DE3229565A1 - Arsenic-containing nucleosides - Google Patents

Abstract

The invention relates to dialkylarsinothionucleosides of the general formula I <IMAGE> processes for the preparation thereof and pharmaceutical products containing them.

Description

The present invention relates to new dialkylarsinothionucleosides, processes for their preparation and their use as active ingredients in medicaments.

The compounds according to the invention correspond to the general formula I.

(I)

where R [high] 1, R [high] 2 can be the same or different and are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, while R [high] 3 is an adenine or uracil -, guanine, cytosine or hypoxanthine residue.

Particularly preferred compounds of the formula I are those in which R [high] 1, R [high] 2 denote a methyl radical and R [high] 3 denotes an adenine or uracil radical, e.g.

and

Examples of compounds according to the invention are:

5'-S-dimethylarsino-5'-thio-5'-deoxyadenosine,

5'-S-diethylarsino-5'-thio-5'-deoxyadenosine,

5'-S-dipropylarsino-5'-thio-5'-deoxyadenosine,

5'-S-diisopropylarsino-5'-thio-5'-deoxyadenosine,

5'-S-dibutylarsino-5'-thio-5'-deoxyadenosine,

5'-S-dimethylarsino-5'-thio-5'-deoxyuridine,

5'-S-diethylarsino-5'-thio-5'-deoxyuridine,

5'-S-dipropylarsino-5'-thio-5'-deoxyuridine,

5'-S-diisopropylarsino-5'-thio-5'-deoxyuridine,

5'-S-dibutylarsino-5'-thio-5'-deoxyuridine,

5'-S-dimethylarsino-5'-thio-5'-deoxyguanosine,

5'-S-dipropylarsino-5'-thio-5'-deoxyguanosine,

5'-S-di-tert-butylarsino-5'-thio-5'-deoxyguanosine,

5'-S-dimethylarsino-5'-thio-5'-deoxyinosine,

5'-S-diisopropylarsino-5'-thio-5'-deoxyinosine,

5'-S-diisobutylarsino-5'-thio-5'-deoxyinosine,

5'-S-dimethylarsino-5'-thio-5'-deoxycytidine,

5'-S-dipropylarsino-5'-thio-5'-deoxycytidine,

5'-S-dibutylarsino-5'-thio-5'-deoxycytidine.

The compounds of the formula I according to the invention have valuable pharmacological properties.

Treatment with arsenic-containing nucleosides in in vitro tests results in a significant inhibition of the metabolism of deoxyribonucleic acids / ribonucleic acids and thus also of the protein synthesis of malaria pathogens (Plasmodium berghei). Infection can no longer be caused with plasmodia treated in this way. The effect of this group of substances is stronger in this test system than when using commercially available antimalarials from the group of 4-aminoquinolines (chloroquine), and thus also of considerable importance with regard to resistance problems, as they were described in the chemotherapy of malaria with chloroquine.

The arsenic-containing nucleosides according to the invention also bring about comparable results in experimental Trypanosoma infections by killing the parasites in vitro and suppressing the parasitemia in vivo.

These findings therefore appear interesting not only for the treatment of sleeping sickness, but above all for the treatment of the nagana caused by trypanosome infection in horses and cattle.

The invention also relates to processes for their production and pharmaceutical preparations of these compounds and their use as medicaments.

The compounds can be prepared in a manner known per se by adding 5-O-tosyl-2,3-isopropylidene nucleosides of the formula II

(II)

where R [high] 3 has the meaning given in formula I and represents an adenine, uracil, guanine, cytosine or hypoxanthine radical, in acetone under reflux conditions with alkali salts of thioacetic acid to form the acylthio compounds of formula III,

(III)

which are saponified alkaline in aqueous ethanol at room temperature to the 5-mercapto compounds and by reaction with dialkyl halo arsines of the formula IV where R [high] 1, R [high] 2 have the meaning given in formula I, are converted into the dialkylarsinothionucleosides of the formula V,

(V)

which give the compounds of the formula I according to the invention in 80% acetic acid under reflux.

Another process starts from 5-deoxyl-5-halogen-2,3-isopropylidene nucleosides of the formula VI

(VI)

where R [high] 3 has the meaning given in formula I and X is halogen, preferably iodine, which are reacted with thiourea in n-propanol under reflux conditions to give the isothiourea derivatives of the formula VII,

(VII) which, after hydrolysis to the 5-mercapto compounds, lead to the dialkylarsinothionucleosides of the formula V by reaction with dialkyl iodarsines, which give compounds of the formula I on acid hydrolysis.

The 5-O-tosyl compounds used as starting substances are prepared by processes known from the literature, e.g. V.M. Clark, A.R. Todd and J.Zussmann, J.Chem.Soc. 2952 (1951); J.Baddiley and E.A. Jamieson, J. Chem. Soc. 1085 (1955).

A representation for 5-deoxy-5-halogen nucleosides is described by S. Hanessian, M.M.Ponpipom and P.Lavallee, Carbohyd. Res. 1972, 24 (1), 45-56.

The present invention also relates to pharmaceutical preparations which contain compounds of the formula I. The pharmaceutical preparations according to the invention are those for enteral, such as oral or rectal and parenteral administration, which contain the pharmacologically active ingredients alone or together with a customary pharmaceutically usable carrier material. The pharmaceutical preparation of the active ingredient is advantageously in the form of individual doses which are tailored to the desired administration, such as tablets, dragees, capsules, suppositories, granules, solutions or suspensions.

The preparation of the compounds according to the invention is illustrated in more detail by the following examples.

example 1

5'-5-dimethylarsino-5'-thio-2 ', 3'-O-isopropylidene-5'-deoxyuridine.

A mixture of 4 g (9.12 mmol) of potassium thioacetate in 250 ml of acetone is refluxed for 2 hours. The precipitate which had separated out from the cooled solution was filtered off and the filtrate was evaporated in vacuo. The residue, which was uniform according to thin-layer chromatography, was stirred for 1 hour at room temperature with a solution of 1.8 g of potassium hydroxide in 70 ml of water and 35 ml of ethanol. 2.2 g (9.66 mmol) dimethyliodarsine are added dropwise. After 5 minutes, enough acetic acid is added until the mixture is just acidified. The reaction product is extracted with dichloromethane, the organic phase is dried with magnesium sulfate and evaporated in vacuo.

Yield: 3.2 g (87% of theory)

After recrystallization from ethanol: mp 136-137 ° C

Analysis calculated for C [deep] 14H [deep] 21N [deep] 2O [deep] 5SAs:

C 41.59%, H 5.20%, N 6.93%,

found:

C 41.44%, H 5.29%, N 6.93%,

[high] 1H NMR (CDCl [low] 3):

small delta 9.0 (1H, broad s, NH); small delta 7.40 (1H, d, H [deep] 6, J [deep] 6-5 = 8.2 H [deep] z); small delta 5.75 (1H, d, H [low] 5); small delta 5.70 (1H, d, H [deep] 1 ', J [deep] 1' [deep] -2 '= 2H [deep] z); small delta 5.00 (1H, m, H [deep] 2 ', J [deep] 4' [deep] -5 '= 6.4 H [deep] z); small delta 2.98 (2H, d, H [low] 5 '); small delta 1.57 and 1.37 (3H-3H, s-s, isopropylidene methyl protons)

small delta 1.37 [6H, s, As (CH [deep] 3) [deep] 2]

Mass spectrum, molecular weight, calculated 404.038, found 404.037

5'-S-dimethylarsino-5'-thio-5'-deoxyuridine.

2.5 g of 5'-S-dimethylarsino-5'-thio-2 ', 3'-O-isopropylidene-5'-deoxyuridine are refluxed in 70 ml of 80% acetic acid for 30 minutes. After evaporation in vacuo, the residue is dissolved in methanol and reprecipitated with ether.

Yield: 2 g (88% of theory), mp 171 ° C

Analysis calculated for C [deep] 11H [deep] 17N [deep] 2O [deep] 5SAs:

C 36.27%; H 4.70%; N 7.69%;

found:

C 36.15%, H 4.7%; N 7.65%;

[high] 1H NMR (CD [low] 3OD / CDCl [low] 3 50:50):

small delta 7.71 (1H, d, H [deep] 6, J [deep] 6-5 = 8.4 H [deep] z), small delta 5.81 (1H, s, H [deep] 1 ' , enlarged), small delta 5.76 (1H, d, H [deep] 5), small delta ca 4.5 (2H, s, H [deep] 2 ', H [deep] 3', enlarged), small Delta 4.13 (1H, H [deep] 4 ', J [deep] 4' [deep] -5 '= 5.2 H [deep] z), small delta 3.02 (2H, d, H [deep ] 5 '), small delta 1.42 [6H, s, As (CH [deep] 3) [deep] 2]

Mass spectrum, molecular weight: 364

Example 2

5'-S-dimethylarsino-5'-thio-2 ', 3'-O-isopropylidene-5'-deoxyadenosine.

A mixture of 4.6 g (11.1 mmol) 5'O-tosyl-2 ', 3'-O-isopropylidene adenosine and 1.3 g (11.4 mmol) potassium thioacetate in 250 ml acetone is refluxed for 2 hours . The precipitate which had separated out from the cooled solution was filtered off and the filtrate was evaporated in vacuo. The residue, which was uniform according to thin-layer chromatography, was stirred for 1 hour at room temperature with a mixture of 40 ml of 0.5 N KOH and 20 ml of ethanol. 2.6 g (11.4 mmol) dimethyliodarsine are added dropwise. After 5 minutes, enough acetic acid is added until the mixture is just acidified. The reaction product is extracted with dichloromethane, the organic phase is dried with magnesium sulfate and evaporated in vacuo. An oil which is uniform according to thin-layer chromatography remains as the residue.

Yield: 3 g (64% of theory)

Analysis, calculated for C [deep] 15H [deep] 22N [deep] 5O [deep] 3SAs:

C 42.16%, H 5.15%, N 16.34%;

found:

C 42.34%, H 5.24%, N 16.11%, [high] 1H NMR (CDCl [low] 3):

small delta 8.23 (1H, s, H [low] 8); small delta 7.9 (1H, s, H [low] 2); small delta 6.8 (2H, broad s, NH [deep] 2); small delta 6.07 (1H, d, H [deep] 1 ', J [deep] 1' [deep] -1 '= 2.0 H [deep] z), small delta 5.5 (1H, m, H [deep] 2 ', J [deep] 2' [deep] -3 '= 6.4 H [deep] z); small delta 5.07 (1H, m, H [deep] 3 ', J [deep] 3' [deep] 4 '= 2.8 H [deep] z); small delta 4.36 (1H, m, H [deep] 4 ', J [deep] 4' [deep] -5 '= 7.4 H [deep] z); small delta 1.60-1.40 (3H-3H, s-s, isopropylmethyl protons); small delta 1.30 [6H, s, As (CH [deep] 3) [deep] 2]

5'-S-dimethylarsino-5'-thio-5-deoxyadenosine.

2.8 g of 5'-dimethylarsino-5'-thio-2 ', 3'-O-isopropylidene-5'-deoxyadenosine are refluxed in 70 ml of 80% acetic acid for 30 minutes. After evaporation in vacuo, the residue is dissolved in methanol and reprecipitated with ether.

Yield: 1.9 g (75% of theory), melting point 75 ° -76 ° C

Analysis calculated for:

C [deep] 12H [deep] 18N [deep] 50 [deep] 3SAs; C 37.22%, H 4.68%, N 18.08%,

found: C 37.16%, H 4.57%, N 17.98%, [high] 1H NMR (DMSO):

small delta 8.36 (1H, s, H [low] 8); small delta 8.18 (1H, s, H [low] 2); small delta 7.24 (2H, broad s, NH [deep] 2); small delta 5.90 (1H, d, H [deep] 1 ', J [deep] 1' [deep] -2 '= 6.0 H [deep] z); small delta 4.80 (1H, m, H [deep] 2 ', J [deep] 2' [deep] -3 '6 H [deep] z); small delta 4.2 (1H, m, H [deep] 3 '); small delta 3.9 (1H, m, H [deep] 4 '); small delta 3.9 (1H, m, H [deep] 4 '); small delta 2.95 (2H, m, H [deep] 5 '); small delta 1.32 [6H, s, As (CH [deep] 3) [deep] 2]

Analogously to Examples 1 and 2, the following are produced:

5'-S-diethylarsino-5'-thio-5'-deoxyadenosine.

5'-S-dipropylarsino-5'-thio-5'-deoxyadenosine.

5'-S-diisopropylarsino-5'-thio-5'-deoxyadenosine.

5'-S-dibutylarsino-5'-thio-5'-deoxyadenosine.

5'-S-diethylarsino-5'-thio-5'-deoxyuridine.

5'-S-dipropylarsino-5'-thio-5'-deoxyuridine.

5'-S-diisopropylarsino-5'-thio-5'-deoxyuridine.

5'-S-dibutylarsino-5'-thio-5'-deoxyuridine.

5'-S-dimethylarsino-5'-thio-5'-deoxyguanosine.

5'-S-dipropylarsino-5'-thio-5'-deoxyguanosine.

5'-S-di-tert-butylarsino-5'-thio-5'-deoxyguanosine.

5'-S-dimethylarsino-5'-thio-5'-deoxyinosine.

5'-S-diisopropylarsino-5'-thio-5'-deoxyinosine.

5'-S-diisobutylarsino-5'-thio-5'-deoxyinosine.

5'-S-dimethylarsino-5'-thio-5'-deoxycytidine.

5'-S-dipropylarsino-5'-thio-5'-deoxycytidine.

5'-S-dibutylarsino-5'-thio-5'-deoxycytidine.

Claims (7)

1. Dialkylarsinothionucleosides of the general formula I. (I) where R [high] 1, R [high] 2 can be the same or different and independently of one another denote a straight-chain or branched alkyl radical with 1-4 carbon atoms, while R [high] 3 is a correspondingly substituted pyrimidine bonded via the ring nitrogen or purine residue. 2. Dialkylarsinothionucleosides according to claim 1, wherein R [high] 1, R [high] 2 can be identical or different and are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and R [high] 3 stands for an adenine, uracil, guanine, cytosine or hypoxanthine residue. 3. Dialkylarsinothionucleoside according to claim 1, wherein R [high] 1, R [high] 2 denote methyl, and R [high] 3 means. 4. Dialkylarsinothionucleoside according to claim 1, wherein R [high] 1, R [high] 2 denote methyl and R [high] 3 means. 5. Process for the preparation of dialkylarsinothionucleosides according to claims 1-4, characterized in that in a manner known per se, 5-O-tosyl-2,3-isopropylidene nucleosides of the formula II (II) where R [high] 3 has the meaning given in formula I, reacts with alkali salts of thioacetic acid to form the acetylthio compounds of the formula III. (III) which after alkaline saponification to the 5-mercapto compounds by reaction with dialkyl halo arsines Formula IV (IV) where R [high] 1, R [high] 2 have the meaning given in formula I and X is halogen, preferably iodine, into the dialkylarsinothionucleosides of the formula V are converted (V) which give the compounds of the formula I according to the invention in the subsequent acid hydrolysis. 6. Process for the preparation of dialkylarsinothionucleosides according to Claims 1-4, characterized in that 5-deoxyl-5-halogen-2,3-isopropylidene nucleosides of the formula VI are used in a manner known per se (VI) where R [high] 3 has the meaning given in formula I and X is halogen, preferably iodine, with thiourea to form the isothiourea derivatives of formula VII, (VII) which after hydrolysis to the 5-mercapto compounds by reaction with dialkyl halo arsines of the formula IV (IV) where R [high] 1, R [high] 2 have the meaning given in formula I and X is halogen, preferably iodine, are converted into the dialkylarsinothionucleosides of the formula V, which give the compounds of the formula I according to the invention in the subsequent acid hydrolysis. 7. Pharmaceutical preparations, characterized in that they contain a compound of the formula I according to claims 1-5 as an active ingredient in a mixture with customary pharmaceutical auxiliaries and carriers.