Xanthine derivatives

Compounds of general formula ##STR1## wherein one of the groups R.sub.1 and R.sub.3 is a straight-chain or branched oxoalkyl group consisting from 5 to 8 carbon atoms and the oxygen atom is attached to a non-terminal carbon atom and is separated from the nearest ring nitrogen atom by at least 3 carbon atoms in (.omega.-1)-oxoalkyl groups and by at least 4 carbon atoms in oxoalkyl groups in which the oxygen atom is separated from the terminal carbon atom by more than one carbon atom, R.sub.2 and the other one of groups R.sub.1 and R.sub.3 are straight chain or branched alkyl groups containing from 1 to 12 carbon atoms but wherein that group R.sub.1 or R.sub.3 which is other than an oxoalkyl group may also be hydrogen, one nitrogen-bound substituent being hydrogen or alkyl containing more than 1 carbon atom, and physiologically acceptable acid addition salts thereof, a process for their preparation and pharmaceutical compositions containing said compounds.

The invention relates to pharmaceuticals suitable for use in the treatment 
of diseases involving deficiencies in the blood vascular system. The 
pharmaceutical compositions contain certain oxoalkyl-(mono- or 
dialkyl)-xanthine derivatives having in particular vascular dilatory 
activity and good fibrinolytic action. 
1-(Oxoalkyl)-3,7-dimethyl-xanthines and 7-(oxoalkyl)-1,3-dimethyl-xanthines 
have been prepared. These oxo compounds are readily soluble both in water 
and in lipoids and have a pronounced vascular dilatory action with a low 
toxicity. 
Medicaments which contain, as active ingredient, xanthine derivatives 
substituted by identical or different alkyl groups with 1 to 6 carbon 
atoms: preferably 1 to 4 carbon atoms, in the 1-, 3- and 7-positions, at 
least one of which alkyl groups carries a hydrophilic group, preferably OH 
or COOH, are also already known. The number of hydrophilic groups per 
alkyl group is generally between 1 and the number of carbon atoms in the 
given alkyl group and the alkyl group which carries the hydrophilic group 
preferably contains 1 to 4 carbon atoms. (Compounds having a 
hydroxylsubstituent on a carbon atom adjacent to a ring nitrogen atom are 
unstable). The last-mentioned prior art does not disclose, however, that 
the hydrophilic group may be an oxoalkyl group, but such prior art 
disclosed only compounds in which the hydrophilising groups contain oxygen 
and have 2 or 3 carbon atoms and one hydrophilising group is in the 
.beta.-position to the nearest ring nitrogen atom and all those alkyl 
groups which are not hydroxylated are methyl groups. Furthermore, the only 
compounds with only one hydrophylic group which have been specifically 
disclosed are derivatives of theobromine and of theophylline. 
Pharmaceutical compositions are also known which contain as active 
ingredient, xanthines havin an oxoalkyl group with 6 to 20 carbon atoms in 
the 1- or 7-position and an alkyl group with 1 or 2 carbon atoms in the 
other of these two positions and in the 3-position. However no specific 
oxoalkyl compounds nor the preferred positions of the carbonyl group have 
been disclosed in the literature describing these compositions. 
According to the present invention we now provide compounds of the formula 
##STR2## 
wherein one of the groups R.sub.1 and R.sub.3 is a straight-chain or 
branched oxoalkyl group containing from 5 to 8 carbon atoms and the oxygen 
atom is attached to a non-terminal carbon-atom and is separated from the 
nearest ring nitrogen atom by at least 3 carbon atoms in 
(.omega.-1)-oxoalkyl groups and by at least 4 carbon atoms in oxoalkyl 
groups in which the oxygen atom is separated from the terminal carbon atom 
by more than one carbon atom, R.sub.2 and the other one of R.sub.1 and 
R.sub.3 are straight-chain or branched alkyl groups containing from 1 to 
12 carbon atoms, but wherein that group R.sub.1 or R.sub.3 which is not 
oxoalkyl may also be hydrogen, one nitrogen-bound substituent being 
hydrogen or an alkyl group containing more than 1 carbon atom, and 
physiologically acceptable acid addition salts thereof. The oxoalkyl group 
is preferably straight-chained. The carbonyl group in the oxoalkyl group 
is preferably in the (.omega.-1)-position. At least one of the alkyl 
groups desirably contains more than 2 carbon atoms. Preferably R.sub.2 is 
methyl. 
In general the new compounds according to the invention have a vascular 
dilatory activity, a good fibrinolytic action and a low toxicity. Certain 
of the new compounds are soluble in lipoids. They additionally have the 
effect of improving the circulatory properties of blood and are therefore 
effective in the treatment of arterial blood flow disturbances. The 
pharmacological activity spectrum of the new compounds is otherwise 
substantially similar to that of the previously known 
oxoalkyl-dimethyl-xanthines (oxoalkyltheophyllines and 
oxoalkyl-theobromines). 
The following are specific examples of the new compounds according to the 
invention: 
1-Alkyl-3-methyl-7-(5-oxohexyl)-xanthines wherein the alkyl group is an 
ethyl propyl, n-butyl, isobutyl, pentyl, hexyl or decyl group, 
1-(5-Oxohexyl)-3-methyl-7-alkyl-xanthines wherein the alkyl group is an 
ethyl, propyl, n-butyl, isobutyl, hexyl or decyl group, 
1-(5-Oxohexyl)-3-butyl-7-propyl xanthine, 
1-Alkyl-3-methyl-7-(5-oxoheptyl)-xanthines wherein the alkyl group is an 
ethyl, propyl, n-butyl, isobutyl, pentyl, hexyl or decyl group, 
1-(5-Oxoheptyl)-3-methyl-7-alkyl-xanthines wherein the alkyl group is an 
ethyl, propyl, n-butyl, isobutyl, hexyl or decyl group, 
1-(5-Oxoheptyl)-3-butyl-7-propyl xanthine, 
1-Alkyl-3-methyl-7-(2-methyl-3-oxobutyl)-xanthines wherein the alkyl group 
is an ethyl, propyl, n-butyl, isobutyl, pentyl, hexyl or decyl group, 
1-(2-Methyl-3-oxobutyl)-3-methyl-7-alkyl-xanthines wherein the alkyl group 
is an ethyl, propyl, n-butyl, isobutyl, hexyl or decyl group, 
1-(2-Methyl-3-oxobutyl)-3-butyl-7-propyl-xanthine, 
1-Alkyl-3-methyl-7-(6-oxoheptyl)-xanthines wherein the alkyl group is an 
ethyl, propyl, n-butyl, isobutyl, pentyl, hexyl or decyl group, 
1-(6-Oxoheptyl)-3-methyl-7-alkyl-xanthines wherein the alkyl group is an 
ethyl, propyl, n-butyl, isobutyl, hexyl or decyl group, 
3-Alkyl-7-(5-oxohexyl)-xanthines wherein the alkyl group is a methyl, 
ethyl, propyl, butyl, isobutyl, hexyl or decyl group. 
3-(n-Butyl)-7-(.omega.-1)-oxoalkyl-xanthines wherein the oxoalkyl group is 
a 4-oxopentyl, 5-oxohexyl, 6-oxoheptyl or 7-oxooctyl group; 
1-Methyl-3-butyl-7-(.omega.-1)-oxoalkyl-xanthines wherein the oxoalkyl 
group is a 4-oxopentyl, 5-oxohexyl, 6-oxoheptyl or 7-oxooctyl group. 
The compounds of general formula I according to the invention may be 
prepared by the following processes, which processes constitute further 
features of the invention: 
(a) Reaction of an appropriate 3-monoalkylxanthine or -1,3- or 3,7-dialkyl 
xanthine with a compound of formula 
##STR3## 
(wherein R is an alkyl group containing from 1 to 4 carbon atoms, 
preferably a methyl or ethyl group) in an alkaline medium. 
(b) Reaction of an alkali metal salt of an appropriate 3-monoalkylxanthine 
or 1,3- or 3,7-dialkyl-xanthine with a compound of formula 
##STR4## 
(wherein A is an alkylene group containing from 3 to 6 carbon atoms, which 
is preferably straight-chained and Hal is a halogen atom, preferably a 
chlorine or bromine atom) or with an acetal, ketal or thioketal therefrom 
and if necessary subsequently hydrolysing the product. 
(c) Reaction of an alkali metal salt of an appropriate 
1-oxoalkyl-3-alkyl-xanthine or 3-alkyl-7-oxoalkyl-xanthine with an 
appropriate alkyl halide or dialkyl sulphate in the presence of a solvent. 
(d) For the preparation of compounds of general formula I as hereinbefore 
defined in which there are at least 3 carbon atoms between the carbonyl 
group and the nearest nitrogen atom (which means that the oxygen atom is 
separated by at least 4 carbon atoms from the nearest nitrogen atom) 
Reaction of a compound of formula 
##STR5## 
or a compound of formula 
##STR6## 
(wherein X is an alkylene group containing from 2 to 5 carbon atoms, which 
is preferably straight chained and Hal is a halogen atom, preferably a 
chlorine or bromine atom) with an alkali metal salt of an acetoacetate, 
preferably a sodium salt, and subsequently subjecting the reaction product 
to ketone splitting. 
(e) Reaction of 3-alkylxanthine, in which the alkyl group has from 1 to 12 
carbon atoms, or of a homologue of theobromine or theophylline having at 
least one methyl group replaced by an alkyl group containing at least 2 
carbon atoms, preferably at least 3 carbon atoms, with a 
.beta.-dialkylamino-alkyl methyl ketone (wherein the alkyl groups contain 
1 to 2 carbon atoms and the alkylene group is branched and has 3 to 6 
carbon atoms but only 2 carbon atoms in the main chain) in a solvent 
mixture comprising water and an organic solvent. 
The reactions mentioned above are carried out in known manner, generally at 
temperatures of 50.degree. to 150.degree. C., preferably 60.degree. to 
120.degree. C., optionally at elevated or reduced pressure but usually at 
atmospheric pressure. The various starting materials may be used in 
stoichiometric quantities or for economic reasons in nonstoichiometric 
quantities. In methods (b) and (c), the alkali metal salts are preferably 
prepared in situ. When reacting the straight chained ketone according to 
method (a), it is particularly advantageous to carry out the reaction in 
an organic amine such as pyridine because working up the reaction product 
is then considerably simplified. Otherwise, method (a) may advantageously 
be carried out in the presence of a strong alkali in a solvent mixture 
comprising water and an organic solvent. Ketone splitting in method (d) is 
carried out in the usual manner. 
The organic solvents used are preferably those which are miscible with 
water, particularly monohydric alcohols, e.g. methanol, ethanol, propanol, 
isopropanol, the various butanols, also comprising ethylene glycol 
monomethyl ether and monoethyl ether, polyhydric alcohols such as ethylene 
glycol, aprotic solvents such as acetone, pyridine, formamide and 
dimethylformamide. 
According to a still further feature of the invention there are provided 
pharmaceutical compositions comprising as active ingredient a compound of 
formula I as hereinbefore defined or a physiologically compatible acid 
addition salt thereof in association with a pharmaceutical carrier or 
excipient. 
The pharmaceutical compositions according to the invention may be presented 
in a form suitable for oral, rectal or parenteral administration. They may 
be administered in solid form or in solution. Many of the xanthine 
derivatives according to the invention are sufficiently soluble in sterile 
water to be made up into injection solutions for parenteral 
administration. 
Suitable forms for administration include for example solutions, emulsions, 
tablets, coated tablets, suppositories, capsules, granulates and sustained 
release forms. These may be prepared in known manner using the usual 
auxiliary agents such as excipients, disintegrants, binders, coating 
substances, swelling agents, lubricants, flavourings, sweeteners, 
substances to produce a sustained release effect and solubilising agents. 
Suitable auxiliary agents include for example lactose, mannitol, talcum, 
lactalbumin, starch, gelatin, cellulose and its derivatives such as methyl 
cellulose: hydroxyethyl cellulose and suitable swelling and non-swelling 
copolymers. Disintegration of the composition and hence also release of 
the active ingredient can be influenced by the addition of larger or 
smaller quantities of extending agents. 
Advantageously the new compositions according to the invention are 
presented in the form of dosage units, each dosage unit being adapted to 
supply a fixed quantity of active ingredient, preferably 40 to 400 mg of 
active ingredient. 
The compounds of the invention may be administered in an amount of e.g. 0.1 
mg to 125 mg, preferably 1 mg to 50 mg per kg of body weight. The 
substances may be administered in a single dose or in a plurality of doses 
per day, if desired per infusionem. 
If desired the new compositions may additionally contain a further active 
ingredient, for example a vitamin.

The following Examples serve to illustrate the preparation of the new 
compounds according to the invention 
EXAMPLES 
EXAMPLE 1 
437.2 g of 3-methyl-7-propyl-xanthine suspended in a mixture of 240 g of 
methanol and 321 g of water are brought into solution by adding 160 g of 
50% sodium hydroxide solution at elevated temperature. The mixture is 
heated to boiling and 358 g of 1-bromohexanone-(5) are then added. The 
mixture is heated under reflux for 4.5 hours. After cooling, the unreacted 
3-methyl-7-propyl-xanthine is separated and the alcohol is distilled off. 
The aqueous solution is adjusted to pH 11 with sodium hydroxide solution 
and extracted with methylene chloride. 
1-(5-Oxohexyl)-3-methyl-7-propyl-xanthine with a melting point of 
69.degree. to 70.degree. C. is obtained in approximately 90% yield (based 
on reacted 3-methyl-7-propyl-xanthine) by recrystallising the residue of 
the methylene chloride solution from 5.2 liters of diisopropyl ether. The 
solubility of the product in water at 25.degree. C. is about 3.2%. The 
solubility in ethanol and dimethyl sulphoxide is over 10%. 
EXAMPLE 2 
126 g of a colourless oil is obtained from 131 g of 
3-methyl-7-n-hexyl-xanthine, 100 g of water, 60 g of methanol, 20 g of 
sodium hydroxide and 89.5 g of 1-bromohexanone-(5) analogously to Example 
1. The oil is recrystallised by dissolving it in 60 ml of methanol and 
reprecipitating it from this methanolic solution with 1500 ml of 
diisopropyl ether. 1-(5-Oxohexyl)-3-methyl-7-n-hexyl-xanthine with a 
melting point of 50.degree.-52.degree. C. is obtained in 90% yield (based 
on reacted 3-methyl-7-n-hexyl-xanthine). The product is only sparingly 
soluble in water. The solubility in ethanol, dimethyl sulphoxide and 
dimethylformamide is over 10%. 
EXAMPLE 3 
86 g of a crude product is obtained from 92.1 g of 
3-methyl-7-isobutyl-xanthine, 80 g of water, 48 g of methanol, 16 g of 
sodium hydroxide and 71.5 g of 1-bromohexanone-(5) analogously to Example 
1. After vacuum distillation (196.degree.-200.degree. C./0.2 mm) and 
recrystallisation from diisopropyl ether, 
1-(5-oxohexyl)-3-methyl7-isobutyl-xanthine with a melting point of 
75.degree.-76.degree. C. is obtained in 90% yield. The solubility in 
ethanol, dimethyl sulphoxide and dimethylformamide is over 10%. 
EXAMPLE 4 
A suspension of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine in a mixture of 
120 g of water and 72 g of methanol is brought into solution by the 
addition of 18 g of sodium hydroxide at about 60.degree. C. 55.5 g of 
n-propyl bromide are then added. After boiling under reflux for 24 hours, 
the reaction mixture is treated with 1 ml of concentrated sulphuric acid 
and cooled. Unreacted 3-methyl-7-(5-oxohexyl)-xanthine is filtered off and 
the alcohol is distilled off in vacuo. The remaining solution is made 
alkaline with 4 ml of 50% sodium hydroxide solution and extracted with 350 
ml of methylene chloride. 1-n-Propyl-3-methyl-7-(5-oxohexyl)-xanthine with 
a melting point of 76.degree.-78.degree. C. is obtained in 85% yield from 
the residue of the methylene chloride solution by recrystallisation from 
isopropanol. The solubility of the product in ethanol, dimethyl sulphoxide 
and dimethylformamide is over 10%. 
EXAMPLE 5 
A crude product is obtained from 20.4 g of 3-methyl-7-ethyl-xanthine, 24 g 
of water, 24 g of methanol, 8 g of 50% sodium hydroxide solution and 17.9 
g of 1-bromohexanone-(5) analogously to Example 1. After recrystallisation 
from a small quantity of methanol, 
1-(5-oxohexyl)-3-methyl-7-ethyl-xanthine with a melting point of 
102.degree.-103.degree. C. is obtained in almost quantitative yield. The 
solubility in water at 25.degree. C. is about 2%. The solubility in 
ethanol and dimethyl sulphoxide is between 1 and 10% and in propylene 
glycol between 0.1 and 1%. 
EXAMPLE 6 
110 g of a yellow oil is obtained from 117 g of 
3-methyl-7-(n-butyl)-xanthine, 140 g of water, 85 g of methanol, 20 g of 
sodium hydroxide and 95 g of 1-bromohexanone-(5) analogously to Example 
The oil is first distilled in vacuo (219.degree. C./0.5 mm) and then 
crystallised from 700 ml of diisopropyl ether. 
1-(5-Oxohexyl)-3-methyl-7-(n-butyl)-xanthine (melting point: 79.degree. to 
80.degree. C.) is obtained in 60% yield. 
Example 7 
A mixture of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine, 75 g of water, 75 
g of methanol, 18 g of sodium hydroxide and 74.4 g of n-hexyl bromide is 
boiled under reflux for 4 days and then worked up in a manner analogous to 
Example 4. 82.9 g of a crude product are obtained from which 
I-(n-hexyl)-3-methyl-7-(5-oxohexyl)-xanthine is obtained in 90% yield 
after vacuum distillation (230.degree.-232.degree. C./0.3 mm). After 
recrystallisation from 500 ml of diisopropyl ether, the melting point is 
35.degree.-38.degree. C. 
Example 8 
A mixture of 106 g of 3-methyl-7-(5-oxohexyl)-xanthine, 100 g of water, 100 
g of methanol, 24 g of sodium hydroxide and 82 g of isobutyl bromide is 
boiled under reflux for 85 hours and then acidified with 5 ml of 
concentrated sulphuric acid. It is then boiled under reflux for a further 
1.5 hours and then the unreacted 3-methyl-7-(5-oxohexyl)-xanthine (58.8 g) 
is removed by filtration. The crude product is worked up in a manner 
analogous to Example 4 to yield 57.7 g of a colourless residue from which 
1-isobutyl-3-methyl-7-(5-oxohexyl)-xanthine with a melting point of 
96.degree.-97.degree. C. is obtained in 95% yield (based on reacted 
3-methyl-7-(5-oxohexyl)-xanthine) by recrystallisation from 1200 ml of 
diisopropyl ether. 
Example 9 
80.3 g of 3-methyl-7-n-decyl-xanthine, 140 g of water, 90 g of methanol, 10 
g of sodium hydroxide and 44.6 g of 1-bromohexanone-(5) are boiled under 
reflux for 4 hours. After acidification with 2 ml of concentrated 
sulphuric acid, the reaction mixture is filtered hot to remove the 
unreacted 3-methyl-7-n-decyl-xanthine and the filtrate is worked up as in 
Example 1. 66.1 g of a crude crystalline product are obtained and are 
recrystallised from 500 ml of diisopropyl ether. The 
1-(5-oxohexyl)-3-methyl-7-(n-decyl)-xanthine which is obtained in 85% 
yield melts at 64.degree.-66.degree. C. 
Example 10 
4.16 g (0.02 mol) of 3-n-butyl xanthine are added to a solution of 5.5 g of 
water, 4.4 g of methanol and 0.8 g (0.02 mol) of sodium hydroxide. The 
mixture is heated to 70.degree. C. and stirred for one hour. 3.7 g (0.0206 
mol) of 1-bromo-hexanone-(5) are added at 70.degree. C. The solution is 
then stirred for 5 hours at 70.degree. C. After cooling down to room 
temperature the crystals are isolated by suction, then washed with 20 ml 
of water and 20 ml of methanol and dried in the vacuum of the water jet 
pump at 70.degree. to 100.degree. C. 
The yield is 4.4 g of a crude product (72% of the theory, referred to the 
butyl xanthine used) melting at 122.degree. C. 
4.3 g of the crude product are dissolved in 15 ml of water and 0.86 g of 
sodium hydroxide at 60.degree. C.; 0.5 g of active carbon is added 
thereto, and the mixture is stirred for 15 minutes and then filtered. The 
filtrate is adjusted with sulphuric acid of 33% strength to pH 9.5 at 
60.degree. C., and the mixture is then cooled in an ice bath. The 
precipitated crystals were isolated by suction, washed with water until 
free from alkali and dried at 100.degree. C. in the vacuum of a water jet 
pump. 
The yield is 2.6 g (42.5% of the theory, referred to the 3-butyl-xanthine 
used). The product proves to be uniform on thin-layer chromatography and 
has a melting point of 134.degree. C. 
Example 11 
166 g (1 mol) of 3-methyl-xanthine are introduced, while stirring into a 
mixture of 275 g of water, 220 g of methanol and 40 g (1 mol) of sodium 
hydroxide. The mixture is heated to 70.degree. C. and stirred for about 
one hour. Then 183 g (1.02 mol) of 1-bromo-hexanone-(5) are dropped at 
this temperature into the mixture in the course of one hour. After about 
half an hour a thick pulp is formed which however can still be stirred and 
is stirred for a further 5 hours at 70.degree. C. The pH-value does fall 
slightly and is in the range of from 5 to 7 at the end of the reaction. It 
is cooled to room temperature and the crystals are isolated by suction. 
These are dried at 70.degree. to 100.degree. C. in the vacuum of a water 
jet pump, after having been washed with 500 ml of water and 500 ml of 
methanol. 210 g of a crude product containing 73% of 3-methyl-7 
-(5-oxohexyl)-xanthine (=88% of the theory, referred to the reacted 
3-methylxanthine) are obtained. 
205 g of the crude product are dissolved at 60.degree. C. in 1000 ml of 
water and 40 g of sodium hydroxide. 13 g of active carbon are added 
thereto; the mixture is then stirred for 15 minutes and filtered. The 
filtrate having a temperature of 60.degree. C. is adjusted to pH 9.5 by 
adding 97 g of sulphuric acid (33% strength) over a period of one hour. 
The mixture is stirred for a further hour at 60.degree. C. The 
precipitated crystals are isolated by suction, washed with water until 
they are free from alkali and dried in the vacuum of the water jet pump at 
100.degree. C. 
The yield is 125 g of 3-methyl-7-(5-oxohexyl)-xanthine (=48% of the theory, 
referred to the 3-methyl-xanthine used). Having a melting point of 
217.degree. C. 
A further 5% of this compound may be obtained from the mother lye by 
acidifying with additional sulphuric acid down to a pH-value of about 4 
and subsequent purification. 
After intraduodenal administration to narcotized cats the compound caused a 
significant and permanent increase in the cerebral blood circulation which 
is by several times superior to that similarly brought about by 
ethylene-diamine-theophylline. The compound is also much more compatible 
when administered intraperitoneally to mice. The LD.sub.50 -value for mice 
is in the range of from 1000 to 1500 mg/kg, while that of 
ethylene-diamine-theophylline is only 217 mg/kg. 
Example 12 
104.1 g of 3-(n-butyl)xanthine are added under stirring to a solution of 
20.4 g of sodium hydroxide in 200 ml of water and 200 ml of methanol. Then 
at 70.degree. C. 83.1 g of the ethylene ketal of 1-chloropentanone-(4) are 
dropwise added to the clear solution. After stirring for 41 hours at 
70.degree. C. the reaction mass is cooled to 20.degree. C. and 34.5 g of 
the ethylene ketal of 3-(n-butyl)-7-(4'-oxopentyl)-xanthine are obtained. 
It has a melting point of 128.degree. to 129.degree. C. This ketal is 
heated to 70.degree. C. for one hour in 1250 ml of 80% aqueous methanol in 
the presence of sulfuric acid and at a pH value of 1 to 2. After 
neutralisation and recrystallisation of the precipitate from alkaline 
solution wherein the pH value was changed from 13.5 to 10 26.8 g of 
3-(n-butyl)-7 -(4'-oxopentyl)-xanthine having a melting point of 
140.5.degree. to 141.degree. C. are obtained (yield: 43.7%, referred to 
reacted xanthine). 
Example 13 
24.8 g of 3-(n-butyl)-7-(4'-oxopentyl)-xanthine are added to a solution of 
3.5 g of sodium hydroxide in 80 ml of methanol and water (1:1). After 
stirring for 30 minutes at 40.degree. C. 12.2 g of methyl iodide are added 
dropwise. After stirring for 50 hours the clear solution is concentrated 
under reduced pressure until dryness and the residue is diluted with ether 
and liberated from the starting material by addition of 1 N sodium 
hydroxide. After concentration of the neutralized ether solution and 
subsequent distillation at a temperature of the mixture of 130.degree. C. 
under a pressure of 0.02 mm Hg 17.8 g of 
1-methyl-3-(n-butyl)-7-(4'-oxopentyl)-xanthine having a melting point of 
65.degree. to 66.degree. C. are obtained (yield: 84.2%, referred to the 
reacted starting xanthine). 
Example 14 
80.1 g of 3-(n-butyl)xanthine are added to a solution of 15.5 g of sodium 
hydroxide in 220 ml of a methanol/water mixture (1:1). After adding 
dropwise 53.7 g of 1-chlorohexanone-(5) to the clear solution which has a 
temperature of 70.degree. C. the mixture is stirred at this temperature 
for 10 hours. After cooling to 20.degree. C. and one recrystallisation of 
the precipitate from alkaline solution (wherein the pH value changes from 
13.5 to 10), 34.4 g of pure 3-(n-butyl)-7-(5'-oxohexyl)-xanthine having a 
melting point of 141.degree. C. are obtained (yield: 51.3%, referred to 
reacted 3-(n-butyl)xanthine). 
Example 15 
60 g of 3-n-butyl-7-(5'-oxohexyl)-xanthine are added to a solution of 8 g 
of sodium hydroxide in 160 ml of a methanol/water mixture (1:1). 28 g of 
methyl iodide are dropwise added to the clear solution having a 
temperature of 40.degree. C. and the mixture is stirred at 48.degree. C. 
for 24 hours. After concentration under reduced pressure the residue is 
diluted with 300 ml of diethylether and the unreacted 
3-(n-butyl)-7-(5'-oxohexyl)-xanthine is removed by shaking with 1 N sodium 
hydroxide. After neutralisation, drying, concentration under reduced 
pressure and distillation at 140.degree. C. temperature of the mixture and 
0.02 mmHg 48.5 g of 1-methyl-3-(n-butyl)-7-(5'-oxohexyl)-xanthine are 
obtained from the ether phase as a viscous oil (n.sub.D.sup.20 =1.5320; 
yield 77.2%, referred to reacted starting xanthine). Analysis: C.sub.16 
H.sub.24 N.sub.4 O.sub.3 =320.396 
______________________________________ 
C H N 
______________________________________ 
calculated: 
59.98% 7.55% 17.49% 
found: 60.05% 7.74% 17.36% 
______________________________________ 
Examles 16 to 19 
In the same way as under example 15 the following compounds were prepared. 
16. 3-(N-Butyl)-7-(6'-oxoheptyl)xanthine, melting point 110.degree. to 
111.degree. C., from 3-(n-butyl)xanthine and 1-chloroheptanone-(6) at 
70.degree. C. temperature of the mixture and under stirring for 43 hours 
(yield 80.8%, referred to reacted 3-butylxanthine). 
17. 3-(n-Butyl)-7-(7'-oxooctyl)-xanthine, melting point 98.5.degree. to 
99.degree. C., from 3-(n-butyl)xanthine and 1-bromooctanone-(7) at a 
mixture temperature of 70.degree. C. under stirring for 39 hours (yield: 
52.2%, referred to reacted 3-butylxanthine). 
18. The reaction is performed according to example 15 from 
3-(n-butyl)-7-(6'-oxoheptyl)-xanthine and methyl iodide, but at a 
temperature of the mixture of 50.degree. C. under stirring for 46 hours. 
Prior to the distillation at a bath temperature of 140.degree. C. and 0.02 
mmHg the product is purified by column chromatography at silica gel 60 
(Merck) with methylene chloride/acetone (80:2) as eluent. 
1-Methyl-3-(n-butyl)-7-(6'-oxoheptyl)-xanthine was obtained as a viscous 
oil (n.sub.D.sup.20 1.5280; yield 80.1%, referred to reacted 
3-(n-butyl)-7-(6'-oxoheptyl)-xanthine. 
Analysis: C.sub.17 H.sub.26 N.sub.4 O.sub.3 =334.423 
______________________________________ 
C H N 
______________________________________ 
calculated: 
61.06% 7.84% 16.75% 
found: 60.85% 7.87% 16.59% 
______________________________________ 
19. 1-Methyl-3-(n-butyl)-7-(7'-oxooctyl)-xanthine from 
3-(n-butyl)-7-(7'-oxooctyl)-xanthine and methyl iodide at a temperature of 
the mixture of 50.degree. C. under stirring for 46 hours. The product is 
obtained in colorless crytals, melting point 52.degree. C. (yield: 94.4%, 
referred to reacted 3-(n-butyl)-7-(7'-oxooctyl)-xanthine. 
Example 20 
40.4 g of 3-(n-Butyl)-7-n-pentylxanthine, 17.8 g of methylvinylketone and 
7.3 ml of triethylamine are refluxed under stirring for 7 hours. After 
concentration under reduced pressure the residue is diluted with 200 ml of 
diethylether and extracted at repeated times with 1 N sodium hydroxide. 
The ether phase was washed to neutrality, dried and concentrated to 
dryness under reduced pressure. After one rerystallisation from 
petrolether (boiling range from 60.degree. to 90.degree. C.) under 
addition of active charcoal 25.6 g of 
3-(n-butyl)-7-(n-pentyl)-1-(3'-oxobutyl)-xanthine having a melting point 
of 65.degree. C. are obtained (yield 71.7%, referred to the reacted 
starting xanthine). 
Analysis: C.sub.18 H.sub.28 N.sub.4 O.sub.3 =348.45 
______________________________________ 
C H N 
______________________________________ 
calculated: 
62.05% 8.10% 16.08% 
found: 62.09% 8.23% 15.87% 
______________________________________ 
PHARMACOLOGICAL EXPERIMENTS 
Animal tests were carried out with various oxoalkylxanthine derivatives, in 
which the toxicity in the mouse, the increase of cerebral and muscular 
blood perfusion at the cat and the fibrinolytic effect in vitro in the 
Hanging-Clot-test were measured. Furthermore the broncholytic effect of 
various compounds was tested. The results were compared with those 
obtained with the known substance 1-(5-oxohexyl)-3,7-dimethylxanthine 
which was known to have a vaso-dilatory effect with a low toxicity (cf. 
U.S. Pat. No. 3,737,433). 
The tested compounds are evident from the following Table 1. 
TABLE 1 
______________________________________ 
Sample 
No. substances melting point .degree.C. 
______________________________________ 
1 1-Propyl-3-methyl-7-oxohexylxanthine 
76-78 
2 1-Isobutyl-3-methyl-7-oxohexylxanthine 
96-97 
3 1-Hexyl-3-methyl-7-oxohexylxanthine 
35-38 
4 1-Oxohexyl-3-methyl-7-propylxanthine 
69-70 
5 1-Oxohexyl-3-methyl-7-n-butylxanthine 
79-80 
6 1-Oxohexyl-3-methyl-7-decylxanthine 
64-66 
7 1-Oxohexyl-3-methyl-7-ethylxanthine 
102-103 
8 1-(5-Oxohexyl)-3,7-dimethylxanthine 
102-105 
(comparison) 
______________________________________ 
PHARMACOLOGICAL TESTS 
1. Cerebral and muscular blood perfusion by fluvography 
These tests were performed at the cat according to K. Popendiker, I. Boksay 
and V. Bollmann ("Arzneimittel Forschung" vol. 21 (1971), page 1160). 
2. Broncholytic effect at the narcotized guinea-pig 
This test was performed according to H. Konsett and R. Rossler ("Archiv 
exp. Path. Pharmak." vol. 195 (1940), page 71). 
3. Broncholytic effect at the isolated trancheal chain 
This test was performed according to J. C. Castillo and E. J. de Beer ("J. 
Pharm. Ther." vol. 90 (1947), page 104). 
4. Fibrinolytic effect 
This effect was measured by the Hanging-Clot-test according to K. N. von 
Kaulla ("Journ. med. Chem." vol. 8 (1965), page 164) in using human blood. 
The incubation time was 24 or 48 hours. 
5. Toxicity in the mouse 
The toxicity was determined as LD.sub.50 --range or as LD.sub.50 according 
to Litchfield and Wilcoxon ("J. Pharmacol. exp. Ther." 97 (1949), page 
399) in the mouse. 
TESTS RESULTS 
The values obtained in the mentioned test 1 are given as .DELTA..lambda. 
and as half-life values in Table 2 and the results of tests 2 to 5 are 
enumerated in Table 3. In Table 2 .DELTA..lambda. is the change of blood 
perfusion. 
TABLE 2 
______________________________________ 
Cerebral Muscular 
blood per- 
blood per- 
fusion fusion 
half- half- 
Sample 
Dose life life Animals 
No. mg/kg i.v. 
.DELTA..lambda. 
min. .DELTA..lambda. 
min. n 
______________________________________ 
2 1 +1.85 1.0 0 -- 2 
5 +3.45 14.3 +0.05 0.60 2 
3 1 +0.97 0.4 -0.05 3.30 3 
2 +1.45 7.0 0 -- 2 
4 1 +4.33 4.0 +0.13 3.70 3 
2 +6.33 5.8 +0.07 0.80 3 
5 +13.00 14.7 +0.08 3.70 3 
5 1 +2.50 1.3 0 -- 2 
2 +2.55 1.3 0 -- 2 
5 +2.40 3.0 0 -- 2 
6 1 +1.40 0.2 0 -- 1 
3 +2.8 0.5 +0.30 4.00 1 
7 1 +2.46 1.5 +0.22 0.40 5 
2 +5.17 5.0 +0.10 5.00 3 
5 +8.07 8.2 +0.20 0.50 3 (1).sup.(+) 
8 1 +0.44 0.9 +0.02 1.10 13 (10) 
5 +0.86 2.4 +0.03 3.30 40 (23) 
10 +1.15 8.6 +0.15 2.80 33 (15) 
20 -- -- +1.38 &gt;15 (2) 
______________________________________ 
TABLE 3 
__________________________________________________________________________ 
Fibrinolytic effect 
Hanging-Clot-Test 
Minimum Concentration 
Change of the bronchospasm in 
Inhibition of isoprenaline 
mMol for 
Dose 
% 2 min. i.p. against 
reaction in % begin- 
Sample 
Toxicity 
mg/kg 
acetyl- 
hista- 
acro- concentration ning 
partial 
complete 
No. mg/kg i.p. 
i.v. 
choline 
mine 
tonine 
n 3 .times. 10.sup.-6 
10.sup.-5 
3 .times. 10.sup.-5 
10.sup.-4 
n lysis 
lysis 
lysis 
__________________________________________________________________________ 
1 100-250 
3.sup.(2) 
-33 -63 -40 each 1 -- 40 (20).sup.(3) 
10.sup.(2) 
-55 -73 -82.sup.(1) 
2 250-500 
3 -- -80 -20 each 1 -- -- -- 
10 -29 -73 -47 
3 250-500 
3 - 23 
-52 -50 each 1 -- -- -- 
10 -85 -90 -100 
4 107 i.v. 
3 -40 -75 -83 each 2 
2 20 94 100 
each 
-- -- 50(25).sup.(3) 
860 per os 
10 -75 -86 -93 2 
5 250-500 
5 -100 
-42 -70 each 1 -- -- -- 
10 -100 
-69 -100 
6 500 10.sup.(2) 
-50 -40 -50 each 1 -- -- -- 
7 250-500 
3 -28 -47 -42 each 2 -- 50(25).sup.(3) 
-- 
10 -96 -90 -81 
8 -- 3 -15 -4 -- 2,2,- 
0 5 30 89 
7,20, 
-- 100(50).sup.(3) 
(Com- 
pari- 5 -- -94 -- 
3,- 17,18 
son) 10 -41 -83 -- 3,5,- 
20 -72 -100 
-- 1,2,- 
__________________________________________________________________________ 
.sup.(1) Longtime effect 
.sup.(2) Sample in propanediol 
.sup.(3) Bracket = 48 hours 
DISCUSSION OF THE RESULTS 
As it is evident from the above Tables sample number 2 shows a stronger and 
longer cerebral blood perfusion. Thus, a dose of 5 mg/kg has an effect 
which is about four times stronger and its half-life is more than five 
times longer than those of the comparison sample. In the dose of 2 mg/kg 
of sample 3 its effect is about two times as strong and its half-life is 
about three times as long as the corresponding effects of comparison 
sample number 8, however with the higher dose of 5 mg/kg. In all dose 
values of sample number 4 an essentially stronger (more than 10 times) and 
longer cerebral blood perfusion and a stronger muscular blood perfusion, 
compared with the values of the corresponding dosages of comparison sample 
number 8 is obtained. Sample number 5 effects an increase of the cerebral 
blood perfusion over the comparison sample which at a dose of 1 mg/kg is 
nearly six times higher and at a dose of 5 mg/kg is about three times 
higher than that of the comparison sample. An improvement over the 
comparison sample is also shown by sample number 7 wherein the cerebral 
blood perfusion at the dose of 1 mg/kg is about five times higher and at 
the dose of 5 mg/kg is about nine times higher than that of sample number 
8. The half-life is 1.5 times longer at a dose of 1 mg/kg and more than 
three times longer at a dose of 5 mg/kg compared with that of sample 
number 8. Besides that it is also evident from Table 2 that samples 1, 4 
and 7 have an improved fibrinolytic effect which is two times as strong as 
that of comparison sample number 8. Furthermore the broncholytic effect 
against acetylcholine of samples 3 to 5 and 7 is better than the 
corresponding effect of sample 8 and additionally samples number 3, 4 and 
7 have also an improved broncholytic effect against histamine, compared 
with sample number 8. 
It is not intended that the examples given herein should be construed to 
limit the invention thereto, but rather they are submitted to illustrate 
some of the specific embodiments of the invention. Resort may be had to 
various modifications and variations of the present invention without 
departing from the spirit of the discovery or the scope of the appended 
claims.