed in Example 13 to give the title compound in a yield of 89%, m.p.: 275-278°C. Example 22 Preparation of 1—[ (16α)—eburnamenine—14—carbonyl]—4—[2 , 6- —bis(pyrrolidino—4—pyrimidinyl]piperazine (16α)—Eburnamenine—14—carbonyl chloride hydrochloride is reacted with piperazine as described in Example 1, then the product obtained is brought into reaction with 4—chloro—2 , 6- —bis(pyrrolidino)pyrimidine as described in Example 15 to obtain the title compound in a yield of 87.7%, m.p.: 235- 238°C, [α] D 25 = +20° (c=l, 1 M HC1) . Example 23 Preparation of 1—[ (3α)—eburnamenine—14—carbonyl]—4—[2, 6—bis- (pyrrolidino)—4—pyrimidinyl]piperazine (3α)—Eburnamenine—14—carbonyl chloride hydrochloride is reacted with piperazine as described in Example 1 and the product obtained is brought into reaction with 4—chloro-2 , 6- —bis(pyrrolidino)pyrimidine according to Example 15 to give the title compound in a yield of 89.4%, m.p.: 241-243°C, [ct] D 25 = +19° (c=l, 1 M HC1) . Example 24 Preparation of 4 , 6—dichloro—2—(1—adamantylamino)pyrimidine and 2,6—dichloro—4—(1—adamantylamino)pyrimidine To a solution of 70.3 g (465.6 mmoles) of 1—aminoadaman- tane in 650 ml of tetrahydrofuran 40.6 g (225.6 mmoles) of 2,4 , 6—trichloropyrimidine are added, and the reaction mix¬ ture is stirred for 24 hours. Thereafter, the crystalline 1- —aminoadamantane hydrochloride iε filtered off, the filtrate is evaporated and the reεidue iε subjected to chromatography on a silica gel column. By using a 49:1 mixture of hexane and acetone as eluent 4,6—dichloro-2—(1—adamantylamino)pyri¬ midine is obtained which is recrystallized from hexane to give a yield of 28.74 (43.5%), m.p.: 151-155°C. ^-H-NMR (60 MHz, CDCl 3 ) <S ppm: 6.55 (ε, 1H, 5-H) By further elution with a 24:1 mixture of hexane and acetone the more polar 2, 6—dichloro—4—(1—adamantylamino)py- - 40 - rimidine is obtained, which is recrystallized from hexane obtain a yield of 35.56 g (53.8%), m.p. 193-196°C. l -H-NMR (60 MHZ, CDC1 3 ) δ ppm: 6.33 (s, 1H, 5-H) Example 25 Preparation of 2,4-bis(l—adamantylamino)—6—chloropyrimidin A solution containing 26.0 g (87.25 mmoles) of 4, —dichloro—2—(1—adamantylamino) yrimidine and 39.5 g (261 mmoles) of 1—aminoadamantane in 200 ml of n—butanol boiled under reflux for 75 hours, then evaporated. T evaporation residue is suspended in 400 ml of ether, t suspension is filtered off and, after drying, the produ filtered off is purified by chromatography on a silica g column. By using chloroform as eluent and recrystallizi the obtained product from ether the title compound obtained in a yield of 23.94 g (66.44%), m.p.: 232-236°C. ■ ^ • H-NMR (60 MHZ, CDCI3) δ PP m: 5 - 64 ( s ■ 1U > 5 ~ H ) Example 26 Preparation of 2,4— is(1—adamantylamino)—6—(1—piperazinyl pyrimidine 2,4—bis(1—adamantylamino)—6—chloropyrimidine is react with piperazine as described in Example 17 to give the tit compound in a yield of 83.36%, m.p. 168-175°C. ■■■ -H-NMR (60 MHZ, CDCI 3 ) δ ppm: 4.97 (s, 1H, 5-H) Example 27 Preparation of 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4—[2, -bis(l—adamantylamino)—6-pyrimidinyl]-piperazine (3α,16α)-Eburnamenine-14-carbonyl chloride hydrochlori is reacted with 2, -bis(l—adamantylamino)-6-(1-piperazinyl pyrimidine as described in Example 20 to obtain the tit compound in a yield of 84.6%, m.p. 270-273°C. Example 28 Preparation of 2—(1—adamantylamino)-4-chloro-6— yrrolidin pyrimidine 10 g (33.53 mmoleε) of 4,6-dichloro-2-(l-adamanty amino)pyrimidine are added in small portions to 40 ml pyrrolidine at a temperature below 10°C under cooling a stirring. After addition the reaction mixture is stirred a room temperature for 1 hour, then evaporated. The residue i distributed between 150 ml of chloroform and 30 ml of 10 sodium hydroxide solution. After separation the organi phase is washed 4 times with 50 ml of water each, then drie and evaporated. The evaporation residue is recrystallize from ethyl acetate to give the title compound in a yield o 9.60 g (86%), m.p. :178-180°C. iH-NMR (60 MHz, CDC1 3 ) 6 ppm: 5.62 (s, 1H, 5-H) Example 29 Preparation of 2—(1—adamantylamino)—4—(1—piperazinyl)—6—pyr rolidinopyrimidine 2—(1— damantylamino)—4—chloro—6—pyrrolidinopyrimidine i reacted with piperazine as described in Example 17 to giv the title compound in a yield of 69.7%, m.p.: 160-164°C. i H- (60 MHz, CDCI 3 ) 5 ppm: 4.87 (s, 1H, 5-H) Example 30 Preparation of 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4—[2 -(1—adamantylamino)—6— yrrolidino—4-pyrimidinyl]piperazine (3α,16α)—Eburnamenine—14—carbonyl chloride hydrochlorid is reacted with 2—(1—adamantylamino)—4—(1—piperazinyl)—6 —pyrrolidinopyrimidine as described in Example 20 to obtai the title compound in a yield of 88.8%, m.p.: 242-246°C. Example 31 Preparation of 4,6—dichloro—2—(1,1—dimethylethylamino)pyri midine and 2,6—dichloro—4—(1,1—dimethylethylamino)pyrimidin 25 g (136.3 mmoles) of 2,4,6-trichloropyrimidine ar dropwise added to a mixture of 31.52 ml (300 mmoles) of 1 amino—1,1—dimethylethane and 200 ml of tetrahydrofuran at temperature between 10°C and 15°C under cooling and stirr ing. Subsequently, the reaction mixture is stirred at roo temperature for additional 5 hours, then evaporated. Afte distributing the residue between 500 ml of chloroform and 5 ml of 10% sodium hydroxide solution and separation, th organic phase is washed 4 times with 150 ml of water each then dried and evaporated. The evaporation reεidue iε sub - 42 - jected to chromatography on a silica gel column. By using 9:1 mixture of hexane and ethyl acetate as eluent 4,6—d chloro—2—(1,1-dimethylethylamino)pyrimidine is obtaine which is recrystallized from hexane to give a yield of 11. g (37.84%), m.p. :70-74°C. ■ T-H- MR (60 MHz, THF-d 8 ) <S ppm: 6.63 (s, 1H, 5-H) By further elution with a 4:1 mixture of hexane a ethyl acetate the more polar 2,6—dichloro—4—(1,1-dimethy ethylamino)pyrimidine is obtained, which is recrystalliz from ethyl acetate to obtain a yield of 13.31 g (44.35%) m.p.: 192-195°C. •T-H-NMR (60 MHz, THF-d 8 ) <S ppm: 6.32 (s, 1H, 5-H) Example 32 Preparation of 4-chloro-2-(l,1—dimethylethylamino)—6-pyrr lidinopyrimidine 4,6—Dichloro—2—(1 ,1-dimethylethylamino)pyrimidine is reacted with pyrrolidine as described in Example 28 to gi the title compound in a yield of 93%, m.p.: 153-157°C. 1 H-NMR (60 MHz, CDC1 3 ) δ ppm: 5.67 (s, 1H, 5-H) Example 33 Preparation of 2—(1,1—dimethylethylamino)—4—(1—piperazinyl) —6—pyrrolidinopyrimidine 4—Chloro-2—(1,1—dimethylethylamino)-6-pyrrolidinopyri dine is reacted with piperazine as described in Example to obtain the title compound in a yield of 78.1%, m.p.: 16 165°C. •T-H-NMR (60 MHZ, CDCI 3 ) δ ppm: 4.87 (s, 1H, 5-H) Example 34 Preparation of 1—[ (3α,i6α)-eburnamenine-14—carbonyl]-4-[ -(1,1—dimethylethylamino)-6-pyrrolidino-4-pyrimidinyl]pipe razine (3α,16α)—Eburnamenine—14—carbonyl chloride hydrochlori is reacted with 2-(l,1-dimethylethylamino)-4-(1-piperaz nyl)—6—pyrrolidinopyrimidine as described in Example 20 give the title compound in a yield of 94.7%, m.p. :225-228° Example 35 Preparation of 4,6-dichloro—2-(2,2-dimethylpropylamino)pyri¬ midine and 2,6-dichloro-4-(2,2-dimethylpropylamino)pyrimi¬ dine 25 g (136.3 mmoles) of 2,4,6—trichloropyrimidine are dropwise added to a mixture of 23.84 g (273.5 mmoles) of 1- —amino—2,2— imethylpropane and 200 ml of tetrahydrofuran at a temperature between 10°C and 15°C while stirring and cool¬ ing. Thereafter, the reaction mixture is stirred at room temperature for additional 30 minutes, then evaporated. After distributing the evaporation residue between 300 ml of chloroform and 50 ml of 10% sodium hydroxide solution, the organic phase is separated, washed 4 times with 100 ml of water each, then dried and evaporated. The evaporation resi- due is subjected to chromatography on a silica gel column. By using a 19:1 mixture of hexane and ethyl acetate, 4,6—di¬ chloro—2—(2,2—dimethylpropylamino)pyrimidine is obtained, which is recrystallized from a mixture of ether and hexane to obtain a yield of 13.60 g (42.6%), m.p.: 63-66°C. ^-H-NMR (60 MHz, CDC1 3 ) δ ppm: 6.60 (s, 1H, 5-H) By further elution with a 6:1 mixture of hexane and ethyl acetate, the more polar 2,6—dichloro—4—(2,2—dimethylpropyl¬ amino)pyrimidine is obtained which is recrystallized from a mixture of ether and hexane to give a yield of 14.24 g (44.6%), m.p.: 77-79°C. ■ iH-N R (60 MHz, CDCI3) -5 ppm: 6.33 (s, 1H, 5-H) Example 36 Preparation of 4-chloro-2-(2,2-dimethylpropylamino)—6-pyrro- lidinopyrimidine The reaction of 4,6-dichloro-2-(2,2-dimethylpropyl- amino)pyrimidine with pyrrolidine as described in Example 28 gives the title compound in a yield of 96.7%, m.p.: 147- 150°C. iH-N R (60 MHZ, CDCI3) δ ppm: 5.67 (s, 1H, 5-H) - 44 - Example 37 Preparation of 2-(2,2-dimethylpropylamino)—4-(l-piperaz nyl)—6—pyrrolidinopyrimidine The reaction of 2-(2,2—dimethylpropylamino)-4-chloro— —pyrrolidinopyrimidine with piperazine as described Example 17 leads to the title compound in a yield of 76 m.p. : 118-120°C. i H-NM (60 MHz, CDC1 3 ) δ ppm: 4.83 (s, 1H, 5-H) Example 38 Preparation of l-[ (3α,I6α)—eburnamenine-14—carbonyl]—4-[ —(2,2—dimethylpropylamino)-6—pyrrolidino-4—pyrimidinyl]pip razine (3α,16α)—Eburnamenine—14—carbonyl chloride hydrochlori is brought into reaction with 2—(2,2—dimethylpropylamino)— -(l-piperazinyl)-6-pyrrolidinopyrimidine as described Example 20 to give the title compound in a yield of 81.0 m.p.: 266-272°C. Example 39 Preparation of l-[ (3α,16α)—eburnamenine-14—carbonyl]—4-[ —(4—morpholinyl)—4—ethylamino—6—pyrimidinyl]piperazine The reaction of 2—(4—morpholinyl)—4—ethylamino—6—(1—p perazinyl)pyrimidine (which is known from the GB pate specification No. 1,345,640) with (3α,16α)—eburnamenine—1 -carbonyl chloride hydrochloride as described in Example gives the title compound. Example 40 Preparation of l-[(3α,16α)—eburnamenine-14—carbonyl]—4-[ —amino—4—(1,1—dimethylethylamino)—6—pyrimidinyl]piperazine The reaction of 1—[ (3α,16α)—eburnamenine—14—carbonyl]p perazine with 2—amino—4—chloro—6—(1,1—dimethylethylamino) rimidine (known from the German patent specification N 2,006,145) as described in Example 15 results in the tit compound. - 45 - Example 41 Preparation of 2—cyclopentylamino—4,6—dichloropyrimidine an 4—cyclopentylamino—2,6—dichloropyrimidine The reaction of 2,4,6—trichloropyrimidine with cyclopen tyla ine carried out as described in Example 35 gives bot compounds. The less polar 2-cyclopentylamino—4,6—dichloropy rimidine is obtained in a yield of 35.2%, m.p.: 48-52°C. ■ T-H-NMR (60 MHz, CDCl 3 ) δ ppm: 6.52 (s, 1H, 5-H) The more polar 4—cyclopentylamino—2,6—dichloropyrimidin is obtained in an oily form in a yield of 57.2%. • - ■ t-H-NMR (60 MHz, CDCI 3 ) δ ppm: 6.30 (s, 1H, 5-H) Example 42 Preparation of 2—cyclopentylamino—4—chloro—6— yrrolidinopy rimidine The reaction of 2—cyclopentylamino—4,6—dichloropyrimi dine with pyrrolidine as described in Example 13 gives th title compound as an oily product in a yield of 72.4%. ^-H-NMR (60 MHz, CDCI 3 ) -5 ppm: 5.72 (s, 1H, 5-H) Example 43 Preparation of 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4—(2 —cyclopentylamino—6—pyrrolidino—4—pyrimidinyl)piperazine The title compound is prepared by reacting 1—[(3α,16α) —eburnamenine—14—carbonyl]piperazine with 2—cyclopentylami no—4—chloro—6-pyrrolidinopyrimidine as described in Exampl 15. Example 44 Preparation of 4,6—dichloro-2-(2,2,6,6—tetra ethyl—1—piperi dinyl)pyrimidine A mixture containing 25 g (136.3 mmoles) of 2,4,6— ri chloropyrimidine and 46.3 ml (272.6 mmoles) of 2,2,4,4—tet ramethylpiperidine is boiled under reflux for 50 hours, the cooled down and suspended in 250 ml of hexane. The insolubl part is filtered off, the filtrate is evaporated and th evaporation residue is distributed between 300 ml of chloro form and 50 ml of 10% sodium hydroxide solution. Afte separation the organic phase is washed 4 times with 100 m of water each, then dried and evaporated. The evaporation residue is purified by chromatography on a silica gel column. By using hexane as eluent the title compound is obtained, which is recrystallized to give a yield of 8.04 g (20.47%), m.p.: 89-90°C. l-H-NMR (60 MHz, CDC1 3 ) <S ppm: 6.53 (s, 1H, 5-H) Example 45 Preparation of 4-chloro—2-(2,2, 6, 6-tetramethyl-l—piperidi- nyl)—6—pyrrolidinopyrimidine The reaction of 4,6—dichloro—2—(2,2,6,6—tetramethyl-1- —piperidinyl)pyrimidine with pyrrolidine as described in Example 13 gives the title compound in a yield of 75.08%, m.p. : 130-135°C. iH-NMR (60 MHz, CDCI3) 5 ppm: 5.76 (s, 1H, 5-H) Example 46 Preparation of 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4—[2- —(2,2,6,6—tetramethyl—1—piperidinyl)—6—pyrrolidino—4—pyrimi¬ dinyl]piperazine The title compound is prepared by reacting 1—[(3α,l6α)- —eburnamenine—14—carbonyl]piperazine with 4—chloro—2- —(2,2,6, 6—tetramethyl—1—piperidinyl)—6—pyrrolidinopyrimidine similarly as described in Example 15. Example 47 Preparation of 1—[ (3α, 16α)-eburnamenine-14—carbonyl]—(hexa- hydro—1H—1,4—diazepine) The reaction of (3α,16α)—eburnamenine—14—carbonyl chlor¬ ide hydrochloride with homopiperazine similarly as described in Example 1 gives the title compound. Example 48 Preparation of 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4— [ 2 , 6- -bis(pyrrolidino)—4-pyrimidiny1]—(hexahydro—1H-1,4-diaze- pine) The title compound is prepared by reacting 1—[(3α,16α)- —eburnamenine—14—carbonyl]—(hexahydro-lH—1,4—diazepine) with 4—chloro—2,6—bis(pyrrolidino)pyrimidine similarly as described in Example 15. - 47 - Example 49 Preparation of l—[ (3α,16α)—eburnamenine—14—ylmethyl]—4—[2,6 —bis(pyrrolidino)—4—pyrimidinyl]piperazine A solution containing 1.95 g (3.2 mmoles) of 1 —[ (3α,16α)—eburnamenine—14—carbonyl]—4—[2,6—bis(pyrrolidi¬ no)—4— yrimidinyl]piperazine in 65 ml of tetrahydrofuran i dropwise added during 10 minutes to 1.3 g (34 mmoles) o lithium aluminum hydride dissolved in 65 ml of tetrahydrofu ran under argon while stirring, then the reaction mixture i boiled under reflux for 3 hours. After cooling down, th excess of the reducing agent is decomposed by successivel adding a mixture of 1.3 ml of water and 1.3 ml of 15% sodiu hydroxide solution and then 5.2 ml of water. After filterin off the precipitate and washing it with tetrahydrofuran, th filtrate combined with the washings is evaporated. Th evaporation residue is purified on a silica gel column. B using a 9:1 mixture of cyclohexane and diethylamine a eluent, the title compound is obtained as a foam in a yiel of 1.00 g, [α]n 22 = -33° (as trihydrobromide, c=l, H2O) . Example 50 Preparation of l—[ (3α,16α)—eburnamenine—14—ylmethyl]—4—[2,6 -bis(pyrrolidino)-4-pyrimidinyl]piperazine trihydrobromide After suspending 1.00 g (1.69 mmoles) of 1—[(3α,16α) —eburnamenine—14—ylmethyl]—4—[2,6—bis(pyrrolidino)—4—pyrimi dinyl]piperazine in 10 ml of isopropanol, 2.02 ml (5,0 mmoles) of a 2.5 M solution of hydrogen bromide in isopropa nol are added to the above suspension. The crystalline pre cipitate is filtered off and dried to obtain 0.65 g (46% of the title salt. Example 51 Preparation of an injectable solution 0.05% by weight of sodium pyrosulfite is dissolved i oxygen-free water for injection and the active ingredient i dissolved therein. Simultaneously, 0.1% by weight o potassium sorbate is dissolved in oxygen-free water fo injection and sodium chloride in an amount required fo isotonization is dissolved therein. After combining bot solutions, the solution is filled up to the final volum desired with oxygen-fee water for injection and finally, i is filtered through a membrane filter with 0.2 μ por diameter for making it free of bacteria and strang materials. The filtrate is filled into ampoules unde nitrogen. A preferable composition of 1 ml volume of injection i as follows: active ingredient 10 mg sodium pyrosulfite 5 mg sodium chloride 7 mg water for injection up to 1 ml

Claims: Claims Novel eburnamenine derivatives of the formula wherein R 1 and R 2 as well as R 3 and R 4 , independently from eac other, stand for hydrogen, C 2 —βalkyl group, C 2 —ς alkenyl group; or a C 3 _ιoalicyclic group involving to 3 rings, and this latter group may be substitute by a C-*L_galkyl or C 2 —βalkenyl group; or R 1 and R 2 and/or R 3 and R 4 , together with the adjacen nitrogen atom and optionally with an additional oxyge or nitrogen atom, form a 4— to 6—membered, saturate or unsaturated cyclic group which may be substitute by a Cι_galkyl or C2_ 6 al enyl group; two of X, Y and Z are nitrogen whereas the third of the means a methine group; n is 1 or 2; W means oxygen or two hydrogen atoms; and the wavy line means α—/α—, a—/β— or R—/a— steric position, as well as acid additions salts and solvates thereof. 2. A compound selected from the group consisting of 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4—[2,4—bis(pyrro¬ lidino)—6—pyrimidiny1]piperazine, 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4—[2,6—bis(pyrro- lidino)—4-pyrimidiny1]piperazine, 1—[ (3α,16α)—eburnamenine-14-carbonyl]—4—[4,6-bis(pyrro- lidino)—2—pyrimidiny1]piperazine, 1—[ (16α)—eburnamenine—14—carbonyl]—4—[2, 6—bis(pyrroli¬ dino)—4—pyrimidiny1]piperazine, 1—[ (3 a)—eburnamenine—14—carbonyl]—4—[2,6—bis(pyrro1i- dino)—4—pyrimidiny1]piperazine, 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4—[2,4—bis(1—ada¬ mantylamino)—6—pyrimidinyl]piperazine, 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4—[2—(1—ada¬ mantylamino)—6—pyrrolidino)—4—pyrimidinyl]piperazine, 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4—[2—(1, 1— i¬ methylethylamino)—6—pyrrolidino—4—pyrimidinyl]piperazine, 1—[ (3α,16α)—eburnamenine—14—carbonyl]—4—[2—(2,2—di¬ methylpropylamino)-6-pyrrolidino)-4-pyrimidinyl]piperazine, 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—[2—(4—morpho- linyl)-4—ethylaminc—6-pyrimidinyl]piperazine , 1—[ (3α, 16α)—eburnamenine—14—carbonyl]—4—[2—amino—4—(1, 1 —dimethylethylamino)—6—pyrimidinyl] iperazine, 1—[ (3α, 16a)—eburnamenine—14—carbonyl]—4—(2—cyclopentyl¬ amino—6—pyrrolidino—4—pyrimidinyl)piperazine, 1—[ (3α,I6α)—eburnamenine—14—carbonyl]—4—[2—(2,2,6, 6—tet ramethyl—1—piperidinyl)—6-pyrrolidino—4—pyrimidinyl]pipe¬ razine, l-[ (3α, 16α)-eburnamenine-14-carbonyl]—4—[2,6—bis(pyrro¬ lidino)—4—pyrimidinyl]—(hexahydro—1H—1,4—diazepine, l-[ (3α, 16α)—eburnamenine-14-carbonyl]-4—[2,6—bis(pyrro¬ lidino)—4—pyrimidinyl]piperazine as well as the acid addition salts of these compounds. 3. A pharmaceutical composition, which comprises a active ingredient a therapeutically effective amount of a eburnamenine derivative of the formula (I), wherein R 1 , R 2 R 3 , R 4 , X, Y, Z, n, W and the wavy line are as defined i claim 1, or pharmaceutically acceptable acid addition sal or solvate thereof. 4. A process for the preparation of novel eburnamenin derivatives of the formula wherein R 1 and R 2 as well as R 3 and R 4 , independently from each other, stand for hydrogen, C2_ 6 lkyl group, C2— s~ alkenyl group; or a C 3 _ιoalicyclic group involving l to 3 rings, and this latter group may be substituted by a Cι_galkyl or C2_ 6 alkenyl group; or R 1 and R 2 and/or R 3 and R 4 , together with the adjacent nitrogen atom and optionally with an additional oxygen or nitrogen atom, form a 4— to 6—membered, saturated or unsaturated cyclic group which may be substituted by a Cι_gal yl or C2_ 6 a lkenyl group; two of X, Y and Z are nitrogen whereas the third of them means a methine group; n is 1 or 2; W means oxygen or two hydrogen atoms; and the wavy line means α—/α—, a—/R— or β— /a— steric position, as well as acid additions salts and solvates thereof, which comprises a) reacting an eburnamenine chloride of the formula EBU-co-ci wherein the wavy line is as defined above, or the hydro¬ chloride salt thereof with a piperazine derivative of the - 52 - formula HN ,NH (CH ( 2.)'n wherein n is as defined above, reacting the thus obtained 1— (eburnamenincarbonyl) pi razine of the formula EBU- CO-N NH (CH 2 ) n ( I wherein n and the wavy line are as defined above, w 2,4,6—trichloropyrimidine, separating the isomeric mixture obtained containing —eburnameninecarbonyl—4—(4,6—dichloropyrimidine-2—yl)pipe zine of the formula and 1—eburnameninecarbonyl—4—(2,4—dichloropyrimidin—6-yl) perazine of the formula EBU wherein n and the wavy line are as defined above, to th individual isomers, then reacting about 1 mole of the obtained 1—eburnameninecar bonyl—4—(4,6—dichloropyrimidin—2—yl)piperazine of the for mula (IHa) with about 2 moles of an amine of formul HNR***-R 2 , wherein R 1 and R 2 are the same as R 3 and R 4 , in on or two step(s) to give eburnamenine derivatives of the for mula (I), wherein R 1 and R 2 are the same as R 3 and R 4 , X an Z mean nitrogen, Y means a methine group and n as well a the wavy line are as defined above; or reacting about 1 mole of the obtained 1—eburnameninecar bonyl—4—(4,6—dichloropyrimidin—2—yl)piperazine of the for mula (IHa) with about 1 mole of an amine of the formul HNR-'-R 2 , wherein R 1 and R 2 are different from R 3 and R 4 then, reacting the obtained 1—eburnameninecarbonyl—4—(4-amino —6—chloropyrimidin—2—yl)piperazine of the formula wherein R 1 , R 2 , n and the wavy line are as defined above with an amine of the formula HNR 3 R , wherein R 3 and R 4 ar as defined above, to obtain eburnamenine derivatives of th formula (I), wherein R 1 and R 2 are different from R 3 and R 4 X and Z mean nitrogen, Y is a methine group and n as well a the wavy line are as defined above; or reacting about 1 mole of the l-eburnameninecarbonyl-4 —(2,4-dichloropyrimidin—6—yl)piperazine of the formul (Illb) with about 2 moles of an amine of the formula HNR^-R 2 wherein R 1 and R 2 are the same as R 3 and R 4 , in one or tw step(ε), to give eburnamenine derivatives of the formul (I), wherein R 1 and R 2 are the same as R 3 and R , X and mean nitrogen, Z is a methine group and n as well as th wavy line are as defined above; or reacting about 1 mole of 1—eburnameninecarbonyl—4—(2,4 —dichloro—pyrimidin—6—yl)—piperazine of the formula (Illb with about 1 mole of an amine of the formula HNR-^R 2 , wherei R 1 and R 2 are different from R 3 and R 4 to obtai eburnamenine derivatives of the formula (I) , wherein R 1 an R 2 are different from R 3 and R 4 , X and Y mean nitrogen; Z i a methine group or Z and Y mean nitrogen and X is a methin group, and n as well as the wavy line are as defined above then separating the obtained isomeric mixture containing 1 —eburnameninecarbonyl—4—(2-amino—4—chloropyrimidin—6—yl)pi¬ perazine of the formula and 1—eburnameninecarbonyl —4—(4—amino—2—chloropyrimidin—6 —yl)piperazine of the formula wherein R 1 , R 2 , n and the wavy line are as defined above, t the individual isomerε and reacting about 1 mole thereo with about 1 mole of an amine of the formula HNR 3 R 4 , wherei R 3 and R 4 are different from R 1 and R 2 , to give eburnamenin derivativeε of the formula (I) , wherein R 1 and R 2 are dif ferent from R 3 and R 4 , X and Y mean nitrogen, Z is a methin group, or Z and Y mean nitrogen and X is a methine group and n as well as the wavy line are as defined above; or al) reacting a 1—(eburnameninecarbonyl)piperazine of th formula (IV) , wherein n and the wavy line are as define above, with 2,4,6—trichloropyrimidine, separating the isomeric mixture containing 1—eburname ninecarbonyl—4—(4,6—dichloropyrimidine—2—yl)piperazine o the formula (Ilia) and 1—eburnameninecarbonyl—4—(2,4—dichlo ropyrimidin—6—yl)piperazine of the formula (Illb) , wherein and the wavy line are as defined above, to the individua isomers, then reacting 1 mole of the obtained 1—eburnameninecarbonyl —4—(4,6— ichloropyrimidin—2—yl)piperazine of the formul (Ilia) with 2 moles of an amine of the formula HNR-**-R 2 wherein R 1 and R 2 are the same as R 3 and R 4 , in one or tw step(s), to give eburnamenine derivatives of the formul (I), wherein R 1 and R 2 are the same as R 3 and R , X and mean nitrogen, Y is a methine group, and as well as the wav line are as defined above; or reacting 1 mole of 1—eburnameninecarbonyl—4-(4,6—dichlo ropyrimidin—2—yl)piperazine of the formula (IHa) with more of an amine of the formula HNR^-R 2 , wherein R 1 and R are different from R 3 and R 4 , to obtain eburnamenine deriva tives of the formula (I) , wherein R 1 and R 2 are differen from R 3 and R 4 , X and Z mean nitrogen, Y is a methine group and n as well as the wavy line are as defined above, then reacting the obtained l-eburnameninecarbonyl—4—(4—amino -6-chloropyrimidin-2-yl)piperazine of the formula (Ha) wherein R 1 , R 2 , n and the wavy line are as defined above with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 ar different from R 1 and R 2 , to obtain eburnamenine derivative of the formula (I) , wherein R 1 and R 2 are different from R and R 4 , X and Z mean nitrogen, Y is a methine group and n a well as the wavy line are as defined above; or reacting 1 mole of l-eburnameninecarbonyl-4-(2,4-dichlo ropyrimidin-6-yl)piperazine of the formula (Illb) with moles of an amine of the formula HNR^-R 2 , wherein R 1 and R are the same as R 3 and R 4 , in one or two step(s) , to giv eburnamenine derivatives of the formula (I) , wherein R 1 an R 2 are the same as R 3 and R 4 , X and Y mean nitrogen, Z is methine group, and n as well as the wavy line are as define above; or reacting 1 mole of 1—eburnameninecarbonyl-4—(2,4-dichlo ropyrimidine—6—yl)piperazine of the formula (Illb) with mole of an amine of the formula HNR-^R 2 , wherein R 1 and R are different from R 3 and R 4 , then separating the isomeric mixture containing 1—eburname ninecarbonyl—4—(2—amino—4—chloropyrimidin—6-yl)piperazine o the formula (Ilba) and 1—eburnameninecarbonyl—4—(4—amino—2 -chloropyrimidin—6-yl)piperazine of the formula (Ilbb), wherein R 1 , R 2 . n and the wavy line are as defined above, t the individual isomers and reacting 1 mole thereof with mole of an amine of the formula HNR 3 R 4 , wherein R 3 and R are different from R 1 and R 2 , to give eburnamenine deriva tives of the formula (I) , wherein R 1 and R 2 are differen from R 3 and R , X and Y mean nitrogen and Z is a methin group or Z and X mean nitrogen and X is a methine group, an n as well as the wavy line are as defined above; or a2a) reacting about 1 mole of 1-eburnameninecarbonyl—4 —(4,6—dichloropyrimidin—2—yl)piperazine of the formul (IHa) , wherein n and the wavy line are as defined above, with about 2 moles of an amine of the formula HNR-^-R 2 , wherein R 1 and R 2 are the same as R 3 and R 4 , in one or tw step(s) to obtain eburnamenine derivatives of the formul (I), wherein R 1 and R 2 are the same as R 3 and R 4 , X and mean nitrogen, Y is a methine group, and n and the wavy lin are as defined above; or a2b) reacting about 1 mole of 1—eburnameninecarbonyl—4 —(4,6—dichloropyrimidin—2—yl)piperazine of the formul (IHa) , wherein n and the wavy line are as defined above, with about 1 mole of an amine of the formula HNR 1 R 2 , wherei R 1 and R 2 are different from R 3 and R 4 , then reacting the obtained 1—eburnameninecarbonyl—4—(4-amino -6—chloropyrimidin—2—yl)piperazine of the formula (Ha) , wherein R 1 , R 2 , n and the wavy line are as defined above, with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 ar different from R 1 and R 2 , to obtain eburnamenine derivative of the formula (I) , wherein R 1 and R 2 are different from R and R 4 , X and Z mean nitrogen, Y is a methine group and n a well as the wavy line are as defined above; or a2c) reacting about 1 mole of 1—eburnameninecarbonyl—4 —(2,4—dichloropyrimidin—6—yl)piperazine of the formul (Illb) , wherein n and the wavy line are as defined above, with about 2 moles of an amine of the formula HNR-**-R 2 , wherein R 1 and R 2 are the same as R 3 and R 4 , in one or tw step(s) , to obtain eburnamenine derivatives of the formul (I), wherein R 1 and R 2 are the same as R 3 and R , X and mean nitrogen, Z is a methine group, n and the wavy line ar as defined above; or a2d) reacting about 1 mole of 1—eburnameninecarbonyl—4 —(2,4—dichloropyrimidin—6—yl)piperazine of the formul (Illb) , wherein n and the wavy line are as defined above, with about 1 mole of an amine of the formula HNR----R 2 , wherei R 1 and R 2 are different from R 3 and R 4 , then separating the obtained isomeric mixture containing 1 —eburnameninecarbonyl—4—(2—amino—4—chloropyrimidin—6-yl)pi- perazine of the formula (Ilba) and l-eburnameninecarbonyl-4 -(4—amino-2-chloropyrimidin-6-yl)piperazine of the formul (Ilbb), wherein R 1 , R 2 , n and the wavy line are as define above, to the individual isomers and then reacting about mole thereof with about 1 mole of an amine of the formul HNR 3 R 4 , wherein R 3 and R 4 are different from R 1 and R , t give eburnamenine derivatives of the formula (I) , wherein R and R 2 are different from R 3 and R 4 , X and Y mean nitroge and Z is a methine group or Z and Y mean nitrogen and X is methine group, n and the wavy line are as defined above; or a3a) reacting 1—eburnameninecarbonyl—4—(4—amino—6—chlo ropyrimidin—2—yl)piperazine of the formula (Ha) , wherei R 1 , R 2 , n and the wavy line are as defined above, with amine of the formula HNR 3 R , wherein R 3 and R 4 are defined above, to obtain eburnamenine derivatives of t formula (I) , wherein X and Z mean nitrogen, Y is a methi group, R 1 , R 2 , R 3 , R 4 , n and the wavy line are as defin above; or a3b) reacting a 1—eburnameninecarbonyl—4—(2—amino— —chloropyrimidine—6—yl)piperazine of the formula (Ilba wherein R 1 , R 2 , n and the wavy line are as defined abov with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 a as defined above, to obtain eburnamenine derivatives of t formula (I) , wherein X and Y mean nitrogen, Z is a methi group, R 1 , R 2 , R 3 , R , n and the wavy line are as defin above; or a3c) reacting a 1—eburnameninecarbonyl—4—(4—amino— -chloropyrimidin-6-yl)piperazine of the formula (Ilbb wherein R 1 , R 2 , n and the wavy line are as defined abov with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 a as defined above, to give eburnamenine derivatives of t formula (I) , wherein Z and Y mean nitrogen, X is a methi group, R 1 , R 2 , R 3 , R 4 , n and the wavy line are as defin above; or ba) reacting a 1—(eburnameninecarbonyl)piperazine of t formula (IV) , wherein n and the wavy line are as defin above, with a 2—amino—4,6—dichloropyrimidine of the formul wherein R 1 and R 2 are as defined above, then reacting the obtained 1—eburnameninecarbonyl—4—(2-amin -4-chloropyrimidin-6-yl)piperazine of the formula (Ilba wherein R 1 , R , n and the wavy line are as defined abov with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 ar as defined above, to obtain eburnamenine derivatives of th formula (I) , wherein X and Y mean nitrogen, Z is a methin group, R 1 , R 2 , R 3 , R 4 , n and the wavy line are as define above; or bb) reacting a 1—(eburnameninecarbonyl)piperazine of th formula (IV) , wherein n and the wavy line are as define above, with a 4—amino-2,6— ichloropyrimidine of the formula wherein R 1 and R 2 are as defined above, then separating the obtained isomeric mixture containing l —eburnameninecarbonyl—4—(4-amino—6—chloropyrimidine-2—yl)pi perazine of the formula (Ha) and 1—eburnameninecarbonyl—4 -(4—amino—2—chloropyri idin-6-yl)piperazine of the formul (Ilbb), wherein R 1 , R 2 , n and the wavy line are as define above, to the individual isomers and reacting about 1 mol thereof with about 1 mole of an amine of the formula HNR 3 R 4 wherein R 3 and R 4 are as defined above, to obtain eburna e nine derivatives of the formula (I) , wherein Z and Y mea nitrogen and X iε a methine group, or X and Z mean nitroge and Y is a methine group, R 1 , R 2 , R 3 , R 4 , n and the wav line are as defined above; or ca) reacting a 1-(eburnameninecarbonyl)piperazine of th formula (IV) , n and the wavy line are as defined above, wit a 4,6—diamino—2—chloropyrimidine of the formula wherein R 1 , R 2 , R 3 and R 4 are as defined above, to gi eburnamenine derivatives of the formula (I) , wherein X and mean nitrogen, Y is a methine group, R 1 , R , R 3 , R 4 , n a the wavy line are as defined above; or cb) reacting a 1—(eburnameninecarbonyl)piperazine of t formula (IV) , wherein n and the wavy line are as defin above, with a 2,4—diamino—6-chloropyrimidine of the formul wherein R 1 , R 2 , R 3 and R 4 are as defined above, to obta eburnamenine derivatives of the formula (I) , wherein X and mean nitrogen, Z is a methine group, R 1 , R 2 , R 3 , R 4 , n a the wavy line are as defined above; or da) reacting an eburnameninecarbonyl chloride of t formula (V) , the wavy line is as defined above, or the hy rochloride salt thereof, with a 4—(4—amino—6—chloropyrim din—2—yl)piperazine of the formula (Villa) wherein R 1 , R 2 and n are as defined above, then reacting the obtained 1—eburnameninecarbonyl—4—(4—amin -6—chloropyrimidin-2-yl)piperazine of the formula (Ha wherein R 1 , R 2 , n and the wavy line are as defined abov with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 a aε defined above, to give eburnamenine derivatives of t formula (I) , X and Z mean nitrogen, Y is a methine grou R 1 , R 2 , R 3 , R 4 , n and the wavy line are as defined above, or db) reacting an eburnameninecarbonyl chloride of the for¬ mula (V) , wherein the wavy line is as defined above, or the hydrochloride salt thereof with a 4—(4—amino—2—chloropyrimi¬ din—6—yl)piperazine of the formula (VHIbb) , wherein R 1 , R 2 and n are as defined above, then reacting the obtained 1-eburnameninecarbonyl—4—(4—amino- —2—chloropyrimidin—6—yl)piperazine of the formula (Ilbb) , wherein R 1 , R 2 , n and the wavy line are aε defined above, with an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 are as defined above, to obtain eburnamenine derivatives of the formula (I) , wherein Y and Z mean nitrogen, X is a methine group, R 1 , R 2 , R 3 , R 4 , n and the wavy line are as defined above, or dc) reacting an eburnameninecarbonyl chloride of the formula (V) , wherein the wavy line is as defined above, or the hydrochloride salt thereof with a 4—(2—amino—4—chloropy¬ rimidin—6—yl)piperazine of the formula ( vni ba) , wherein R 1 , R 2 and n are as defined above, then reacting the obtained l-eburnameninecarbonyl-4-(2-amino- -4-chloropyrimidin-6-yl)piperazine of the formula (Ilba) , wherein R 1 , R 2 , n and the wavy line are as defined abov with 'an amine of the formula HNR 3 R 4 , wherein R 3 and R 4 a as defined above, to give eburnamenine derivatives of t formula (I) , wherein X and Y mean nitrogen, Z is a methi group, R 1 , R 2 , R 3 . R . n and the wavy line are as defin above, or e) reacting an eburnameninecarbonyl chloride of the fo mula (V) , wherein the wavy line is as defined above, or t hydrochloride salt thereof with a 4—(dia inopyrimidinyl)pi perazine of the formula wherein R 1 , R 2 , R 3 , R 4 , X, Y, Z and n are as defined above, and, if desired, reducing a thus obtained eburnamenin derivative of the formula (I) containing an oxo group as W wherein R 1 , R 2 , R 3 , R 4 , X, Y, Z, n and the wavy line are a defined above, and/or converting an eburnamenine derivativ of the formula (I), wherein R 1 , R 2 , R 3 , R 4 , X, Y, Z, n an the wavy line are aε defined above, obtained as the fre base to an acid addition salt thereof by reacting it with a acid, and/or liberating the free base from an obtained sal of an eburnamenine derivative of the formula (I) , wherei R 1 , R 2 , R 3 , R 4 , X, Y, Z, n and the wavy line are as define above, and/or transforming an obtained eburnamenine deriva tive of the formula (I), wherein R 1 , R 2 , R 3 , R 4 , X, Y, Z, and the wavy line are as defined above, to a solvat thereof. 5. A proceεs as claimed in proceεs a) of claim 4, whic compriseε reacting a 1—eburnameninecarbonyl chloride of th formula (IV) , wherein the wavy line is as defined above, o a hydrochloride salt thereof, with a large excess of a pipe razine derivative of the formula (X) , wherein n is a defined above, at a temperature between —70°C and —20°C. 6. A process as claimed in process a) of claim 4 o claim 5, which comprises reacting a 1—(eburnameninecarbo nyl)piperazine of formula (IV), wherein n and the wavy lin are as defined above, with 2,4,6—trichloropyrimidine in a ether-type solvent at a temperature between —20°C and +50°C. 7. A process as claimed in claim 6, which comprise carrying out the reaction of 1—eburnameninecarbonyl—4—(4,6 —dichloropyrimidin—2—yl)piperazine of the formula (Ilia) o 1—eburnameninecarbonyl—4-(2,4—dichloropyrimidin-6-yl)pipera¬ zine of the formula (Illb) , respectively, wherein n and th wavy line are as defined above, with amines of the formula HNR-^-R 2 , wherein R 1 and R 2 are as defined above, at a tem- perature between 0°C and 150°C. 8. A process as claimed in any of the processes da), db) and dc) of claim 4, which comprises carrying out the reac¬ tion of eburnameninecarbonyl chloride of the formula (V) , wherein the wavy line is as defined above, or a hydrochlor- ide salt thereof with the 4—(amino—chloro—pyrimidinyl)pipe¬ razine derivatives of the formula (Villa) , (VHIbb) or (VHIba) , respectively, wherein R 1 , R 2 and n are as defined above, at a temperature between —50°C and room temperature. 9. A process as claimed in process e) of claim 4, which comprises carrying out the reaction of an eburnameninecar¬ bonyl chloride of the formula (V) , wherein the wavy line is as defined above, or a hydrochloride salt thereof, with a 4- -(diaminopyrimidinyl)piperazine of the formula (IX) , wherein R 1 , R 2 , R 3 , R 4 , X, Y, z and n are as defined above, at a temperature between —50°C and room temperature. 10. A process as claimed in claim 4, which comprises reducing an eburnamenine derivative of the formula (I) con¬ taining an oxo group as W, wherein R 1 , R 2 , R 3 , R 4 , x, Y, Z, n and the wavy line are as defined above, by using lithiu aluminum hydride in an ether-type solvent. 11. A process as claimed in claim 6 or claim 10, whic comprises using tetrahydrofuran as an ether-type solvent. 12. A process as claimed in claim 6, which comprise carrying out the reaction at 0°C. 13. A process as claimed in any of claims 4 to 12, whic comprises reacting an eburnamenine derivative of the formul (I), wherein R 1 , R 2 , R 3 , R 4 , X, Y, Z, n and the wavy lin are as defined above, obtained as the free base, wit organic or inorganic acids in a Cι_4al anol, preferabl ethanol and, if desired, precipitating the acid additio salt formed by using an ether-type solvent, preferabl diethyl ether. 14. Method for inhibiting the peroxidation of lipids i mammals, including humans, characterized by administering t said mammal a therapeutically effective amount of an eburna menine derivative of the formula (I), wherein R 1 , R 2 , R 3 R 4 , X, Y, Z, n, W and the wavy line are as defined in clai 1, or a pharmaceutically acceptable acid addition salt o solvate thereof, alone or in the form of a pharmaceutica composition.

Inventors: BALOGH GABOR, BALOGHNE KARDOS ZSUZSA, GAZDAG MARIA, GERE ANIKO, INCZE MARIA, KISS BELA, MAHO SANDOR, PALOSI EVA, SOTI FERENC, SZANTAY CSABA, SZPORNY LASZLO, TUBA ZOLTAN, VITTAY PAL, BALOGH, GABOR, BALOGHNE KARDOS, ZSUZSA, GAZDAG, MARIA                                            N, GERE, ANIKO, INCZE, MARIA, KISS, BELA, MAHO, SANDOR, PALOSI, EVA, SOTI, FERENC, SZANTAY, CSABA, SZPORNY, LASZLO, TUBA, ZOLTAN, VITTAY, PAL
Applicants: BALOGH GABOR, BALOGHNE KARDOS ZSUZSA, GAZDAG MARIA, GERE ANIKO, INCZE MARIA, KISS BELA, MAHO SANDOR, PALOSI EVA, RICHETER GEDEON VEGYESZETI GYA, SOTI FERENC, SZANTAY CSABA, SZPORNY LASZLO, TUBA ZOLTAN, VITTAY PAL, RICHTER GEDEON VEGYESZETI
Application year: 1993
Main classification: C07D461
IPC codes: A61K31, A61P9, A61P13, A61P15, A61P25, C07D239, C07D295, C07D461, C07D471