DD232492A1 - METHOD FOR PRODUCING NUCLEOSIDE ANALOGUE 6-AMINO SUBSTITUTED THYMINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of 6-substituted thymines. Field of application is the chemical or pharmaceutical industry. The invention aims to develop a technically applicable process for the preparation of the above-mentioned compounds. According to the invention, 6-fluorothymine compounds are reacted with ammonia or primary amines in a molar ratio of 1: 2 to 1: 3, optionally in the corresponding amine itself, if appropriate in an inert solvent.

Description

in which R ¹ and R ^{2 have} the meaning given with ammonia or primary amines of the general formula III

H ₂ NO

in the R is an alkyl radical having a chain length of 1 to 4 carbon atoms, a cycloalkyl radical having predominantly 6 C atoms or an aromatic ring system having 6 C atoms, via an n-alkyl group having 1 to 4 carbon atoms, especially with a CH ₂ group is bonded to the nitrogen atom, in the molar ratio 1: 2 to 1: 3, optionally in the amine itself, if appropriate in the presence of an inert solvent and then isolated after expelling the solvent from the residue.

The invention relates to a process for the preparation of derivatives of thymine of general formula I.

-l / Sn

CH ₃ NH-R ^:

in which R ¹ = an alkyl, O-alkyl ether ^ or cyclic O-alkyl ether radical, or hydrogen

R ² = an alkyl, haloalkyl, O-alkyl ether or cyclic O-alkyl ether radical and

R ³ = an alkyl, cycloalkyl or aryl radical or hydrogen.

The method is applicable in the chemical or pharmaceutical industry, wherein the product produced in medicine can be used as Virostatictim. - ..-- ..

Characteristic of the known technical solutions

Compounds of the formula I are hitherto unknown.

These compounds may be considered analogues of C-6 substituted thymine nucleosides, some of which have biological activity. In contrast to the naturally occurring derivatives of the heterocycle thymine and heretofore modified compounds, the inventively prepared instead of the hydrogen at the C-6 atom have an organic radical.

The introduction of substituents into the C-6 position of pyrimidine nucleosides or their analogs had little practical importance until recently, despite the knowledge that especially at the C-5 atom modified pyrimidine derivatives a variety of biochemical De CERCQ, PFTORRENCE, J. Carbohydr Nucleos Nucleot, 5 (1978) 187-224, S. NAKAMURA, H. KONDO, Heterocycles, 8 (1977) 583-607, A.BLOCH ( Ed.), Ann. NY Acad., 255 (1975); E. DeCLERCQ, Meth. And Find, Ex. Clin. Pharmacol., 2 (5) (1980) 253-267, PJBARR, ASJONES, G .VERHELST, RTWALKER, J.Chem.Soc, Perkin Trans. I, (1981), 1665-1670; J. LKELLEY, L BEAUCHAMP, Ann. Rep. Med. Chem., 18 (1983) 139-148). The cause was the difficulty of the synthesis. A direct condensation of 6-substituted pyrimidines, such as 6-methyluracil (M.PRYSTAS, F. SORM, Collect. Czech Chem., Commun., 34 (1969) 2316; U. NIEDBALLA, H. VORBRUGGGEN, J. Org. Chem , 31 (1974) 3660) or orotic acid (WV CURRAN, RB ANGIER, J. Org. Chem., 31 (1966) 201) with suitable sugar derivatives generally leads to the formation of N-3 compounds, probably because of the directing steric Influences of the substituent on the C-6 atom.

Therefore, special attention has been paid to such methods based on the modification of preformed N-1 structures. Thus, simple alkyl groups can be introduced into the C-6 position of uridine by a Claisen rearrangement of 5-allyloxyuridine to 6-allyl-5-hydroxyuridine (BA OTTER, A. TAUBE, JJFOX, J. Org. Chem , 36 (1971) 1251-1255). Other authors describe addition of the cyanide ion to the C-6 atom of 5-bromouridine protected in the sugar moiety with subsequent debromination to 6-cyanouridine, which permits further modifications (H. INOUE, T. UEDA, Chem. Pharm. Bull., 19 (1971) 1743-1744).

Furthermore, uridine derivatives could be lithiated in a regiospecific manner at the C-6 atom and different 6-aroyl or 6-alkylthiouridines could be obtained from the compounds thus obtained with electrophiles (H.TANAKA, H. HAYAKAWA, T. MIYASAKA, T. UEDA, Chem. Pharm. Bull., 31 (1983) 1222-1227).

Reacts protected 5-bromouridine with 2-lithio-1,3-thian _; For example, the addition product can be modified to 6-formyluridine (A. ROSENTHAL, RH DODD, Carbohyd, Res., 85 (1980) 15-22).

These reaction possibilities are limited to uracil derivatives. It has been found that 6-fluorothymine nucleosides affect influenza virus replication (C. SCHROEDER, Vth International Symposium of Socialist Countries, Riga, Sept. 6-8, 1982; C. SCHROEDER et al., V. International Congress of Virology, Vol. Strasbourg, 1981, Abstr.), Interest in C-6 substituted thymine derivatives has increased both in their DNA synthesis inhibitory properties and in their virostatic effects. On the basis of these findings, the fluorine atom in 6-fluorothymine nucleosides with a pyranoid sugar ring system was replaced by n-alkylamino groups having 1-3 C atoms in the alkyl radical (M. v. JANTALIPINSKI, P. LANGEN, Nucleic Acids Res., Symp. Series, 9 (1981) 41).

On the other hand, methods for the preparation of N-1-alkyl, -alkyl ether or -cycioalkyl ether-thymine derivatives having a substituent other than fluorine on the C-6 atom have hitherto not been described.

Object of the invention

The invention aims to develop a suitable, technically applicable process for the preparation of type I nucleoside analogous 6-substituted thymine derivatives.

Explanation of the essence of the invention

According to the invention, compounds of the general formula I are prepared by adding 6-fluorothymine compounds of the formula II,

 0

^{c H}

R '

in which R ¹ = hydrogen, an n-alkyl, n-alkyl ether, or cycloalkyl ether radical and R ² = an n-alkyl, ri-alkyl halide, alkyl ether or Cycioalkyletherrest means, with ammonia or primary amines of Formula III

in the R is an n-alkyl radical having notably 1 to 4 carbon atoms, a cycloalkyl radical having predominantly 6 carbon atoms, or an aromatic ring system having predominantly 6 carbon atoms, which has an n-alkyl group having 1 to 4 carbon atoms, but especially with a CH ₂ - Group is bound to the nitrogen atom, means in a molar ratio of 1: 2 to 1: 3 in an anhydrous halogenated hydrocarbon, preferably dichloromethane, or in an anhydrous ether or cyclic ether, mainly 1.4 dioxane, is reacted as a solvent. The reaction is generally carried out in - running a manner that the 6-Fluorthymin compound Il added in an anhydrous solvent, preferably in dichloromethane or 1,4-dioxane with the corresponding molar amount of the respective amine of the formula III and with exclusion of moisture, preferably at 100 ° C for 1 to 2 hours. In some cases, the reaction can be carried out in the particular amine of formula III without using the solvents. After cooling to room temperature, the precipitated salts are filtered off and the filtrate is concentrated to dryness. From the residue, the compounds of type I are obtained with methanol crystalline. The compounds according to the invention are virostatically active. The invention will be described in more detail in the following examples.

embodiments example 1

563 mg (1.92 mmol) of 1,3-bis (2-hydroxyethoxymethyl) -6-fluorothymine are admixed with 5 ml of n-propylamine and left at room temperature for 2 hours. The solution is then concentrated to dryness in vacuo. The residue obtained is dissolved several times in ethanol (in total in 60 ml) and the resulting solution is concentrated again. Finally, the residue is taken up in 1,4-dioxane and freed from salts by filtration. The solvent is evaporated in vacuo. This leaves 263 mg (0.79 mmol) of 1,3-bis (2-hydroxyethoxymethyl) -6-propylaminothymine as a colorless oil (yield 41% of theory). M / z 331 (M ⁺ ), 286 (IvI-CH ₂ CH ₂ OH), 184 (C ₈ H ₁₁ N ₃ O ₂ , 6-n-propylaminothymine) C ₁₄ H ₂₅ N ₃ O ₂ (331.36) Ber. C 50.74 H 7.60 N 12.68 Gef. C 50.47 H 7.53 N 12.51.

Example 2

898mg (4.1 mmol) of 1- (2-hydroxyethoxy methyl) -6-fluorthymin are heated in 20 ml of 1,4-dioxane with 1 g (1OmMoI) cyclohexylamine for 2 hours at 100 ⁰ C. After cooling, the insolubles are filtered off and the solution is concentrated to dryness in vacuo. The residue is extracted in portions with a total of 60 ml of chloroform. The combined chloroform extracts, after evaporation of the solvent under reduced pressure, give 469 mg (1.57 mmol) of 1- (2-hydroxyethoxymethyl) -6-cyclohexylaminothymine (yield 38.5% of theory) as a colorless oil.

M / z 297 (M ⁺ ), 236 (M-OCH ₂ CH ₂ OH), 223 (6-cyclohexylaminothymine) C ₁₄ H ₂₃ N ₃ O ₄ (297.34). C 56.54 H 7.79 N 14.13 Gef. C 55.98 H 7.67 N 14.09.

Example 3

590 mg (2.7 mmol) of 1- (2-hydroxyethoxy methyl) -6-fluorthymin be mit3ml Benzylaminfür heated for 1 hour at 100 ⁰ C and, after cooling in vacuum (2mm) concentrated to dryness.

Upon addition of methanol, some of the residue becomes crystalline. The mother liquor provides more crystalline material after standing for several days at room temperature. Total yield 495 mg (1.6 mmol), 59% of theory) F .: 198-199 ° C, uncorr. (Ethyl acetate) M / z 305 (M ⁺ ), 231 (6-benzylaminothymine) C _1s H ₁₉ N ₃ O 4 (305.52) Ber. C 59.0 H 6.27 N 13.76 Gef. C 59.07 H 6.12 N 13.61.

Example 4

300 mg (1.4 mmol) of i-tetrahydrofuryl-6-fluorothymine are dissolved in 5 ml of NH ₃ -saturated dioxane and left at 50 ° C. for 4 h. After evaporation of the solvent, 174mg (0.82 mmol) of 1-tetrahydrofuryl-6-aminothymin obtained from the residue with methanol (y. 58% d. Th.) F .: from 225 ⁰ C decomposition.

M / z 211 (M ⁺ ), 141 (C ₅ H ₇ N ₃ O ₂ , 6-aminothymine), 70 (C ₄ H ₆ O) C ₉ H ₁₃ IM ₃ O ₃ → 11.21). C 51.17 H 6.20 N 19.89 Gef. C 50.98 H 6.13 N 19.37.

Example 5

To dissolve 360 mg (1.36 mmol) 1- (3-bromopropyl) -6-fluorothymine in 10 mL dichloromethane add 300 mg (4.08 mmol) n-butylamine. The solution remains 2 hours at room temperature and is then concentrated. Be from the residue with methanol, 287mg (0.9 mmol) of 1- (3-bromopropyl) -6-butylaminothymin (y. 66% d. Th.) M.p .: 153-154 ⁰ C.

M / z 318 (M ⁺ ), 197 (C ₉ H ₁₅ N ₃ O ₂ , 6-butylaminothymine) C ₁₂ H ₂₀ N ₃ O ₂ BrOI 8.21). C 45.29 H 6.33 N 13.20 Gef.C45,20H6,23N13,11.

Claims (1)

Invention claim: Process for the preparation of nucleoside analogous 6-amino-substituted thymine derivatives of general formula I, NH-R in the R ^{1 is} hydrogen or an alkyl, O-alkyl ether or cyclic O-alkyl ether, R ^{2 is} a hydrocarbon radical having a chain length of 2 to 6 carbon atoms, a Haiogenalkylrest having a chain length of 2 to 6 carbon atoms and a Halogen atom to terminal carbon atom, an O-alkyl ether radical having mainly 3 to 5 carbon atoms or a cyclic
O-alkyl ether radical having preferably 4 to 5 carbon atoms and R ^{3 is} hydrogen, an alkyl radical having a chain length of 1 to 4 C atoms, a cycloalkyl radical having predominantly 6 C atoms or an aromatic ring system having 6 C atoms, which has an Alkyl group having 1 to 4 carbon atoms, but especially with a CH ₂ group is bonded to the nitrogen atom,
means, characterized in that 6-fluorothymines of the general forms! Il