DK142790B - Monoalken-1-yl-alkylxanthines for use as intermediates in the production of hydroxyalkyl-alkylxanthines. - Google Patents

Description

142790

Drugs are known which contain, as active substances, dimethylxanthine derivatives having in the 1- or 7-position a (w-1) hydroxyalkyl group. These can be prepared by reducing the corresponding keto compounds, the preparation of which is e.g.

5 occurs over halogen ketones, and as e.g. is reduced by metal hydrides. Halogen ketones and hydrides are in part only slightly resistant, which is especially a disadvantage of larger chargers.

Furthermore, from German Patent No. 1,067,025, a process for the preparation of 1- (β-hydroxypropyl) -3,7-dimethylxanthine (= 1- (β-hydroxypropyl) -theobromine) in which water is added to 1-allyl is known. -3,7-dimethylxanthine using water soaking catalysts such as concentrated sulfuric acid. However, according to this patent, the known reaction is specific for 1-allyl-theobromine, for 7-allyl-theophylline is not already available for this reaction.

It has now been found that these (iu-1) -hydroxyalkylalkyl xanthines can be prepared in almost quantitative yield by the addition of water to alken-1-yl alkylxanthines when the reaction is carried out in the presence of dilute sulfuric acid, cf. example 1 in danish presentation no.140.214. However, to date, the alkene-1-yl alkylxanthines have been novel compounds.

Accordingly, the invention relates to novel monoalken-1-yl-alkylxanthines for use as intermediates in the preparation of corresponding monohydroxyalkyl-alkylxanthines. The monoalken-1-yl alkylxanthines of the invention are peculiar in that they have the general formula (I).

Wherein one of the groups R, R and R is mono-alkene-1-yl.

4 to 8 carbon atoms which are not branched in (tu-1) position and the other two groups are alkyl groups having 1 to 12 to 15 carbon atoms, however, R or R may also be hydrogen.

The monoalken-1-yl alkylxanthines of formula (I) can be prepared by reacting a halogen alkene with a terminal double bond containing no tertiary carbon atom and a halogen atom bonded to a saturated carbon atom with an alkali metal salt of a mono or dialkylxanthin. Preferably, unbranched halogen alkenes are used, the halogen atom and the double bond being spatially far apart.

Suitable intermediates for the preparation of monohydroxy-alkyl-alkylxanthines are e.g. 1- (3'-Buten-1'-yl) -, 1- (4'-penten-1'-yl) -, 1- (S'-hexen-1'-yl) - and 1- (2 ') -methyl-3'-buten-1'-yl) -theobromine, 1- (5'-hexen-1'-yl) -3-methyl-7-ethyl-, -7-propyl, -7-butyl , -7-isobutyl and -7-decyl-xanthine, moreover 7- (2'-methyl-3'-buten-1'-yl) -, 7- (3 * - 20-buten-1'-yl) - , 7- (4'-pentene-1'-yl) -, 7- (5'-hexen-1'-yl) and 7- (6'-hepten-1'-yl) -theophylline and 3-methyl 7- (S'-hexen-1'-yl) -xan thin and its derivatives having in the 1-position propyl, isobutyl, pentyl or hexyl groups.

As intermediates for use in the preparation of monohydroxyalkyl-alkylxanthines, both monalken-1-yl-methylxanthines and their homologues can be used, wherein at least one methyl group is replaced by an alkyl group having 2 to 12 C atoms. Eg. these latter connections may be 1 2

30 are such that at least one of the groups R, R

Or R has at least 5 C atoms.

The reaction between the halogen alkene and the alkaline metal salt of the xanthine compound can be carried out in the usual manner, e.g. using dimethylformamide as aprotic solvent at 120 ° C. The course of the reaction and the time of complete reaction can be very easily followed by thin-layer chromatographic methods. The reaction products can be isolated by evaporation of solvent, e.g. under reduced pressure.

The hydroxyalkylxanthine compounds prepared from the monoalken-1-yl alkylxanthines of the invention are therapeutically useful. Thus, e.g. 1- (5'-hydroxyhexyl) -theobromine itself by promoting blood flow.

The invention is further illustrated in the following examples, wherein the ratios stated are on a volume basis.

Example 1.

1,3-dimethyl-7- (31-butenyl) -xanthine.

13.4 g of 4-bromo-butene (1) are reacted with 20.2 g of theophylline sodium in 200 ml of dimethylformamide at 120 ° C with stirring, until the completion of the reaction can be recognized in thin layer chromatogram after about 6 to 8 hours. Then the solvent is removed under reduced pressure. The residue is dissolved in 100 ml of methylene chloride at 20 ° C, the insoluble sodium bromide is separated and the solution is purified to remove 25 small amounts of dark colored companion on a neutral alumina column. Mp. 110 ° C (acetone). Yield: 21.6 g (91% of theory based on starting material used). By thin layer chromatography on the Merck DC-Fertig plate Kieselgel 60 F2 ^ 4 with benzene / acetone (6: 4) as the 10-30 agent, the product has an Rf value of 0.54 and with nitromethane / benzene / pyridine (20: 10: 3) as a running agent, an R 2 value of 0.65. As an indicator, UV light served, however, whereby the pyridine in the solvent due to its fluorescence quenching properties must be removed at 50 ° C under reduced pressure.

Examples 2-5.

From the corresponding dimethyl compounds, by analogy to the procedure described in Example 1, the following compounds are prepared: 3'-Butenyl) -3,7-dimethyl-xanthine 1- (4'-pentenyl) -3,7-dimethyl-xanthine The physical data for these compounds are given in the following table.

Example 6

1- (31-butenyl) -3-methyl-7-n-propyl-xanthine.

20.8 g of 3-methyl-7-propylxanthine, 13.8 g of anhydrous potassium carbonate and 13.5 g of 4-bromobutene (1) are boiled in 150 ml of dimethylformamide for 8 hours under reflux, then the solvent is removed reduced pressure. The residue is taken up in 150 ml of 1 N sodium hydroxide solution and the basic solution extracted with methylene chloride. The methylene chloride is evaporated and the residue is triturated with 100 ml of diisopropyl ether and unreacted 3-methyl-7-propyl-xanthine is separated. The filtrate is worked up and 15.6 g (70% of theory), calculated on spent 3-methyl-7-propylxanthine, is isolated, with m.p. 48 ° C (from n-hexane).

Examples 7-10.

Analogous to the procedure described in Example 6, the following compounds are prepared from the corresponding dialkylxanthine compounds: 1- (3'-butenyl) -3-methyl-7-hexyl-xanthine 1- (51-hexenyl) -3-methyl 7-Propyl-xanthine 1- (5'-hexenyl) -3-methyl-7-hexyl-xanthine 1- (5'-hexenyl) -3-methyl-7-decyl-xanthine

The physical data for the compounds are given in the following table.

Example 11.

l-Ethyl-3-methyl-7- (5'-hexenyl) -xanthine.

20 g of 3-methyl-7- (5'-hexenyl) xanthine (see Example 22) are added to a solution of ca. 3.3 g of NaOH in 70 ml of a mixture of methanol and water in the 1: 1 mixture ratio and 10 g of ethyl bromide are added. The mixture is kept for 40 hours at 40 ° C under nitrogen. Then, the solvent is removed under reduced pressure, the residue is taken up in diethyl ether and unreacted 3-methyl-7- (5'-hexenyl) xanthine is removed by adding aqueous sodium hydroxide solution to a pH of 13.5.

The 1-ethyl-3-methyl-7- (5'-hexenyl) xanthine isolated from the ether phase is subjected to column chromatography on silica gel with a mixture of methylene chloride and acetone in the 8: 2 mixture as eluent and then the isolated product is subjected to distillation under reduced pressure. pressure to give the product in the form of colorless oil. Yield: 11.2 g (81.3% of theory), based on crude starting product, nD = 1.5415.

Example 12.

l-propyl-3-methyl-7- (31-butenyl) -xanthine.

Analogous to the procedure described in Example 11, the desired compound is prepared from 3-methyl-7- (3'-butenyl) xanthine (see Example 20), with the difference that the reaction temperature is 70 ° C.

Example 13

1-Hexyl-3-methyl-7- (31-butenyl) -xanthine.

The above compound is prepared by analogy to the method described in Example 1.

Example 14.

l-Hexyl-3-methyl-7- (41-pentenyl) -xanthln.

The above compound is prepared by analogy to the procedure described in Example 1.

Example 15

l-decyl-3-methyl-7- (31-butenyl) -xanthine.

The above compound is prepared by analogy with the method described in Example 12.

Example 16.

l-methyl-3-ethyl-7- (51-hexenyl) -xanthine.

The above compound is prepared analogously to the process described in Example 11 from 3-ethyl-7- (5'-hexenyl) xanthine (see Example 24).

Example 17.

1,3- Diethyl-7- (41-pentenyl) xanthine.

The above compound is prepared by analogy to the procedure described in Example 12 from 1,3-diethylxanthine and .5-bromopentene- (1). The yield calculated on the starting material used is given in the following table.

Example 18.

Third-diethyl-7- (51-hexenyl) -xanthine.

The above compound is prepared analogously to the process described in Example 12 from 1,3-diethylxanthine.

The yield calculated on the starting material used is given in the following table.

Example 19.

1,3-Pi-n-butyl-7- (3β-butyl) xanthine.

7 142790

To a solution of 3.4 g of sodium in 200 ml of absolute ethanol is added 38.9 g of 1,3-di-n-butyl-xarthine at 25 ° C. Then 20.5 g of 4-bromobutene (1) are added at 50 ° C. The reaction mixture is stirred for 46 hours under nitrogen at 70 ° C, then cooled to 20 ° C, the precipitated sodium bromide is suctioned off and the filtrate is evaporated under reduced pressure. 1,3-di-n-butyl-xanthine with chloroform and 1N sodium hydroxide solution are removed from the residue. From the chloroform extract, a yellow oily residue is isolated from which, by column chromatography on silica gel with a mixture of methylene chloride and acetone in the 8: 2 mixture as eluent and subsequent distillation under reduced pressure, 29.7 g of product (78.8% of the theoretical), calculated on reacted 1,3-di-n-butyl-xanthine, mp 41-42 ° C.

Example 20.

3-Methyl-7- (31-butenyl) -xanthine.

To a solution of 10/2 g of sodium hydroxide in 400 ml of a mixture of methanol and water in the 1: 1 mixture ratio, 41.5 g of 3-methylxanthine are added with stirring at 70 ° C.

After addition of 35.1 g of 4-brambutene (1), the mixture is stirred under nitrogen for 27 hours at 70 ° C. The reaction mixture is then cooled to 20 ° C and the precipitate is suctioned. By reaction from a basic solution (pH 13.5) and acidification with dilute sulfuric acid to pH 10, after drying 25 29.6 g (89.7% of theory), calculated on reacted 3-methyl xanthine, are obtained. with m.p. 245-246 ° C.

Example 21.

3-Methyl-7- (41-pentenyl) -xanthine.

The above compound is prepared by analogy to the method described in Example 1.

Example 22.

3-Methyl-7- (5'-hexenyl) -xanthine.

Analogous to the process described in Example 20, the above compound is prepared from the corresponding alkylxanthine.

Example 23

3-ethyl-7- (31-butenyl) -xanthine.

The above compound is prepared analogously to the process described in Example 20 from the corresponding alkylxanthine.

Example 24.

3-ethyl-7- (5'-hexenyl) -xanthine.

The above compound is prepared analogously to the process described in Example 20 from the corresponding alkylxanthine.

Example 25

1,7-Dimethyl-3- (51-hexenyl) -xanthine.

The above compound is prepared analogously to the process described in Example 6 from 1,7-dimethylxanthine and 6-bromohexene- (1).

Example 26

1-Hexyl-3-methyl-7- (51-hexenyl) -xanthine.

The above compound is prepared by analogy to the method described in Example 1.

Example 27

1- (51-Hexenyl) -3,7-dimethyl-xanthine.

The above compound is prepared analogously to the procedure described in Example 1.

Example 28.

1- (5-Hexenyl) -3-ethyl-7-methyl-xanthine.

The above compound is prepared by analogy to the method described in Example 12.

9 142790

Example 29.

1- (41-pentenyl) -3-ethyl-7-methylxanthine.

The above compound is prepared by analogy with the method described in Example 12.

5 Table.

Ex. Substituent in m.p. Kp Rf 20 Yield No. Position ° C ° C / mbar ^ 1_3_7___ 1 CH3 CH3 31 -Butenyl 110 1) 0.54 91% 10 2) 0.65 2 CH3 CH3 4'-pentenyl 92 1) 0.66 92% 2) 0.52 3 CH3 CH3 5'-hexenyl 42 1) 0.61 94% 2) 0.67 4 3'-butenyl CH3 CH3 115 1) 0.52 93% 2) 0.50 5 4 1) 0.54 91% 2) 0.46 20 6 3'-Butenyl CH 3 propyl 48 3) 0.77 70% 7 3'-Butenyl CH 3 hexyl 190 / 1.1 3} 0, 68 1.5310 80% 8 5'-hexenyl CH 3 propyl 43 3) 0.67 81% 9 5'-hexenyl CH 3 hexyl 195 / 0.33 3) 0.82 1.5265 75% 10 5'-hexenyl CH 3 decyl 3) 0.87 69% 25 11 CH 3 5'-hexenyl 1.5415 81% 12 propyl CH, 3'-butenyl 55-56 71% 13 hexyl CH 3 3'-butenyl 92+) 1) 0.54 89% 2) 0.58 14 hexyl CH3 4'-pentenyl 98 + 1) 0.54 92% 2) 0.61 15 decyl CH3 3'-butenyl 74 82% 16 CH3 5'-hexenyl 1.5400 89% 17 CJH ,. C2H3 4'-penteryl 1.5384 84% 35 C2H5 C2H5 4 '-hexenyl 1.5345 79% 19 butyl butyl 3'-butenyl 41-42 79% 20H CH, 3'-butenyl 245-246 90%

Claims (6)

142790 ίο Table continued. 21. CH3 4'-pentenyl 202 1) 0.50 87% 2) 0.27 22. CH3 5 '-hexenyl 206 83% 5 23 H C 24. C2H5 5'-hexenyl 130 85% 25 CH, 5'-hexenyl CH, 69- JJ 70 75% 26 hexyl CH 3 5'-hexenyl 193 / 0.4 92% 27 5'-hexenyl CH CH 76- JJ 77 1) 0.47 92% 2) 0.60 28 5'-hexenyl C 2 H 5 CH 3 64 75% 15 29 4 '-pentenyl C 2 CH 3 1,5460 78% +) = melting point of the hydrochloride. Thin layer chromatogram eluent: 1) = benzene / acetone (6: 4). 2) = nitromethane / benzene / pyridine (20: 10: 3). 3) = chloroform / benzene / acetone (1: 1: 1). Claims. Monoalken-1-yl-alkylxanthines for use as intermediates for the preparation of corresponding monohydroxyalkyl-alkyl-xanthines, characterized in that they have the general formula 10 EvV * in i m 0 in R 2 12 3 wherein one of the groups R, R and R is mono-alkene-1-yl having 4 to 8 carbon atoms which are not branched in (αι-1) position,