LT3071B - Novel steroids with pregnane skeleton,pharmaceutical compositions containing them and process for preparing thereof - Google Patents

Abstract

This invention is attributed to the new therapy-active 21-amynosteroyds. Their formula is <IMAGE> (I) and they have a pregnan skeleton, where: two of X, Y and Z are nitrogen atoms and the third being a methyl group; not depending on each other R<1> and R<2> is a primary amino group having as a substitute branched chain of C4-8-alkyl, -alkene or -alkyne groups or C4-10-cycloalkyne groups that comprise of 1-3 rings where there may be C1-3-alkyne group(-s); or R<1> and R<2> together comprise of spiro-heterocyclic secondary amino-group having a maximum of 10 carbon atoms and the one that may, as an additional heteroatom have at least one oxygen atom; or one of R<1> and R<2> is not changed heterocyclic secondary amino group having from 4 to 7 carbon atoms and another is the afore-mentioned primary amino-group, afore-mentioned spiro-heterocyclic secondary amino group or heterocyclic secondary amino group having from 4 to 7 C-atoms with C1-4-alkyne(-s) substitutes; and n is equal to 1 or 2 and their additive salts and pharmaceutical composition that incorporates these compounds. Besides that, the invention is attributed to the afore-mentioned compound production method. The formula (I) compounds are distinguished by an antioxidant inhibiting effect especially of lipid peroxidation and therefore they may be useful for the treatment of pathological effects of lipid peroxidation manifesting itself in mammal organisms, including human organism.

Description

having a pregnan skeleton in which;

two of X, Y. and Z are nitrogen atoms and the third is _; / i: methine group; i

R ¹ and R ² are, independently of one another, a primary amino group substituted with C ₄ branched chain. _8- alkyl, -alkenyl or -alkynyl groups. ₄ or C ₁₀ cycloalkyl group, which includes In-three rings, which may be in the C _{first 3-} alkali group (s);

R ¹ and R ² . together form a spiro-heterocyclic secondary amino group containing up to 10 carbon atoms and which may contain at least. one oxygen atom as an additional heteroatom; or: one of R ¹ and R ² is an unsubstituted heterocyclic secondary

3077 // amino group having 4 to 7 carbon atoms and the other being the above primary amino group,

- 77777 the aforementioned spiro heteroacyclic secondary amino group, or heterocyclic secondary amino group, -. containing 4-7 C-atoms, with. C ₁ . _4- alkyl (s);

357 7 7, / _: .gir 7 / '' 7 7;) +; 7) ··, are 1 or 2, / 7 / o and their addition salts obtained by addition of acids and pharmaceutical compositions to which includes the following compounds.

'

The invention also relates to a process for preparing the above compounds.

According to the present invention, the compounds of formula (I) are novel and possess important biological activity, in particular antioxidant (inhibiting lipid peroxidation) activity when tested in vitro. Some of these compounds have high efficacy in vivo using a cerebral trauma model.

^The invention also relates to a method of treatment comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Administration of an amount of I ¹ to inhibit lipid peroxidation,

Herein, hereinafter and in the definition of the invention, the term ^B primary amino group means that one of these substituents is hydrogen and the other substituent is an alkyl, -alkenyl or -alkynyl group of a C 0 ₈ branched chain, or C ₄ . _A cycloalkyl group of ₁₀ , consisting of 1-3 rings and having a C./alkyl group (s), branched C ₄ . ₈ alkyl, .beta.-alkenyl, and -alkynyl groups may be various iodo, secondary or tertiary.

-44-, 4, 4, 4 ', 4', 4 ', 4', 4 ', 4', 4 ', 4', 4 ', 4', 4 ', 4', 4 ', 4'.

35. 44 ///, 0 /, // ,, ._ 4/4 0 /. -0 // 0. // - ^ / 0-4 / 4 ^: - \ 7 /

7 '4.4. C ₄ . _{A 10-} cycloalkyl group consisting of _; of 1-3 rings, and capable of having C ₁ . _3- alkyl group (s) may be - 'e.g. , 'Cyclobutyl, _{cyclopentyl,?} cyclohexyl, or adamantyl group '. These groups may be substituted or may be substituted by one methyl, ethyl or propyl group.

c cycloheptyl may or may not be present

R ¹ and R ² forming / spiro-heterocyclic secondary amino groups having up to 10 carbon atoms which may have at least one additional oxygen heteroatom, for example 4,4-ethylenedioxy-1'-piperidinyl, but this case does not limit other possibilities either.

An unsubstituted heterocyclic secondary amino group, y. having from 4 to 7 carbon atoms, v is one of R ² or R ² - preferably a pyrrolidone, piperidine or azepine group. * In this case, the other R ¹ and R ² are either the above-mentioned primary amino group, or the above-outlined ^seven secondary heterocyclic group having spiro structure, or above ⁷ / outlined heterocyclic secondary amine groups. having a group (es) of -4 -4 carbon atoms. These C 1-6 alkyl groups may be different, e.g., methyl, ethyl, propyl, or n-, iso, secondary or groups; Most preferred: the following substituted amino groups: the representative is, for example, 2,2,2,6, piperidinyl group.

and C ₁ -C ₄ -alkyl be the same as n- or isotret. -butyl heterocyclic 6-tetramethyl-lThere are many pathological processes known for the accumulation of non-essential / free radicals. These free radicals oxidize unsaturated fatty acids (lipid peroxidism), which are important components of cell membranes. ; It is a low specificity, steely disrupting process that replaces or destroys biomolecules. In this v process, the functions of cells at various levels, ⁷ organs and the body as a whole can be compromised.

<47. V-:

Thanks to its lipid peroxidation inhibitory effect, antioxidants provide protection against free radical damage.

. There is no doubt that the active ingredients; belonging to this -structural-pharmacological group included in the compositions, are incorporated into cells of neurons or parotid nerve tissue and counteract the pathomechanism associated with lipid peroxidation, which is the result of reactive free radicals. It is believed that the formation of such radicals plays a pivotal role in the pathological processes caused by injuries accompanied by cell death. Because the role of these mechanisms is very widespread and can be considered as this. mechanism is common in almost all areas of molecular pathology and pathobiology, it is clear that any one capable of having therapeutic benefits

- Compounds that inhibit lipid peroxidation will be associated with a very wide and diverse spectrum of syndromes, pathologies and disease groups.

Thus, compounds that inhibit lipid peroxidation may have therapeutic value beyond acute injury (such as concussion, cerebral palsy, softening of the brain, brain compression) or acute cerebral circulation shock (arterial or venous thrombosis, cerebral vascular occlusion, post-cerebral haemorrhage). , but also in many other pathological conditions or conditions affecting the central nervous system or other organ systems. Potential indications may include neuropsychiatric pathologies such as Alzheimer's disease or Alzheimer's-type dementia, alcoholic dementia, and central nervous system disorders that accompany alcoholism, so-called "schizophrenia symptoms, amyotrophic lateral sclerosis, multiple sclerosis,

^, · // - '// ⁵ ' 7 'I disorders associated with alcoholism, so-called 7; ”negative 2: 2: symptoms of schizophrenia, amyotrophic lateral sclerosis, multiple sclerosis, cluster headache, and complications , accompanying tumorous lesions of the brain. .

Indications for use of compounds which inhibit lipid peroxidation 2 in pathological processes of origin outside the central nervous system may include, for example, radiation damage of varying severity, septic or endotoxic shock, bleeding shock, ulcerative stress due to 'cataract injuries': burn shock, status after cardio-pulmanological resuscitation, reperfusion after organ transplantation, retrolent fibroplasia associated with oxygen therapy in immature neonates, protection against adriamycin cardiotoxicity, protection against reperfusion injury resulting from severe myocardial infarction complications (eg) allergic reactions, insect bites, * inflammatory processes of the skin (e.g.

psoriasis, eczema), nephrotic syndrome (of immunological origin), rheumatoid arthritis, systemic lupus erythematosus, endogenous inflammation of the eyelid, bronchial asthma, emphysema and vascular atherosclerosis.

The importance of compounds that inhibit lipid peroxidation is evidenced by a large body of recent literature (both patent applications and scientific publications).

In PCT patent application no. WO 87/01706 describes the synthesis of a number of aminosteroids in which the amino group is attached to the C-17 side-chain terminal carbon atom. These steroids have a double bond (s) at the 4-position or 1,4-position of the steroid skeleton ring A and the 3-position contains oxo.

\. . '. 5 β'. or a hydroxyl group, the 6-position being an a- or a-alkyl group or a halogen, and in particular the α-hydroxyl group at the 11-position, as well as the a- or jS-methyl group at the 16-position and the double bond 9 (11).

. The steroid skeleton ring may be saturated or - ··. aromatic. Some 21-amino-, steroids having a double bond at the 17 (20) position are also described. In the compounds described herein, the substituted pyrimidine, triazine or pyridine ring is in most cases linked via the piperazinyl group to the 21-position. Among the published compounds, 1βα-methyl-21 {4- / 2,4-bis (pyrrolidine) -6-pyrimidinyl / -1-piperazinyl} pregna-1,4,9 (11) -trien-3,20-dione 5 methanesulfonate (accepted name: tir i1a zad-mez iat) is now in the second phase of clinical trials.

Similarly, the synthesis of a steroid that inhibits lipid peroxidation is described in published PCT application no. WO 87/077895. Joj e ap t a r i ama ami noe s t h e r a t i o n. 20 amino acids, most preferably 17-amino

Synthesis of 11,17-bis (amino) esters and 3-amino esters having ⁷ androstane structure. According to this publication; these compounds may be useful as inhibitors of lipid peroxidation resulting from spinal, head and other injuries. The structure of the amino substituents is similar to that of the above publication.

The preparation of novel amino-9,10-secosteroids is described in published application PCT patent no. WO 88/07527.

The amino-substituent is attached to the terminal carbon atom of the secosteroid C-17 side chain. Amino substituents are similar to those described in the above publication. . '...

The synthesis of compounds which inhibit lipid peroxidation is also described in published patent application Nos. 0 389 368, 0 389 369 and 0 389 370.

'.. ⁷ ' ·

Corticoid type,? The preparation of '' 21 -aminosteroids is described in Publication Application European Patent Publication No. 7,194.

389,368. For example, a 4- / 2,5-bis (diethylamino) -6-r pyridinyl / piperazinyl group may be attached to

C-21 carbon atom. The sterane skeleton ring A has one 7 / or two double bonds, 7 and the substituents characteristic of the 7 corticoids can be in positions 6, 9, 11, 16 and 17.

The 9 (11) position may also have a double connector.

The amino acid synthesis of 710 d 3-0-oxo-19-nor-steroids is as described in published European Patent Application No. · 0

Specific compounds exemplified in the examples are: 17? -Hydroxy-11? - (4-dimethylaminophenyl) -17? - {3- / 4 / 2,6-bis (pyrrolidino) -4-pyrimidinyl}. -1-piperazinyl / -1-7,7,7d. Propinyl} estra-4,9-dien-3-one, 17? -Hydroxy-11? - (4-dimethylaminophenyl) -17? - {3- / 4- (5,6-bis (diethylamino) -2-dd pyridyl / -1-piperazinyl / -1-propynyl} estra-4,9-dien-3'-one, 17? - hydroxy-11? - (4- dimethylaminophenyl) -17a- {3- / 4 / 2,6-bis (diethylamino) -2-pyridyl / -1-piperazinyl / -120-propynyl} -estra-4,9-dien-3-one, 7,717 /? -hydroxy-11β- (4-dimethylaminophenyl) -17β- {3- [4- [2,6-bis (1-pyrrolidinyl) -4-pyrimidinyl] -1-piperazinyl] -1-propynyl} estra-4,9- dien-37/7-one and 17β-hydroxy-11β- (4-dimethylaminophenyl) -17α- {3/4- [2,6-bis (pyrrolidino) -4-pyrimidinyl] -1-piperazinyl] . 1-Propynyl} estra-4,9-dien-3-one.

The synthesis of amino-steroid containing androstane skeleton derivatives also having lipid peroxidation inhibitory activity is described in

30. in a European patent application. No. 0 389 369; these • 7 compounds also have an inhibitory effect on lipid peroxidation. Examples of such compounds are e.g. , ββ, 17β-Dihydroxy-17α- {3 / 4- / 2β, β-bis (pyrrolidino) 4-pyrimidinyl / -1-piperazinyl / -1-propynyl} - androsta-4, 6-7 dien-3-one, 11β, 17β-dihydroxy-6-methyl-17β- {3- [4- [2,6-bis (pyrrolidino) -4-pyrimidinyl] -1-piperazinyl-1 -printinyl} androsta-1,4,6-trien-3-one, 11β, 17β-dihydroxy-6-methyl-17β - {3- / 4- / 5,6-bis (dimethylamino) - 2-pyridyl [-1-piperazinyl] -1-propynyl} androsta-1,4,6-trien-3-one and [beta], 17 [beta] -dihydroxy-6-methyl t-17 [beta] - {-3- / 4- / 3, β-bis (diethylamino) -4-pyridyl / -1-piperazinyl / -1-propynyl} androstase, 4,6-trien-3-one ./y 7 Λ 7

In the published European patent application no. 0 156 643 describes the synthesis of predominantly water-soluble: corticosteroid derivatives which are predominantly yicheactivated by the fact that their hydroxyl group or ester derivative at position 71 has a ω-configuration or a double bond at position 9 (11). 17 «-hydroxy-11« - (2,2-dimethylpropylcarbonyloxy) pregna-1,4-diene-3,20-dione-21yl sodium succinate is believed to be the most effective lipid peroxidation agent among the compounds described. . :

In published application PCT patent no. WO 91/11453 describes bis (amino) pyrimidinyl-piperazinyl derivatives having an oxygen group at the 5-position, wherein the 3,4-dihydro-6-hydroxy-1 is 2,5 in the molecule; The 7.8-1g of the th 12 H 7 -benzopyran-2-ylmethyl group or derivative thereof may be attached to the nitrogen at the 1- position of the piperazine residue. This application also discloses alkyl-substituted 5-hydroxypyrimidine derivatives.

It is logical that the synthesis of lipid peroxidation-'' /: ilrihi'bu'6jan''-compounds has been extended to amine derivatives containing ^{: a} non-steroidal skeleton. For example, in PCT patent application no. WO 88/084 24 describes novel aromatic and aliphatic bicyclic amines. obtaining derivatives of cycloamine, quinonamine, aminoether and bi-cyclic aminoether, which may be useful, for example, in the treatment of brain and spinal cord injuries. . From the compounds described in detail, -2 - ([4- (2,6-bis (1-pyrrolidinyl)) - 4-pyrimidinyl] -1- piperazinyl] -methyl} -3,4-dihydro-

'Λ / υυ ^9. '<-Υ /,

2,5,7,8-Tetravalent-2Ή-1-behopyran-6-ol / dihydrochloride. 7th

It is an object of the present invention to provide compounds which have a <RTI ID = 0.0> 5, </RTI> higher 7, biological / efficacy and / or lower toxicity than compounds known in the art. . It is because of the properties of these compounds that they would be better suited to 'therapy' compared to the active drug gomif γο Yyy 'j'Y- / / Y .Y - Yv ^: ' currently used in this field. ··· Υ / ^Λ / // Υν-Υ '' / Y / Y · Yj? ^; 'Y> // 7 / -7 // - /. Y / Unexpectedly / found that new. The 21-amino acid formula (I) having a pregnane skeleton exhibits excellent lipid peroxidation inhibitory activity for these purposes.

'

The new 21-aminosteroids of formula (I) containing / pregnan squash 'are obtained by / Υ / 7Υ / 7 / ΥΥ · γ:

acylating / 2'-hydroxy-16α-methylpregna-1,4,9 (11) ′ 20/7 ′ trien-3, ZO-dione ′ respectively with 4-bromobenzenesulfonyl chloride, ′ or Y 4 -nitrobenzenesulfonyl chloride, and ′ / ′ V / · / YYpd 21-substituted pregnane derivatives obtained by this action,

(/ 10, (- ..

wherein = R '· ... is a 4-bromobenzenesulfonyl' or 4-nitrobenzenesulfonyl group, 'with a piperazinylbis (alkylamino) pyrimidine derivative of formula ¹

wherein X, Y, Z, ^R: R ² and n are as defined in? . 15, and, if appropriate, the resulting pregnandi derivatives of formula (I) wherein X, Y, Z,. R ¹ , R ² and n are as defined above, when converted to the free base and / or, if necessary, the resulting free base is converted into the addition salts with an appropriate acid.

21- (4-bromobenzenesulfonyl) -16α-methylpregna-1,4,9 (11) -; triene-3,20-dione and 16 "-methyl-21- (4-nitrobenzolsulfo25 nil) -pregna-1,4,9 (11) ^{-triene-3,20-dione:} which formula

- ^; (II) used as starting materials are also: new compounds which can be obtained according to the procedure described below. 3/3-:

(3 21-Hydroxy-16cr-methylpregna-1,4,9 (11) -trien-3,20-dione 3 (known from French Patent No. 1,296,544) is dissolved in tetrahydrofuran and to the resulting solution is added triethiamine. and excess 4-nitrobenzenesulfonyl chloride at about 0 [deg.] C. and then store at room temperature for about 2-4 hours., When the reaction is complete (the reaction can be controlled by thin layer chromatography (TLC)), the solution '' '3 .. · ·' '

/ U. Is poured into water in small quantities. After settling of the precipitate, the mixture is filtered / washed and the precipitate is washed.

with water until the water becomes'neutral; dried and; recrystallized. /: /: / -: 7-7 / 7 7/7: / / 7/5 '- /', //. 7/77 .. //.- _; / 7 - B /: - 77 /'.:// '//.7 7 /. \ 7 // '

Reaction of the resulting b21-substituted pregnan derivatives of formula (II) with the piperazinyl-bis (alkylamino) pyrimidine derivatives of formula (III). Preferably carried out as follows: /, 21- {4-bromobenzenesulfonyloxy ) .- 16a-methyl-pregna-1,4,9 / 7 jll) ^; -trieri-3/20-dione or t6aHethyl-2-l- (4-nitrobenzenesulfonyloxy) -pregna-1,4,9 (11) -trien-3,20-dione. dissolved in a polar solvent, preferably acetone / 7 or acetonitrile, and / piper az f nyl -bis (alkylamino) pyrimidine derivative is added to the resulting solution; a '/ 15 of the formula (III j, and potassium carbonate. in Reaction mixture was stirred vigorously for about // / 50-70 ^c C. until, / B, the reaction occurs. Then, the solvent nudistiliuo_ at all times, and the residue was partitioned between a halogenated /./ mixture of hydrocarbon, preferably chloroform, and water, Organic '20 layer / separable, / washed several times with water

b ../. · Β; ·· - //: ';. ·· χχ · B / - .. B.; Hijoviri / a.'inaš., .. · // -'-' · Nugarinuš, - .organic. .the solvent from the dried solution, the residue is cleaned by chromato- graphing on

B through a column of silica gel and, if necessary, crossed / 7 lined. : · ;; / '/

The piperazihyl-bis (alkylamino) pyrimidine derivatives of the formula (III) are prepared as follows: 2,4,6-Trichloropyrimidine is treated with a primary or / or secondary b-amine having R ¹ or / or 7 R ² in an ethereal solvent, e.g.

in tetrahydrofuran, / temperature range / from approx

-20 ° C to about 40 ° C; the reaction lasts from about 30 min. Up to a few days depending on / amino

/.//- reactingurho. / 7 In the case of the sterically unfavorable 2,2,6, 6/7 / tetramethylpiperidine (which may be used /, and / 35 / b as a solvent), the reaction mixture must be refluxed for approx. 50 hours. At the end of the reaction, solvent / distillation,.

- 12 / the residue is dissolved in a halogenated hydrocarbon-, preferably chloroform, washed with aqueous sodium hydroxide solution and water + The separated organic layer is dried, the solvent is evaporated and the reaction is carried out. . the resulting 4,6-dichloro-2-alkylaminopyrimidine and 2,6-dichloro-4-alkylaminopyrimidine derivatives are separated by chromatography on a silica gel column. The separated isomers are purified by recrystallization. The monoalkylamino-dichloropyrimidine isomers thus obtained are again reacted with the same or different amine as in the first step.

The parameters of this reaction are / are primarily determined by _: - the reactivity of the reacting amine. For example, when reacting monoalkylamino-dichloro-pyrimidine derivatives with pyrrolidine, the reaction is complete at room temperature, and complete reaction with tert-butylamine requires heating at about 130 ° C for about 15 hours. The Neopentylamine reaction. with monoalkylamino-dichloropyrimidines can be carried out under milder reaction conditions: it is fully accomplished by boiling in isopropanol / 2 0 e for about 20 hours. Metabolic reaction 5-amino-4,4-dimethyl-1-pentane reacts with pyrimidine derivatives only at elevated temperatures. The reaction of 1-amino-adamantane with high spherical 'limitations' can be accomplished by boiling in n-butanol for about 75 hours.

3 y '''y''- /? //.y/ ./-,y 7; . . _? j ·. ΐ y 'Bis (alkylamino) -chloropyrimidine derivatives ,. resulting from the second reaction may be isolated in the same manner as the monoalkylamino-dichloropyrimidine derivatives described.

P. ·

The piperazinylpyrimidine derivatives of formula (III) may be prepared by reaction of bis (alkylamino) chloropyrimidine derivatives with piperazine according to the following procedure. The bis (alkylamino) -chloropyrimidine derivatives are dissolved in a tertiary amine, preferably N-ethylmorpholine, and the reaction mixture is refluxed under a nitrogen atmosphere in the presence of excess piperazine for about 25 hours. N13 / ethylmorphylblirias and most of the piperazine excess _; is distilled, water is added to the residue, which is also distilled. Distillation under atmospheric pressure until the temperature reaches 100 ° C. The residue is dissolved in chloroform, and the solution is washed first with an aqueous sodium hydroxide solution and then with water. The organic layer was separated, quenched with chloroform, and the residue chromatographed on a silica gel column, followed by recrystallization.

Pharmacological studies of the Pregnan derivatives of formula (I) according to the present invention were performed on non-anesthetized mice using a known experimental model of cephalic trauma (J.

(1980)), which we modified to investigate intravenous protective effects of compounds.

Neurosurg., 62, 882

In these experiments (i. V.) 'Doses of cerebrospinal force. After a cephalic injury, the test substance in the tail of the animal is neurological

A metal ax of a certain weight was allowed to fall on the surface of the experimental animals' skull at a certain height from a predetermined height, 5 minutes after such a closed dose of a blood vessel, and conditions were assessed for 60 minutes after cephalic trauma. This assessment was performed using a simple click test to determine the intact or palpable motor functions of both front and hind limbs. In addition, the frequency of cases considered as mild to severe in the different test groups and the proportion of animals suffering from paraparesis / sub-paraplegia were recorded. Finally, the development of onset symptoms of nervous system failure was evaluated in the / 7 neurological characteristics of the treated additive animals with control animals.

¹⁴ animals covered. 'was given only · solvent, with neurological characteristics.

At the most appropriate dose, 0.1 mg / kg, 21- {4- / 2.45. bis (adanantylamino) -6-pyrimidinyl] -1-piperazihyl} -16a7y. jetylpregna-1, 4, 9 (11) -trien-3,20-dione methanesulfonate 7, which has a 33% increase in the number of cases known as 'mild' (according to neurological symptoms induced by a traumatic injury) in formula (I), and the like, the incidence of paraparesis-paraplegia decreased by 33%.

Known thyrylazed mesylate (see PCT Patent Publication No. WO 87/01706), chemical name -16-methyl-21- {4- / 2,4-bis (pyrrolidino) -6-pyrimidinyl / -1-piperazinyl } with pregna-1,4,9 (11) triene-3,20-dione methanesulfones, this was used as a control. The use of strained thyrylazed mesylate at the most effective dose of 0.3 mg / kg increased the number of animals showing mild symptomatic insufficiency by only 23% and reduced the frequency of paraplegic animals by only 20%.

2Oyyyy 7,; 3-3. <3y3'.33 ' ^: - / 3' · 3 / 7j 3/3/37 -'- / y 33 /// ... '^; 3y / 3 _? 'y ^: ·; , · //../Y; / 3

From these experimental results it follows that the compounds described. In our invention, the lipid peroxidation inhibitory effect is enhanced, and they exceed the effect of known compounds. 37 3 ^{: / v;} 7y y ///7-3../.

7 3373/33/33 3; .7-73 / 7 /, / 73 -777 .3.3 / 3 -. , '

The novel 21-aminosteroid derivatives of formula (I) having a pregnane skeleton are used alone or salts thereof, 3 most commonly included in conventional therapeutic compositions. These compositions can be solid, liquid. or semi-liquid. These formulations use conventional excipients, /, stabilizers, • 3 pH-adjusting additives, osmotic pressure-modifying additives, flavoring agents to form a pharmaceutical form, or giving a formulation auxiliaries and excipients.

¹⁵ / / to / to / · '/

..Solid: Pharmaceutical compositions can be, e.g., / tablets, / drops',. various capsules ./or. ampoules with a mixture of 11, for use in the preparation of injections. S ky s to s_? compositions, are injectable or infusion compositions, 5 liquids packaged. liquids and .lays./Semi / Liquid / Compositions include ointments, balms,. creams, shakes, and / or preservatives. /

In order to achieve the desired effect, the patient is administered a / '/ pharmaceutical' / composition containing a certain dose of the active ingredient. : This dose depends on the patient / condition, pathological: / condition to be treated / / severity / patient, weight, patient sensitivity to i: delayed substance, / / treatment / day, / dose / < .frequency. The dosages of the active / active ingredient used can be // readily /./ set // experienced. -The physician observing '20 .For simplifying the use of drugs' in the formulation /// the composition would contain / substance // amount, :, doses, /: / as / half ,, sh i p s, /. / composition i c i j 6 s.

or a few .quarters is: handy to do so once a dose // dose, / .third '/: or:: Such: dosing' chew- / ^: /tu.ri,/ ^! ; eg:.>: l :: tablets, which may have grooves;: / to facilitate / split them in half or in four /? in order to obtain the exact amount of 'active / active ingredient'.

; /? // //blown/:''/:gąąi/:./.'been '^; coated / not soluble in acids; 30 layers, /. in order to release the active substance /. Such tablets are coated with a special enteric coating. A similar effect can be achieved by accessing the active ingredient. /// .//

The pharmaceutical composition comprising the active ingredient of the present invention generally contains from 1 to 100 mg. of active substance per unit dosage form. Of course,. that some of the compositions -. 'i ;; _{iųkš.čiaa:} · įminėtas upper and lower limits can be extended.

The present invention also relates to a method of inhibiting lipid peroxidation, which occurs in the body. This method comprises administering to a patient a therapeutically effective amount of an active ingredient of formula (I) or a pharmaceutically acceptable addition salt thereof.

The invention is illustrated in detail below. examples which do not limit its scope.

example

-. Preparation of 21- (4-Bromobenzenesulfonyloxy) -16? -Methylpregna-1,4,9 (11) triene-3,20-dione

Dissolve 10.0 g (29.4 mol) of 21-hydroxy-16? -Methylpregna-1,4,9 (11) -trien-3,20-dione in 100 ml of tetrahydrofuran, add 7.14 ml (51.4 mmol) of triethylamine and 13.1 g (51.4 mmol) of 4-bromobenzenesulfonyl chloride are added at 0 ° C. The reaction mixture is stirred at room temperature for 4 hours, after which 450 ml of water are added dropwise with stirring. The precipitate is filtered off, dried and recrystallized from ether. 11.0 g (67.07%) of product are obtained. temp. 124-129 ° C.

(s, 3H, 18-CH ₃₎

19 ~ CH ₃ ), 4.54 and

11-H), 6.07 (t, 1H, 1H), 7.72 2H, C2 feniįeno ^X H-NMR (300 MHz ,. CDC1 ₃₎ § ppm: 0.65

0.93 (d, 1H, 16 '-CH ₃ ), 1.40 (s, - 3H,

4.66 (d, d, 2H, 21-CH _2), 5.5 (m, 1H,

1H, 4-H); 6.29 (dd, 1H, 2-H), 7.16 (d (d, 2H, phenylene C3-H, C5-H), 7.83 (d,

H, C6.-H).

7 </. Α. 17 y 'Ά / Ά' · /.

; 16g-methyl-21- (4-nitro-benzenesulfonyloxy) -pregna-γ-?

Preparation of 1,4,9 (11) -tfi.en-3,20-dione

10.0 g (29.4 mmol). 7 7 21 -hydroxy-16 °: -methylpregria, 1,9,9 (11) -trien-3,20-dione. dissolve / y in 100 mL, tetrahydrofuran, v; added. 7.14 ml (/ /(5174.7/mmol) / / triethylamine. and 13.4 g of 7 (51.4 mmol) / 4-nitrobenzenesulphonyl chloride / chloride is added to this solution at 0 [deg.] C. After this time, the reaction mixture is stirred at room temperature for 7 minutes. / <'temperature setting / -2 7 hours A The precipitate is filtered off, dried and recrystallized from ether. 13.5 g (87, 66%) of product are obtained. Lyd A temp. 151-160 ° C.

/ AA. // j 7. ., / 7/7 / A 7 yf. y - A ..jA ... · 7 ¹ H-NMR (300 / ^ ^Μ0ζ; Α; € .ροΐ3) δ ppm: 0.67 (s, 3H, 18 yCH3 ⁵⁾

0.94 (d, 1 H, 16 <X-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, 2H), 7.17 (d, 1H, 1-H), 8.17 (d, 2H, phenylene C2-H, C6-H). , 8.42 (d, 2B, phenylene C3H, C5-H).

3 · example /'..·; /./ ·, /. ·, «'A // ·, A A' · '. 7 '' ¹ '' A / 7 ;. . . '. . -, '. y. . , - · - yy '· y; . ·, Y, -, .. /

Preparation of 4,6-Dichloro-2- (1,1-dimethylethylamino) pyrimidine and 2,6-Dichloro-4- (1,1-dimethylethylamino) pyrimidine

To a solution of 31.52 ml (300 mmol; 1-amino-1,1ul dimethyl ethane) in 200 ml of tetrahydrofuran was added 25 g (136.3 mmol) of 2,4,6-trichloropyrimidine at 10-15 ° C. The reaction mixture is stirred for another 5 hours at room temperature and then evaporated. The residue is shaken with a mixture of 500 ml of chloroform and 50 ml of a 10% sodium hydroxide solution. The organic layer is separated, washed 4 times with water. / 150 ^; / / ml ·) / ^,; // dried / evaporated solvent. The residue was poured onto a silica gel column and eluted with various mixtures of hexane and ethyl acetate.

A Using 9: 1 mixture as eluent, yields 4,618, -, - dichloro-2- (1,1-dimethylethylamino) pyrimidine which is recrystallized from / hexane. Yield: 11.35 g (37.84%); melt therapist. 70-74 ° C. 777 ¹ H-NMR (60MHz, THF-d ₈ ) _δ md: .6, 63 (s, 1H / 5-H).

Further elution with a 4: 1 mixture of hexane and ethyl acetate yields 74 more 4 polar; 2,6-Dichloro-4- (1,1-methyl-dimethylethylmibo) -] - (2-methyl) -ethyl acetate gives 713, 314 g4 (44.35%) of the title product.

Lyd. therapist. ^; 192-195 ° C ../ 7

K / H-BME (60 MHz, 7 THF-d _e )? 7m.d.,? 6, 32 (s, 7H, 7'5-H) .. / 7 (Example 7.15 4 4

72 ^{,, 6-bis;} (14l ^: -dlmethyllethylamiho ^, ) 7-4-Chlpripylidine

5.0 g of 4,6-dichloro-2- (1,1-dimethylamine) pyrimidine ti rpa. 204 4 las 25 mi -yl-amine '/ l-dimethylamine / heated ^ sealed ,. 4 in a 7-tube at 7/7130 ° C for 15 hours. Thereafter, the reaction mixture is evaporated and the residue is shaken with 15 ml of 10% sodium hydroxide solution. The organic layer is separated, washed with 7 4, .25 / times water (20 / ml each); 77dpi07a.7.1r:/hugar./ 7.77ίίΐέΧ3η3; Yield: 5, -45 g (93, 4%) of product. Lyd. mp.128-130 ° C. -7 '-. 1 H-NMR (60 MHz, 4THF-d ₈ ) F 75 ~ Hp. / 7

30 / 7- - / 7 ^{: <} '' 4 <774 774 '4' .4 Example 5 '. ^: 2r 4-Bis (1,1'-dimethylethylamino) -6- (7'-piperazinyl) pyrimido. _ Receiving 7 Din. 7 ·. .

- ³⁵

Mixture containing. 10.0 g (38.9 ramol) of 4-chloro-2,6bis- (1,1-dimethylethylamino) pyrimidine, 13, 42, g (--55.8 / -.2 / .. 77-71-9 : - /. 7 - / ---.-.-7..

/ miriol) piperazine and 150 mL of ^ -ethylmorpholine were refluxed under nitrogen for 25 hours. This is followed by distillation of the solvent and piperazine at atmospheric pressure. - /. / Add water to residue / 7 and distil until the vapor temperature reaches 2100 ° C. Cool and shake the residue with a mixture of 200 ml / chloroform and 30 ml of 10% sodium hydroxide solution. The organic layer was separated, washed 4 times with water (50 ml each), dried and the solvent was evaporated. The residue is purified by chromatography on a silica gel column,. using a mixture of chloroform and methanol (9: 1) as eluent. The isolated product is recrystallized from hexane. Yield: 7.65 g (64%). Lyd. te.mp. 142-145 ° C.

1 H-NMR (60 MHz, CDCl ₃ ) δ, md: 4.99 (s, 1H, 5-H).

example *

Preparation of 21- (4- / 2,4-bis (1,1-dimethylethylamino) -6-pyrimidinyl / 120-piperazinyl} -16g-methylpregna-1 / 4,9 (11) -trien-3,20-dione

To a solution of 2.00 g (3.805 mmol) of 21- (4-nitrobenzenesulfonyloxy) 16a-methylpregna-1,4,9 (11) -trhen-3,20-dione in 100 ml of acetone was added 1.40 g (4.57). mmol) of 2,4-bis (1,1-dimethylethylamino) -6- (1-piperazinyl) pyrimidine and 0.63 g of potassium carbonate and the mixture was refluxed for 8.5 hours. Evaporate and shake the residue with a mixture of 40 ml of chloroform and 10 ml of water. The chloroform layer was dried and evaporated. The residue was purified by column chromatography over silica gel using chloroform / methanol (98: 2) as eluent. Recrystallization gave 1.53 g (64%) of product. Lyd. temp. 145-155 ° C.

/ 3577 '' 777- -: /...--/- 7 /: --- .7, / .. -, 7 - .. 7,. ''^; 7-j ^; '// p: Γρ _; , 772 // '77/7 //

2/7 / 1 H-NMR (250 MHz, CDCl ₃ ) δ md: 0.68 (s, 3H, 18-CH ₃ ),

0.96 (d, 1H, 16-CH ₃₎ .1,39 (s, 18H, 2xNHC (CH _{3) 3),} 1.40

V _'r 20 (s, 3H, I9-CH5 Λ}, 3.13, and 43.23 ⁷ (d, d, 2H, 21 CH _2),' '4, 99 (s, IH, pyrimidine C5-H), 5.51 (m, 1H, 11-H), 6.07 (m, 1H, 4-H), 6.28 (dd, 1H, 2-H), 7.16; (d , Ifl, 1-H), 4 'example

Preparation of 4-chloro-2- (1,1-dimethylethylamino) -6-pyrrolidinedipyrimidine ·

To 40 ml of crolidin at a temperature below 10 ° C, mix 10 g in small portions with stirring and cooling

4,6-Dichloro-2- (1,1-dimethylethylamine) pyrimidine, the reaction mixture was stirred at room temperature for a further 1 hour and evaporated. The residue is shaken with a mixture of 150 ml of chloroform and 30 ml of 10% sodium hydroxide solution, the organic layer is separated, washed 4 times with water (50 ml each), dried and the solvent is evaporated. Recrystallization from ethyl acetate gave 10.76 g (33%) of product. Lyd. temp. 153-157 ° C.

¹ H-NMR (60 MHz, CDCl 3) δ md: 0.67 (s, 1H, 5-H).

example

Preparation of 2- (1,1-dimethylethylamino) -4- (1-piperazinyl) -6-pyrrolidinepyrimidine

The reaction of 4-chloro-2- (1,1-diraethylethylamino) -6-pyrrolidinepyrimidine with piperazine is carried out according to the procedure described in Example 5. Yield 78.1%, m.p. temp. 162-165 ° C.

¹ H-NMR (60 MHz, CDCl 3, δ d, 4.87 (s, 1H, 5-H).

'example,

Preparation of 21- (4- / 2- ( ¹ H -dimethylethylaminol-erpyrrolidinone pyrimidin- ^1- yl) -1-plperazinyl ·} -ISa-methylpregri-1,4,9 (11) / 5 · ΐΓΐβη-3,20-dione

16a-Methyl-21- (4-nitrobenzenesulfonyloxy) -pregna-1,4,9 (11) -trien-3, 10-dione with 2- (1,1-dimethylethylamine) -4- (ϊ-piperazinyl) -6-pyrrolidinepyrimidine- .

din 'is carried out on a blizzard according to the procedure described in Example 6. The title compound is obtained in a yield of 74.7%. Lyd. temp. 145-170 ° C.

¹ H-NMR (250 MHz, CDCl ₃ ) δmd: 0.68 (s, 3H, 18-CH ₃ ),

0, 96 (d, 3H, _3-CH I6a), 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- (m , 1H, 11-H), 6.07 (d, 3H, 4-H), 6.28 (dd, 1H, 2-H), 7.16 (d, 1H, 1-H).

/ ·· / :: / '· 7/7', .. / .- / y ·. 7 ... '7 · - · ^ / y / y

Example 10

Preparation of 2- (1-adamantylamino) -4,6-dichloropyrimidine and 4- (ladamantylamino) -2, G-dichloro-pyrimidine

To a solution of 1-aminoadamantane (70.3 g, 465.6 mmol) in tetrahydrofuran (650 mL) was added 40.6 g (225.6 mmol) of 2,4,6-trichloropyrimidine and the reaction mixture was stirred for 24 hours. The crystalline 1-aminoadamantane hydrochloride is then filtered off, the filtrate is evaporated and the residue is chromatographed on a silica gel column. Elution with hexane / acetone (9: 1) gives 2- (1-adamantylamino) -4,6-dichloropyrimidine which is recrystallized from hexane. Yield 28.74 g (42.5%).

Lyd. temp. 151-155 ° C. '

-35.37 / 7 / '' //7.77·/ -.// 7. ' / 7 7 .2 · / ^

7 H-NMR (60 MHz, CDCl ₃ ) δ mxd; 6.55 (s, 1H, 5-H). 73/7 /./ ..y ....- /. y® / yy / 'yy®. : 3122 - / 33 /

3- Continue / eluting with hexane / acetone (24: 1),

B / is obtained; //. More; polar; 4- (1-adamantylamino) -2,6-dichloropyrimidine, which is recrystallized from hexane.

Yield: 35.56 g (53.8%), m.p. temp. 193-196 ° C.

¹ H-NMR (60 MHz, CDCl ₃ )? Md: 6.33 (s, 1H, 5-H).

example

Preparation of 2,4-bis (1-adamdnt ii amino) - ~ 6-chloropyrimidine

200 ml of n-butanol are dissolved in 26.0 g (87.25 mmol) of 4,6-dichloro-2- (1-adamantylamino) pyrimidine and 39.5 g (261.6 mmol) of 1-aminoadamantane and the reaction mixture is refluxed Refrigerate for 24 hours and evaporate. The residue is suspended in 400 ml of ether and filtered.

• The dried filtered residue is purified by chromatography on a silica gel column. Chloroform is used as eluent. Recrystallization from ether gives the product with a yield of 23, 94 g (66.44%); melt mp 232-236 ° C.

Ni-NMR (60 MHz, CDC1 ₃₎ Sm.d. : 5.64 (s, 1H, 5-H).

Example 12

Preparation of 2,4-bis (1-adamantylamino) -6- (1-piperazinyl) pyrimidine

The reaction of 2,4-bi-s- (1-adamantylamino) -6-chloropyrimidine with piperazine is carried out according to the procedure described in Example 5. The product is obtained in a yield of 83 »36%. temp. 168-175 ° C.

¹ H-NMR (60 MHz, CDCl ₃ )? Ppm: 4.97 (s, 1H, 5-H).

. 21- (4 '- / 2,4-Bis (1-adamantylamino) -: 6-pyrimidinyl 1 / 1- (0-piperazinyl) -16 g-methyl lpr egna, 1,49 (11) -1 r yen-3,2 0 -di thio / {5 (((-. Yield, 0 ((0 (7 To 2 ', 00 g / {3,57 21- (4 = bromobenzenesulfonyloxy)) -16a ~ methylpregna To a solution of -1,4,4,9 (11) -trien-3,20-dione in 100 ml of acetonitrile was added 0.56 g of potassium carbonate and 1.88 g (4.0 µmol 1) 2,4-bi A mixture of {1 -adamantylamino) -6- (1-piperazinyl) pyrimidine and the reaction mixture ((stirred at 6 5 C for 5 hours. After evaporation of the solvent, the residue was shaken with 40 ml of chloroform and 10 ml of water) Chloroform ((single layer / dilute solvent, dried and evaporated. The residue was purified by chromatography on a silica gel column, eluting with a 98: 2 mixture of chloroform / methanol.). Yield: 2.48 g (88.5%) Melting point, 210-220 ° C.

'20 ((- (- / - // - {0 {0 /: / {('..'<'///{('(';.((>' - '/ t ·' ( ./,//. 7 <^ ((- ((. ^ -0 (¾ 0 (0 (((0 / '.''/ (/ (- S ^X H-NMR (250 MHz, CDC1 ₃ Δ S md: 0.68 (s, 3H, 18-CH ₃ ),

0.96 '(d, 1H, 16-CH _3), 1.40 (s, 3H, 19-CH _3), 3.13 and

3.23 (d, d, 2H, 21-CH2 _O ), 4.98 (s, 1H, pyrimidine C5-H), 5.51 (m, 1H, 11-H), 6.07 (m, 1 H, 4-H), (6.28 (dd, 1H, 225 H), 7, -16 (d, 1H, 1-H).

/. {/./ {'/ {(Example 14.

(l-adamachylamiho) -4-chloro-β-pyrrolidinepyrimidine

Preparation 0 / (B C (., 0. {0 / {2 - [(1-adamantylamino) 4,6-dichloropyrimidine) with (pyrrolidine (carried out according to the procedure described in Example 7 /). Yield 86%, m.p.

0 melts temp. 178-189 ° C. -0 ..- (0 '·.-0 - {/ B ./-, {0. ( ^: (- (.. ./(· ^; ( ^; - · 0' / 0 jH-BMr {'60 MHz, CDCl3S / md-; 5-, 62 0 <s (((1H, 5-H)., Example

............ Preparation of 2- (1-adamantylamino) -4- (1-piperazinyl) -6-pyrrolidinepyrimidine '•' 2 '(1-adamantylamino) -4- ^! The reaction of chloro-6-pyrrolidinepyrimidine with piperazine is carried out according to the procedure described in Example 5. Yield 69.7% m.p. temp. 16G-J64 ° C.

¹ H-NMR Χ.60 MHz, CDCl ₃ δ md: 4.87 (s, 1H, 5-H).

example

21- {4- [2- (1-adamantylamino) -6-pyrrolidin-4-pyrimidinyl] -1-piperazinyl} -16a-methylpregna-1,4,9 (11) -trien. 3,20-Dione Obtaining '·' - '..- Z \ S /' i · ¹ '· / ^; ; '. ·;' / · Y- · X / '' ^to H: ./ <ZZ z / '' Z · ': / Z' -. · Z ·. 7- - '' ΖΖ.Ζ ',' ΖΖ ·. . -'Z / 'χ y ^: ·.: · Χ ·; - · - ·

Reaction of 21- (4-bromobenzenesulfonyloxy) -16a-methylpregna-1,4,9 (11) -trien-3,20'-diol with 2- (1-adamantylamino) 4- (1-piperazinyl) -6- pyrrolidine-pyrimidine is performed according to. See Example 6. The product is obtained in a yield of 79.94%, m.p. temp. 155-172 ° C.

¹ H-NMR (60 MHz, CDCl ₃ ) δ md: 0.69 '(s, 3H /' 18 -CH ₃ ), 0.94 (d, 3H, 16a-CH ₃ ), -1.41 (s , 3H, 19-CH _3), 4.89 (s, 1H, pyrimidine C5-H), 5.51 (m, 1H, 11-H), 6.08 (br, 1H, 4H), 6, 28 (dd, 1H, 2-H), 7.21 (d, 1H, 1-H).

'Ζ / χζ-χ ^; · ^Λ x ../ · .j. <Χ Ζγ ./.- χ /, Ζ / Η: xx ;,; -'Z ·. · / '·''\ Χζ ^; '- ·''χΖ''ZŽ'7'®®>-xx,' xZ®7 ';·;.Z''x? X® - .//</-'-'7 xZ7 / ·· '' 7 ·: · \ 'Λ; -. Χ z'7,.;Z' ^: '·· '30 Example 17'

4,6-dichloro-2- (2,2-dimethylethylamino) pyrimidine; and 2,6-Z

- - dichloro-4- (2,2-dimethylethylamino) pyrimidine gaVimap

To a solution of 23.84 g (273.5 mmol) of l-amino-2,2-dimethylpropane in 20 ml of tetrahydrofuran at 10-15 ° C was added 25 g (136.3 -3 mmol) of water with cooling and stirring. 2, 4,6 '25. .:

trichloropyrimidine and reaction mixture? stirred for 30 minutes at room temperature. .. After evaporation of the solvent, the residue <7 is shaken with 300 ml of chloroform 71r 50 ml / 10% sodium hydroxide solution. The organic layer was separated, washed 4 times with water (100 mL each), dried and evaporated. The residue is chromatographed on a silica gel column. // using hexane / ethyl acetate mixtures as eluents. Elution with a 9: 1 mixture gives 4, 6 ~ dichloro-2 ~ (2,2 'dimethylpropylamine) .pi r to r. ^; 7 midin, which is recrystallized from // ether / and. ./hexahyde + mixture to give 13.60 g (42.6%) of the product. Lyd. temp.

. Mp 63-66 ° C.

¹ H-NMR (60 MHz, CDCl ₃ ) δ ppm: 6.60 (s, 1H, 5-H).

Further elution with 6: 1 gives the more polar -2,6-dichloro-4- (2,2-dimethylpropylamino) -pyimidine. Recrystallization from ether / hexane gave 14.24 g (44/6%) of product. Lyd. temp. 77-79 ° C.

¹ H-NMR (60 MHz, CDCl ₃ )? Ppm: 6.33 (s, 1H, 5-H).

/ - · 77 7 /> + '-7+' _ς . '''/ 7, 77/77. ·. /. .7; ·· 7- / 7 / '. ·. ///// '' · '7-7 / -''·' · 'example

Preparation of 4-chloro-2,6-bis (2,2-dimethylpropylamino) pyrimidine To a solution of 5.0 g of 4,6-dichloro-2- (2,2-dimethylpropylan) pyrimidine was added 5 ml of l-amino- in 725 ml of isopropanol. The 2,230 dimethylpropane / and + reaction mixture was refluxed for 20 hours. After evaporation of the solvent, the residue is shaken with 80 ml of a mixture of chloroform and 15 ml of a 10% sodium hydroxide solution, washed four times with water (20 ml each, dried and the solvent is evaporated). product, yield 2/994 g 149, 4%). Accompanied by temps 95- ^; mp 98 ° C. . <.// 'Z.' .. '·'. '777 · / + /' /

//, // 26 / <·.

'7 / 5i-NMR (60MHz, {H, // l.H, 5-H} Example 577

Preparation of 2,4-bis (2,2-dimethylpropylamino) -6- (1-piperazinyl) pyrimidine 7,4-chloro-2,6-bis (2,2 ~ <Hmethylpropyl &lt; 0 &gt;) p! The reaction of piperazine with i: rinii <RTIgt; 7 </RTI> is carried out according to the procedure described in Example 5: Yield 51.1%, mp 138-140 ° C.

¹ H-NMR (60 MHz, CDCl ₃ ) δ md: 4.98 (s ^,; 71H, 75-H) </ 7

Example 20

21- (4- / 2,4-bis (2,2-dimethylpropylamino) -6-pyrimidinyl)

1-piperazinyl} ^: -I'6a-methylpregna-: In) 54, / 9 / (II): - trlen-3,) 20-:: Preparation of Dione '/ - /// c / 7/5 / 77, - ///. to / 7J. /; -7- / 77 /// 7: 5/7 -.///// 7-5: 7 /../ '/ -, /// 5./7. // - /

Reaction of 7a, 6a-methyl-21- (4-nitrobenzenesulfonylphenoxy) -pregha-1,4,9,9 (11) -tris-ene-3,20-dione with 2,4-bis (1,1-dimethylpropylamino) -6- (1 -piperazinyl) pyrimidine is carried out according to the procedure described in Example 6 for the preparation ^{of the} product (yield: 68.95%). Lyd. temp. 1405 // 1500C.,)) 5/55777 / 5-7 5777577/7 // 57/5) - /// - /: //)) //./.7) -, 7. '·. - /: 5 7

7 / // Α ^, - ΒΜΙί / ίβύχΜΗζ) ^ / {s,) 3H; _C 19 -CH ₃ ) > 4.96 (s, 1H, pyrimidiho C 5 -H), δ 5.51 ^; ) 5 (m> /) pg / '/ II-m ^; r / ^ / 10/7 / 1plr 1H, 4-H), / 7: 6 ⁷ 28 (dd, / 1H, 7 2 -H),

7 (:) /) / 7, '77, 20 (d, 1H, .1-H). 773 ^ / 5

7) 5 '</.521 /example.-.//Z))

- [4-Chloro-2- (2,2- ^to- dimethyl) -propylamino] -:

5 / mldin receipt.) -) .7

R 27

The reaction of 4,6 ^ dichloro-2- (2,2-dimethylpropylamino) pyrimidine with pyrrolidine is carried out according to the procedure described in Example 7. Product obtained, -. whose yield is

R 96.7%: m.p. 147-150 ⁰ C.

5. '. '- - \; RR ·' · 'R-' '-R' · A- A.r9A ^

R60 ffiz, CDC1 ₃₎ 5 ppm: 5.67 (s, 1H, 5-H).

- ', ν;., v;'. 2.2 - '' example · .. · '

Preparation of 2- (2,2-dimethylpropylamino) -4- (1-piperazinyl) -6-pyrrolidinepyrimidine The reaction of (2, 2-dimethylpropylamino) -4-chloro-6-pyrrolidinepyrimidine with piperazine is carried out according to? See Example 5. Yield 76%. Lyd. temp. 118-120 ° C.

R '·'. ·>. ·· ',' ··· · · R .. '· RR' ^X H-NMR (60RMHz, CDC1 ₃₎ 6 ppm ': 4.83 (s, 1H, 5-H).

R ... ·. R- * · '·, C ·' · '> ·' R R '' 'R-R · ...

Example 23

'..R ··. · * ·' ', R', '· R' - '; '<R;' R y ·,

21- {4- [2- (2,2-Dimethyl-propylamino) -6-pyrimidine-4-pyrimidinyl] -1-piperazinyl} -R-16g-methyl-prehia-1,4,9 (11) -: triene-3,20-dione receipt

Reaction of 16a-methyl-21- (4-bromobenzenesulfonyloxy) -pregna-1,4,9 (11) -trien-3,20-dione with 2- (2,2-dimethylpropylamino) -4- (1-piperazinyl) - 6-pyrrolidine-pyrimidine ./C''C- 'is: available in accordance with the procedure described in Example R13. 30 The product is obtained with a yield of 74.1%. Lyd: temp.

130 ° C.

RRR * H 2 NMR R 60 Wz, CDCl ₃ ) δ md: / 0.68 (s, 3H, 18-CH ₃ ), 0.93 (s, 9Ή, -C (CH ₃ ) ₃ ), 0, 96 ( s 3H, 16ot-CH ₃ ) 1.39 (s, 3.H,

RR 19 -CH ₃ ), 4.85 (s, 1H, pyrimidine-C 5 -H), 5.51 (m, 1H, 11-H) R 6.06 (pi, 1H, 4-H) R 6, 26 (dd, 1H, 2-H) \ 7, 17 (d,

R to H, 1- H).

// + /, '// 2, & 7 /; - + / ++. .; ++. // / - / y ·.

example

4, 6-άίσΜοΓ-2- / ^{(4.4-dimethyl-l-j-5-} penteh Li) amino / PIRIMED? Preparation of .dino and 2,6-dichloro-4 - [(4,4-domethyl-1-penten-5-yl) amine] pyrimidine

To a solution of 6.23 g (55 mmol) of 5-amino-4,4-dimethyl-11-pentenoic acid / 50 ml of tetrahydrofuran at room temperature is added .4.59 g (25 ipmol) of 2,4,6-trichloropyrimidine and 10 After stirring the solvent, the residue is shaken with 60 ml of chloroform / 5 ml of 10% sodium hydroxide solution / The organic layer is separated, washed 4 times with water (10 ml each), dried and the solvent is evaporated. The residue is chromatographed on a silica gel column using hexane / ethyl acetate mixtures as eluent. Elution with a 19: 1 mixture gives 4,6-dichloro-2 - [(4,4-dimethyl-1-penten-5-yl) amino] pyrimidine as an oil in a yield of 2.62 g (40.3%).

1 H-NMR (60 MHz, CDCl ₃ ) δ md: 6.61. (s, 1H, 5-H).

Elution with 9: 1 hexane / ethyl acetate affords the more polar 2,6-dichloro in the form of an oil. 4 - [(4,4-Dimethyl-1-penten-5-yl) amino] pyrimidine, yield 2.99 g (45.9%)

/.+ + ·. ·. . / · .... + / '//.'/ · ../+ ·' / '. // + '+. + / '1 ·' / ·: './ / y' / · '+? 1 H NMR (60 MHz, CDCl ₃ ) δppm: 6.34 (s, 1H, 5-H).

Example 25

4-Chloro-2,6-bis ((4,4-dimethyl-1-penten-5-yl) amipo). - Preparation of pyrimidine

2.5 g (9.61 mmol) of 4,6-dichloro-2- / (44-dimethyl-1-penten5-yl) amino / pyrimidine are dissolved in 25 ml of n-butanol and + 2.29 g are added to this solution. (10.2 mmol) 5-dihydro-4,4LT 3071 B y / y 29/77 / dimethyl-1-peritenene ·. ... Reaction · meal-yvirinig / with '/. Reflux for 10 hours, c · pa.//tube//volatilized //.

/// Remaining shake with '50 ml of chloroform and 5 ml of 10% sodium / / - / alkaline * / thiocarbons. /// The organic / - / layer is separated, /

- washed / 4 / times with water / (10 ml each), dried and / evaporated. The residue is purified by chromatography on a per.

using a hexane / ethyl acetate / acetate (19: 1) mixture as eluent / 7 silica gel column, eluting with 2.25 g (69.5%) of an oil.

/ 10 /. 1 H-NMR (60 MHz, CDCl ₃ )? Md: 5.70 (s, 1H, 5-H).

example

Preparation of 2,4-bis / (4,4-dimethyl-1-penten-5-yl) amino / 6- (1-piperazinyl) pyrimidine. '··' · / ···. · · · '^; _7 7 '' 7 /.././, / .7 '''7/7 · Ύ - / Y''' · -YY · '.. 7 /.-.7/.- / ⁱⁿ /.' . · '// //' ///. / ':

The reaction of 4-chloro-2,6-bis / (4,4-dimethyl-1-penten-5-yl) -amino / pyrimidine with piperazine is carried out according to the procedure described in Example 5. Yield 73.2%. Lyd. temp. 72-84 ° C.

¹ H-NMR (60 MHz, CDCl ₃ )? Md: 4.83 (s, 1H, 5-H).

Example 27

21- {4- / 2,4-Bis (4,4-dimethyl-1-penten-5-yl) amino] -6-pyrimidinylZ-1-piperazinyl) -16a-methylpregna-1,4,9 (II) trien • 3,20-Dione Obtaining · ...........

16a-Methyl-2.1 - ((4-bromobenzenesulfanyloxy) pregna '1,4,9 (11) -trien-3,20-dione Reaction with 2', 4-bisZ (4,4-dimethyl-penten-5- il) Amino-6- (1-piperazinyl) pyrimidine is carried out according to the procedure described in Example 13.

35. product,. whose / yield / is · /4.6%/Melt //temp./ 98-INQp ° C.

¹ H-NMR (300 3 / MHz, .delta. O. 0.69 (s, y 1 · 3H, y 18 -CH ₃ ),

0.96 (d, ^1H,; I6a-CH _3} ^ 33.3123 and y '/ 3 _# E / 3įd / 4r; 32H _r 21-CH _2), 4.92 (s, 1H, pyrimidine C5-H 3, 5.51 (m, 1H, 11-H), 6.07 (m, 1H, 4-H), 6.28 (dd, 1H, 25-H), 7.17 (d, 1H, 1 H) -H).

example

Preparation of 2- (4,4-ethylenedioxy-1-piperidinyl) -4,6-dichloropyrimidine and 4- (4,4-ethylenedioxy-1-piperidinyl) -2,6-dichloropyrimidine

A solution of 25.6 g (136.3 mmol) of 2,4,6-trichloropyrimidine in 200 ml of tetrahydrofuran is added dropwise at 0 ° C.

43.32 g (286 mmol) of 1,4-dioxa-8-aza spiro / 4.5 / decane and the reaction mixture are stirred at room temperature for 1 hour. After evaporation of the solvent, the residue is shaken with a mixture of 30 () ml of chloroform and 100 ml of 10% sodium hydroxide solution. The organic layer was separated, washed 4 times with water (100 mL each) and the solvent evaporated. The residue was chromatographed on a silica gel column using chloroform as eluent. Initially less polar 2- (4,4-ethylenedi [d] xy-l-piperidinyl) -4,6-dichloropyrimidine was leached and recrystallized from ethyl

25th acetate yields 13.98 104-105 ° C. g (35.36%) · product. Lyd. temp. • ¹ H-NMR (60 MHz, CDCl ₃ ) δ m.d.6, 5.0 (s, 1H, 5-H). 30th Further eluting, is obtained polar 4- (4,4-

ethylenedioxy-1-piperidinyl) -2,6-dichloropyrimidine which is recrystallized from ethyl acetate. Yield 20.98 g (53.04%). Mp 133-136 ° C.

rrv.d .: 6, 40 / (s, ΪΗ / 735 ~ H) 3 3

: 31 Example i

/. Preparation of 2,6-bis (4,4-ethylenedioxy-1-piperidinyl) -4-chloropyrimidine '7 /': /, /: 7 ==.: ..-. / - 7 /. ..-, '· -' // - = {'/' / ^; //: 7: 7

2.0 g of 7 / (6, 89 mmol) 2- (4,4-ethylenedioxy-1-piperidinyl):. 23 mmol) 1,4-dioxa-8-aza: spiro / 4,5 / decane and the reaction mixture is refluxed with; : Refrigerated / 4 <. hours. ': After evaporation of the solvent, = 7 //-.:/ · / residue / shake with / 50 ml. Chloroform and 5 ml 10% sodium. =: //. Alkaline solution, a mixture. The organic layer is separated, /, = / washed: 4 / times with water / (10 mL each), dried and:; evaporated =: =. solvent. 'During the fall t alinus' in: hekšan / o, /1.5. .,: 7 / yield: product, yield ^: 2.51 g ^: (91.8%). Lyd. temp. l30-13 ¹⁰ C.

. ¹ H-NMR (60 MHz, CDCl ₃ ) δ md: 5.88 (s / 1H, · 5-H).

20 ///: Example 30 :: /,: ./77: / = 72: //7/=7./=/

2,4-bis ^; Preparation of (4,4-Ethylenedioxy-1-piperidinyl) -6- (1-piperazin-2-one) m.p.

Reaction of 2,6-bis / 4,4-ethylenedioxy-1-piperidinyl) -4-chloropyrimidine with 7 ppm according to the procedure described in Example 5. The product is obtained having the following // // yield // ira ==55>:6%',/dl: temp - 130-14 0 ° G. / = / 7

730 δ H-NMR δ (60 MHz // CDCl ₃ ) δ m; d7: 5.01: / (S, · 1H, 5-H); /// 7, 7 /: Example 31 '7? 7 =: /////: ===: / ==' 7 7 ./ 21- (4- / 2, / 4-bis (4.4 -ethylenedioxy-1-piperidinyl) -6-pyrimidin-35-ylmethyl-7'-16a-methylpregna-1,4,9 (11) -.

/ / /,.: trien-3,20 ~ Dione Preparation 7:, = //

4 / 16d-Methyl-2.1 -. (4-n ± trdberi.solsulfonyloxy) -... <4.

^: 1,: 4, 9 (11> / t-thien-3, 2O-dione y reaction -: 4. With .. 2,4-bis (4,4e tylenedioxy-1-piperidinyl) -6 - (1-piperaziri i1) pyrimidine is carried out according to the procedure described in Example 5.

- product with a yield of 77.5%, m.p. pace 156 · 174 ^Q C.

1 H NMR (60 MHz, CDCl ₃ ) δ md: 0.67 (s, 3H, 18-CH ₃ ), 0.94 (s, 3H, 16a-CH ₃ ), 1 H 38, (s) , 3H, 19-CH _3), 3.99 (s, 8H, 2 x ethylenedioxy) · 5.12 (s, IH, pyrimidine C5-H), 5.5 (m,

1H, 11-, 6.06 (pi, 1H, 14-H), 6.25 (dd, 1H, 2-H), 7.15 (d, 1H, 1-H).

. • ..'-... i ..-. · V, Example 32.

Preparation of 4,6-dichloro-2- (2,2,6,6-tetramethyl-1-piperidinyl) pyrimidine

A mixture of 25 g (136.3 mmol) of 2,4,620 trichloropyrimidine and 46.3 ml (272.6 mmol) of 2,2,6,6-tetramethylpiperidine was refluxed for 50 hours, cooled and suspended in 250 ml of hexane. The insoluble matter is filtered off, the filtrate (mother liquor) is evaporated and the residue is shaken with

300 ml of chloroform and 50 ml of 1% sodium hydroxide solution. The organic layer was separated, washed 4 times with water (100 mL each), dried and the solvent evaporated. The residue is chromatographed on a silica gel column using hexane as the eluent. Recrystallization from hexane gave the product in a yield of 8.04 g (20.47%). Lyd. temp. 89-90 ° C.

1 H-NMR (60 MHz, CDCl ₃ ) δ md: 6.53 (s, 1H, 5-H)

Preparation of 4-chloro-2- (2,2,6,6-tetra-methyl-1-piperidinyl) -6-pyrrolidinepyrimidine

The reaction of 4,6-dichloro-2- (2,2,6,6-tetramethyl-1-piperidinyl) pyridine 'with pyrrolidine is carried out according to the procedure described in Example 7. The product is obtained in a yield of 75.08%. mp 130-135 ° C.

¹ H-NMR (60 MHz, CDCl ₃ ) δ md: 5.76 (s, IK, 5-H).

example. .

Preparation of 2- (2,2,6,6-tetramethyl-1-piperidinyl) -4- (1-piperazinyl) 6- (1-pyrrolidinyl) pyrimidine 15 '

The reaction of 4-chloro-2- (2,2,6,6-tetramethyl-1-piperidinyl) -6- (1-pyrrolidinyl) pyrimidine with piperazine is carried out according to the procedure described in Example 5. Yield 80.2%. Lyd. temp. 13,420 137 ° C.

1 H-NMR (60 MHz, CDCl ₃ ) δ md: 5.01 (s, 1H, 5-H).

example i25 / 7 </ 7/777 // // 77777777 //: 16? -methyl-21-α 4- / 2- (2,2,6,6-tetramethyl-1-piperidinyl) 6-pyrrolidine-4- Preparation of pyrimidinyl / -1-piperazinyl} -pregna-1,4,9 (11) -trien-3,20-dione

Reaction of T6a-methyl-21- (4-bromobenzenesulfonyloxy) pregna-1,4,9 (11) -trien-3,20-dione with 2- (2,2,6,6-tetramethyl-1-piperidinyl) -4 - (Piperazinyl) -6-pyrrolidinepyrimidine is performed according to the procedure described in Example 13. The product is obtained in a yield of 64; 1%. Lyd. temp. 171-181 ° C.

1 H NMR ^; / (60 MHz / ₃ · CDČ1) 5 MD /: 0.67 (s, 3H, 18-CH _3), 0.94 (s, 3Η, 16a ~ CH ₃₎ and 40 (s, / 3H, / 19-CH ₃ )

I 48 / šj'- lSHy 4/3 ® ⁴ · '·' • χ tetrametiipiperidinilo ~ CH.), 5.01 (s, 1Η, pyrimidine C5-H), 5.51 (m, 1H, 11- ri), 3 6, 09 (pi, IH, 4-H), 6, 2Ί (dd, Iti, 2-ΐί), Ί, 2ΰ (ά, UH, 1-Ά) 3y 3 '/ 3 3

- Example 35

6-chloro-2- (1,1-dimethylamino) -4- (2, 2-dimethylpropyl) tert.

of amino) pyrimidine

5.0 g of 4,6-dichloro-2- (1,1-dimethylethylamino) pyrimidine are dissolved in 25 ml of isopropanol, 5 'ml of 1-amino-2,2-dimethylpropane are added and the reaction mixture is refluxed for 20 hours. The reaction mixture is then evaporated and the residue is shaken with 80 ml of a mixture of chloroform and 15 ml of 10% sodium hydroxide solution. 3/3 '/ · j O organic layers: / :, / separable, p1au narna s 3 4 / ka / r t u s. water (20 mL each), dried and the solvent was evaporated. Recrystallization from hexane gave the product in a yield of 4.49 g (73%). Lyd. temp.

109.5-111 ° C.

¹ H-NMR (60 MHz, CDCl ₃ )? Ppm: 5.71 (s, 1H, 5-H).

.example · '' ·

Preparation of 2- (1,1-dimethylethylamino) -4- (2,2-dimethylpropylamino) -6 (1-piperazinyl) pyrimidine

Reaction of 6-chloro-2- (1,1-dimethylethylamino) -4- (2,2-dimethylpropyl30-amino) -pyrimidine with piperazine according to the procedure described in the Example .3 / The product I is obtained with a yield of 86 »0%. Lyd. / temp.//120-12,439.3 3, ¹ H-NMR (60 MHz, 3 CDCl ₃ )? md t '4.96 (s, 1H,? 5-H). 'example

Example 16a-Methyl-21- {4- / 2- (1,1-dimethylethylamino) -4- (2,2-dimethyl-propylamino) -6-pyrimidinyl / -1-piperazinyl} , Preparation of 9 (11) -trien-3,20-dione

Reaction of 16? -Methyl-2? - (4-nitrobenzenesulfonyloxy) pregna-? -1,4,9 (11) -triene-3; 20-dione with 2- (1,1-dimethylethylamino) -4- (2, 2-dimethylpropylamino) -6- (i-.

piperazinyl) pyrimidine is performed according to the procedure described in Example 6. Yield 85.7%. Lyd. temp. 155-160 ° C. . ¹ H-NMR (60 MHz, CDCl ₃ ) δ md: 0.68 (s, 3H, 18-CH ₃ ), 10.96 and 0.98, (s,. S, 12H, 16a-CH ₃ and C (CH ₅ ) ₃ ), 1.39 (s, 9H,

N (CH ₃ ) ₃ ), 1.40 (s, 3H, 19-CH ₃ ), 4.97 (s, 1H, pyrimidino-C 5 -H), 5.52 (m, 1H, 11-H) / . 6.10 (pi, 7H, 74-H), 62. 28/77 (dd, 1H, 2-H),. 7.20 (d, 1H, 1-H). 7 '<6 1/6 / 1 • 20 Example 39 · 7 6 · 6 ./,/.6 61'

21- (4- / 2,4-bis (1-adamantylamino) -6-pyrimidinyl / piperazinyl) -16a-methylpregna-1,4,9 (11) -trien-3,20-dione 6. · _: yielding of methanesulfonate

6: / '/ 1.1 g. (1.4 mmol) 21 - {4- / 2,4-bis (1-adamantylamino) -6-pyrimidinyl] -1-piperazinyl} -16a-methylpregna-1,4,9 (11) -

The 7-6y triene-3,20-dione is suspended in 35 ml of anhydrous ethanol and 135 ml (1.4 mmol) of methanesulfonic acid are added with stirring. When the precipitate dissolves, solution 7 is filtered and evaporated to dryness. The foamy residue is slurried in ether, filtered off and obtained

1.18 g (95.5%) of product. . .

'example

2,4-bis (1-adamantylamiripj-6-.alpha.: Preparation of orpyrimidine and 4,6bis (1-adamantylamino) -2-chloropyrimidine in mmol) 4- (1-adamantylamino) -2,6-? and. 39.5 g (261.6 mmol) in 1200 mL n-butanol for 75 hrs

26.0 g (87.25 dichloropyrimidine aminoadamantane) are dissolved in the reaction mixture. The mixture is boiled under reduced pressure. The residue is suspended in 400 ml of ether and filtered off. Separated by passing through a silica gel column using hexane: ethyl acetate (49: 1) as eluent. 2,4bis (1-adamantylamino) -6-chloropyrimidine is obtained from hexane and has a melting point of 21.67 g and 1 H-NMR. The product itself, as in Example 11, was recrystallized (60.14%)

Further elution of the above solvents with a 6: 1 mixture gives a more 'polar' 4,6-bis (1-adarhantylamino) -2-chloropyrimidine, which is recrystallized from hexane to give 1.88 g (5.22%) ) product. Lyd. temp. 260-266 ° C.

¹ H-NMR (60 MHz, CDCl 3 / δ md: 5.49 (s, 1H, 5-H)

Example 41

Preparation of 4,6-bis (1-adamantylamino) -2- (1-piperazinyl) pyrimidine

4, 6-bis. The reaction of (1-adamantylamino) -2-chloropyrimidine with piperazine is carried out according to the procedure described in Example 4 -

• Methodology 37. The product yields a yield of $ 4.4%. Lyd. mp 210-220 ° C. . *. .

1 H-NMR (60 MHz, CDCl ₃ ), δ md: 4.97 (s, 1Η, 5-Η).

</; '' '..' / · <

example. ?. '7 ···

Preparation of 21- {4- / 4,6-bis (1-adamantylamino) -2-pyrimidinyl] -1-piperazinyl} -16a-methylpregna-1,4,9 (11) -trien-3,20-diorium .7 / 7 ·

The reaction of 21- (4-bromobenzenesulfonyloxy) -16a-methylpregna-1,4,9 (11) -trien-3,20-dione with 4,6-bis (1-adamantylamino) -2- (1-piperazinyl) pyrimidine is carried out according to the procedure described in Example 6. The product is obtained in a yield of 52.9% .Melt. temp. 190-200 ° C.

¹ H-NMR (300 MHz, CDCl ₃ ) δ m. d / 0, 68 (s, · / 3H, 18-CH,), / 0.96 (d, 3H, 16-CH _3), 1.40 (s, 3H, '19-CH ₃₎ 7 1 , 67, / 2.02. and 2.09 (pi, pi, pi, 3OH, adamantyl-CH and -CH ₂ ), 3.07 and 3.19 (d, d, 1H, 1H, 21-CH ₂ ), 4.23 (ppl , 2H, 2 x NH), 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, LH, 1-H). : 7

Example 43,

Preparation of 2- (cyclopentylamino) -4,6-dichloropyrimidine and 4- (cyclopentylamino) -2,6-dichloropyrimidine The reaction of '7.2, · 4,6-trichloropyrimidineb7 with · cyclopentiamine is carried out according to the procedure described in Example 37. ) -4,6-dichloropyrimidine yield 35.2%, m.p. temp. 48-52 ° C.

-H-3MR (δ MHz, CDCl ₃ ) δ md: 6.52 (s, 1H, 5-H).

/ 0 · '·. 38

The yield of the more polar (- (cyclopentylamino) 2,6-dichloropyrimidine) as an oil is 57.2%.

¹ H-NMR (60 MHz, CDCl ₃ ) δ md: 6.30 (s, 1H, 5-H) 7 / - /: /: / 4

- ⁵ 7 - / 4 / '0 / .4 ///: 04 /////./ -.4 // 4 / - 0 // / 4 _; .

. /.-•4/ Example 44.- //: / 4 // 44. ' .y / '/// /. Preparation of 2, 4-bis (ci kopentylamino) -6-chloropyridine

5.0 g of 2- (cyclopentylamino) -4, β-dichloropyrimidine are dissolved in 4-O-0/0. '25 ml of isopropanol are added, 7.5 ml of 4 / / cyclopentylamine are added and the reaction mixture is refluxed for 6.4 hours. The reaction mixture was evaporated and the residue was shaken with 80 tL of chloroform and 15 mL of 10% ^; caustic soda solution. The organic layer was separated, washed with 4 volumes of water (20 mL each), dried and the solvent was evaporated. Recrystallization from hexane gave 5.24 g (86.7%) of product. Lyd. temp. 94-98 ° C.

¹ H-NMR (60 MHz, CDCl 3) δ md: 5.67 (s, 1H, 5-H).

4 '.' 4 ---. 4: 5 'Example: 4j ...

Preparation of 2,4-bis (cyclopentylamino) -6- (1-piperazinyl) pyrimidine / 4 / .//4/// / .--. / -4- / /: .. /:-./ '// //.-.

The reaction of 2, 4-bis (cyclopentylamino) -6-chloropyrimidine with piperazine is carried out4. according to the procedure described in Example 4. The product is obtained with a yield of 81.9%.

30/7 Lyd. temp. 142-148 ° C. '//,. // '4-y. -4 / 7-4 / - - '7.'. / · / Ή-ΒΜΗ (60 MHz, CDC1 ₃₎ 5 ppm: 4.94 (s, IH, 5-H).

35 ^;

3.

Preparation of 21- {4- / 2,4-bis (cyclopentylamino) -6-pyrimidinyl] -1-piperazinyl} -1g-methylpregna ···, 4,9 (11) -trien-3,20-dione 3 ·. ./ '?

... 21- (4-Bromobenzenesulfone 'oxy) -ββ-methylpregna-1,4,9 (11) -trien-3,20-dione reaction with 2,4-bis (cyclopentylammo) -6- ( 1-piperazinyl) pyrimidine is carried out according to the procedure described in Example 6. The product is obtained in a yield of 73.1%. temp. 180-185 ° C.

3-37? 'O3 37yy3'7; 3 · .7: /' ·. 7 '/ 33 ^: y.37. _? 3 / · 3'33-3 3 3 - / '3 y; ,? '3 3 73.-y? / 3/3; 7'773 ¹ H-NMR (300 MHz, CDCl ₃ )? Md: 0.69 33 (s, 3H, 18-CH;),

0.96 (d, 3H, 16-CH _3), 1.40 (s, 3H, 19-CH-J, 3.12 and 3.21 (d, d, 1H, 21-CH ₂₎ 3, 8Q and 4.19 (m, m, 1H, 2 x N, CH <), 4-, 58 and 4.62 (1 pi, 1 pi, 1H, 1H, 2 x NH), / 4.93

315 (s, 1H, pyrimidine C5-H), 5.51 (m, 1H, 11-H), 6.07 (m,

1 H, 4-H), 6.28 (dd, 1H, 2-H), 7.16 (d, 1H, 1-H).

Example 20 Preparation of solution for injection

0.05% by weight of sodium. pyrosulphite is dissolved in 3 ml deoxygenated vanilla and the active substance dissolved in this solution. At the same time, the deoxygenated water for injection is dissolved in 0.1% by weight of sodium chloride to give an isotonic solution of potassium sorbate. . Mix the two solutions by injection. Dilute deionized water to a desired volume of 3 and bacteria and foreign matter is filtered through a membrane filter with an average pore size of 0.2 µm. The solution is filtered and the ampoules are filled under a nitrogen atmosphere.

20; Most suitable / in j e kc i js for compass 1 ·; ml. t ū r y j e is, for example, the following: // '··:.

active substance · _{: 1} · - + ^to . 10 mg sodium redsulfite '. / 5 mg Sodium Chloride ^: '/', //. / '7 mg water for injections up to 1 ml

DEFINITION OF INVENTION

Claims (7)

DEFINITION OF INVENTION 1. New 21-aminosteroids of the formula: iii Ώχ), R 'having a pregnane skeleton in which two of X, Y and Z are nitrogen atoms and the third is a methine group; . R ' ¹ and R ² are, independently of one another, primary 20 T amino group substituted with branched chain C ₄ . _8- alkyl, -alkenyl or -alkynyl groups, or / to gTi '/ i: C ₄ . a? -cycloalkyl group containing 1-3 rings which may contain C ₁ . _3- alkyl group (s); a ^ ba R ¹ and R ² together form a spiro-heterocyclic secondary amino group containing up to 10 carbon atoms and which may be present; _; at least one oxygen atom, as an addition: hehteroat ohms; or One of R ^{1 to} R ² is an unsubstituted, heterocyclic, secondary amino group containing from 4 to 7 carbon atoms, the other being 'above. said primary: an amino group, said spiroheterocyclic. secondary or heterocyclic secondary amino ;, toad, 35 having 4-7 C atoms,. with C 1 -C 6 alkyl; . ^: and · above the amino group,. n is 1 or 2, -. and their addition salts. . 5 - .. 2. A compound selected from the group consisting of: γ 21- {4- / 2,4-Bis (1,1-dimethylethylamino) -6-pyrimidinyl] -1-piperazinyl} -16a-methylpregna-1,4,9 (11) triene-3,20-dione, '. , r 10 21 - {4- / 2-bis' (1,1,1-dimethylethylamino) -6-pyrrolidin-4-pyrimidinyl] -1-piperazinyl} -16a-methylpregna-1,4,9 (11) trien-3, 20-Dion, "?,. ./// 'y 21- {4- / 2,4-Bis (1-adamantylamino) -6-pyridinyl / -115 piperazinyl} -16a-methylpregna-1,4,9 (11) -trien-3,20-dione, / .21 - {4- / 2- (1-adamantylamino) -6-pyrrolidin-4-pyrimidinyl / 1-piperazinyl} -16a-methylpregna-1,4,9 (11) triene-3,20-dione, 20/21- (4- / 2-bis (2,2-dimethylpropylamino) -6-pyrimidinidin-1-yl-piperazinyl) -16a-methylpregna-1,4,9 (11) - trien-3, 20y.y ^; YY dion, 21- (4- / 2- (2,2-Dimethylpropylamino) -6-pyrrolidine-4 -. 25 Pyrimidinyl] -1-piperazinyl} -16a-methylpropane-1,4,9 (11). trien-3, 20-dione, /.}} ?; 2- {4- (2,4-Bis ((4,4-dimethyl-1-penten-5-yl) amino) -6-pyrimidinyl] -1-piperazinyl} -16a-methylpregna-1,4,9 (11) 30 trien 3,20-dione, ·. 21- {4- / 2,4-bis (4,4-ethylenedioxy-l-piperidinyl) .- 6pirimidinil / -l-piperazinyl} _{-16a-methylpregna-Λ} 9 1.4 (11) trien-3,20- dion, 35 / · '· ^; Α // 7’α}. 16α-methyl-21- {4- [2- (2,2,6,6-tetramethyl-1-piperidinyl) 6-pyrrolidine-4-pyrimidine], 4'-yl] -1-piperazinyl} -pregna-1, 4,9 (11) -trien-3,20-dior, as, 16a-methyl-21- {4- [2- (1,1-dimethylethylamino) -4- (2,2-dimethylpropylamino) -6- pyrimidinyl / -1-piperazinyl}. ': pregna1,4,9 (11) -trien-3,20-dione, ⁵ .7' k / Ή '7-. '//// - / .7. : 7 -.// 7 / ///Λ/./-/,Η'/ 21- {4- / 4,6-bis (1-adamantylamino) -2-pyrimidinyl] -1-piperazinyl} -16a-methylpregna-1,1,9,9 (11) -trien-3,20-dione, .7: // 7.f '-'-'. 710 21- {4- / 2,4-Bis (cyclopentylamino) -6-pyrimidinyl-1-piperazinyl} -16α-methyl-pregna-1,4 / 9. (11) -trien-3,20-dione, as well as addition salts of these compounds. // - // 7 // 7 // 3 3 Pharmaceutical composition, characterized in that it contains as active ingredient / 21 aminosteroid containing pregnane skeleton of formula (I) in which X, Y, Z, R ¹ , R ² and n have the meanings described in point 1, or .7j _o /. pharmaceutically acceptable salts, in a therapeutically effective amount. 4. New 21-aminosteroids of formula 30 - //// '7 // containing a pregnane skeleton in which 35 two of 'X, Y, and. Z is a nitrogen atom and the third is a methine group; 7th R ¹ and R are, independently of one another, a primary amino group as substituted with a branched C _{4th 8-} alkyl, -alkenyl or -alkynyl groups, or ZC ₄ . _{A 10-} cycloalkyl group containing from 1 to 3 rings which may contain C 1. _3- alkyl group (s); or. R ¹ and R ² together form a spiro-1 amino group containing up to 10 carbon atoms and which may have at least one oxygen atom as an additional heteroatom; or the other is an amino group above, one of R ¹ and R ² is an unsubstituted heterocyclic secondary amino group having 4 to 7 carbon atoms, and the above primary amino group, said spiroheterocyclic secondary or heterocyclic secondary amino group having 4-7 C atoms, with C ₁ . _4- alkyl (s); Zir ΖΖχ / ΧΖΖΖΖζΖ ^ ΧΖζΖ ·· /Z./ZC ZD'7 '^; ZZZ ' ⁷ Z ^; ZZZ ': - ZΖΖ · -ζΖ - · ν *', Z: ZZ’Z7 / z Z · ^Ύ ’· Χζz’ - ‘Z7- t’ · / .. · n is 1 or 2 and also a process for the preparation of their addition salts, characterized in that they are obtained By salification of 21-hydroxy-16a-methylpregna-1,4,9 (11) -trien-3,20-dione with 4-bromobenzenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride, respectively, followed by yielding; 21-Contains pregnan: derivatives of the formula wherein R is 4-bromobenzenesulfohyl or 4. ··. . · '/ ·'.; ·. / Y t '.'. '. Y y y y. .y nitrobenzenesulfonyl, -group; acted on by piperazinylbis (alkylamino) pyrimidine derivatives having the formula:. <O / z 7 _n 2 (m) wherein X, Y, Z, R ¹ , R ² and n have the meanings given above, '15 and, if necessary, the resulting pregnane derivatives of formula (I) wherein X, Y, Z, R ¹ , R ² and n have the meanings described above, convert them to the free base, and / or (a) convert the free base into the addition salt, if necessary with a suitable acid. Process according to claim 4, characterized in that the reaction of 21-hydroxy-16a-methylpregna-1,4,9 (11) -trien-3,20-dione with 4-bromobenzenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride, respectively 25 performed in an ether-like solvent in the presence of a tertiary amine at room temperature. 6. A process according to claim 4 wherein the 21- (nitrobenzenesulfonyloxy) -16α-methylpregna 30 is 1,4,9 (11) -trien-3,20-di-one. with piperazinylbis (alkylamino) pyrimidine derivatives of the formula. (III) wherein X, Y, Z, R ¹ , -R ² and n have the meanings described in Claim 4 are carried out in a polar solvent such as C ₃ -C ₅ aliphatic ketone, preferably 35 in acetone, or C ₂ ; _4- aliphatic nitrile, preferably acetonitrile: in the presence of a solid phase acid crosslinker. preferably potassium carbonate, 55-7 ° C (temperature range The addition salt of a 21-aminostaroid of the formula (7) having the meanings given in ( _r ), one of a derivative containing pregnan wherein X, Y, Z, R ¹ , R ^2, and either pharmaceutically or skeleton thereof, have 4 suitable use in the inhibition of lipid peroxidation.