DD281614A5 - PROCESS FOR THE PREPARATION OF VIRUSATIVE DIAZINE SUBSTITUTED 1-ADAMANTANES - Google Patents

Abstract

The invention relates to a process for the preparation of virostatically active, diazine-substituted 1-adamantanes. The invention can be used in the pharmaceutical industry as well as in human and veterinary medicine. According to the invention, diazine-substituted 1-adamantanes are prepared by electrochemical reaction of a 1-halo adamantane with a pyrazine, pyrimidine or pyridazine. The reaction is carried out in an anhydrous solvent with addition of a conducting salt in a diaphragm-separated electrolysis cell with cathodic reduction. {Virostatic; 1-Adamantane; diazine-substituted 1-adamantanes; electrochemical reaction; 1-haloadamantane; pyrazine; pyrimidine; pyridazine; conductive salt; cathodic reduction}

Description

Field of application of the invention

The invention relates to a process for the preparation of virostatically active, diazine-substituted 1-adamantanes. The invention can be used in the pharmaceutical industry as well as in human and veterinary medicine.

Characteristic of the known state of the art

It is known that 1-substituted adamantanes have various pharmacological activities. Heterocyclic functionalized 1-adamantanes such as 2- (adamant-1-yl) -uracil, -cytosine (J. Med. Chem. 1975, 18, 713) and 4 (6) - (adamant-1-yl) -pyrimidine (J. Chem., Educ.50 (1973) 780) and 5- (adamant-1-yl) -pyrimidine (JP 7104370) show virostatic activity against Newcastle viruses, the latter also being indicated for immunosuppressive and cancerostatic activity against influenza viruses, in contrast to such an effect, is 1-amino- and 1-aminomethyladamantanes and their N-substituted derivatives ("'" Med. Chem. 1411971J 535; ibid. β [1963) 760; Latv. RGR Akad. Vestis 1972 , 32) unknown.

Diazine-substituted 1-adamantanes of the abovementioned structures are prepared predominantly by multistage ring closure reactions from a component containing the 1-adamantyl radical and the corresponding cyclosion synthon (J. Med. Chem. 1311970) 1170; ibid.14 [1971] 408; ibid.15 [1972] 6621; Ger. Offen.2142385 (CI.C 07 d) of 02.03.1972; U.S.A. Appl. 6,66872, Aug. 25, 1972; U. Wiesner, Diss. A TU Aachen 1981), where appropriate, the reaction of trimethylsilyloxylierter intermediates by substitution using 1-chloroadamantane in the presence of Lewis acids leads to the target point (J. Org. Chem.45 (1980) 3559, Chem. Bull. 30 (1982) 2051).

4- (adamant-1-yl) -pyrimidine and 4- (adamant-1-yl) -5-methyl-pyrimidine, of which a pharmacological action is not described, are prepared from 3- (adamant-1-yl) -3 chloroacrylic or methacrylaldehyde and formamidine (Isv. Akad. Nauk SSSR Ser. Chim. 8 [1985] 1858, 2549). Uracil or cytosine adamantylated in the 2-position is prepared from adamant-1-ylformamidine and dimethyl malonate or cyanoacetic ester by ring closure reaction (J. Med. Chem. 18 [1975] 713). Pyrazine-substituted 1-adamantanes are known only in the form of benzo-fused representatives (quinoxalines). 2- (adamant-1-yl) -quinoxaline is prepared from adamant-1-yl-glyoxal and o-diaminoenzenzenes (Bull. Chem. Soc. Japan 116 [1969] 1617) by chemical

Ring-closing synthons, 2- (adamant-1-yl) -3-ethyl- and • 3-bentyl-quinoxaline from corresponding 1,2-dicarbonyl-substituted

1-Adamantanes (Ree, Trav Chim Pays-Bas 104 (1985) 50.) Pharmacological effects of these Chlnoxalinsubstltuierten 1-adamantanes were not reported.

Pyridazole-substituted 1-adamantanes are not known. The known processes are complicated, since they use the AdamanM-yl function on top of multi-stage starting materials

introduce. Direct substitutions with haloadamantane on diavines are not known. They only succeed in the perhydrogenated

Analogs of these heterocycles and invariably lead to N- (adamant-1-yl) derivatives (CA 88 [1978] 136675y). Object of the invention

The object of the invention is to provide novel, virostatically active, diazine-substituted 1-adamantanes, preferably those which are active against influenza virus type A and / or type B.

Explanation of the essence of the invention

The object of the invention is the development of a process for the preparation of novel, virostatically active, diazine-substituted 1-adamantanes, in particular those with an inhibiting action against influenza viruses. According to the invention, diazine-substituted 1-adamantanes of the general formula I,

in the R for an unsubstituted or one or more times in the same possible positions identically or differently by alkyl, alkoxy, aryl, amino, acylamino, hydroxy, adamant-1-yl, halogen or pseudohalogen substituted PyridazlnoderPyrazin "Radical or an alkoxy, aryl, acylamino, halogen, pseudohalogen, 2-amino, 4 (6) -alkyl or 4 (6) - (adamant-1-yl) -substituted pyrimidine radical, prepared by an unsubstituted or mono- or polysubstituted by identical or different alkyl, alkoxy, aryl, amino, acylamino, hydroxy, adamant-1-yl, halogen or pseudohalogen-substituted pyridazine or pyrazine or an alkoxy, aryl, acylamino, halogen, pseudohalogen, 2-aminofo, 4 (6) -alkyl or 4 (6) (adamant-1-yl) -substituted pyrimidine with a 1-haloadamantane mixed and in an anhydrous solvent after addition of a conductive salt under a protective gas atmosphere, preferably under nitrogen, in a known Ele ktrolysezelle with diaphragm on a Metbllkatode is reacted electrochemically. Mercury or lead is suitable as metal electrode, for the diaphragm frit glass or porous material made of ceramics as well as plastics or ion exchange membranes.

After removal of the solvent, extraction of the residue with a solvent in which the conducting salt is insoluble, preferably ether or petroleum ether and evaporation of the solvent to obtain a dlazinsubstituiertes 1-adamantane of the general formula I with the meaning explained for R. The purification is carried out by crystallization or chromatography by known methods.

The reaction is preferably carried out with 1-bromoadamantane (prepared according to H. Stetter, M. Schwarz and H. Hirschborn, Chem. Ber. 93 (1959) 1629. Preferred solvents are dimethylformamide, acetonitrile, propylene carbonate or else methanol, as conducting salt a tetraalkylammonium salt, for example, tetraethyl, tetrabutylammonium iodide, bromide, perchlorate or tetrafluoroborate.

As diazines, for example, pyridazine or 3,6-dichloropyridazine, pyrazine, 2-Me'.hyl-pyrazine, 2- (adamant-1-y!) - pyrazine, 4 (6) -methyl-pyrimidine, 2-amino -pyrimidine or 4 (6) - (adamantan-1-yl) -pyrimidine used. In the electrochemical synthesis of the invention, the substitution by the adamant-1-yl radical is carried out in the pyridazines in 4 (5) -, bfci the pyrimidines in 4- and / or 6 and in the pyrazines in 2 (3,5,6 ) - or 2- and 6-position. The diazines used may be identical or different in possible positions by alkyl, alkoxy, aryl, amino, acylamino, hydroxy, adamam-1-yl or by one or more elec- tructively removable groups such as halogen and / or Be substituted pseudohalogen. For example, by electrochemical reaction of 1-bromoadamantane with pyridazine or 3,6-dichloropyricazole, 4- (adamant-1-yl) -pyridazine, with 4-methylpyrimidine 6- (adamant-1-ylM-methylpyrinidine, with 2-aminopyrimidine 4- (adamant-1-yl) -2-amino-pyrlmidine, with pyrazine 2- (adamant-1-yl) -pyrazine, with 2-methylpyrazine 6- (adamant-1-yl) -2-methyl-pyrazine and with pyrimidine 2- (adamant-1-yl) -pyrimidine and the already known, previously prepared by other method 4- (adamant-1-yl) -pyrimidine synthesized.

When using adamantylated diazines, for example 4- {adamant-1-yl) -pyrimidine, it is possible to introduce a second adamantyl radical into the heterocyclic by the process according to the invention. But diadamantylated diazines such as 4,6-di (adamant-1-y-pyrimidine, 2,6-di (adamant-1-yl-y-pyrazine or 2,5-di (adamant-1-yd-pyrazine) can also be used directly from the relevant, previously non-adamantylated diazine by reaction with a 1-halo-adamantane in only one reaction step.

In contrast to the known processes for the preparation of diazine-substituted 1-adamantanes, in which the carbotricycle can not be functionalized directly with these substituents, the process according to the invention allows for the first time the direct introduction of pyridazin-4-yl, 2-amino or 4- Methylpyrimide-4 (6) -yl, pyrazine-2 (3,5,6) -yl-radicals as well as already adamantylated diazine residues in the adamantane molecule.

The compounds prepared are hitherto unknown and have virostatic activity. In particular, the 2- (adamant-1-yD-pyrazine, 6- (adamanM-yl) -2) methylpyrazine, e-tAdamanM-ylM-methyl-pyrimidine ^ -t-adamant-i-yD ^ -aminopyrimidine and also inhibit the known 4- (adamanM-yl) -pyrimidine in influenza viruses of the various subtypes of type A, and some of these substances also inhibit type B influenza viruses, with an average inhibition of virus proliferation ranging from 90% to 70% . ' (Virus yield test: test system, allantoie on shell').

§ The diazine-substituted 1-adamantanes according to the invention differ from the previously known ones

Influenza virus effective 1-amino, 1-Aminosub8tituierten- and 1-Aminomethylenadamantanen by theirs of these

jjt '· deviating, heteroaromatic substitution and by an unpredictable inhibitory effect on the

human pathogenic influenza viruses of type A and / or B. In contrast, so far in the known in the introduction mentioned

If. Heteroaromatically substituted 1-adamantanes only an antiviral activity against the non-human pathogenic New »I. castle disease virus (NDV) with high cytotoxicity.

Particularly noteworthy is the property of the compounds of the invention that an inhibitory effect against type B influenza viruses can be detected. Chemical compounds that appear to be suitable for the systematic treatment of infectious diseases caused by this type of virus have so far been completely unknown. Also rimantadine is not specifically active against influenza virus type B, its known antiviral activity against type A influenza virus is exceeded by the substances of the invention in some subtypes, in many cases it is of comparable magnitude. The new active compounds can be converted in a known manner into the customary formulations, such as tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic pharmaceutically suitable excipients or solvents. Here, the pharmaceutically active compound should be present in each case in a concentration of about 0.5 to 80 wt .-% of the total mixture, d. H. in amounts sufficient to achieve the stated dosage margin

 The invention will be explained below on AusfOhrungsbeispielen, the inhibitory effects in Table 1.

AusfOhrungsbelsplele

example 1

4,6-D! (Adam8nt-1-yl) -pyrimidine.

0.5 g of pyrimidine (0.006 mol) is dissolved in an electrolytic cell with a double G 5 frit diaphragm in 200 ml of water-free DMF / 0.1 M tetrabutylammonium chloride with the addition of 1.7 g of 1-bromadamantane (0.008 mol) at E = -2.0V (vs. Ag / 01 M Ag I) between 300 and 20 mA on a 25 cm ² Hg cathode while passing dry N ₂ electrolyzed as a protective gas. Thereafter, the flow of current is interrupted and passed about 60min of dry air through the electrolysate. After addition of a further 1.7 g of 1-bromadamantane, the potential is adjusted to E = -2.20 V and further electrolyzed until the initial current intensity has fallen from 250 mA to 10 mA (n = 10.6). After completion of the reaction is separated from the Hg and the DMF solution with about the same volume of water and cooled for some time. The precipitating crystalline product mixture (0.93 g) is filtered off, washed with a little ice-cold alcohol and dried. Filtrate and washing liquid are combined and the solvent mixture I. Vak. evaporated. The residue is extracted with ether, the combined ether extracts washed with water, upper Na) dried SO ₄ and the solvent evaporated. The separation of the crude product (1.21 g), carried out on preparation silica gel layers with benzene: ethyl acetate = 10: 1, u. 0.57 g (27% of theory based on the amount of pyimidine used) of colorless 4,6-di (adamant-1-yl) -pyrimidine having a melting point of 316-318 ⁰ C.

C ₂₄ H ₃₂ N ₁ (348.58) Ben: C 82.69 H 9.27 N 8.04

Gef .: C82.53 H 9.11 N 8.20

Example 2

6- {Adamant-1-yl) -4-methyl-pyrimidine

1g (0.011 mol) of 4-methylpyrimidine is prepared analogously to Example 1 in the presence of 3g (0.014 mol) 1-bromadamantane elE = -2.05V (vs. Ag / 0.1M AgBF ₄ reference electrode) in dry acetonitrile / 0.1M tetrabutylammonium Tetrafluoroborate between 30OmA at the beginning and 35mA electrolyzed at the end of the reaction at a Pb cathode (n = 5.6). Thereafter, the acetonitrile i is removed. Vak., The residue extracted several times with ether, washed, dried and evaporated the ethereal phase. The cleaning de *

obtained crude product (1.55g) is carried out by preparative layer chromatography on silica gel with benzene:

Ethyl acetate = 1: 1 and gives 1.25 g (50% of theory) of 6- (adamant-1-yl) -4-methyl-pyrimidine as colorless crystals with

Mp = 74-75 ⁰ C.

C ₁₆ H ₁₀ N, (228.37) Ben: C 78.88 H 8.85 N 12.27

Gef .: C79.03 · H8.70 N 12.10

Example 3

4- (Adamant-1-yl) -2-amino-pyrimidine

From 1.6 g of crude product obtained after the electrolysis of 1 g (0.011 mol) of 2-aminopyrimidine and 3 g (0.014 mol) of 1-bromadamantane at a reduction potential of F. = -2.05V (vs. Ag / 0.1M AgBF ₄ reference electrode) in anhydrous DMF / 0.1 M tetraethylammonium tetrafluoroborate and working up as in Example 2, is isolated by chromatographic separation on preparative silica gel layers (eluent system benzene: acetic acid = 1: 1) 1.27 g (53% of theory) and subsequent Recrystallization from aqueous methanol gave pure 4- (adamant-1-yl) -2-amino-pyrimidine as colorless crystals of melting point 163-164 ⁰ C.

C ₁₄ H ₁₁ N ₃ (229.36) Calc .: C 73.31 H 8.37 N 18.32

Gef .: C73.20 H 8,31 N 18.60

'- -. :, .-- "- Λ j" "" '

Example 4

2- (Adamant-1-yl) -pyrazln

1 g of pyrazine (0.012 mol) is in an unburnt clay material with two divided electrolysis cell in abs. Acetonitrile / ges. Tetraethylammoniumbromld with the addition of 3g 1-Bromadamantan according to Example 1 potenbostatisch at E = -1.80V (v *. Ag / 0.1 M AgBr reference electrode) reduced. After the initial current strength has dropped from 300 mA to 200 m A (n - 2), the electrolysis is stopped, separated from the Hg, since "CH ₃ CN i. Vak. evaporated, the residue extracted with ether, washed with water, dried and the solvent removed. The resulting crude product (2.8 g) is purified by preparative silica gel chromatography in an eluent system benzotheneic acid ethyl ester = 10: 1 and yields 2.21 g (86% of theory) of colorless crystalline 2- (adamant-1-yl) pyrazine of melting point 61 -62 ⁹ C.

C _{) 4} H, «N ₂ (214.34) Bar .: C 78.45 H 8.48 N 13.07

Found: C 78.29 H 8.60 N 12.89

Example S

2,6-di (adamant-1-yl) pyrazine and 2,5-di (adamant-1-yl) pyrazine

The analogous to Example 4 electrosynthesis of 1 g of pyrazine (0.012 mol) and 6g of 1-bromadamantane (0.028mol) at E = -1.85V, the

however, after an Arif current value of 30OmA is terminated at a final value of 20 mA (n '2.8), it gives It after corresponding workup. Example 3 (2.44 g of crude electrolysate) and chromatographic purification (preparative

Silica gel layer, benzene: ethyl acetate 10: 1) 0.43 g (21% of theory) of 2,6-di (adamant-1-yl) -pyrazine and 0.25 g (12% of theory)

2,5-DI (adamant-1-yl) -pyrazine in each case as colorless crystals of mp = 218-220 ⁹ C and mp = 259-260 ⁹ C.

C ₂₄ H ₁₂ N ₂ (348.58) boron .: C 82.69 H 9.27 N 8.04

(2,6-di) Fe .: C 82.45 H 9.30 N 8.20

C ₂₄ H ₃₂ N ₂ (348.58) boron .: C82,69 H 9.27 N "\ 04

(2,5-di) dish: C 82.50 H 9,35 N «, 22

Example β

6- (AdamanM-yl) -2-methyl-pyrazine, 5- (adamant-1-yl) -2-methyl-pyrazine, and 3- (adamant-1-yl) -2-methyl-pyrazine 1 g of 2-methyl-pyrazine (0.011 mol) is converted analogously to Example 1 in the presence of 3 g of 1-bromoadamantane elec- tructively at a constant potential of E = -1.85 V (vs. Ag / 0.1 M Agl reference electrode) (n = 4.6). The resulting after working up resinous product mixture (2.96 g) is taken up in a little hot methanol / chloroform and cooled. The precipitating colorless crystals of 6- (adamant-1-yl) -2-methyl-pyrazine are filtered off and recrystallized from methanol. From the methanolic mother liquor, further 6- (adamant-1-yl) -2-methylpyrazine is obtained by column chromatography (silica gel; benzene: cyclohexane 3: 1). From the residue of the evaporated MeOH / CHCl 3 solution is then again 6- (adamant-1-yl) -2-methyl-pyrazine as a colorless solid with mp = 55-56 ⁹ C and a total yield of 30% d. Th. (0.75 g) by chromatography on preparative silica gel layers (benzene: ethyl acetate = 6: 1). Chromatography involves 5- (adamant-1-yl) -2-methylpyrazine (22% of theory) and 3- (adamant-1-yl) -2-methylpyrazine (11% of theory). ) as a mixture whose composition can be determined by NMR analysis.

C ₁₅ H ₂₀ N ₂ (228.37) Boron: C 78.88 H ₈ .85 N 12.27

Found: C 78.60 H 9.08 N 12.28

Example 7

4- (adamant-1-y-pyridazine)

From 1.41 g of crude electrolysate, which after the electrochemical reduction of 1 g of 3,6-dichloropyridazine (0.007 mol) with the addition of

3g 1 -Bromadamantan at a potential of E = -1.85 V (vs. Ag / 0.1 M Agl reference electrode) and work up accordingly

Example 1 is obtained, obtained after separation of the product mixture by means of preparative silica gel layers Benzene: ethyl acetate: methanol = 15: 3: 2 0.39 g (15% of theory) of 4- (adamant-1-yl) -pyridazine as colorless crystals with a Melting point of 88-90 ⁹ C.

C, ₄ H "N ₂ (214.34) Calc .: C 78.45 H 8.48 Antiviral active substance N 13.07 ID ", * ¹ titres Found .: C 78.70 H 8,52 effect Konzentra N 12,89 With diffe Table 1 virus yield test; Test system "Allantois on Shell (AOS)" against tion more Conference adamantane virus strain (Molarity) material tyliertes (Ig 10) (Ig 10) diazine 5.17 1.33 SubtypH2N2 10 "* M Virusertragshemmtest 4.67 1.33 A / Singapore 10 "* M ID «, · ¹ 5.33 1.5 1/57 ΙΟ "* Μ without 4.83 1.34 4- (adamant- ΙΟ "* Μ more 5.17 1.17 1-VI) - SubtypH3N2 10- * M material 5.17 0.66 pyrimidine A / Philippines 2/82 10- * M (Ig 10) C) ₄ HuN ₂ 6.5 6.0 6.83 6.17 6.33 5.83

Continuation Table 1

adamantane

tyljertes

diazine

4- (adamant-

aminopyrimldin

Antiviral effect, against virus strain

Influenza virus type A subtype H1N1 A / Brasil 11/78

H2N2

A / Singaporo

1/67

Active substance · concentration (molarity)

Virus yield inhibition test ID »· ¹ ID« · ¹

without with

Active ingredient substance

(Ig 10) (Ig 10)

0.5 · 10 "* M 0.5 -10" * M

0.5 x 10 "* M 0.5 x 10" ⁴ M

2.50 3.33

4.0 3.83

Titer difference

(Ig 10)

6- (Adamant Type A: Sub- 10 " ⁴ m 4.83 3.83 1.0 i-yO-4- typH1N1 10 " ⁴ m 5.67 3.33 2.34 methyl- A / Brasil ΙΟ "* Μ 5.67 3.0 2.67 pyrimidln 11/78 CuHmN] SubtypH2N2 10- * M 6.66 5.17 1.49 A / Singapore 10- * M 5.33 3.33 2.00 1/57 10 " ⁴ m 4.33 3.33 1.0 A / Krasnodar 10 " ⁴ m 5.0 2.5 2.5 * 101/59 SubtypH3N2 10 " ⁴ m 6.08 5.0 1.08 A / Philippi ΙΟ "* Μ 6.33 5.67 0.66 nes 2/82 A / Hong Kong 10- * M 4.75 3.83 0.92 1/68 Type B 10- * 6.33 5.67 0.66 B / Singapore ΙΟ "* Μ 6.17 5.67 0.5 222/79

2.8 2.0

1.55 1.67

Type B 0.5-10 " ⁴ sts 3.5 2.5 1.0 B / Singapore 0.5 x 10 " ⁴ sts 4.33 3.5 0.83 222/79 2- (Adamant SubtypH2N2 10 " ⁴ m 6.66 5.33 1.33 1-yl) · A / Singapore 10 " ⁴ m β, Ο 4.83 1.17 pyrazine 1/57 10 " ⁴ m 6.17 4.67 1.51 C ₁₄ H ₁₁ N, SubtypH3N2 10 " ⁴ m 5.83 5.5 0.33 A / Philippi 10 " ⁴ m 6.33 5.5 0.83 nes 2/82 6- (Adamant influenza 1-yl) -2- virus type A m ethyl · SubtypH1N1 0,5 · 10 "* M 5.30 3.33 1.97 pyrazine A / Brasil 0.5 · ΙΟ '* Μ 5.33 3.67 1.66 C-HMN " 11/78

H2N2 0,5 · 10 "* M 5.55 4.33 1.22 A / Singapore 0.5 · 10 " ⁴ m 5.50 2.5 3.0 1/57 H3N2 0.5-10- ⁴ M 6.33 5.67 0.66 A / Hong Kong 0.5 x 10 " ⁴ sts 5.83 5.5 0.33 1/68 10 " ⁴ m 5.67 5.33 0.34 10 " ⁴ m 5.60 4.83 0.77

Type B 0.5-10 " ⁴ sts 3.5 2.5 1.0 B / Singapore 0,5-10 "* M 4.33 3.67 0.66 222/79 ΙΟ "* Μ 5.17 4.33 0.84 B / Hong Kong 10- * M 5.33 4.0 1:33 5/72

·> ID ₁₀ : Infection dose at which 50% of the substrate is infected: Infection

Antiviral effect of rimantadine (α-methyl-1-adamantanemethylamine hydrochloride) against influenza virus type A and type B test system: allanxole-on-ehell

Antiviral activity against virus strain Active substance concentrate. Mg / ml or (molarity) Virus yield inhibition test ID _n (log 10) without active substance ID ₅₀ (log 10) with active ingredient Titer reduction (log 10) Influenza virus type A subtype HiN1 A / Taiwan 1/86 lOpg / ml (about 0.5 χ 10 " ⁴ ) 5.5 4.83 4.0 3.33 IO IO SubtypH2N2 A / Slngapore 1/57 (about " ⁴ ) 4:67 5:17 3.17 3.33 1.5 1.84 10pg / ml (about 0.5 x 10 ^-4 ) 5.0 6.0 2.5 2.5 IO IO σι σι SubtypH3N2 A / Hong Kong 1/68 20pg / ml (about 10 ^-4 ) 5.67 5.83 2.5 2.5 3.17 3.33 10 pg / ml (about 0.6 X 10 " ⁴ ) 6,83 6,83 5.28 5.36 1.55 1.47 A / Philippines 2/82 20pg / ml (about 10 "*) 6.17 6.67 2.83 3.0 3.34 2.67 Influenza virus type B B / Ann Arbor 1/86 20 pg / ml (etwalO ^'4) 5:17 5.0 5.0 4.83 0.17 0.17 (about 0.5 x 10 " ⁴ ) 6,83 6,83 7:17, 6.83 -0.34 0 (about " ⁴ ) 6.17 6.33 6.17 6.33 0 0

Claims (3)

Ki · - - Claim: fc-- - "'. ·." - ... Verfahren 1. A process for the preparation of virostatic, dlazlnsubstltuierten 1-adamantanes the * general formula I, In the R for an unsubstitulerten or one or more times in the same positions identically or differently by alkyl, alkoxy, aryl, amino, acylamino, hydroxy, adamant-1-yl, halogen or pseudohalogen-substituted pyridazine - or pyrazine radical or an alkoxy, aryl, acylamino, halogen, psoudohalogen, 2-amino, 4 (6) -alkyl or 4 (6) - (adamant-1-yl) -substituted pyrimidine Radical, characterized in that an unsubstituted or monosubstituted or polysubstituted in the same or different positions by alkyl, alkoxy, aryl, amino, acylamino, hydroxy, adamant-1-yl, halogen or Pseudohalogen-substituted pyridazine or pyrazine or an alkoxy, aryl, acylamino, halogeno, pseudohalogeno, 2-amino, 4 (6) -alkyl or 4 (6) - (adamant-1-yl) -substituted Pyrimidine mixed with e'nern 1-Halogenadamantan and electrochemically reacted in an anhydrous solvent after addition of a conducting salt under a protective gas atmosphere we d. 2. The method according to claim 1, characterized in that, for example, pyridazine, 3,6-dichloropyridazine, pyrazine, 2-methyl-pyrazine, 2- (adamant-1-yl) -pyrazine, 4 (6) -methyl-pyrimidine, 2nd Amino-pyrimidine or 4 (6) - (adamant-1-yl) -pyrimidine is used. 3. The method according to claim 1, characterized in that is preferably used as 1-haloadamantane 1-bromadamantane. i. Process according to claims 1 to 3, characterized in that the reaction is preferably in Dimethylformamide, acetonitrile, propylene carbonate or methanol takes place. 5. Process according to claims 1 to 4, characterized in that preferably a conductive salt Tetraalkylammonium salt, for example tetraethyl, tetrabutyl arnnru nium iodide, bromide, perchlorate or tetrafluoroborate is added.