The invention relates to novel therapeutically active 21—aminosteroids of the formula

with pregnane skeleton, wherein two of X, Y and Z mean a nitrogen atom each and the third one is a methine group;

R ¹ and R ² represent, independently from each other, a prim¬ ary amino group bearing as substituent a branched-chain C ₄ _salkyl, —alkenyl or —alkynyl group, or a C^iocyclo- alkyl group comprising 1 to 3 ring(s) and being option¬ ally substituted by Cι_ ₃ al yl group(s) ; or

R ¹ and R ² stand together for a spiro-heterocyclic secondary amino group containing at most 10 carbon atoms and optionally at least one oxygen atom as additional heteroatom; or one of R ¹ and R ² means an unsubstituted heterocyclic second¬ ary amino group containing 4 to 7 carbon atoms and the other one is an above-identified primary amino group,

A4868-67 MR

an above-identified spiro-heterocyclic secondary amin group, or a heterocyclic secondary amino group con taining 4 to 7 carbon atoms and substituted by Cι_4 alkyl grou (s) ; and n is 1 or 2, as well as their acid addition salts and pharmaceutical com positions containing these compounds.

Furthermore, the invention relates to a process for th preparation of the above compounds. The compounds of the formula (I) according to th invention are new and possess a valuable biological activ ity, mainly antioxidant (lipid peroxidation-inhibiting effect, when investigated under in vitro conditions. Som representatives of them show a remarkable effectivit in vivo on the cerebral trauma model.

Accordingly, the invention relates also to a method o treatment which comprises administering a therapeuticall effective amount of a compound of the formula (I) or pharmaceutically acceptable acid addition salt thereof int the organism of a patient for inhibiting the peroxidation o lipids.

Hereinafter and in the claims primary amino groups ar meant to contain a hydrogen atom as one substituent wherea the other substituent is a branched—chain C^g-^lkyl, —alke nyl or —alkynyl group, or a C4_*-Locycloalkyl group, compris ing 1 to 3 rings, and being optionally substituted by Cι_ ₃ alkyl group(s) . The branched-chain C4_galkyl, —alkenyl an —alkynyl groups may be various iso—, sec— and tert—butyl butenyl, pentyl, pentenyl, pentynyl, hexyl, hexenyl, hexy nyl, pentyl, heptenyl, heptynyl, octyl, octenyl and octyny groups. Preferred representatives of these are the l,l-di methylethyl, 2,2-dimethylpropyl and ,4-dimethyl—l-penten-5 —yl groups.

The group comprising 1 to 3 rings an being optionally substituted by Cι_ ₃ alkyl grou (s) can b e.g. a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl o

adamantyl group. These groups may be unsubstituted or bear one or more methyl, ethyl or propyl group(s) as substi- tuents.

As R ¹ and R , the spiro-heterocyclic secondary amino group containing at most 10 carbon atoms and optionally at least one additional oxygen heteroatom is exemplified by the 4,4—ethylenedioxy-1—piperidinyl group, without any limita¬ tion thereto.

When representing an unsubstituted heterocyclic second- ary amino group containing 4 to 7 carbon atoms, one of R ¹ and R ² may preferably be a pyrrolidino, piperidino or aze- pino group. In this case, the other one of R ¹ and R ² means either a primary amino group mentioned above, or an above- defined secondary heterocyclic group having spiro structure, or an above-defined heterocyclic secondary amino group con¬ taining 4 to 7 carbon atoms and substituted by Cι_4alkyl group(s) . These Cι_ ₄ alkyl groups may be the same or differ¬ ent, e.g. methyl, ethyl, n— or isopropyl, or n—, iso—, sec— or tert— utyl groups. A preferred representative of these substituted heterocyclic secondary amino groups is e.g. the 2,2,6,6— etramethyl—1—piperidinyl group.

There are a high number of pathological processes known, in the case of which extremely reactive free radicals are accumulated. The formation of these free radicals leads to the oxydation of unsaturated fatty acids (lipid peroxid- ation) , which are important components of the cell mem¬ branes. This is a less specific, cell—destroying process altering or damaging the biomolecules. In this process func¬ tions of various levels of cells, organs or the whole organ- ism may suffer injuries.

Due to their lipid peroxidation-inhibiting effect, antioxidant compounds assure protection against injuries induced by free radicals.

Active agents of compositions belonging to this struc- tural and pharmacological group can be supposed for thorough reasons to be incorporated to the membrane of neurons or

glian cells and thereto counter balance pathomechanisms connected with lipid peroxidation which is a consequence of formation of reactive free oxygen radicals. The formation of such radicals is considered to play a decisive role in pathologic processes induced by injuries, accompanied by cell death. Since the role of the mechanisms mentioned is widespread and can be considered to the general in nearly all sectors of molecular pathology or pathobiology, respect¬ ively, it is obvious that any potential therapeutic utility of lipid peroxidation-inhibiting compounds should be in con¬ nection with an especially extended and diversified spectrum of syndromes, pathological pictures and disease groups.

Thus, compounds inhibiting the lipid peroxidation may have a therapeutical benefit not only in acute injuries (such as brain concussion, brain contusion, cerebral macera¬ tion, brain compression) or in acute shock of the brain cir¬ culation (arterial or venous thromboses, brain embolism, subarachnoidal haemorhages) but also in a number of other pathologic alterations or conditions affecting the central nervous system or other organ systems. The potential area of indication may involve such neuropsychiatric pathologic pic¬ tures as the Alzheimer's disease and Alzheimer-type de en- tiae, alcoholic dementia and central nervous system injuries accompanying the alcoholism, some so-called "negative" sy p- toms of schizophrenia, Parkinson's disease and Parkinson syndrome, amyotrophic lateral sclerosis, sclerosis multi¬ plex, cluster headache as well as complications accompanying the neoplastic alterations of the brain.

Potential indications of using lipid peroxidation- inhibiting compounds in pathologic pictures of non-central nervous system origin may be e.g. forms of various severity of irradiation damages, septic or endotoxic shock, hae orr- hagic shock, traumatic shock, stress-ulcus occurring as a consequence of major laesions, burn shock, conditions fol- lowing extended surgical interventions, conditions following cardiopulmonar reani ation, reperfusion following organ

transplantation, prevention of retrolental fibroplasia con¬ nected with the oxygen therapy of immature newburns, protec¬ tion from the adriamycin cardiotoxicity, prevention of the reperfusion injury occurring as a complication of acute myo- cardial infarction (e.g. after thrombolytic treatment) , some allergic reactions, insect bites, inflammatory processes of the skin (e.g. psoriasis, eczema) , nephrosis syndrome (of immunological origin), rheumatoid arthritis, systematic lupus erythematosus, endogenic uveitis, bronchial asthma, emphysema as well as atherosclerosis of the blood vessels.

The importance of such compounds inhibiting lipid per¬ oxidation is proven also by the high number of the most recent literature references (patent applications as well as scientific publications) . In the published PCT patent application No. WO 87/01706 the preparation of mainly aminosteroids is described, wherein an "amino group" is bound to the terminal carbon atom of the C—17 side chain. Double bond(s) in position 4 or positions 1,4 of ring A of the steroid skeleton, oxo- or hydroxyl group in position 3, α- or β-alkyl group or halogen in position 6 and chiefly α-hydroxyl group in position 11 as well as - or β-methyl group in position 16 and a double bond in position 9(11) are present. The ring of the steroid skeleton may be saturated or aromatic. Some 21—aminosteroids are also described in which the double bond is present in position 17(20). In the case of compounds disclosed in this publication the disubstituted pyrimidine, triazine or pyri- dine ring is bound in the most cases through a piperazinyl group to the position 21. Among the compounds published 16a:- -methyl—21—{4-[2,4-bis(pyrrolidino)-6-pyrimidinyl]-l-pip era- zinyl}pregna—1,4 ,9(11)—triene—3,20-dione methanesulfonate (generic name: tirilazad mesylate) is in the second stage of clinical trials at present.

Similarly, the synthesis of steroid lipid peroxidation- inhibiting compounds is described in the published PCT application No. WO 87/07895. The synthesis of "amino esters"

and "corticoid amino esters", above all "17-amino esters" "11,17-bis(amino) esters", "3,17-bis(amino) esters", "11 —amino esters" and "3—amino esters", all of androstan structure, is discussed. According to this publication thes compounds may be useful as inhibitors of lipid peroxidatio occurring as consequences of spinal, cephalic and othe injuries. The amino substituents have a structure similar t those mentioned 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 bound to the termina carbon atom of the C—17 side chain of the secosteroid. Th amino substituents are similar to those described in th preceding publications. The synthesis of lipid peroxidation-inhibiting com pounds is described in the published European patent appli cations Nos. 0,389,368, 0,389,369 and 0,389,370, too.

The preparation of corticoid-type "21—aminosteroids" i described in the published European patent application No 0,389,368. For example, a 4—[2,5-bis(diethylamino)—6—pyridi nyl]—piperazinyl group may be bound to the C—21 carbon atom The ring A of the sterane skeleton contains one or tw double bond(s) whereas substituents characteristic of th corticoids may be present in positions 6, 9, 11, 16 and 17 A double bond may be present in position 9(11), too.

The synthesis of "amine derivatives" of 3—oxo—19—nor steroids is described in the published European paten application No. 0,389,370. As specific compounds 17β-hydr oxy-llβ-(4-dimethylaminophenyl)-17α-{3-[4-[2,6-bis(pyrroli - dino)—4-pyrimidinyl]—1- iperazinyl]-l-propynyl}estra-4,9-

-diene—3—one, 17β—hydroxy—llβ—(4-dimethylaminophenyl)—17α —{3-[4-[5,6-bis(diethylamino)—2-pyridy1]-1-piperaziny1]- 1- —propynyl}estra-4,9-diene—3—one, 17B-hydroxy-llB—(4-di- methylaminophenyl)-17α—{3—[4-[2,6-bis(diethylamino)-2-p yri- dyl]—l-piperazinyl]-l-propynyl}estra-4,9-diene-3—one, 17β -hydroxy—llβ-(4-dimethylaminophenyl)-17α-{3-[4-[2,6-bis( 1-

—pyrrolidinyl)-4-pyrimidinyl]-l-piperazinyl]-l-propy- nyl}estra—4,9—diene—3—one and 17β—hydroxy—llβ—(4—dimethy1- aminopheny1)—17α—{3—[4—[2,6—bis(pyrrolidino)—4â €”pyrimidiny1]- —1—piperazinyl]—1—propynyl}estra—4,9—diene—3†”one are exemp- lified.

The synthesis of aminosteroid derivatives with andro- stane skeleton, similarly showing a lipid peroxidation- inhibiting affect, are described in the published European patent application 0,389,369; these compounds similarly possess a lipid peroxidation-inhibiting effect. Examples of such compounds are e.g. llβ,17β—dihydroxy—17α-{3-[4—[2,6- —bis(pyrrolidino)—4— yrimidiny1]—1—piperazinyl]-l—propynyl}- androsta—4,6—diene—3—one, llβ,17β—dihydroxy—6—methyl—17α—{3- —[4—[2,6—bis(pyrrolidino)-4—pyrimidiny1]-1-piperazin y1]-1- —propynyl}androsta—1,4,6—triene—3—one, llβ,17β—dihydroxy—6- —methyl-17α—{3—[4-[5,6-bis(dimethylamino)-2—pyridyl ]-1-pipe- razinyl]—l—propynyl}androsta—1,4,6—triene—3—one and llβ,l7β- —dihydroxy—6-methy1—17α—{3—[4—[3,6—bis(diethy lamino)-4-pyri- dyl]—1-piperazinyl]—l-propynyl}androsta-l,4,6—triene-3 -one. In the published European patent application No.

0,156,643 primarily the synthesis of water-soluble cortico- steroid derivatives is described which are mainly character¬ ized thereby that the hydroxyl group or an ester derivative thereof in position 11 is in α-configuration or a double bond is present in position 9(11). Among the compounds described 17α—hydroxy-llα-(2,2-dimethylpropylcarbonyloxy)- pregna—1,4—diene-3,20-dione-21-yl succinate sodium salt is considered to be the most effective lipid peroxidation- inhibiting agent. In the published PCT patent application No. WO 91/11453 bis("amino")pyrimidiny1-piperazinyl derivatives containing an oxygen function in position 5 are disclosed, wherein a steroid molecule, 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethy1- —2H—1—benzopiran-2-ylmethyl group or a derivative thereof may be connected to the nitrogen in position 1 of the pipe- razine moiety. In this description 5-hydroxypyrimidine

derivatives substituted by an alkyl group are als described.

Logically, the preparation of lipid peroxidation inhibiting compounds was extended to the investigation o amine derivatives containing non-steroid skeleton. Thus e.g. in the published PCT patent application No. WO 88/0842 the preparation of novel aromatic and aliphatic bicycli amine, cycloalkylamine, quinone-amine, amino ether and bi cyclic amino ether derivatives are described which may b useful e.g. for healing cephalic and spinal injuries. Fro the derivatives described 2—{[4—2,6—bis(l—pyrrolidinyl)—4 —pyrimidinyl]-l-piperazinyl]methyl}—3,4—dihydro—2,5, 7,8-tet ramethyl—2H—1—benzopyran-6-ol dihydrochloride was investi gated in detail. The aim of the present invention is at the preparatio of compounds showing a higher biological effectivity and/o a less toxicity in comparison to those known in the art Namely, the properties mentioned result in a more advanta geous therapeutical applicability in comparison to th active agents known in the art.

Surprisingly, it has been found that the novel 21—ami nosteroids of formula (I) , having pregnane skeleton, posses the aimed excellent lipid peroxidation-inhibiting effect.

The novel 21—aminosteroids of the formula (I) havin pregnane skeleton are prepared by acylating 21—hydroxy—16α—methylpregna—1,4,9(11)—triene —3,20— ione with 4—bromobenzenesulfonyl chloride or 4—nitro benzenesulfonyl chloride, respectively, then reacting the obtained 21—substituted pregnane deriva tive of the formula

wherein R stands for 4—bromobenzenesulfonyl or 4—nitrobenze- nesulfonyl group, with a piperazinyl—bis(alkylamino)pyrimi- dine derivative of the formula

wherein X, Y, Z, R ¹ , R ² and n are as defined above, and, if desired, liberating an obtained pregnane derivative of the formula (I) , wherein X, Y, Z, R ¹ , R ² and n are as defined above, from a salt and/or, if desired, trans¬ forming an obtained free base to an acid addition salt by reacting it with an appropriate acid.

21—(4—bromobenzenesulfonyloxy)—16a—methylpregna- —1,4,9(11)—triene—3,20—dione and 16α—methyl—21—(4—nitroben- zenesulfonyloxy)-pregna—l,4,9(ll)-triene-3,20-dione of the formula (II) used as starting substances are also new com¬ pounds, which can be prepared as described hereinafter.

After dissolving 21-hydroxy-16α-methylpregna-l,4,9(11)- -triene-3,20-dione (known from the French patent specifica- tion No. 1,296,544) in tetrahydrofuran, triethylamine as well as an excess of 4—bromobenzenesulfonyl chloride or 4- —nitrobenzenesulfonyl chloride, respectively, is added to the above solution at a temperature of about 0°C. The reac¬ tion is continued at room temperature for about additional 2 to 4 hours and after the reaction has become complete [which can be followed by thin layer chromatography (TLC) ] , the

solution is portionwise added to water. After compacting the precipitate the mixture is filtered, the precipitate is washed with water up to neutral, then dried and recrystal- lized. The reaction of the obtained 21—substituted pregnane derivatives of the formula (II) with piperazinyl—bis(alkyl- amino)pyrimidine derivatives of the formula (III) is prefer¬ ably carried out in such a way that 21—(4—bromobenzenesul- fonyloxy)—16α—methyl—pregna—1,4,9(11)—triene—3, 20—dione or 16α—methy1-21—(4—nitrobenzenesulfonyloxy)—pregna-1, 4,9(11)- —triene—3,20—dione, respectively, is dissolved in a polar solvent, preferably acetone or acetonitrile, then the pipe¬ razinyl—bis(alkylamino)pyrimidine derivative of the formula (III) and potassium carbonate are added to the above solu¬ tion. The reaction mixture is vigorously stirred at about 50 to 70°C until the reaction becomes complete, then the sol¬ vent is distilled off, the evaporation residue is distributed between a halogenated hydrocarbon, preferably chloroform, and water. After separation the organic phase is washed several times with water, then dried. After evaporat- ing the organic solvent from the anhydrous solution the residue is purified by chromatography on a silica gel column and subsequently, if desired, recrystallized.

The piperazinyl—bis(alkylamino)pyrimidine derivatives of the formula (III) are prepared in such a manner that 2,4,6—trichloropyrimidine is reacted with a primary or secondary amine corresponding to the R ¹ or R ² amino group in an ether-type solvent, e.g. tetrahydrofuran, in a tempera¬ ture range from about —20°C to about 40°C, for a time of about 30 minutes up to several days depending on the react- ivity of the amine. In the case of the sterically hindered 2,2,6,6-tetramethylpiperidine (which can be used as solvent, too) , a reaction lasting for about 50 hours at the boiling point of the reaction mixture is necessary for making the reaction complete. After termination of the reaction the solvent is distilled off, the residue is dissolved in a halogenated hydrocarbon, preferably chloroform, then washed

with aqueous sodium hydroxide solution and water. After separation the organic phase is dried, the solvent is evap¬ orated, the 4,6—dichloro—2—alkylaminopyrimidine as well as 2,6—dichloro—4—alkylaminopyrimidine derivatives formed in the reaction are separated by chromatography on a silica gel column. The separated isomers are purified by recrystalliza- tion. The thus obtained monoalkylamino—dichloropyrimidine isomers are again reacted with an amine being the same as or different from that used in the first step. The parameters of this reaction are primarily determined by the reactivity of the amine reactant. Thus, when reacting monoalkylamino- —dichloropyrimidine derivatives with pyrrolidine, the reac¬ tion becomes complete at about room temperature whereas a reaction lasting for about 15 hours at about 130°C is required for a reaction with tert—butylamine. The reaction of neopentylamine with monoalkylamino-dichloropyrimidines can be accomplished under milder reaction conditions: this reaction becomes complete by boiling in isopropanol for 20 hours. The less reactive 5—amino—4,4— imethyl—1—pentene re¬ acts with pyrimidine derivatives only at higher tempera¬ tures. The reaction of 1—aminoadamantane having a large space demand can be achieved by boiling in n—butanol for about 75 hours.

The bis(alkylamino)—chloropyrimidine derivatives formed in the second step can be recovered in the same way as described for the recovery of monoalkylamino—dichloropyrimi¬ dine derivatives.

The piperazinylpyrimidine derivatives of the formula (III) can be prepared by reacting bis(alkylamino)-chloro¬ pyrimidine derivatives with piperazine as follows. After dissolving the bis(alkylamino)-chloropyrimidine derivatives in a tertiary amine, preferably N—ethylmorpholine, the reac¬ tion mixture is boiled under reflux and nitrogen with an excess of piperazine for about 25 hours. After the reaction has become complete, N—ethylmorpholine used as solvent and the major part of the excess piperazine are distilled off, and water is added to the residue which is similarly

distilled off. This distillation is continued under atmos pheric pressure until the head temperature reaches 100°C The residue is dissolved in chloroform and washed first wit aqueous sodium hydroxide solution, then with water. Afte separation the organic phase is dried, the chloroform i evaporated and the residue is purified by chromatography o a silica gel column, then by recrystallization.

The pharmacological study of the pregnane derivative of the formula (I) according to the present invention wa carried out on unanesthetized mice by using a know experimental cephalic trauma model [J. Neurosurg. j6_2, pag 882 (1980)] modified by us. In this study, the potentia cerebroprotective effects of intravenous (i.v.) doses of th compounds were investigated. A metal cleaver of defined weight was let fall onto defined part of the scullcap surface of the experimenta animals from a defined height under the force of gravity Within 5 minutes following the closed cephalic injur induced by the cleaver, a suitable dose of the substanc under test was injected to a tail vein of the animals an the neurological condition of the animals was evaluated i the 60th minute following the cephalic trauma. This evalu ation was performed by using a simple grip test, by examina tion of the intactness or affectedness of the motor func tions of both the upper and lower limbs. In addition, th frequency of cases considered to be "mild" or "severe", based on predetermined criteria, as well as the ratio o animals suffering from paraparesis-paraplegia were regis tered in the various treatment groups. The development o eventually occurring deficiency symptoms of the nervous sys tem was made quantitative by comparison of the neurologica condition of animals treated with the active agent to th condition of controls treated only with the vehicle.

When administered in the most favourable dose of 0. mg/kg, 21—{4-[2,4—bis(adamantylamino)—6—pyrimidinyl]—1-pi pe razinyl}—16α-methylpregna—1,4,9(11)triene—3,20—dion e

methanesulfonate of formula (I) increased by 33% the number of cases signed as "mild" (based on the neurological symp¬ toms induced by the cephalic trauma) and similarly, it decreased by 33% the frequency of cases involving para- paresis-paraplegia. The known tirilazad mesylate (see the published PCT patent specification No. WO 87/01706) , chemi¬ cally I6α-methyl—21—{4-[2,4-bis(pyrrolidino)-6-pyrimidiny1]- —1—piperazinyl}pregna—1,4,9(11)triene—3,20-dione methanesul¬ fonate, was used as control. When administered in the most effective dose of 0.3 mg/kg, tirilazad mesylate increased only by 23% the number of animals showing "mild" deficiency symptoms and decreased only by 20% the frequency of para¬ plegic animals.

Thus, it is obvious from the experimental results that the compounds according to our invention increase the lipid peroxidation-inhibiting effect exceeding those of known sub¬ stances.

The novel 21—aminosteroid derivatives of the formula (I) having pregnane skeleton are used alone or in the form of their salts, suitably in the commonly used therapeutical compositions. These compositions may be in solid, liquid or semisolid state. Commonly used filling, diluting, stabiliz¬ ing, pH- and osmotic pressure-influencing, flavouring and aromatizing as well as formulation-promoting or for ulation- providing additives and auxiliaries can be used for the preparation of these compositions.

The solid pharmaceutical compositions may be e.g. tab¬ lets, dragees, capsules, cachets or powder ampoules useful for the preparation of injections. Liquid compositions ar the injectable and infusable compositions, fluid medicines, packing fluids and drops. Semisolid compositions are oint¬ ments, balsams, creams, shaking mixtures and suppositories.

From the pharmaceutical composition an amount containin a dose of the active agent required to achieve the aime effect is administered to the patient. This dose depends o the stage of the disease, the severity of the pathologica

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 simple administration it is suitable if the pharmaceutical compositions comprise dosage units 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 in order to exactly administer the required amount of the active agent. Tablets can be coated with an acid-insoluble layer in order to assure the release of the active agent content after leaving the stomach. Such tablets are enteric-coated. A similar effect can be achieved also by encapsulating the active agent. The pharmaceutical compositions containing the active agent according to the invention usually contain 1 to 100 mg of active agent in a single dosage unit. It is, of course, possible that the amount of the active agent in some compo¬ sitions exceeds the upper or lower limits defined above. The invention also relates to a method for inhibiting the peroxidation of lipids occurring in the organism. This method comprises administering a therapeutically effective amount of an active agent of the formula (I) or a pharma¬ ceutically acceptable acid addition salt thereof to the patient.

The invention is illustrated in detail by the aid of the following non-limiting Examples.

Example 1 Preparation of 21—(4—bromobenzenesulfonyloxy)—16α—methyl- pregna—1,4,9(11)—triene-3,20—dione

After dissolving 10.0 g (29.4 mmoles) of 21— ydroxy- —16α—methylpregna—1,4,9(11)—triene—3,20—dione in 100 ml of tetrahydrofuran, 7.14 ml (51.4 mmoles) of triethylamine, then at 0°C 13.1 g (51.4 mmoles) of 4—bromobenzenesulfonyl chloride are added to the above solution and the reaction mixture is stirred at room temperature for 4 hours, then dropwise added to 450 ml of water while stirring. The preci¬ pitate is filtered off, dried and recrystallized from ether to give the title compound in a yield of 11.0 g (67.07%), .p. :124-129°C. ^• T-H-NMR (300 MHz, CDCl ₃ ) δ ppm: 0.65 (s, 3H, I8-CH ₃ ), 0.93 (d, 1H, 16α-CH ₃ ), 1.40 (s, 3H, 19-CH ₃ ) , 4.54 and 4.66 (d, d, 2H, 21-CH ₂ ), 5.5 (m, 1H, 11-H) , 6.07 (t, 1H, 4-H) , 6.29 (dd, 1H, 2-H) , 7.16 (d, 1H, 1-H) , 7,72 (d, 2H, phenylene C3-H, C5-H) , 7.83 (d, 2H, phenylene C2-H, C6-H) . Example 2 Preparation of lβα—methyl—21—(4—nitrobenzenesulfonyloxy)- — regna—1,4,9(11)— riene—3 ,2O—dione

After dissolving 10.0 g (29.4 mmoles) of 21-hydroxy- —16α—methylpregna-1,4,9(ll)-triene-3,20-dione in 100 ml of tetrahydrofuran, 7.14 ml (51.4 mmoles) of triethylamine, then at 0°C 11.4 g (51.4 mmoles) of 4—nitrobenzenesulfonyl chloride are added to the above solution. Subsequently, the reaction mixture is stirred at room temperature for 2 hours, then dropwise added to 450 ml of water while stirring. The precipitate is filtered off, dried and recrystallized from ether to obtain the title compound in a yield of 13.5 g (87.66%), m.p. :151-160°C.

^-NMR (300 MHz, CDCI ₃ ) S ppm: 0.67 (s, 3H, I8-CH ₃ ) , 0.94 (d, 1H, 16α-CH ₃ ), 1.40 (s, 3H, 19-CH ₃ ) , 4.68 and 4.81 (d, d, 2H, 21-CH ₂ ), 5.51 (m, 1H, 11-H) , 6.07 (t, 1H, 4-H) , 6.29 (dd, 1H, 2-H) , 7.17 (d, 1H, 1-H) , 8,17 (d, 2H, phenylene C2-H, C6-H) , 8.42 (d, 2H, phenylene C3-H, C5-H) .

Example 3 Preparation of 4,6- ichloro—2—(1,1—dimethylethylamino)pyri midine and 2,6—dichloro—4—(1,1—dimethylethylamino)pyrimidin

After dropwise adding 25 g (136.3 mmoles) of 2,4,6—tri chloropyrimidine to a solution containing 31.52 ml (30 mmoles) of 1—amino—1,1—dimethylethane in 200 ml of tetrahyd rofuran at a temperature between 10 and 15°C while coolin under stirring, the reaction mixture is stirred at room tem perature for additional 5 hours and then evaporated. Th residue is distributed between 500 ml of chloroform and 5 ml of 10% sodium hydroxide solution. After separation th organic phase is washed 4 times with 150 ml of water each dried and evaporated. The residue is subjected to chromato graphy on a silica gel column and eluted with various mix tures of hexane and ethyl acetate. By using a 9:1 mixture a eluent 4 ,6-dichloro—2-(l,1—dimethylethylamino)pyrimidine i obtained which is recrystallized from hexane to give a yiel of 11.35 g (37.84%), m.p.: 70-74°C. -l-H-NMR (60 MHz, THF-d ₈ ) δ ppm: 6.63 (s, 1H, 5-H) . By further elution with a 4:1 mixture of hexane an ethyl acetate, the more polar 2,6—dichloro—4-(l,1—dimethyl ethylamino)pyrimidine is obtained which is recrystallize from ethyl acetate to give a yield of 13.31 g (44.35%) m.p.: 192-195°C. ***-H-NMR (60 MHz, THF-d ₈ ) δ ppm: 6.32 (s, 1H, 5-H) . Example 4 Preparation of 2,6—bis(1,1-dimethylethylamino)—4—chloropyri midine

A solution of 5.0 g 4,6-dichloro-2-(l,l-dimethylethyl amino)pyrimidine in 25 ml of l-amino-l,l-dimethylethane i heated in a close tube at 130°C for 15 hours. The, the reac tion mixture is evaporated and the residue is distribute between 80 ml of chloroform and 15 ml of 10% sodium hydr oxide solution. After separation the organic phase is washe 4 times with 20 ml of water each, then dried and evaporated After recrystallization from hexane the title compound i

obtained in a yield of 5.45 g (93.4%), m.p.: 128-130°C ⁱ R-NMR (60 MHz, THF-d ₈ ) δ ppm: 5.67 (s, 1H, 5-H) .

Example 5 Preparation of 2,4—bis(1,1—dimethylethylamino)—6—(1-pipera- ziny1)pyrimidine

A mixture containing 10.0 g (38.9 mmoles) of 4-chloro- -2,6-bis(1,1—dimethylethylamino)pyrimidine, 13,42 g (155.8 mmoles) of piperazine and 150 ml of N—ethylmorpholine is boiled under reflux under nitrogen for 25 hours, then the solvent and piperazine are distilled off under atmospheric pressure. Water is added to the residue and distilled off until the head temperature reaches 100°C. After cooling down the residue is distributed between 200 ml of chloroform and 30 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 50 ml of water each, then dried and evaporated. The residue is purified by chro¬ matography on a silica gel column by using a 9:1 mixture of chloroform and methanol. After recrystallizing the eluted product from hexane, the title compound is obtained in a yield of 7.65 g (64%), m.p. :142-145°C.

^X H-NMR (60 MHz, CDC1 ₃ ) δ ppm: 4.99 (s, 1H, 5-H) .

Example 6 Preparation of 21—{4—[2,4^ois(l,l—dimethylethylamino)—6—py- rimidinyl]—1—piperazinyl}—16α-methylpregna—1,4,9(11 )—triene- —3,20-dione

After adding 1.40 g (4.57 moles) of 2,4-bis(l,l-di- methylethylamino)-6-(l-piperazinyl}pyrimidine and 0.63 g of potassium carbonate to a solution containing 2.00 g (3.805 mmoles) of 21—(4-nitrobenzenesulfonyloxy)—I6α—methylpregna- —1,4,9(11)—triene-3,20-dione in 100 ml of acetone, the reac¬ tion mixture is boiled under reflux for 8.5 hours, then evaporated. The residue is distributed between 40 ml of chloroform and 10 ml of water. The chloroform layer is dried and evaporated. The residue is purified on a silica gel column by using a 98:2 mixture of chloroform/methanol as eluent. After recrystallization the title compound is

obtained in a yield of 1.53 g (64%), m.p.: 145-155°C. ^l -H-NMR (250 MHz, CDC1 ₃ ) δ ppm: 0.68 (s, 3H, I8-CH ₃ ), 0.96 (d, 1H, 16α-CH ₃ ), 1.39 (s, 18H, 2xNHC(CH ₃ ) ₃ ) , 1.40 (s, 3H, I9-CH ₃ ), 3.13 and 3.23 (d, d, 2H, 21-CH ₂ ), 4.99 (s, 1H, pyrimidine C5-H) , 5.51 (m, 1H, 11-H) , 6.07 ( , 1H, 4-H) , 6.28 (dd, 1H, 2-H) , 7.16 (d, 1H, 1-H) .

Example 7 Preparation of 4—chloro-2—(1,1—dimethylethylamino)—6—pyrro- lidinopyrimidine After adding in small portions 10 g of 4,6-dichloro-2- —(1,1—dimethylethylamino)pyrimidine to 40 ml of pyrrolidine at a temperature below 10°C under cooling while stirring, the reaction mixture is stirred at room temperature for 1 hour, then evaporated. After distributing the residue bet- ween 150 ml of chloroform and 30 ml of 10% sodium hydroxide solution, the organic phase is separated, washed 4 times with 50 ml of water each, then dried and evaporated. After recrystallization from ethyl acetate the title compound is obtained in a yield of 10.76 g (93%), m.p.: 153-157°C. ^l -H-NMR (60 MHz, CDCI ₃ ) δ ppm: 5.67 (s, 1H, 5-H) .

Example 8 Preparation of 2—(1,1—dimethylethylamino)—4—(1—piperaziny1)- —6— yrrolidinopyrimidine

The reaction of 4-chloro-2-(l,1-dimethylethylamino)—6- —pyrrolidinopyrimidine with piperazine, similarly as described in Example 5, gives the title compound in a yield of 78.1%, m.p.: 162-165°C. !H-NMR (60 MHZ, CDCI ₃ ) δ ppm: 4.87 (s, 1H, 5-H) .

Example 9 Preparation of 21—{4—[2—(1,1—dimethylethylamino)—6— yrroli¬ dino—4-^yrimidinyl]—l-piperazinyl}—16a-methylpregna- —1,4,9(11)—triene—3,20—dione

The reaction of 16α—methyl—21—(4—nitrobenzenesulfonyl- oxy)—pregna-l,4,9(ll)-triene-3,20-dione with 2-(l,l-di- methylethylamino)-4—(1-piperazinyl)—6—pyrrolidinopyrim idine as described in Example 6 affords the title compound in a

yield of 74.7%, m.p.: 145-170°C.

^-NMR (250 MHZ, CDC1 ₃ ) δ ppm: 0.68 (s, 3H, I8-CH ₃ ), 0.96 (d, 3H, 16α-CH ₃ ), 1.39 (s, 3H, 19-CH ₃ ) , 1,42 (s, 9H, NC(CH ₃ ) ₃ ), 3.13 and 3.23 (d, d, 2H, 21-CH ₂ ), 4.86 (s, 1H, pyrimidine C5-H) , 5.51 ( , 1H, 11-H) , 6.07 (br, 1H, 4-H) , 6.28 (dd, 1H, 2-H) , 7.16 (d, 1H, 1-H) .

Example 10 Preparation of 2—(1—adamantylamino)—4,6-dichloropyrimidine and 4—(1— damantylamino)—2,6— ichloropyrimidine After adding 40.6 g (225.6mmoles) of 2,4,6-trichloropy- rimidine to a solution of 70.3 g (465.6 mmoles) of 1—a ino- adamantane in 650 ml of tetrahydrofuran, the reaction mix¬ ture is stirred for 24 hours, then the crystalline 1-amino- adamantane hydrochloride precipitate is filtered off, the filtrate is evaporated and the residue is subjected to chro¬ matography on a silica gel column. By elution with a 9:1 mixture of hexane and acetone 2—(1—adamantylamino)—4,6- —dichloropyrimidine is obtained,which is recrystallized from hexane to give a yield of 28.74 g (43.5%), m.p.: 151-155°C. -H-NMR (60 MHz, CDCI ₃ ) δ ppm: 6.55 (s, 1H, 5-H) .

By continuing the elution with a 24:1 mixture of hexane and acetone the more polar 4—(l-adamantylamino)—2,6-di- chloropyrimidine is obtained which is recrystallized from hexane to result a yield of 35.56 g (53.8%), m.p.: 193- 196°C.

!H-NMR (60 MHz, CDCI ₃ ) δ ppm: 6.33 (s, 1H, 5-H) .

Example 11 Preparation of 2,4—bis(1—adamantylamino)—6—chloropyrimidine A solution of 26.0 g (87.25 mmoles) of 4,6-dichloro-2- —(l-adamantylamino)pyrimidine and 39.5 g (261.6 mmoles) of 1—aminoadamantane in 200 ml of n-butanol, the reaction mix¬ ture is boiled under reflux for 24 hours, and evaporated. The residue is suspended in 400 ml of ether and filtered off. After drying, the filtered-off residue is purified by chromatography on a silica gel column and eluted with chloroform. After recrystallization from ether, the title

compound is obtained in a yield of 23.94 g (66.44%), m.p.: 232-236°C

•T-H-NMR (60 MHz, CDCl ₃ ) 5 ppm: 5.64 (s, 1H, 5-H) . Example 12 Preparation of 2,4—bis(1—adamantylamino)—6—(1— iperazinyl) pyrimidine

2,4—bis—(1—Adamantylamino)—6—chloropyrimidine is reacted with piperazine similarly as described in Example 5 to give the title compound in a yield of 83.36%, m.p.: 168- 175°C.

^ ^• H-NMR (60 MHz, CDCI3) <S ppm: 4.97 (s, 1H, 5-H) .

Example 13 Preparation of 21—{4—[2,4—bis(1—adamantylamino)—6—pyrimidi ny1]—1— iperazinyl}—16α-methylpregna—l,4,9(11)—triene—3,20- —dione

After adding 1.88 g (4.07 mmoles) of 2,4—bis(l—adaman¬ tylamino)—6—(1—piperazinyl)pyrimidine and 0.56 g of potass¬ ium carbonate to a solution containing 2.00 g (3.57 mmoles) of 21—(4—bromobenzenesulfonyloxy)—16α—methylpregna- —1,4,9(11)—triene—3,20—dione in 100 ml of acetonitrile, the reaction mixture is stirred at a temperature of 65°C for 5 hours, then evaporated. The residue is distributed between 40 ml of chloroform and 10 ml of water. After separation the chloroform layer is dried and evaporated. The residue is purified by chromatography on a silica gel column by using a 98:2 mixture of chloroform/methanol as eluent. After recrys¬ tallization from ether the title compound is obtained in a yield of 2.48 g (88.5%), m.p.: 210-220°C. ^â– i H-NMR (250 MHz, CDCI3) δ ppm: 0.68 (s, 3H, I8-CH3) , 0.96 (d, 1H, 16α-CH ₃ ) , 1.40 (s, 3H, 19-CH ₃ ) , 3.13 and 3.23 (d, d, 2H, 21-CH ₂ ) , 4.98 (s, 1H, pyrimidine C5-H) , 5.51 (m, 1H, 11-H) , 6.07 (m, 1H, 4-H) , 6.28 (dd, 1H, 2-H) , 7.16 (d, 1H, 1-H) .

Example 14 Preparation of 2—(1—adamantylamino)——chloro—6—pyrrolidino pyrimidine

2—(1—Adamantylamino)—4,6-dichloropyrimidine is reacte with pyrrolidine similarly as described in Example 7 to giv the title compound in a yield of 86%, m.p.: 178-180°C. iH-NMR (60 MHz, CDC1 ₃ ) 5 ppm: 5.62 (s, 1H, 5-H) .

Example 15 Preparation of 2—(1—adamantylamino)—4—(l—piperazinyl)—6—pyr rolidinopyrimidine

2—(1—Adamantylamino)—4—chloro—6—pyrrolidinopy rimidine is reacted with piperazine as described in Example 5 t obtain the title compound in a yield of 69.7%, m.p.: 160 164°C. iH-NMR (60 MHz, CDCI ₃ ) δ ppm: 4.87 (s, 1H, 5-H) . Example 16 Preparation of 21—{4—[2—(1—adamantylamino)—6—pyrrolidino—4 — yrimidinyl]—1-piperazinyl}—16α-Ï€nethylpregna—1,4,9(1 1)- —triene-3,20—dione The reaction of 21—(4—bromobenzenesulfonyloxy)—16α

—methylpregna—1,4,9(11)—triene—3,20—dione with 2—(1—adaman tylamino)—4—(l—piperazinyl)—6—pyrrolidinopyrimidin e as described in Example 6 gives the title compound in a yiel Of 79.94%, m.p.: 155-172°C. -T-H-NMR (60 MHz, CDCI ₃ ) -5 ppm: 0.69 (s, 3H, I8-CH ₃ ) , 0.94 (d 3H, 16α-CH ₃ ), 1.41 (s, 3H, 19-CH ₃ ) , 4.89 (s, 1H, pyrimidin C5-H) , 5.51 (m, 1H, 11-H) , 6.08 (br, 1H, 4-H) , 6.28 (dd, 1H 2-H) , 7.21 (d, 1H, 1-H) . Example 17 Preparation of 4,6-dichloro—2—(2,2-dimethylethylamino)pyri midine and 2,6-dichloro-4—(2,2-dimethylethyla ino)pyrimidin After dropwise adding 25 g (136.3 mmoles) of 2,4,6—tri chloropyrimidine to a solution of 23.84 g (273.5 mmoles) o 1—amino—2,2—dimethylpropane in 200 ml of tetrahydrofuran a a temperature between 10 and 15°C while cooling unde stirring, the reaction mixture is stirred at room tempera

ture for 30 minutes, then evaporated. The residue is distri¬ buted between 300 ml of chloroform and 50 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 100 ml of water each, dried and evapor- ated. The residue is subjected to chromatography on a silica gel column by using mixtures of hexane/ethyl acetate elu¬ tion. By eluting with a 19:1 mixture, 4, 6-dichloro-2-(2,2- —dimethylpropylamino)pyrimidine is obtained which is recrys¬ tallized from a mixture of ether and hexane to give a yield of 13.60 g (42.6%), m.p.: 63-66°C. l-H-NMR (60 MHz, CDCl ₃ ) δ ppm: 6.60 (s, 1H, 5-H) .

By further elution with a 6:1 mixture, the more polar 2, 6—dichloro—4—(2,2—dimethylpropylamino)pyrimidine is obtained which is recrystallized from a mixture of ether and hexane to result in a yield of 14.24 g (44.6%), m.p.: 77- 79°C. iH-NMR (60 MHz, CDCl ₃ ) δ ppm: 6.33 (s, 1H, 5-H) .

Example 18 Preparation of 4—chloro—2,6—bis(2,2—dimethylpropylamino)-py- rimidine

After adding 5 ml of 1—amino—2,2—dimethylpropane to a solution of 5.0 g of 4,6—dichloro—2—(2,2—dimethylpropyl¬ amino)pyrimidine in 25 ml of isopropanol the reaction mix¬ ture is boiled under reflux for 20 hours, then evaporated. The residue is distributed between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. After recrystallization from hexane the title compound is obtained in a yield of 2.994 g (49.4%), m.p.: 95-98°C. iH-NMR (60 MHz, CDCI3) δ ppm: 5.71 (s, 1H, 5-H) .

Example 19 Preparation of 2,4—bis(2,2—dimethylpropylamino)—6—(1—pipera- ziny1)pyrimidine The reaction of 4-~chloro-2,6-bis(2,2—dimethylpropyl¬ amino)pyrimidine with piperazine as described in Example 5

gives the title compound in a yield of 51.1%, m.p.: 138- 140°C. ⁱ H-NMR (60 MHz, CDC1 ₃ ) δ ppm: 4.98 (s, 1H, 5-H) . Example 20 Preparation of 21—{4—[2,4—bis(2,2—dimethylpropylamino)—6—py rimidinyl]—1-piperazinyl}—16α—methylpregna—1,4,9(11 )—triene —3,20-dione

16α—Methyl—21—(4—nitrobenzenesulfonyloxy)—preg na- —l,4,9(ll)-triene-3,20-dione is reacted with 2,4-bis(l,1-di- methylethylamino)-6-(1-piperazinyl)pyrimidine as described in Example 6 to obtain the title compound in a yield of 68.95%, m.p.: 140-150°C.

!H-NMR (60 MHz, CDCI ₃ ) δ ppm: 0.68 (s, 3H, I8-CH ₃ ) , 1.40 (s, 3H, I9-CH ₃ ), 4.96 (s, 1H, pyrimidine C5-H) , 5.51 (m, 1H, 11-H) , 6.10 (br, 1H, 4-H) , 6.28 (dd, 1H, 2-H) , 7.20 (d, 1H, 1-H) .

Example 21 Preparation of 4—chloro—2—(2,2—dimethylpropylamino)—6-pyrro- lidinopyrimidine 4,6—Dichloro—2-(2,2—dimethylpropylamino)pyrimidine is reacted with pyrrolidine as described in Example 7 to give the title compound in a yield of 96.7%, m.p.: 147-150°C. ^l -H-NMR (60 MHz, CDCI ₃ ) <S ppm: 5.67 (s, 1H, 5-H) . Example 22 Preparation of 2—(2,2—dimethylpropylamino)—4—(l—piperazi¬ nyl)—6-pyrrolidinopyrimidine

(2,2—Dimethylpropylamino)-4-chloro—6-pyrrolidinopyrim i- dine is reacted with piperazine as described in Example 5 to obtain the title compound in a yield of 76%, m.p.: 118- 120°C. ^l -H-NMR (60 MHz, CDCI ₃ ) δ ppm: 4.83 (s, 1H, 5-H) .

Example 23 Preparation of 21—{4—[2—(2,2-dimethylpropylamino)—6-pyrimi- dino-4-pirimidiny1]—1-piperaziny1}—I6α-methylpregna- -l,4,9(ll)-triene-3,20-dione

16α—Methy1-21-(4-bromobenzenesulfonyloxy)-pregna-

—1,4,9(11)—triene—3,20—dione is reacted with 2—(2,2—di methylpropylamino)—4-(1-piperaziny1)-6—pyrrolidinopyrimi din as described in Example 13 to obtain the title compound in yield of 74.1%, m.p.: 130°C. -T-H-NMR (60 MHz, CDC1 ₃ ) <S ppm: 0.68 (s, 3H, I8-CH ₃ ) , 0.93 (s, 9H, -C(CH ₃ ) ₃ ), 0.96 (s, 3H, 16α-CH ₃ ) , 1.39 (s, 3H, 19-CH ₃ ), 4.85 (s, 1H, pyrimidine C5-H) , 5.51 (m, 1H, 11-H) , 6.06 (br, 1H, 4-H) , 6.26 (dd, 1H, 2-H) , 7.17 (d, 1H, 1-H) . Example 24 Preparation of 4,6—dichloro-2—[(4,4-dimethy1—1-penten—5—y1) amino]pyrimidine and 2,6-dichloro—4—[(4,4-dimethy1—1-penten —5—yl)amino]pyrimidine

After adding 4.59 g (25 mmoles) of 2,4,6—trichloropyri- midine to the solution of 6.23 g (55 mmoles) of 5—amino—4,4- —dimethyl—1—pentene in 50 ml of tetrahydrofuran at room tem¬ perature, the mixture is further stirred at the same tem¬ perature for 4 hours, then evaporated. After distributing the residue between 60 ml of chloroform and 5 ml of 10% sodium hydroxide solution the organic phase is separated, washed 4 times with 10 ml of water each, then dried and evaporated. The residue is separated by chromatography on a silica gel column by using mixtures of hexane and ethyl acetate for elution. By eluting with a 19:1 mixture of hexane/ethyl acetate oily 4,6-dichloro-2-[ (4,4-dimethyl-l- —penten-5—yl)amino]pyrimidine is obtained in a yield of 2.62 g (40.3%) . ^l -H-NMR (60 MHz, CDCI ₃ ) δ ppm: 6.61 (s, 1H, 5-H) .

By carrying out the elution with a 9:1 mixture of hexane/ethyl acetate the more polar 2,6-dichloro-4—[ (4,4-di- methyl—1—penten-5—y1)amino]pyrimidine is obtained in oily form in a yield of 2.99 g (45.9%) l-H-NMR (60 MHz, CDCI ₃ ) δ ppm: 6.34 (s, 1H, 5-H) .

Example 25 Preparation of 4—chloro-2,6—bis[(4,4-dimethy1—1— enten—5- —y1)amino]pyrimidine

After dissolving 2.5 g (9.61 mmoles) of 4,6-dichloro-2-

—[ (4,4-dimethy1—l-penten-5-yl)amino]pyrimidine in 25 ml of n—butanol 2.29 g (10.2 mmoles) of 5—amino—4,4—dimethyl—1- —penten are added to the above solution, the reaction mix¬ ture is boiled under reflux for 10 hours, then evaporated. The residue is distributed between 50 ml of chloroform and 5 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 10 ml of water each, then dried and evaporated. The residue is purified by chro¬ matography on a silica gel column by using a 19:1 mixture of hexane/ethyl acetate as eluent to give the oily title com¬ pound in a yield of 2.25 g (69.5%). l-H-NMR (60 MHz, CDCl ₃ ) δ ppm: 5.70 (s, 1H, 5-H) .

Example 26 Preparation of 2,4—bis[(4,4—dimethyl—1-penten—5—y1)amino]—6- —(1-piperaziny1)pyrimidine

The reaction of 4—chloro—2,6—bis[ (4,4—dimethyl—l—pen- ten-5-yl)amino]pyrimidine with piperazine as described in Example 5 results in a yield of 73.2% of the title compound, m.p.: 72-84°C. l-H-NMR (60 MHz, CDCI3) <5 ppm: 4.83 (s, 1H, 5-H) . Example 27 Preparation of 21—{4—[2,4—bis(4,4—dimethyl—1-penten—5—y1)- amino]—-S-pyrimidiny1]—1-piperaziny1}—16α-methylpregn a- —1,4,9(11)—triene-3,20-dione 16α—Methyl—21—(4—bromobenzenesulfonyloxy)pregna-

—l,4,9(ll)-triene-3,20-dione is reacted with 2,4-bis[ (4,4- -dimethyl—1—penten—5-yl)amino]—6-(l—piperazinyl)py rimidine as described in Example 13 to obtain the title compound in a yield of 46%, m.p.: 98-100°C. -H-NMR (300 MHz, CDCI3) δ ppm: 0.69 (s, 3H, I8-CH3) , 0.96 (d, 1H, 16α-CH ₃ ), 1.40 (s, 3H, 19-CH ₃ ) , 3.12 and 3.21 (d, d, 2H, 21-CH ₂ ), 4.92 (s, 1H, pyrimidine C5-H) , 5.51 (m, 1H, 11-H) , 6.07 (m, 1H, 4-H) , 6.28 (dd, 1H, 2-H) , 7.17 (d, 1H, 1-H) .

Example 28 Prepara ion of 2—(4,4—ethylenedioxy—1-piperidiny1)—4,6—di chloropyrimidine and 4—(4,4—ethylenedioxy—1-piperidiny1) —2, 6—dichloropyrimidine After dropwise adding 43.32 g (286 mmoles) of 1,4-

—dioxa—8—azaspiro[4,5]decane to a solution of 25 g (136.3 mmoles) of 2,4,6—trichloropyrimidine in 200 ml of tetra¬ hydrofuran at 0°C, the reaction mixture is stirred at roo temperature for 1 hour, then evaporated. The residue is distributed between 300 ml of chloroform and 100 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 100 ml of water each and evap¬ orated. The residue is subjected to chromatography on a silica gel column by using chloroform as eluent. In the first stage the less polar 2-(4 ,4-ethylenedioxy-l-piperidi¬ ny1)—4,6—dichloropyrimidine is eluted which is recrys¬ tallized from ethyl acetate to obtain a yield of 13.98 g (35.36%), m.p.: 104-105°C. ÷-t-H-NMR (60 MHz, CDC1 ₃ ) δ ppm: 6.50 (s, 1H, 5-H) . By further elution the more polar 4—(4,4—ethylenedioxy-

—1—piperidinyl)-2,6—dichloropyrimidine is obtained which is recrystallized from ethyl acetate to give a yield of 20.98 g (53.04%), m.p.: 133-136°C. ⁱ H-NMR (60 MHz, CDCI ₃ ) δ ppm: 6.40 (s, 1H, 5-H) . Example 29

Preparation of 2,6—bis(4,4—ethylenedioxy—1-piperidiny1)—4- —chloropyrimidine

After dissolving 2.0 g (6.89 mmoles) of 2-(4,4-ethyle¬ nedioxy—1-piperidiny1)-4,6-dichloropyrimidine in 40 ml of n- —butanol and adding 2.6 ml (17.23 mmoles) of 1,4-dioxa—8- —azaspiro[4,5]decane, the reaction mixture is boiled under reflux for 4 hours, then evaporated. The residue is distri¬ buted between 50 ml of chloroform and 5 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 10 ml of water each, dried and evapor¬ ated. After recrystallization from hexane the title compound

is obtained in a yield of 2.51 g (91.8%)d, m.p.: 130-131°C. ^ ^• H-NMR (60 MHz, CDC1 ₃ ) <S ppm: 5.88 (s, 1H, 5-H) .

Example 30 Preparation of 2,4—bis(4, -ethylenedioxy—1- iperidiny1)—6- —(1— iperaziny1)pyrimidine

2,6-bis(4,4-Ethylenedioxy-1-piperidinyl)-4-chloropyri- idine is reacted with piperazine in the way described in Example 5 to obtain the title compound in a yield of 55.7%, m.p.: 130-140°C. ⁱ H-NMR (60 MHz, CDCI ₃ ) δ ppm: 5.01 (s, 1H, 5-H) . Example 31 Preparation of 21—{4—[2,4—bis(4,4—ethylenedioxy—1—piperidi- ny1)—6-pyrimidiny1]—1-piperazinyl}—16α-methylpregna- —1,4 ,9(11)—triene—3,20—dione The reaction of 16α—methy1-21—(4—nitrobenzenesulfonyl- oxy)pregna-l,4,9(ll)—triene-3,20-dione with 2,4—bis(4,4- —ethylenedioxy—1-piperidiny1)-6-(l—piperazinyl)pyrimid ine as described in Example 5 leads to the title compound in a yield of 77.5%, m.p.: 156-174°C. ^-NMR (60 MHZ, CDCI ₃ ) δ ppm: 0.67 (s, 3H, I8-CH ₃ ), 0.94 (s, 3H, 16α-CH ₃ ) , 1.38 (s, 3H, 19-CH ₃ ) , 3,99 (s, 8H, 2 X ethyle¬ nedioxy), 5.12 (s, 1H, pyrimidine C5-H) , 5,5 (m, 1H, 11-H) , 6.06 (br, 1H, 4-H) , 6.25 (dd, 1H, 2-H) , 7.15 (d, 1H, 1-H) . Example 32 Preparation of 4,6-dichloro-2—(2,2,6,6—tetramethyl—1—piperi- diny1)pyrimidine

A mixture containing 25 g (136.3 mmoles) of 2,4,6-tri- chloropyrimidine and 46.3 ml (272.6 mmoles) of 2,2,6,6,-tet- ramethylpiperidine is boiled under reflux for 50 hours, then the reaction mixture is cooled down and suspended in 250 ml of hexane. The insoluble part is filtered off, the filtrate (mother liquor) is evaporated and the residue is distributed between 300 ml of chloroform and 50 ml of 10% sodium hydr¬ oxide solution. After separation the organic phase is washed 4 times with 100 ml of water each, dried and evaporated. The residue is purified by chromatography on a silica gel column

by using hexane as eluent. After recrystallization fro hexane the title compound is obtained in a yield of 8.04 (20.47%), m.p.: 89-90°C.

^â–  T-H-NMR (60 MHz, CDC1 ₃ ) δ ppm: 6.53 (s, 1H, 5-H) . Example 33

Preparation of 4—chloro—2—(2,2,6,6— etramethy1—l—piperidi ny1)—6— yrrolidinopyrimidine

The reaction of 4,6-dichloro-2-(2,2,6,6—tetramethy1-1 —piperidiny1)pyrimidine with pyrrolidine as described i Example 7 gives the title compound in a yield of 75.08% m.p.: 130-135°C. l-H-NMR (60 MHZ, CDCI3) δ ppm: 5.76 (s, 1H, 5-H) .

Example 34 Preparation of 2—(2,2,6,6—tetramethy1—1— iperidiny1)-4—(1 piperazinyl)—6—(1-pyrrolidinyl)pyrimidine

4-chloro-2—(2,2,6,6—tetramethy1-1—piperidiny1)-6— (1- —pyrrolidinyl)pyrimidine is reacted with piperazine a described in Example 5 to obtain the title compound in yield of 80.2%, m.p.: 134-137°C. l-H-NMR (60 MHz, CDCI3) δ ppm: 5.01 (s, 1H, 5-H) . Example 35 Preparation of 16α-»ethy1—21—{4—[2, (2,2,6,6— etramethy1—1 —piperidiny1)—6—pyrrolidino—4—pyrimidiny1]—1-pip eraziny1}- -pregna—1,4,9(11)— riene—3,20-dione The reaction of 16α—methyl—21—(4—bromobenzenesulfonyl oxy)pregna-l,4,9(ll)-triene-3,20-dione with 2-(2,2,6, 6-tet ramethyl—1—piperidinyl)—4—(piperazinyl)-6—pyrrolid inopyrimi dine as described in Example 13 gives the title compound i a yield of 64.1%, m.p.: 171-181°C. iH-NMR (60 MHz, CDCI3) δ ppm: 0.67 (s, 3H, I8-CH3) , 0.94 (s, 3H, 16α-CH ₃ ), 1.40 (s, 3H, 19-CH ₃ ) , 1,48 (s, 12H, 4 tetramethylpiperidinyI-CH3) , 5,01 (s, 1H, .pyrimidine C5-H) , 5,51 (m, 1H, 11-H), 6.09 (br, 1H, 4-H) , 6.27 (dd, 1H, 2-H) , 7.20 (d, 1H, 1-H) .

Example 36 Preparation of 6-chloro—2—(1,1-dxmethylethyla ino)—4—(2,2- — imethylpropylamino)pyrimidine

After dissolving 5.0 g of 4,6—dichloro—2—(1,1—dimethyl- ethylamino)pyrimidine in 25 ml of isopropanol and adding 5 ml of 1—amino—2,2—dimethylpropane, the reaction mixture is boiled under reflux for 20 hours, then the reaction mixture is evaporated and the residue is distributed between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. The residue is recrystallized from hexane to give the title compound in a yield of 4.49 g (73%), m.p.: 109.5-111°C. -H-NMR (60 MHz, CDCl ₃ ) δ ppm: 5.71 (s, 1H, 5-H) . Example 37

Preparation of 2—(1,1—dimethylethylamino)—4—(2,2—dimethyl¬ propylamino)—6—(1-piperazinyl)pyrimidine

The reaction of 6-chloro-2-(l, l-dimethylethylamino)—4- —(2,2—dimethylpropylamino)pyrimidine with piperazine as described in Example 5 gives the title compound in a yield of 86.0%, m.p.: 120-124°C. ^-NMR (60 MHz, CDCI3) δ ppm: 4.96 (s, 1H, 5-H) .

Example 38 Preparation of lβα-methyl—21—{4—[2—(1,1—dimethylethylamino)- —4—(2,2—dimethylpropylamino)—6-pyrimidiny1]—1-pipe raziny1}- pregna—1,4,9(11)—triene—3,20-dione

16α—Methyl—21—(4—nitrobenzenesulfonyloxy)pregna- —1,4,9 (11)—triene-3,20—dione is reacted with 2,4—bis(4,4- —ethylenedioxy—1-piperidinyl)—β-(l-piperazinyl)pyrimi dine as described in Example 6 to obtain the title compound in a yield of 85.7%, m.p.: 155-160°C. iH-NMR (60 MHz, CDCI3) δ ppm: 0.68 (s, 3H, I8-CH3) , 0.96 and 0.98 (s, s, 12H, 16α-CH ₃ es C(CH ₃ ) ₃ ), 1.39 (s, 9H, N(CH ₃ ) ₃ ), 1.40 (s, 3H, I9-CH3) , 4.97 (s, 1H, pyrimidine C5-H) , 5,52 (m, 1H, 11-H) , 6.10 (br, 1H, 4-H) , 6-28 (dd, 1H, 2-H) , 7.20 (d, 1H, 1-H) .

Example 39

Preparation of 21—{4—[2,4—bis(1—adamantylamino)—6-pyri- midinyl]piperazinyl}—16α-methylpregna—1,4,9(11)—trien e—3,20- —dione methanesulfonate After suspending 1.1 g (1.4 mmoles) of 21—{4—[2,4—bis-

(1—adamantylamino)—6-pyrimidinyl]—l—piperazinyl}- 16α-methyl- pregna-l,4,9(ll)-triene-3,20-dione in 35 ml of anhydrous ethanol, 135 mg (1.4 mmoles) of methanesulfonic acid is added under stirring. After dissolution the solution is fil- tered and evaporated to dryness. The foam-like residue is suspended in ether and filtered off to obtain 1.18 g (95.5%) of the title compound. Example 40 Preparation of 2,4—bis(1—adamantylamino)—6—chloropyri- midine and 4,6—bis(1—adamantylamino)—2—chloropyrimidine

26.0 g (87.25 mmoles) of 4—(1—adamantylamino)—2,6—di¬ chloropyrimidine and 39.5 g (261.6 mmoles) of 1—aminoadaman- tane are dissolved in 200 ml of n—butanol, the reaction mix¬ ture is boiled for 75 hours and evaporated. The residue is suspended in 400 ml of ether and filtered. The filtered sub¬ stance is chromatographed after drying on a silica gel column by using chloroform as eluent. The substance obtained is a mixture of the title isomers. The isomers are separated on a silica gel column by using as eluent a 49:1 mixture of hexane and ethyl acetate. 2,4-Bis(l-adamantylamino)-6- —chloropyrimidine is obtained which is recrystallized from hexane to obtain a yield of 21.67 g (60.14%). Its melting point and ¹ H— MR are identical to those of the product according to Example 11. By continuing the elution with a 6:1 mixture of the above solvents the more polar 4,6—bis(1—adamantylamino)—2- —chloropyrimidine is obtained which is also recrystallized from hexane to result a yield of 1.88 g (5.22%), m.p.: 260- 266°C. ^X H-NMR (60 MHz, CDC1 ₃ ) δ ppm: 5.49 (s, 1H, 5-H) .

Example 41 Preparation of 4,6—bis(1—adamantylamino)—2—(l—piperazinyl)- pyrimidine

4,6—bis(1—adamantylamino)—2—chloropyrimidine is reacted with piperazine according to the method of Example 4 to obtain the title compound in a yield of 94.4%, m.p.: 210- 220°C. l-H-NMR (60 MHz, CDC1 ₃ ) δ ppm: 4.97 (s, 1H, 5-H) . Example 42 Preparation of 21—{4—[4,6—bis(1—adamantylamino)—2—pirimidi- nyl]—1-piperazinyl}—16αe-Hnethyl-pregna—1,4,9(11)—t riene—3,20- —dione

21—(4-Bromobenzenesulfonyloxy)-16α-methyl—pregna- —1,4,9(11)—triene-3,20—dione is reacted with 4,6-bis(l-ada- mantylamino)—2—(l—piperazinyl)pyrimidine according to the method of Example 6 to obtain the title compound in a yield Of 52.9%, m.p.: 190-200°C.

÷- ^l -H-NMR (300 MHz, CDCI ₃ ) δ ppm: 0.68 (s, 3H, I8-CH ₃ ) , 0.96 (d, 3H, 16α-CH ₃ ), 1.40 (s, 3H, 19-CH ₃ ) , 1.67, 2.02 and 2.09 (br, br, br, 30H, adamantyl-CH and -CH ₂ ) , 3.07 and 3.19 (d, d, 1H, 1H, 21-CH ₂ ), 4.23 (vbr, 2H, 2xNH) , 4,96 (s, 1H, pyrimidine C5-H) , 5,51 (m, 1H, 11-H) , 6.07 (m, 1H, 4-H) , 6.29 (dd, 1H, 2-H) , 7.17 (d, 1H, 1-H) . Example 43 Preparation of 2—(cyclopentylamino)—4,6—dichloropyrimidine and 4—(cyclopentylamino)—2.6—dichloropyrimidine

2,4,6—Trichloropyrimidine is reacted with cyclopentyl- amine according to the method of Example 3. The less polar 2—(cyclopentylamino)—4,6-dichloropyrimidine is obtained in a yield of 35.2%, m.p.: 48-52°C.

!H-NMR (60 MHz, CDCI ₃ ) δ ppm: 6.52 (s, 1H, 5-H) .

The more polar 4—(cyclopentylamino)—2,6—dichloropyrimi¬ dine is obtained as an oil in a yield of 57.2% !H- MR (60 MHz, CDCI3) δ ppm: 6.30 (s, 1H, 5-H) .

Example 44 Preparation of 2,4—bis(cyclopentylamino)—6—chloropyrimidine

5.0 g of 2-(cyclopentylamino)—4,6—dichloropyrimidine are dissolved in 25 ml of isopropanol, 7.5 ml of cyclo- pentylamine are added thereto and the reaction mixture is boiled for 6 hours. Then the reaction mixture is evaporated, the residue is separated between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. The title compound is obtained after recrystallization from hexane in a yield of 5.24 g (86.7%) , m.p. : 94-98°C.

^â–  T-H-NMR (60 MHz, CDC1 ₃ ) δ ppm: 5.67 (s, 1H, 5-H) . Example 45 Preparation of 2,4—bis(cyclopentylamino)—6—(l—piperazinyl)- —pyrimidine

2,4—Bis(cyclopentylamino)—6—chloropyrimidine is reacted with piperazine according to the method of Example 4. The title compound is obtained in a yield of 81.9%, m.p.: 142- 148°C.

^-H-NMR (60 MHz, CDCI ₃ ) δ ppm: 4.94 (s, 1H, 5-H) .

Example 46 Preparation of 21—{4—[2,4—bis(cyclopentylamino)—6-pirimidi- nyl]—1-piperazinyl}—16α-methyl-pregna—1,4,9(11)—tri ene—3,20- -dione

21—(4—Bromobenzenesulfonyloxy)—16α—methyl—preg na- —1,4,9(11)—triene—3,20-dione is reacted with 2,4-bis(cyclo¬ pentylamino)—6—(l—piperazinyl)pyrimidine according to the method of Example 6 to obtain the title compound in a yield of 73.1%, m.p.: 180-185°C. ^l -H-NMR (300 MHz, CDCI ₃ ) δ ppm: 0.69 (s, 3H, I8-CH ₃ ) , 0.96 (d, 3H, 16α-CH ₃ ), 1.40 (s, 3H, 19-CH ₃ ) , 3.12 and 3.21 (d, d, 1H, 1H, 21-CH ₂ ), 3.88 and 4.19 (m, m, 1H, 2xN-CH<) , 4,58 and 4.62 (vbr, vbr, 1H, 1H, 2xNH) , 4.93 (s, 1H, pyrimidine C5-H) , 5.51 (m, 1H, 11-H) , 6.07 (m, 1H, 4-H) , 6.28 (dd, 1H, 2-H) , 7.16 (d, 1H, -H) .

Example 47 Preparation of an injectable solution

After dissolving 0.05% by weight of sodium pyrosulfite in deoxygenated water for injection use, the active agent is dissolved in the above solution. Simultaneously, 0.1% by weight of potassium sorbate is dissolved in deoxygenated water for injection use and an amount of sodium chloride required for isotonization is dissolved therein. The two above solutions are mixed, filled up to the desired final volume with deoxygenated water for injection use and finally, the solution is filtered through a membrane filter with a 0.2 μm mean pore size until free of bacteria and strange materials. The solution is filtered and filled into ampoules under nitrogen. A preferable composition of an injection of 1 ml volume is e.g. as follows: active ingredient 10 mg sodium pyrosulfite 5 mg sodium chloride 7 mg water for injection use, up to 1 ml