IE42944B1 - 1,3-dialkyl-7-oxoalkylxanthines - Google Patents

Abstract

By reaction of an alkali metal salt of a compound of the formula II in which R is ethyl or n-propyl, with a compound of the formula X-A-CO-CH3 (III> in which X is a radical which can be eliminated with the alkali metal and A is an n-alkylene radical having 1-4 carbon atoms, which can be substituted by methyl and the carbonyl group is optionally intermediately protected or by reaction of a compound of the formula II with a compound of the formula CH2=CY-CO-CH3 (IV> in which Y is hydrogen or methyl, the corresponding xanthene derivatives are obtained which contain an -A-CO-CH3 group in the 7-position. The novel compounds prepared according to the invention have advantageous pharmacological actions and favour the blood circulation through the skeletal musculature, and some show antiarrhythmic activity.

Description

REFERENCE LIBRARY PATENT APPLICATION BY (71) JOHANN A. WULFiNG, A LIMITED PARTNERSHIP ORGANISED UNDER THE LAWS OF GERMANY, OF STRESEMANNALLEE 6, 404 NEUSS, WEST ΠΕΡΜΔΜν Price I2$p The present invention relates to pharmaceutical compositions useful for treating disorders of the cardiovascular system containing xanthine derivatives, to certain novel xanthines and to their preparation.

West German Specification Nos. 1,233,504, 1,235,320, 932,489 and 2,234,202 and Swiss Specification No. 325,292 disclose various xanthine derivatives. However none of the prepared compounds were shown to possess antiarrythmic or blood flow improving properties.

It has now been found, that certain hitherto unprepared xanthine derivatives have the ability to improve the flow of blood through skeletal muscles and some of which also the distinct utility of anti-arrythmio activity.

Accordingly the present invention provides pharmaceutical compositions which comprise a pharmaceutically acceptable carrier and a compound of the formula (I): CHgCHjCI^a^ (I) wherein A is methylene, 1,1-ethylene or 1,2-ethylene and R is an ethyl or n-propyl group.

Most suitably the total number of carbon atoms present in the groups R and A together is greater than 3, for example 4 or 5.

Thus suitable compounds for inclusion in the compositions of this invention includes (a) 1 - n - butyl - 3 - ethyl - 7 - (3 - oxobutyl)xanthine (b) 1 - n - butyl - 3 - ethyl - 7 - (1 - methyl - 2 oxopropyl)xanthine (c) 1 - n - butyl - 3 - n - propyl - 7 - (2 - oxopropyl)xanthine (d) 1 - n - butyl - 3 - π - propyl - 7 - (3 - oxobutyl)xanthine j (e) 1 - n - butyl - 3 - n - propyl - 7 - (1 - methyl - 2 oxopropyl)xanthine.

Compositions containing (a) or (c) are particularly suitable for treating arrythmias while compositions containing (b) are particularly suitable for improving blood flow.

The compositions of the present invention are normally adapted for administration to humans, for example in the form of oral or parenteral compositions.

Typical oral formulations will include tablets, 2o capsules, sachets, granules, powders, suspensions, emulsions and solutions. The formulations may include conventional diluents, binding agents, dispersing agents; surface-active agents, lubricating agents, coating materials, flavouring agents, colouring agents, solvents, thickening agents, - 4 4294 suspending agents, sweeteners or any other pharmaceutically acceptable additives, for example, gelatin, lactose, starch, talc, magnesium stearate, hydrogenated oils, polyglycols and syrups. Where the formulations are e.g. tablets or capsules, they represent pre-measured unit doses but in the case of e.g, granules, powders and suspensions, the formulations may be presented as pre-measured unit doses or in multidose containers from which the appropriate unit dose may be withdrawn.

Injectable compositions may be as solutions, suspensions or emulsions in a pharmaceutically acceptable liquid or as a solid form or concentrate which can be used to quickly prepare an injectable formulation.

The compositions of the invention may be prepared by conventional methods of mixing, blending, tabletting and the like.

The preferred compositions of this invention are orally-administrable compositions especially unit-dose compositions such as tablets and capsules.

Most suitably the compositions of this invention will be administered once or more times a day so that the total daily dose will be in the region of 1 to 1000 mg for a 70 kg adult, for example from 20 to 500 mg. Unit dosage forms according to this invention will frequently contain from 5 to 500 mg, for example from 25 to 250 mg.

The compounds of the formula (I) are novel and as such form an important part of this invention. Preferred novel compounds of the formula (I) are those previously described as being particularly useful for inclusion in the compositions of this invention. - 5 The present invention also provides g process for the preparation of the compounds of the invention which process comprises either (a) the reaction of an alkali metal salt of a compound of the formula (II): (II) wherein R is as defined in relation to formula (I) with a compound of the formula (III): * tf X—A—CO—CH3 (III) wherein A is as defined in relation to formula (I) and X is a chlorine, bromine or iodine atom: or, when A is a —CH2—CH2— group, (b) the reaction of a compound of the formula (II) with a oompound of the formula (IV): CH2= CH —CO—CH3 (IV) in an alkaline medium at an elevated temperature.

The described reactions are preferably carried out at temperatures in the range from 40 to 80°C., optionally under elevated or reduced pressure, but usually at atmospheric pressure. The individual starting compounds may be used either in stoichiometric quantities or in excess.

The alkali salts in reaction (b) may either be prepared beforehand or in the reaction itself.

Suitable solvents are water-miscible compounds, preferably lower alcohols containing 1 to 6 carbon atoms such as methanol, propanol, isopropanol and various butanols, also acetone, pyridine, triethylamine, polyhydric alcohols such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether.

The compounds of this invention do not normally have LDg0 values of less than lg/kg/po.

When tested on cats anaesthetized with urethanechloralose using the system described in German Offenlegungsschrift No. 2,402,908 it was found that l-n-butyl-3-n-propyl-7-(l-methyl-2-oxopropyl)xanthine significantly improved the blood flow through skeletal muscles at doses within the range 4.4-27.9 mg/kg/id.

When tested on guinea pigs anaethetised with urethane-ohloralose it was found that the arrythmias produced by electrical stimulation of the right ventricle with an increasing voltage could be reduced by the administration 30 minutes before of 32 mg/kg/id of l-n-butyl-3-ethyl-7(3-oxobutyl)xanthine or l-n-butyl-3-n-propyl-7-(l-methyl-2oxopropyl) xanthine.

Example 1. l-n-Butyl-3-ethyl-7-(2-oxopropyl)xanthine. l-Bromo-propan-2-one (41.1 g) was dissolved in absolute ethanol (400 ml) in a 1 litre three necked flask.

To this was slowly added at boiling temperature a solution of Z13944 sodium l-n-butyi-3-ethylxanthine (51.8 g) in ethanol (300 ml) The reaction mixture was heated under reflux for 5 hours. After cooling, solid sodium bromide was removed by filtration and the solvent removed from the filtrate by evaporation on a rotary evaporator. The resulting solid was dissolved in chloroform and washed with IN NaOH solution to extract unreacted starting material. The chloroform phase was dried, filtered and evaporated in vacuo to yield a material which crystallised under petroleum/ether to yield l-n-butyl-3ethyl-7-(2-oxopropyl)xanthine (33.8 g), m.p. 1O3°C.

Analysis: Required: C, 57.52: H, 6.90: N, 19.16: 0, 16.42 Found: C, 57.30: H, 6.91: N, 19.11: 0, 16.66 C, 57.34: H, 6.83: N, 19.13: 0, 16.76 Example 2. l-n-Butyl-3-ethyl-7-(3-oxobutyl)xanthine. l-n-Butyl-3-ethylxanthine (16.8 g), methylvinylketone (160 ml), methanol (160 ml) and triethylamine (7.5 ml) were introduced into a 250 ml three necked flask and the mixture slowly heated with stirring to 40 to 45°C. The reaction mixture was maintained at this temperature until hardly any l-n-butyl-3-ethylxanthine was detectable by thin-layer chromatography. This point was reached at after about 45 to 60 minutes of reaction Lime. The mixture waB evaporated in a rotary evaporator and the resulting material 429 44 was crystallized from ethyl acetate/petrol to yield 1 - n butyl - 3 - ethyl - 7 - (3 - oxobutyl)xanthine, m.p. 106107“C.

Analysis: Required: C, 58.81: H, 7.24: N, 18.29: 0, 15.67 C, 58.67: H, 7.13: N, 18.60: 0, 15.27 Examples 3-6.

Using procedures analogous to those described above 10 compounds of the formula (I) were prepared as follows: Κ a° co «—1 in in H «—I «d> co C\ Cl co Η rj* ο ιη ιο ID ΙΟ Η Η *3« Η σι οο ΓΗ ιο •Η W >1 Η d β O dP fd Η φ Η >ί C ο Η -* -Ρ d ρ ιο β Η -Η Η Ο Η fe d +» tn w >1 Μ Ο <Η Ο *d Φ Ο Η Λ Q. fi § Φ d S Μ Φ Η £» -Φ Ρ- Ο CM CM CM ΓΟ 5ί* 03 Η Ο » • • • • Γ- Γ- Ρ- Ρ- Ρ- ρ- (Μ ιη Η CM ο CO CM CM 00 *4* ιη 00 <71 σ» co cd co ιη ιη ιη ιη ιη ιη fd Φ -P td H β ϋ Η d υ fd β β Ο fe »ΰ <ΰ •μ d Η α α Η nJ υ ηί β β ο fe Η •rl Ο in Η Η Η φ & \ Μ Φ Λ -μ Η ΓΟ W Ο Κ Ο ιη a CM U > a co α ι G co CO co 00 m σι σι ο σ» ιο 10 • • « « • <3* ιη <* <3* Η Η Η Η Η Η σ» σι Η σι Ρ* *3< ^3* <* ιη Ο σι • • • β • • Γ— ρ- ρ- ρ* 00 ρ* Η Η Η Η Η Η ιη Η m ιη 00 ο ιη η ιη ΓΟ CM • • « • » • ρ- Γ- ρ* ρ- Ρ* Γ** co CM Η 00 *3» Η σι cn σι σι *3« Η σι σι σ σ» ο ο tn ιη ιη ιη ID ιο τ, ω •μ nJ Η β ο Η β υ co > ιη Ο Η I *4· Ο Η β β ο fe Μ Φ •μ d £ Η Ο β d Λ •μ Φ S “CM a ο ι CM a υ > a co Ο I β »d φ •μ d Η β Ο Η d Ο ιη fd β β ο fe co ρ* Μ φ Λ •μ Η <Τ> a υ ι a u /\ Ρa m Ο β

Claims (11)

1. A pharmaceutical composition which, comprises a pharmaceutically acceptable carrier and a compound of the formula (I): CH, (I) R wherein A is methylene, 1,1-ethylene or 1,2-ethylene and R is an ethyl or n-propyl group.

2. A composition according to claim 1 wherein the total number of carbon atoms in the groups A and R is greater than 3.

3. A composition according to claim 1 wherein A is a - CH 2 - group.

4. A composition according to claim 1 wherein A is j a ^CH(CH 3 ) group.

5. A composition according to claim 1 wherein A is a - CH 2 -.CH 2 - group.

6. A composition according to claim 1 wherein the compound of formula I is selected from 1 - n - butyl - 3 - ethyl - 7 - (3 - oxobutyl)xanthine, 1 - n - butyl - 3 - ethyl - 7 - (1 - methyl - 2 - oxopropyl) xanthine, 1 - n - butyl - 3 - n - propyl - 7 - (2 - oxopropyl)xanthine - il 48944 1 - η - butyl - 3 - η - propyl -7-(3- oxobutyl) xanthine, 1 - n - butyl - 3 - n - propyl - 7 - (1 - methyl - 2 oxopropyl)xanthine.

7. A composition according to claims 1-6 adapted for oral administration.

8. A unit dose composition according to claim 7 which contains from 25 to 250 mg of a compound of formula (I). 0

9. A compound of the formula (I) as defined in claim 1.

10. A compound according to claim 9 wherein the total number of carbon atoms present in the groups A and R is greater than 3. 5 11. A compound according to claim 9 wherein A is a - CH 2 ~ group. 12. A compound according to claim 9 wherein A is a J)CH(CH 3 ) group. 13. A compound according to claim 9 wherein A is 0 a - CH 2 - CH 2 - group. 14. ,A compound acoording to claim 9 selected from 1 - n - butyl - 3 - ethyl - 7 - (3-oxobutyl)xanthine, 1 - n - butyl - 3 - ethyl - 7 - (1 - methyl - 2 oxopropyl)xanthine, 5 1 - n - butyl - 3 - n - propyl - 7 - (2 - oxopropyl)xanthine, 1 - n - butyl - 3 - n - propyl -7-(3- oxobutyl) xanthine, 1 - n - butyl - 3 - n - propyl - 7 - (1 - methyl- - 2 oxopropyl) xanthine. - 12 4 89 <3 4

11. 15. A process for the preparation of a compound according to claim 9 which process comprises either: (a) the reaction of an alkali metal salt of a compound of the formula (II): CH 3 - CHg - (¾ - (¾ (II) wherein R is as defined in relation to formula (I) with a compound of the formula (III): X - A - CO - CH 3 (III) wherein A is as defined in claim 1 and X is a chlorine, Iq bromine or iodine atom: or, when A is a - CH 2 - CH 2 - group, (b) the reaction of a compound of the formula (II) with a compound of the formula (IV): CH 2 = CH - CO - CH 3 (IV) 15 in an alkaline medium at an elevated temperature.