CA1075690A - Xanthine derivatives - Google Patents
Xanthine derivativesInfo
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- CA1075690A CA1075690A CA215,977A CA215977A CA1075690A CA 1075690 A CA1075690 A CA 1075690A CA 215977 A CA215977 A CA 215977A CA 1075690 A CA1075690 A CA 1075690A
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- xanthine
- methyl
- oxohexyl
- butyl
- carbon atoms
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Abstract
A b s t r a c t Compounds of general formula
Description
~7569~
"Xanthine derivatives"
The invention relates to pharmac~uticals suitable ~or use in the treatment of diseases involving deficiencies in ~hle blood vascular system.
The phar~ac.eutical compositions contain certain oxoalkyl~dialkyl-xanthine derivatives havin~ in particular vascular dilatory activity and good fibrin-olytic action.
l-~Oxoalkyl)-3,7-dimethyl-xanthines and 7 (oxoalkyl~-1,3-dimethyl-xanthines have been prepared. These oxo compounds are Teadily 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 deriva-tives substituted by identical or diferent alkyl groups with 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in the 1-, 3- and 7-positio~s, at least one of which alkyl groups carries a hydrophilic group, preferably 0H or C00H, or also already known. The number of hydrophilic groups per alkyl group is generally between 1 and the number of carbon atoms in the gi~en alkyl group and the alkyl group which carries the hydrophilic group preferably contains 1 to 4 carbon atoms. ~Compounds having a hydroxyl substituent on a carbon atom adjacent to a ring nitrogen atom are unstable). lhe last-mentioned prior art does not disclose, however, that the hydrophilic group may be an oxoalkyl group, but there have only been disclosed compounds in which the hydrophilising groups contain oxygen and have 2 or 3 carbon atoms and one hydrophilising group is in the ~-position to the nearest ring nitrogen atom and all those alkyl groups which are not hydroxylated are methyl groups.
Furthe~more, the only compounds with only one hydrophilic group which have been specifically disclosed are derivatives of theobromine and of theophyl-line.
Pharmaceutical composi~ions are also kno~n which contain as active ingredient, xanthines having an oxoalkyl group with 6 to 20 car~on 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 .~' .
:~756~3 [) 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 general formula R
o 13 ~ 7 ~ (I) wherein one of the groups Rl and R3 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 (`~-l) oxoalkyl groups and by at least ~
carbon atoms in oxoalkyl groups in which the oxygen atom is separated from the terminal carbon atom by more than one carbon atom, R2 and the other one of Rl and R3 are straight-chain or branched aIkyl groups containing from 1 ; to 12 carbon atoms, but wherein that group Rl or R3 which is no oxoalkyl group, may also be hydrogen, one of the said substituents being hydrogen or an alkyl group containing more than l carbon atom, and physiologically acceptable acid addition salts thereof. The oxoalkyl group is preferably straight-chained. me carbonyl group in the oxoalkyl group is preferably in the (~-l)-position. At least one of the alkyl groups desirably contains more than 2 carbon atoms.
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. mey additionally have ; the éffect of improving the circulatory properties of blood and are therefore effective in the treatment of arterial blood flow disturbances. The pharma- ~-cological activity spectrum of the new compounds is otherwise substantially 29 similar to that of the previously known oxoallcyl-dimethyl-xanthines (oxo-~. . . . . . . .
~i~7~6~) alkyl-theophyl]ines and oxoalkyl-theobromines).
The following are specific examples of the new compounds according to the invention:-l-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, l-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, l-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)-xant~nes wherein the alkyl group is a methyl, ethyl, propyl~ butyl, isobutyl, hexyl or decyl group.
. The compounds of general formula I according to the invention may be prepared by the following processes, which processes constitute further ~eatures of the invention:
29 a) ~eaction of an appropriate 3-monoalkylxanthine or 1,3- or 3,7- : .
-4- : -~C~7SG~O
dialkyl-xanthine with a compound of formula R R
CH2 ~ -C-CH3 (II) (wherein R is an alkyl group containing from 1 to ~ carbon atoms, preferably a methyl or ethyl group) in an alkaline medium.
b) Reaction of an alkali metal salt of an appropriate 3-monoalkyl~an-thine or 1,3- or 3,7-dialkyl-xanthine with a compound of for~ula C113 - ~ - A -Hal (IIl) (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 subsequent:Ly hydrolysing the product.
c) Reaction of an alkali metal salt of an appropriate l-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 form-ula I as herein-before defined in which there are at least 3 carbon atoms between the car-bonyl group and the nearest nitrogen atom (which means that the o~ygen atom is separated by at least ~ carbon atoms from the nearest nitrogen atom) Reaction of a compound of formula X-Hal 0 ~ ~ N
R2 :
or a compound of formula 0 IR3 ~al -X
N I /~ (V) 29 0 ~ IN ~ N~/ -R2 ~ ~
~, , ~ ..
~37~
.
(wherein X is an alkylene group containing from 2 to 5 carbon atoms, which is preferably straight chained and Hal is a halogen atom, pre~erably a chlor-ine 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 ~-dialkylamino-alkyl 10 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. In embodiment a), b) d) and e) the alkyl group of 3-monoalkylxanthines may have from 1 to 12 carbon atoms.
The reactions mentioned above are carr~ed out in known manner, generally at temperatures of ~0 to 150 C, preferably 60 to 120 ~, 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. Retone splitting in method b) is carried out in the usual manner~
The organic solvents used are preferably those which are miscible with water, particularly ~onohydric alcohols, e.g. methanol, ethanol, pro-29 panol, isopropanol, the various butanols, also comprising ethylene glycol monomethyl ether and monoethyl ether, polyhydric alcohols such as ethyleneglycol, aprotic solvents such as acetone, pyridine, formamide and dimethyl-formamide.
According to a still further feature of the invention there are provided pharmaceutical compositions comprising as active ingredient a com-pound 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 3S 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, gelatine, 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 ingre-dient 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 10 to 400 mg of 29 active ingredient.
~:, ~7~ 0 me compounds of the invention may be administered in an amount of e.g. 0.1 mg to 125 mg, pre-ferably 1 mg to 50 mg per kg/body weight. The substances may be administered in a single dose or 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 methanoIand 321 g of water are brought into sol~tion 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 mix-- ture is heated under reflux for ~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 solutiQn and ex-; tracted with methylene chloride. 1-(5-Oxohexy1)-3-methyl-7-propyl-xanthine with a melting point of 69 ~o 70 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 litres of diisopropyl ether.
The solubility of the product in water at 25 C is about 3.2%. The solubility in ethanol and dimethyl sulphoxide is over 10%.
~ .
126 g of a colourless oil is obtained from 131 g of 3-methyl-7-n-hexyl-xanthine, 100 g of waterg 60 g of methanol, 20 g of sodium hydroxide and 89.5 g of 1-bromohexanone-(5~ analogously to Example 1. The oil is re-crystallised by dissolving it in 60 ml of methanol and reprecipitating it 29 from this methanolic solution with 1500 ml of diisopropyl ether. 1-(5-~L~7~6~3~
Oxohexyl)-3-methyl-7-n-hexyl-xanthine with a melting point of 50 - 52 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-iso-butyl-xanthine, 80 g of water, 48 g of methanol, 16 g of sodium hydroxide and 71.5 g of l-bromohexanone-(S) analogously to Example 1. After vacuum distillation (196-200 C/0.2 mm) and recrystallisation from diisopropyl etherg 10 1-(5-oxohexyl)-3_methyl-7-isobutyl_xanthine with a melting point of 75-76 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)-xanthi,ne in a mixture of 120 g af water and 72 g of methanol is brought into solution by the addition of 18 g of sodium hydroxide at about 60 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. Un-reacted 3-methyl-7-(5-oxohexyl)-xanthine is filtered off and the alcohol is `i 20 distilled off in ~racuo. me remaining so:lution is made alkaline with 4 ml of SO~ sodium hydroxide solution and exkracted with 350 ml of methylene chlor-ide. l-n-Propyl-3-methyl-7-(5-oxohexyl)-xanthine with a melting point of 76-78 C is obtained in 85% yield from the residue of the methylene chloride solution by recrystallisation from isopropanol. The solubility of the pro-duct 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-xanthineg 24 g of water, 24 g of methanol, 8 g of 50% sodium hydroxide solution and 29 17.9 g of 1-bromohexanone-(5) analogously to ~xample 1. After recrystallisa-_g_ , - - - - ~ .. .. .....
1~7~69~ ~
tion from a small quan-tity of methanol, 1-(5-oxohexyl)-3-methyl-7-ethyl-xanthine with a melting point of 102-103 C is obtained in almos~ quantitative yield. The solubility in water at 25 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%.
~xam~le 6 110 g of a yellow oil is obtained from lL7 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 l-bromohexanone-(5) analogously to Example 1. The oil is first distilled in vacuo (219 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 to 80 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 bro-mide is boiled under reflux for 4 days and then worked up in a manner ana-logous to ~xample 4. 82.9 g of a crude product are obtained from which ~l_n-hexyl-3-methyl-7-(5-oxohexyl)-xanthine is obtained in 90% yield after vacuum distillation (230-232 C 0.3 mml). After recrystallisation from 500 ml of diisopropyl ether, the melting point is 35-38 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 o~ isobutyl bromide is boiled under reflux fGr 85 hours and then acidified with 5 ml of concentrated sulphuric acid. ~* 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 ana-logous to Example 4 to yield 57.7 g of a colourless residue from which 1-t 29 isobu*yl-3-methyl-7-(S-oxohexyl)-xanthine with a melting point of 96-97 C
', :. . ~ . .; : . - . -~: , . . . - . ~ , ~7~6~
is obtained in 95~ yield (based on reacted 3-methyl-7-(5-oxohexyl)-xanthine) by recrystallisation from 1200 ml of diisopropyl ether.
xample 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 10 from 500 ml of diisopro~yl ether. The 1-(5-oxohexyl)3-methyl-7-n-decyl-xan-thine which is obtained in 85% yield melts at 64-66 C.
Fxample 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.
me mixture is heated to 70 C and stirred for one hour. 3.7 g (0.0206 mol) of l-bromohexanone-(5) are added at 70 C. The solution is then stirred for 5 hours at 70 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 to 100C.
The yield is 4.4 g of a crude product (72% of the theory, referred O : -to the butyl xanthine used) melting at 122 C.
4.3 g of the crude product are dissolved in lS mlofwater and 0.85 g of sodium hydroxide at 60 C; O.S g of active carbon-is added thereto, and the mixture is stirred for 15 minutes and then filtered. The filtrate is adjusted ~ith sulphuric acid of 33~0 strength to pH 9.5 at 60 C, and the mixture is then cooled in an ice bath. The precipitated crystals were isolated by suction, washed with water until they were free from aIkali and dried at 100 C in the ~acuum of a water je~ pump.
29 The yield is 2.6 g (42.5% of the theory, referred to the 3-butyl-. . . ., . . . . . . ., -:
~i7569~l xanthine used). ~he product proves to be uniform on thin layer chromatography and has a melting point of 134 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 C and stirred for about one hour. Then 183 g (1.02 mol) of 1-bromohexanone-(5) are dropped at this temperature into the mixture in the course of one hour. After about ha]f an hour a thick pulp is formed which however can still be stirred and is stirred for further 5 hours at 70 C. The pH-value does slightly fall and is at the end of the reaction in the range from 5 to 7. It is cooled to room temperature and the crystals are isolated by suction. These are dried at 70 to 100 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 C in 1000 ml of water and 40 g of sodium hydroxideO 13 g of active carbon are added thereto;
the mixture is then stirred for 15 minutes and filtered. The filtrate having 20 a temperature of 60 C is adjusted to pH 9.5 by adding 97 g of sulphuric acid (33% strength) during one hour. The mixture is stirred for a further hour at 60 C. The crystals precipitated are isolated by suction, washed with water until they are free from alkali and dried in the vacuum of the water jet pump at 100C.
The yield is 125 of 3-methyl-7-(5-oxohexyl~-xanthine (= 48% of the theory, referred to the 3-methyl-xanthine used). ~elting point 217 C.
~ further 5% of this compound may be obtained from the motherlye by acidifying with additional sulphuric acid down to a pH-value of about 4 29 and subsequent purification.
~1~75~
After intraduodenal administration to narcoti~ed cats the compound caused a significant and permanent increase in the cerebral blood circulation which is by several times superior to that of ethylenediamine-theophylline.
The compound is also much more compatible if administered intraperitoneally to mice. The LD50 -value at mice is in the range from 1000 to 1500 mg/kg, while that of ethylenediamine-theophylline is 217 mg/kg only.
Supplementary Disclosure Example 12 104.1 g of 3-n-butylxanthine are added under stirring to a solution of 20.4 g of sodium hydroxide in 200 ml of ~rater and 200 ml of methanol. Then at 70C 83.1 of the ethylene ketal of 1-chloropentanone-(4) are dropwise added to the clear solution~ After stirring for ~1 hours at 70C the reaction mass is cooled to 20 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 to 129 C.
This ketal is heated to 70 C for one hour in 1250 ml of 80% aqueous methanol in the presence of sulfuric acid-and at a p~ value of 1 to 2~ After neutral-isation and recrystallization of the precipitate from alkaline solution wherein the pH value was changed from 13.5 to 10 there are obtained 26.8 g of 3-n-butyl-7-(4~-oxopentyl)-xanthine having a melting point of 140.5 to 141 C (yield ~3.7%, referred to reacted xanthine).
Exam~e 13 24.8 g of 3-n-butyl-7-(4~-oxopentyl)-xanthine are added to a soIu-tion of 3.5 g of sodium hydroxide in 80 ml of methanol and water (1:1). After stirring for 30 minutes at 40 C 12O2 g of methyliodide are dropwise added.
After stirring for 50 hours the clear solution is concentrated under reduced pressure until dryness and the residue is diluted with ether and deliberated ~ from the starting material by addition of 1 n sodium hydroxide. After con-; centration the neutrali~ed ether solution and subsequent distillation at a 29 temperature of the mixture of 130 C under a pressure of 0~02 mm Hg 17.8 g of .
.,.. :.......... , .,.. . . - , . , . , .. . . , . . ; . .
~75~9~
l-methyl-3-n-butyl-7-(4~-oxopentyl)-xanthine having a melting point of 65 to 66 C are obtained (yield: 84.2%, referred to the reacted starting xanthine).
Example 14 80.1 g of 3-n-butylxanthine are added to a solution of 15.5 g of sodium hydroxide in 220 ml of a methanol/water mixture (1:1). After dropwise adding 53.7 g of 1-chlorohexanone-(5) to the clear solution which has a temperature of 70 C the mixture is stirred ak this temperature for 10 hours.
After cooling to 20C and one recrystallization of the precipitate from alka-line solution wherein the pH value changes from 13.5 to 10 there are obtained 34.4 g of pure 3-n-butyl-7-(5'-oxohexyl)-xanthine having a melting point of 141 C (yield: 51.3%, referred to reacted 3-n-butylxanthine).
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 solu~ion having a temperature of 40 C and the mixture is stirred at 48 C for 24 hours. After concentration under reduced pressure the residue is diluted with 300 ml of diethylether and ~he 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 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 VlSCOUS oil (n D = 1.5320; yield 77.2%, referred to reacted starting xa~thine). Analysis: C16H24N403 = 320.396 C H N
calculated: 59.98% 7.55% 17.49%
found: 60.05% 7.74% 17.36%
Examples 16 to 19 In the same way as ~lder example 15 the following eompounds were 29 prepared.
-1~- :' ,, ~75~
16. 3-n-Butyl-7-(6'-oxoheptyl)-xanthine, melting point 110 to 111 C, from 3-n-butylxanthine and 1-chloroheptanone-(6) at 70 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 ~o 99 C, from 3-n-butylxanthine and 1-bromooctanone-(7) at a mixture temperature of 70 C
under stirring for 39 hours (yield: 52.2%, referred to reacted 3-butylxan-thine).
18. ~he reaction is performed according to example 21 from 3-n-butyl-7-(6'-oxoheptyl~-xanthine and methyl iodide, but at a temperature of the mix-ture of 50 C under stirring for 46 hours. Prior to the distillation at a bath temperature of 140 C and 0.02 mmHg the product is purified by column chromatography at silicagel 60 (Merck) with methylene chloride/acelone (80;2) as eluent. l-Methyl-3-n-butyl-7-(6'-oxoheptyl)-xanthine was obtained as a viscous oil (n OD = 1.5280; yield: 80.1%, referred to reacted 3-n-butyl-7-(6'-oxoheptyl) xanthine. Analysis: C17H26N403 = 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 C
under stirring for 46 hours. The product is obtained in colorless crystals, melting point 52 C (yield: 94.4% re~erred to reacted 3-n-butyl-7-(7'-oxooctyl) -xanthine.
20. A solution of 2.3 g of sodium in 150 ml of absolute e~hanol is ad-mixed with 26.4 g of 1,3-dibutylx~nthine and 16.6 g of 1-chloro-4-pentanone-ethyleneketal and subsequently refluxed under stirring for 26 hours. After heating for one hour with 30 ml of water and 10 ml of 33% sulfuric acid at 29 a temperature of 80 C of the mixture and subsequent cooling the reaction mass ~75~9C~
is neutralized with a saturated solution of sodiumbicarbonate and concen-trated under reduced pressure. The residue is adjusted with diluted sodium hydroxide to a pH value of 13 and repeatedly extracted with chloroform. The chloroform extracts are combined and after washing with water and drying over sodium sulphate they are concentrated. After column chromatography at silica gel with methylene chloride/acetone in a ratio by volume 8:1 as the solvent and bulb tube destillation at a bath temperature between 145 and 150C and 0.02 mm/Hg 7.3 g of 1,3-dibutyl-7-~4-oxopentyl)-xanthine having a melting point of 75 to 75.5C is obtained in a yield of 64.8% (referred to reacted 1,3-dibutylxanthine).
21. 2.1 g of 3-methyl-7-propylxanthine, 0.7 g of l-chloro-heptanone-~6) and 1.4 g of potassium carbonate are refluxed in 15 ml of dimethyl~orm-amide at 120C under stirring for 7 1/2 hours. After concentration under reduced pressure the residue is poured into 100 ml of water. Subsequently the mass is three times extracted with 100 ml of chloroform each, the combined chloroform extracts are subsequently treated with 1 n -sodium hydroxide and water and then dried over sodium sulphate. The concentration residue is then submitted to chromatography in a column containing silica gel 60 and chloroform/ethanol (9:1~ as a solvent. After recrystallisation from petrol ether/diisopropyl ether (3:1) 2.45 g of 1-~6-oxoheptyl)-3-methyl-7-propylxanthine having a melting point of 69 to 70C are obtained in a yield of 76.6%.
22. 20.8 g of 3-methyl-7-propylxanthine, 16.9 g of l-chloropentanone-(4)-ekhyleneketal and 14.2 g of potassium carbonate are stirred in 150 ml of dimethylformamide at 120C ~or 7 hours and a half. Af~er conccntration under reduced pressure the residue is admixed with 250 ml of water and twice ex-tracted with 300 ~1 of chloroform each. The combined chloroform phases are washed with 100 ml of 1 n~sodiumhydroxide and water. After concentration the residue is dissolved with 1 1 of methanollwater ~$:2~J then 15 ml of 33%
sulphuric acid are added and the mass is heated under sti~ring for one hour "
..... ,.. , ., , . . . ~
1~7S~9~
at 70 C. A-fter cooling it is neutralised with a saturated solution of sodium bicarbonate and concentrated to about 100 ml. By three times extraction with 300 ~1 of chloroform each, washing of the chloroform phase with water, drying over sodium sulphate and concentration 34 g of raw product are obtained. This product is then submitted to chromatography at silica gel 60 with chloroform/
ethanol (9:1) as a solvent. After recrystallisation from diisopropylether/
acetic ester (18:1) 19.1 g of 1-(4-oxopentyl)-3-methyl-7-propylxanthine having a melting point of 67.5 to 68 C are obtained in a yield of 67.4%
23. 22.2 g of 3-ethyl-7-propylxanthine, 14.1 g of 1-chlorohexanone-(5~
and 14.2 g of potassium carbonate in 150 ml of dimethylfo~mamide are stirred at 120 C for 8 hours. After concentration under reduced pressure the residue is suspended in 100 ml of water~ three times extracted with 200 ml of chloro-form each, the combined chloroform extracts are successively treated with 1 n-sodium hydroxide and water and then they are dried over sodium sulphate.
The concentration residue is submitted to chromatography in a column with silica gel 60 and with chloroform/ethanol (9:1) as a solvent. After recrystal-lization of the pure fractions from diisopropylether 12.2 g of 1-(5-oxohexyl) -3-ethyl-7-propylxanthine having a melting point of 81 to 82 C are obtained in a yield of 38%.
24. 17.1 g of 1-(4-hydroxypentyl)-3-methyl-7-propylxanthine in 25 ml of methylene chloride are dropwise added under stirring at 25 C within 10 minutes to 19.4 of pyridinium chlorochromate (E.J. Corey and J.W. Suggs, Tetrahedron Letters, Volume 31 (1975) page 2647 to 2650). Within 20 minutes the temperature increases to 34 C. After three hours stirring and staying over night it is decanted from the greasy precipitate and four times washed with 200 ml diethylether each. ~fter washing with water and dr~ing over sodium sulphate the combined organic phases are concentrated under reduced pressure. After column chromatography of the residue at silica gel 60 wi~h 29 chloroform/ethanol (9:1) as a solvent and recr~stallisation from diisopropyl ~L~'756~CJ
ether/acetic ester (18:1) 14.5 g of 1-(4-oxopentyl)-3-methyl--7-propyl-xanthine having a melting point of 67 to 68 C are obtained in a yield of 82.5%.
25. It is worked as in example 24, however, :L9.3 g of 1 (6-hydroxyheptyl) -3-methyl-7-propyl-xanthine are used as starting xanthine substance. 14.1 g of l-(6-oxoheptyl)-3-methyl-7-propyl-xanthine having a melting point of 69 C are obtained after recrystallisation from petrol ether/diisopropyl ether (3:1) in a yield of 73.4%.
26. It is worked as in example 24, however, 1805 g of 1-(5--hydroxyhexyl) -3-methyl-7-propyl~anthine are used as starting xanthine substance. 14 g of 1-(5-oxohexyl)-3-methyl-7-propylxanthine are obtained in a yield of 76.3%.
27. It is worked as in example 24, however, 17.7 g of 1-(5-hydroxyhexyl) -3-methyl-7-ethylxanthine are used as starting xanthine substance. 13.2 g of 1_(5-oxohexyl)-3-methyl-7-ethylxanthine are obtained in a yield of 78%.
28. It is worked as in example 24, however, 19.3 g of 1-(5-hydroxyhexyl) -3-methyl-7-butylxanthine are used as starting xanthine substance. 13.7 g of 1-(5-oxohexyl)-3-methyl-7-butylxanthine are obtained in a yield of 71.2%.
29. It is worked as in example 24, however, 19.4 g 1-(5-hydroxyhexyl) -3-ethyl-7-propylxanthine are used as starting xanthine substance. 13.4 g of 1-(5-oxohexyl)-3-ethyl-7-propylxanthine are obtained in a yield of 69%.
"Xanthine derivatives"
The invention relates to pharmac~uticals suitable ~or use in the treatment of diseases involving deficiencies in ~hle blood vascular system.
The phar~ac.eutical compositions contain certain oxoalkyl~dialkyl-xanthine derivatives havin~ in particular vascular dilatory activity and good fibrin-olytic action.
l-~Oxoalkyl)-3,7-dimethyl-xanthines and 7 (oxoalkyl~-1,3-dimethyl-xanthines have been prepared. These oxo compounds are Teadily 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 deriva-tives substituted by identical or diferent alkyl groups with 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in the 1-, 3- and 7-positio~s, at least one of which alkyl groups carries a hydrophilic group, preferably 0H or C00H, or also already known. The number of hydrophilic groups per alkyl group is generally between 1 and the number of carbon atoms in the gi~en alkyl group and the alkyl group which carries the hydrophilic group preferably contains 1 to 4 carbon atoms. ~Compounds having a hydroxyl substituent on a carbon atom adjacent to a ring nitrogen atom are unstable). lhe last-mentioned prior art does not disclose, however, that the hydrophilic group may be an oxoalkyl group, but there have only been disclosed compounds in which the hydrophilising groups contain oxygen and have 2 or 3 carbon atoms and one hydrophilising group is in the ~-position to the nearest ring nitrogen atom and all those alkyl groups which are not hydroxylated are methyl groups.
Furthe~more, the only compounds with only one hydrophilic group which have been specifically disclosed are derivatives of theobromine and of theophyl-line.
Pharmaceutical composi~ions are also kno~n which contain as active ingredient, xanthines having an oxoalkyl group with 6 to 20 car~on 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 .~' .
:~756~3 [) 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 general formula R
o 13 ~ 7 ~ (I) wherein one of the groups Rl and R3 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 (`~-l) oxoalkyl groups and by at least ~
carbon atoms in oxoalkyl groups in which the oxygen atom is separated from the terminal carbon atom by more than one carbon atom, R2 and the other one of Rl and R3 are straight-chain or branched aIkyl groups containing from 1 ; to 12 carbon atoms, but wherein that group Rl or R3 which is no oxoalkyl group, may also be hydrogen, one of the said substituents being hydrogen or an alkyl group containing more than l carbon atom, and physiologically acceptable acid addition salts thereof. The oxoalkyl group is preferably straight-chained. me carbonyl group in the oxoalkyl group is preferably in the (~-l)-position. At least one of the alkyl groups desirably contains more than 2 carbon atoms.
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. mey additionally have ; the éffect of improving the circulatory properties of blood and are therefore effective in the treatment of arterial blood flow disturbances. The pharma- ~-cological activity spectrum of the new compounds is otherwise substantially 29 similar to that of the previously known oxoallcyl-dimethyl-xanthines (oxo-~. . . . . . . .
~i~7~6~) alkyl-theophyl]ines and oxoalkyl-theobromines).
The following are specific examples of the new compounds according to the invention:-l-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, l-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, l-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)-xant~nes wherein the alkyl group is a methyl, ethyl, propyl~ butyl, isobutyl, hexyl or decyl group.
. The compounds of general formula I according to the invention may be prepared by the following processes, which processes constitute further ~eatures of the invention:
29 a) ~eaction of an appropriate 3-monoalkylxanthine or 1,3- or 3,7- : .
-4- : -~C~7SG~O
dialkyl-xanthine with a compound of formula R R
CH2 ~ -C-CH3 (II) (wherein R is an alkyl group containing from 1 to ~ carbon atoms, preferably a methyl or ethyl group) in an alkaline medium.
b) Reaction of an alkali metal salt of an appropriate 3-monoalkyl~an-thine or 1,3- or 3,7-dialkyl-xanthine with a compound of for~ula C113 - ~ - A -Hal (IIl) (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 subsequent:Ly hydrolysing the product.
c) Reaction of an alkali metal salt of an appropriate l-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 form-ula I as herein-before defined in which there are at least 3 carbon atoms between the car-bonyl group and the nearest nitrogen atom (which means that the o~ygen atom is separated by at least ~ carbon atoms from the nearest nitrogen atom) Reaction of a compound of formula X-Hal 0 ~ ~ N
R2 :
or a compound of formula 0 IR3 ~al -X
N I /~ (V) 29 0 ~ IN ~ N~/ -R2 ~ ~
~, , ~ ..
~37~
.
(wherein X is an alkylene group containing from 2 to 5 carbon atoms, which is preferably straight chained and Hal is a halogen atom, pre~erably a chlor-ine 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 ~-dialkylamino-alkyl 10 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. In embodiment a), b) d) and e) the alkyl group of 3-monoalkylxanthines may have from 1 to 12 carbon atoms.
The reactions mentioned above are carr~ed out in known manner, generally at temperatures of ~0 to 150 C, preferably 60 to 120 ~, 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. Retone splitting in method b) is carried out in the usual manner~
The organic solvents used are preferably those which are miscible with water, particularly ~onohydric alcohols, e.g. methanol, ethanol, pro-29 panol, isopropanol, the various butanols, also comprising ethylene glycol monomethyl ether and monoethyl ether, polyhydric alcohols such as ethyleneglycol, aprotic solvents such as acetone, pyridine, formamide and dimethyl-formamide.
According to a still further feature of the invention there are provided pharmaceutical compositions comprising as active ingredient a com-pound 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 3S 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, gelatine, 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 ingre-dient 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 10 to 400 mg of 29 active ingredient.
~:, ~7~ 0 me compounds of the invention may be administered in an amount of e.g. 0.1 mg to 125 mg, pre-ferably 1 mg to 50 mg per kg/body weight. The substances may be administered in a single dose or 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 methanoIand 321 g of water are brought into sol~tion 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 mix-- ture is heated under reflux for ~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 solutiQn and ex-; tracted with methylene chloride. 1-(5-Oxohexy1)-3-methyl-7-propyl-xanthine with a melting point of 69 ~o 70 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 litres of diisopropyl ether.
The solubility of the product in water at 25 C is about 3.2%. The solubility in ethanol and dimethyl sulphoxide is over 10%.
~ .
126 g of a colourless oil is obtained from 131 g of 3-methyl-7-n-hexyl-xanthine, 100 g of waterg 60 g of methanol, 20 g of sodium hydroxide and 89.5 g of 1-bromohexanone-(5~ analogously to Example 1. The oil is re-crystallised by dissolving it in 60 ml of methanol and reprecipitating it 29 from this methanolic solution with 1500 ml of diisopropyl ether. 1-(5-~L~7~6~3~
Oxohexyl)-3-methyl-7-n-hexyl-xanthine with a melting point of 50 - 52 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-iso-butyl-xanthine, 80 g of water, 48 g of methanol, 16 g of sodium hydroxide and 71.5 g of l-bromohexanone-(S) analogously to Example 1. After vacuum distillation (196-200 C/0.2 mm) and recrystallisation from diisopropyl etherg 10 1-(5-oxohexyl)-3_methyl-7-isobutyl_xanthine with a melting point of 75-76 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)-xanthi,ne in a mixture of 120 g af water and 72 g of methanol is brought into solution by the addition of 18 g of sodium hydroxide at about 60 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. Un-reacted 3-methyl-7-(5-oxohexyl)-xanthine is filtered off and the alcohol is `i 20 distilled off in ~racuo. me remaining so:lution is made alkaline with 4 ml of SO~ sodium hydroxide solution and exkracted with 350 ml of methylene chlor-ide. l-n-Propyl-3-methyl-7-(5-oxohexyl)-xanthine with a melting point of 76-78 C is obtained in 85% yield from the residue of the methylene chloride solution by recrystallisation from isopropanol. The solubility of the pro-duct 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-xanthineg 24 g of water, 24 g of methanol, 8 g of 50% sodium hydroxide solution and 29 17.9 g of 1-bromohexanone-(5) analogously to ~xample 1. After recrystallisa-_g_ , - - - - ~ .. .. .....
1~7~69~ ~
tion from a small quan-tity of methanol, 1-(5-oxohexyl)-3-methyl-7-ethyl-xanthine with a melting point of 102-103 C is obtained in almos~ quantitative yield. The solubility in water at 25 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%.
~xam~le 6 110 g of a yellow oil is obtained from lL7 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 l-bromohexanone-(5) analogously to Example 1. The oil is first distilled in vacuo (219 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 to 80 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 bro-mide is boiled under reflux for 4 days and then worked up in a manner ana-logous to ~xample 4. 82.9 g of a crude product are obtained from which ~l_n-hexyl-3-methyl-7-(5-oxohexyl)-xanthine is obtained in 90% yield after vacuum distillation (230-232 C 0.3 mml). After recrystallisation from 500 ml of diisopropyl ether, the melting point is 35-38 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 o~ isobutyl bromide is boiled under reflux fGr 85 hours and then acidified with 5 ml of concentrated sulphuric acid. ~* 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 ana-logous to Example 4 to yield 57.7 g of a colourless residue from which 1-t 29 isobu*yl-3-methyl-7-(S-oxohexyl)-xanthine with a melting point of 96-97 C
', :. . ~ . .; : . - . -~: , . . . - . ~ , ~7~6~
is obtained in 95~ yield (based on reacted 3-methyl-7-(5-oxohexyl)-xanthine) by recrystallisation from 1200 ml of diisopropyl ether.
xample 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 10 from 500 ml of diisopro~yl ether. The 1-(5-oxohexyl)3-methyl-7-n-decyl-xan-thine which is obtained in 85% yield melts at 64-66 C.
Fxample 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.
me mixture is heated to 70 C and stirred for one hour. 3.7 g (0.0206 mol) of l-bromohexanone-(5) are added at 70 C. The solution is then stirred for 5 hours at 70 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 to 100C.
The yield is 4.4 g of a crude product (72% of the theory, referred O : -to the butyl xanthine used) melting at 122 C.
4.3 g of the crude product are dissolved in lS mlofwater and 0.85 g of sodium hydroxide at 60 C; O.S g of active carbon-is added thereto, and the mixture is stirred for 15 minutes and then filtered. The filtrate is adjusted ~ith sulphuric acid of 33~0 strength to pH 9.5 at 60 C, and the mixture is then cooled in an ice bath. The precipitated crystals were isolated by suction, washed with water until they were free from aIkali and dried at 100 C in the ~acuum of a water je~ pump.
29 The yield is 2.6 g (42.5% of the theory, referred to the 3-butyl-. . . ., . . . . . . ., -:
~i7569~l xanthine used). ~he product proves to be uniform on thin layer chromatography and has a melting point of 134 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 C and stirred for about one hour. Then 183 g (1.02 mol) of 1-bromohexanone-(5) are dropped at this temperature into the mixture in the course of one hour. After about ha]f an hour a thick pulp is formed which however can still be stirred and is stirred for further 5 hours at 70 C. The pH-value does slightly fall and is at the end of the reaction in the range from 5 to 7. It is cooled to room temperature and the crystals are isolated by suction. These are dried at 70 to 100 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 C in 1000 ml of water and 40 g of sodium hydroxideO 13 g of active carbon are added thereto;
the mixture is then stirred for 15 minutes and filtered. The filtrate having 20 a temperature of 60 C is adjusted to pH 9.5 by adding 97 g of sulphuric acid (33% strength) during one hour. The mixture is stirred for a further hour at 60 C. The crystals precipitated are isolated by suction, washed with water until they are free from alkali and dried in the vacuum of the water jet pump at 100C.
The yield is 125 of 3-methyl-7-(5-oxohexyl~-xanthine (= 48% of the theory, referred to the 3-methyl-xanthine used). ~elting point 217 C.
~ further 5% of this compound may be obtained from the motherlye by acidifying with additional sulphuric acid down to a pH-value of about 4 29 and subsequent purification.
~1~75~
After intraduodenal administration to narcoti~ed cats the compound caused a significant and permanent increase in the cerebral blood circulation which is by several times superior to that of ethylenediamine-theophylline.
The compound is also much more compatible if administered intraperitoneally to mice. The LD50 -value at mice is in the range from 1000 to 1500 mg/kg, while that of ethylenediamine-theophylline is 217 mg/kg only.
Supplementary Disclosure Example 12 104.1 g of 3-n-butylxanthine are added under stirring to a solution of 20.4 g of sodium hydroxide in 200 ml of ~rater and 200 ml of methanol. Then at 70C 83.1 of the ethylene ketal of 1-chloropentanone-(4) are dropwise added to the clear solution~ After stirring for ~1 hours at 70C the reaction mass is cooled to 20 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 to 129 C.
This ketal is heated to 70 C for one hour in 1250 ml of 80% aqueous methanol in the presence of sulfuric acid-and at a p~ value of 1 to 2~ After neutral-isation and recrystallization of the precipitate from alkaline solution wherein the pH value was changed from 13.5 to 10 there are obtained 26.8 g of 3-n-butyl-7-(4~-oxopentyl)-xanthine having a melting point of 140.5 to 141 C (yield ~3.7%, referred to reacted xanthine).
Exam~e 13 24.8 g of 3-n-butyl-7-(4~-oxopentyl)-xanthine are added to a soIu-tion of 3.5 g of sodium hydroxide in 80 ml of methanol and water (1:1). After stirring for 30 minutes at 40 C 12O2 g of methyliodide are dropwise added.
After stirring for 50 hours the clear solution is concentrated under reduced pressure until dryness and the residue is diluted with ether and deliberated ~ from the starting material by addition of 1 n sodium hydroxide. After con-; centration the neutrali~ed ether solution and subsequent distillation at a 29 temperature of the mixture of 130 C under a pressure of 0~02 mm Hg 17.8 g of .
.,.. :.......... , .,.. . . - , . , . , .. . . , . . ; . .
~75~9~
l-methyl-3-n-butyl-7-(4~-oxopentyl)-xanthine having a melting point of 65 to 66 C are obtained (yield: 84.2%, referred to the reacted starting xanthine).
Example 14 80.1 g of 3-n-butylxanthine are added to a solution of 15.5 g of sodium hydroxide in 220 ml of a methanol/water mixture (1:1). After dropwise adding 53.7 g of 1-chlorohexanone-(5) to the clear solution which has a temperature of 70 C the mixture is stirred ak this temperature for 10 hours.
After cooling to 20C and one recrystallization of the precipitate from alka-line solution wherein the pH value changes from 13.5 to 10 there are obtained 34.4 g of pure 3-n-butyl-7-(5'-oxohexyl)-xanthine having a melting point of 141 C (yield: 51.3%, referred to reacted 3-n-butylxanthine).
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 solu~ion having a temperature of 40 C and the mixture is stirred at 48 C for 24 hours. After concentration under reduced pressure the residue is diluted with 300 ml of diethylether and ~he 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 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 VlSCOUS oil (n D = 1.5320; yield 77.2%, referred to reacted starting xa~thine). Analysis: C16H24N403 = 320.396 C H N
calculated: 59.98% 7.55% 17.49%
found: 60.05% 7.74% 17.36%
Examples 16 to 19 In the same way as ~lder example 15 the following eompounds were 29 prepared.
-1~- :' ,, ~75~
16. 3-n-Butyl-7-(6'-oxoheptyl)-xanthine, melting point 110 to 111 C, from 3-n-butylxanthine and 1-chloroheptanone-(6) at 70 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 ~o 99 C, from 3-n-butylxanthine and 1-bromooctanone-(7) at a mixture temperature of 70 C
under stirring for 39 hours (yield: 52.2%, referred to reacted 3-butylxan-thine).
18. ~he reaction is performed according to example 21 from 3-n-butyl-7-(6'-oxoheptyl~-xanthine and methyl iodide, but at a temperature of the mix-ture of 50 C under stirring for 46 hours. Prior to the distillation at a bath temperature of 140 C and 0.02 mmHg the product is purified by column chromatography at silicagel 60 (Merck) with methylene chloride/acelone (80;2) as eluent. l-Methyl-3-n-butyl-7-(6'-oxoheptyl)-xanthine was obtained as a viscous oil (n OD = 1.5280; yield: 80.1%, referred to reacted 3-n-butyl-7-(6'-oxoheptyl) xanthine. Analysis: C17H26N403 = 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 C
under stirring for 46 hours. The product is obtained in colorless crystals, melting point 52 C (yield: 94.4% re~erred to reacted 3-n-butyl-7-(7'-oxooctyl) -xanthine.
20. A solution of 2.3 g of sodium in 150 ml of absolute e~hanol is ad-mixed with 26.4 g of 1,3-dibutylx~nthine and 16.6 g of 1-chloro-4-pentanone-ethyleneketal and subsequently refluxed under stirring for 26 hours. After heating for one hour with 30 ml of water and 10 ml of 33% sulfuric acid at 29 a temperature of 80 C of the mixture and subsequent cooling the reaction mass ~75~9C~
is neutralized with a saturated solution of sodiumbicarbonate and concen-trated under reduced pressure. The residue is adjusted with diluted sodium hydroxide to a pH value of 13 and repeatedly extracted with chloroform. The chloroform extracts are combined and after washing with water and drying over sodium sulphate they are concentrated. After column chromatography at silica gel with methylene chloride/acetone in a ratio by volume 8:1 as the solvent and bulb tube destillation at a bath temperature between 145 and 150C and 0.02 mm/Hg 7.3 g of 1,3-dibutyl-7-~4-oxopentyl)-xanthine having a melting point of 75 to 75.5C is obtained in a yield of 64.8% (referred to reacted 1,3-dibutylxanthine).
21. 2.1 g of 3-methyl-7-propylxanthine, 0.7 g of l-chloro-heptanone-~6) and 1.4 g of potassium carbonate are refluxed in 15 ml of dimethyl~orm-amide at 120C under stirring for 7 1/2 hours. After concentration under reduced pressure the residue is poured into 100 ml of water. Subsequently the mass is three times extracted with 100 ml of chloroform each, the combined chloroform extracts are subsequently treated with 1 n -sodium hydroxide and water and then dried over sodium sulphate. The concentration residue is then submitted to chromatography in a column containing silica gel 60 and chloroform/ethanol (9:1~ as a solvent. After recrystallisation from petrol ether/diisopropyl ether (3:1) 2.45 g of 1-~6-oxoheptyl)-3-methyl-7-propylxanthine having a melting point of 69 to 70C are obtained in a yield of 76.6%.
22. 20.8 g of 3-methyl-7-propylxanthine, 16.9 g of l-chloropentanone-(4)-ekhyleneketal and 14.2 g of potassium carbonate are stirred in 150 ml of dimethylformamide at 120C ~or 7 hours and a half. Af~er conccntration under reduced pressure the residue is admixed with 250 ml of water and twice ex-tracted with 300 ~1 of chloroform each. The combined chloroform phases are washed with 100 ml of 1 n~sodiumhydroxide and water. After concentration the residue is dissolved with 1 1 of methanollwater ~$:2~J then 15 ml of 33%
sulphuric acid are added and the mass is heated under sti~ring for one hour "
..... ,.. , ., , . . . ~
1~7S~9~
at 70 C. A-fter cooling it is neutralised with a saturated solution of sodium bicarbonate and concentrated to about 100 ml. By three times extraction with 300 ~1 of chloroform each, washing of the chloroform phase with water, drying over sodium sulphate and concentration 34 g of raw product are obtained. This product is then submitted to chromatography at silica gel 60 with chloroform/
ethanol (9:1) as a solvent. After recrystallisation from diisopropylether/
acetic ester (18:1) 19.1 g of 1-(4-oxopentyl)-3-methyl-7-propylxanthine having a melting point of 67.5 to 68 C are obtained in a yield of 67.4%
23. 22.2 g of 3-ethyl-7-propylxanthine, 14.1 g of 1-chlorohexanone-(5~
and 14.2 g of potassium carbonate in 150 ml of dimethylfo~mamide are stirred at 120 C for 8 hours. After concentration under reduced pressure the residue is suspended in 100 ml of water~ three times extracted with 200 ml of chloro-form each, the combined chloroform extracts are successively treated with 1 n-sodium hydroxide and water and then they are dried over sodium sulphate.
The concentration residue is submitted to chromatography in a column with silica gel 60 and with chloroform/ethanol (9:1) as a solvent. After recrystal-lization of the pure fractions from diisopropylether 12.2 g of 1-(5-oxohexyl) -3-ethyl-7-propylxanthine having a melting point of 81 to 82 C are obtained in a yield of 38%.
24. 17.1 g of 1-(4-hydroxypentyl)-3-methyl-7-propylxanthine in 25 ml of methylene chloride are dropwise added under stirring at 25 C within 10 minutes to 19.4 of pyridinium chlorochromate (E.J. Corey and J.W. Suggs, Tetrahedron Letters, Volume 31 (1975) page 2647 to 2650). Within 20 minutes the temperature increases to 34 C. After three hours stirring and staying over night it is decanted from the greasy precipitate and four times washed with 200 ml diethylether each. ~fter washing with water and dr~ing over sodium sulphate the combined organic phases are concentrated under reduced pressure. After column chromatography of the residue at silica gel 60 wi~h 29 chloroform/ethanol (9:1) as a solvent and recr~stallisation from diisopropyl ~L~'756~CJ
ether/acetic ester (18:1) 14.5 g of 1-(4-oxopentyl)-3-methyl--7-propyl-xanthine having a melting point of 67 to 68 C are obtained in a yield of 82.5%.
25. It is worked as in example 24, however, :L9.3 g of 1 (6-hydroxyheptyl) -3-methyl-7-propyl-xanthine are used as starting xanthine substance. 14.1 g of l-(6-oxoheptyl)-3-methyl-7-propyl-xanthine having a melting point of 69 C are obtained after recrystallisation from petrol ether/diisopropyl ether (3:1) in a yield of 73.4%.
26. It is worked as in example 24, however, 1805 g of 1-(5--hydroxyhexyl) -3-methyl-7-propyl~anthine are used as starting xanthine substance. 14 g of 1-(5-oxohexyl)-3-methyl-7-propylxanthine are obtained in a yield of 76.3%.
27. It is worked as in example 24, however, 17.7 g of 1-(5-hydroxyhexyl) -3-methyl-7-ethylxanthine are used as starting xanthine substance. 13.2 g of 1_(5-oxohexyl)-3-methyl-7-ethylxanthine are obtained in a yield of 78%.
28. It is worked as in example 24, however, 19.3 g of 1-(5-hydroxyhexyl) -3-methyl-7-butylxanthine are used as starting xanthine substance. 13.7 g of 1-(5-oxohexyl)-3-methyl-7-butylxanthine are obtained in a yield of 71.2%.
29. It is worked as in example 24, however, 19.4 g 1-(5-hydroxyhexyl) -3-ethyl-7-propylxanthine are used as starting xanthine substance. 13.4 g of 1-(5-oxohexyl)-3-ethyl-7-propylxanthine are obtained in a yield of 69%.
2~ 30. It is worked as in example 24, howe~er, 18 g of 1-propyl-3-methyl-7-(5-hydroxyhexyl~-xanthine are used as starting xanthine substance~ 11.6 of l-propyl-3-methyl-7-(5-oxohexyl)-xanthine are obtained in a yield of 65%.
; 31. 6.6 (23 mol) 3-methyl-7-(3-bromopropyl)-xanthine are added at ambient temperature to a solution prepared from 6.0 g acetic acid ethyl ester, 1,06 g sodium and 100 ml absolute ethanol. The mixture is refluxed for 2 hours. After cooling the precipit~ted crystals are filtered off and the fil-trate is evaporated to dryness. The residue is first treated at ambient temperature for 2 hours with 100 ml of 5 percent aqueous sodium hydroxide 29 solution. then acidified with 14 ml of 50 percent sulphuric acid and then ~756~
boiled for 1 hour. After standing for 2 days the 3-metllyl-7-(S-oxohexyl)-xan~hine is filtered off. The yield is 3.5 g = 50% of theory.
For purification the crude product is dissol~ed in a little aqueous sodium hydroxide solution and 3-methyl-7-(5-oxohexyl)-xanthine is then ob-tained by precipitating with aqueous hydrochloric acid in a yield of 40 per-cent. Melting point 215 C.
32. 437.2 g of 3-methyl-7-propylxanthine, suspended in a mixture of 2~0 g of methanol and 321 g of water are dissolved in 160 g of 50% sodium hydroxide, heated to boiling temperature and at this temperature admixed with 35~ g of 1-bromohexanone-(5) and refluxed for 4 and a half hour. After cool-ing the unreacted 3-methyl-7-propylxanthine is separated and the alcohol is distilled off. The aqueous solution is adjusted with sodium hydroxide to a pH-value of 11 and extracted with methylene chloride. ~rom the residue of the methylene chloride solution and after recrystallisation from 5.2 1 of diisopropylether 1-(5-oxohexyl)-3-methyl-7-propylxan~hine ha~ing a melting pOillt of 69 to 70 G is obtained in a yield of about 90% (refer~ed to unreacted
; 31. 6.6 (23 mol) 3-methyl-7-(3-bromopropyl)-xanthine are added at ambient temperature to a solution prepared from 6.0 g acetic acid ethyl ester, 1,06 g sodium and 100 ml absolute ethanol. The mixture is refluxed for 2 hours. After cooling the precipit~ted crystals are filtered off and the fil-trate is evaporated to dryness. The residue is first treated at ambient temperature for 2 hours with 100 ml of 5 percent aqueous sodium hydroxide 29 solution. then acidified with 14 ml of 50 percent sulphuric acid and then ~756~
boiled for 1 hour. After standing for 2 days the 3-metllyl-7-(S-oxohexyl)-xan~hine is filtered off. The yield is 3.5 g = 50% of theory.
For purification the crude product is dissol~ed in a little aqueous sodium hydroxide solution and 3-methyl-7-(5-oxohexyl)-xanthine is then ob-tained by precipitating with aqueous hydrochloric acid in a yield of 40 per-cent. Melting point 215 C.
32. 437.2 g of 3-methyl-7-propylxanthine, suspended in a mixture of 2~0 g of methanol and 321 g of water are dissolved in 160 g of 50% sodium hydroxide, heated to boiling temperature and at this temperature admixed with 35~ g of 1-bromohexanone-(5) and refluxed for 4 and a half hour. After cool-ing the unreacted 3-methyl-7-propylxanthine is separated and the alcohol is distilled off. The aqueous solution is adjusted with sodium hydroxide to a pH-value of 11 and extracted with methylene chloride. ~rom the residue of the methylene chloride solution and after recrystallisation from 5.2 1 of diisopropylether 1-(5-oxohexyl)-3-methyl-7-propylxan~hine ha~ing a melting pOillt of 69 to 70 G is obtained in a yield of about 90% (refer~ed to unreacted
3-methyl-7-propylxanthine). (The solubility in water/25 C is about 3.1%, that in ethanol and dimethylsulphoxide above 10%).
; 33. 26.4 g of 1-(5-oxohexyl)-3-methylxanthine7 13.~ g of propylbromide and 13.8 g of potassium carbonate in 100 ml dimethylformamide are heated under stirring to 120 C for 3 hours. After destillation off of the solvent under reduced pressure and after addition of 100 ml of water the residue is ex-tracted with methylene chloride. The organic solvent is dis~illed off under - reduced pressure and the residue is re~rystallised from diisopropylether.
-~ 22 g of 1-(5-oxohexy1)-3-methyl-7-propylxanthine ha~ing a melting point of 69 to 70 C are obtained in a yield of 72%.
34. ¦ A solution of 2.5 g of sodiuml in 150 ml of absolute ethanol is admixed with 1~.3 g of acetoacetic acid ethylester and 32.9 g o-f 1-(3-bromo-29 propyl)-3-methyl-7-propylxanthine and refluxed for 5 hours. The alcohol is ~569~
practically distilled off and the residue is refluxed with 150 ml of 5% of sodium hydroxide for 3 hours. ~or decarboxylation the mass is acidified with half-concentrated sulphuric acid and heated for further 2 hours. The reaction mass is made alkaline with sodium hydroxide and extracted with methylene chloride. After evaporation of the solvent the obt:ained residue is submitted to chromatography over silica gel with ben3ene/acetone (7:3) as a solvent.
After recrystallisation of the residue of the main fraction from diisopropyl-ether l-(5-oxohexyl)~3-methyl-7-propylxanthine having a melting point of 69 to 70 C is obtained in a yield of 41%.
35. IIt is worked according to example 33, but in using 12.5 g of 1-(4-oxopentyl)-3-methylxanthine, 6.8 g of propylbromide and 7 g of potassium carbonate in 100 ml dimethylformamide as starting materials. 11 g of 1-(4-oxopentyl)-3-methyl-7-propylxanthine having a melting point of 67 to 68 C
are obtained in~a yield of 75~ (recrystallisation from diisopropylether/
acetic ester).
36. It is worked as in example 34, but in using 1.9 g of sodium, dis-solved in 120 ml of absolute ethanol, 10.4 g of acetoacetic acid ethylester and 25.2 g of 1-(2-bromoethyl)-3-methyl-?-propylxanthine. 20 g of a raw product is obtained which is submitted to chromatography at silica gel ~ith chloro~orm/ethanol (9:1) as a sol~ent. After recrystallisation 9.2 g 1-(4-oxopentyl)-3-methyl-7-propylxanthine are obtained in a yield of 48%.
37. It is worked as in example 33, but in using 27.8 g of 1-~6-oxo-heptyl)-3-methylxanthine, 9 g of propylchloride and 13.8 g of potassium carbonate in 100 ml of dimethylformamide as starting substances. 26.6 g of 1-(6-oxoheptyl)-3~methyl-7-propylxanthine having a melting point of 69 to 70 C are obtained in a yield of 83%.
38. It is worked according to example 34, but in using 3.4 g of 1 (4-- bromobutyl)-3-methyl-7-propylxanthine, 0.3 g of sodium and 1.7 g of aceto-29 acetic acid ethylester. 1.7 g of 1-(6-oxoheptyl)-3-methyl-7-propylxanthine .. . . . . . .
- . . ~ . ; , , , . ~ . : . . .
7~691~
are obtained.
39. It is worked according to example 32, but in using 117 g of 3-methyl-7-n-butylxanthine, 140 g of water7 85 g of methanol, 20 g of sodium hydroxide and 95 g of 1-bromohexanone-(5) as starting substances. 110 g of a yellow oil is obtained which is firstly submitted to a distillation under reduced pressure (219 C/005 mm) and then it is crystallised with 700 ml diisopropyl-ether. In a yield of 60% 1-(5-oxohexyl)-3-methyl-7-n-butylxanthine having a melting point of 79 to 80 C is obtained.
40. It is worked as in example 33, but in using 26.4 g 1-(5-oxohexyl)-3-methylxanthine, 10.2 g of n-butylchloride, 13.8 g of potassium carbonate and 100 ml of dimethylformamide as starting substances. 28 g of 1-(5-oxo-hexyl)-3-methyl-7-butylxanthine having a melting point of 79 to 80 C are obtained in a yield of 87%.
41. It is worked as in example 34, but in using 0.3 g of sodium, dis solved in 25 ml of absolute ethanol, 1.4 g of acetoacetic acid ethylester and 3 4 g of 3-~bromopropyl)-3-methyl-7-butylxanthine. 3 g of an oily raw product are obtained which is two times submitted to chromatography at silica gel with chloroform/ethanol (9:1) as a solvent and after recrystallisation from diisopropylether 1-(5-oxohexyl)-3-methyl-7-butylxanthine having a ;~
20 melting point of 79 C is obtained in a yield of 48%. ;
42. It is worked according to example 32, but in using 20.4 g o~ 3-methyl -7-ethylxanthine, 24 g of water, 24 g of methanol, 8 g of 50% sodium hydroxide and 17.9 of 1-bromohexanone-~5). A raw product is obtained from which after recrystallisation from a little methanol 1-(5-oxohexyl)-3-methyl-7-ethylxan-thine having a melting point of 102 to 103 C is obtained in a nearly quanti-tative yield.
43. It is worked as in example 33, but in using 13.2 g of 1-(5-oxo-hexyl)-3-methylxanthine, 7 g of potassium carbonate and 6.6 g of ethyl bromide 29 in 100 ml of dimethylformamide as startîng substances. 10 g of 1-(5-oxohexyl) ~75~
-3-methyl-7-e-thylxanthine are obtained which is recrystallised two times from a little methanol~ The final product has a melting point of 103 C.
; 33. 26.4 g of 1-(5-oxohexyl)-3-methylxanthine7 13.~ g of propylbromide and 13.8 g of potassium carbonate in 100 ml dimethylformamide are heated under stirring to 120 C for 3 hours. After destillation off of the solvent under reduced pressure and after addition of 100 ml of water the residue is ex-tracted with methylene chloride. The organic solvent is dis~illed off under - reduced pressure and the residue is re~rystallised from diisopropylether.
-~ 22 g of 1-(5-oxohexy1)-3-methyl-7-propylxanthine ha~ing a melting point of 69 to 70 C are obtained in a yield of 72%.
34. ¦ A solution of 2.5 g of sodiuml in 150 ml of absolute ethanol is admixed with 1~.3 g of acetoacetic acid ethylester and 32.9 g o-f 1-(3-bromo-29 propyl)-3-methyl-7-propylxanthine and refluxed for 5 hours. The alcohol is ~569~
practically distilled off and the residue is refluxed with 150 ml of 5% of sodium hydroxide for 3 hours. ~or decarboxylation the mass is acidified with half-concentrated sulphuric acid and heated for further 2 hours. The reaction mass is made alkaline with sodium hydroxide and extracted with methylene chloride. After evaporation of the solvent the obt:ained residue is submitted to chromatography over silica gel with ben3ene/acetone (7:3) as a solvent.
After recrystallisation of the residue of the main fraction from diisopropyl-ether l-(5-oxohexyl)~3-methyl-7-propylxanthine having a melting point of 69 to 70 C is obtained in a yield of 41%.
35. IIt is worked according to example 33, but in using 12.5 g of 1-(4-oxopentyl)-3-methylxanthine, 6.8 g of propylbromide and 7 g of potassium carbonate in 100 ml dimethylformamide as starting materials. 11 g of 1-(4-oxopentyl)-3-methyl-7-propylxanthine having a melting point of 67 to 68 C
are obtained in~a yield of 75~ (recrystallisation from diisopropylether/
acetic ester).
36. It is worked as in example 34, but in using 1.9 g of sodium, dis-solved in 120 ml of absolute ethanol, 10.4 g of acetoacetic acid ethylester and 25.2 g of 1-(2-bromoethyl)-3-methyl-?-propylxanthine. 20 g of a raw product is obtained which is submitted to chromatography at silica gel ~ith chloro~orm/ethanol (9:1) as a sol~ent. After recrystallisation 9.2 g 1-(4-oxopentyl)-3-methyl-7-propylxanthine are obtained in a yield of 48%.
37. It is worked as in example 33, but in using 27.8 g of 1-~6-oxo-heptyl)-3-methylxanthine, 9 g of propylchloride and 13.8 g of potassium carbonate in 100 ml of dimethylformamide as starting substances. 26.6 g of 1-(6-oxoheptyl)-3~methyl-7-propylxanthine having a melting point of 69 to 70 C are obtained in a yield of 83%.
38. It is worked according to example 34, but in using 3.4 g of 1 (4-- bromobutyl)-3-methyl-7-propylxanthine, 0.3 g of sodium and 1.7 g of aceto-29 acetic acid ethylester. 1.7 g of 1-(6-oxoheptyl)-3-methyl-7-propylxanthine .. . . . . . .
- . . ~ . ; , , , . ~ . : . . .
7~691~
are obtained.
39. It is worked according to example 32, but in using 117 g of 3-methyl-7-n-butylxanthine, 140 g of water7 85 g of methanol, 20 g of sodium hydroxide and 95 g of 1-bromohexanone-(5) as starting substances. 110 g of a yellow oil is obtained which is firstly submitted to a distillation under reduced pressure (219 C/005 mm) and then it is crystallised with 700 ml diisopropyl-ether. In a yield of 60% 1-(5-oxohexyl)-3-methyl-7-n-butylxanthine having a melting point of 79 to 80 C is obtained.
40. It is worked as in example 33, but in using 26.4 g 1-(5-oxohexyl)-3-methylxanthine, 10.2 g of n-butylchloride, 13.8 g of potassium carbonate and 100 ml of dimethylformamide as starting substances. 28 g of 1-(5-oxo-hexyl)-3-methyl-7-butylxanthine having a melting point of 79 to 80 C are obtained in a yield of 87%.
41. It is worked as in example 34, but in using 0.3 g of sodium, dis solved in 25 ml of absolute ethanol, 1.4 g of acetoacetic acid ethylester and 3 4 g of 3-~bromopropyl)-3-methyl-7-butylxanthine. 3 g of an oily raw product are obtained which is two times submitted to chromatography at silica gel with chloroform/ethanol (9:1) as a solvent and after recrystallisation from diisopropylether 1-(5-oxohexyl)-3-methyl-7-butylxanthine having a ;~
20 melting point of 79 C is obtained in a yield of 48%. ;
42. It is worked according to example 32, but in using 20.4 g o~ 3-methyl -7-ethylxanthine, 24 g of water, 24 g of methanol, 8 g of 50% sodium hydroxide and 17.9 of 1-bromohexanone-~5). A raw product is obtained from which after recrystallisation from a little methanol 1-(5-oxohexyl)-3-methyl-7-ethylxan-thine having a melting point of 102 to 103 C is obtained in a nearly quanti-tative yield.
43. It is worked as in example 33, but in using 13.2 g of 1-(5-oxo-hexyl)-3-methylxanthine, 7 g of potassium carbonate and 6.6 g of ethyl bromide 29 in 100 ml of dimethylformamide as startîng substances. 10 g of 1-(5-oxohexyl) ~75~
-3-methyl-7-e-thylxanthine are obtained which is recrystallised two times from a little methanol~ The final product has a melting point of 103 C.
4~. It is worked as in example 34, but in using 15 g of 1-(3-oromo-propyl)-3-methyl-7-ethylxanthine, 7.5 g of acetoacetic acid ethyl ester and 1.3 g of sodium as starting substances. 8 g of 1-l(5-oxohexyl)-3-methyl-7-ethylxanthine having a melting point of 103 C are obtained.
45. 27.8 g of 1-(5-oxohexyl)-3-ethylxanthine, 8.5 f of propylbromide, 13.8 g of potassium carbonate in 150 ml of dimethylformamide are reacted as in example 33. After recrystallisation from diisopropylether 24 g of 1-(5-oxohexyl)-3-ethyl-7-propylxanthine having a melting point between 81 and 82 C
are obtained in a yield of 75%.
46. 3.4 of 1-(3-bromopropyl)-3-ethyl-7-propylxanthine, 1.3 g of aceto-acetic acid ethyl ester and 0.3 of sodium are reacted as in example 34.
1-(5-oxohexyl)-3-ethyl-7-propylxanthine is obtained in a yield of about 20%.
47. 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 dissolved with 18 g of sodium hydroxide at about ~0 C and admixed with 55.5 g of n-propylbromide.
After refluxing for 24 hours 1 ml of concentrated sulphuric acid is added ko the reaction mixture and the mixture is cooled reacted 3-methyl-7-(5-oxo-hexyl)-xanthine is filtered off and the alcohol is distilled off under reduced pressure. me residue is made alkaline with 4 ml of 50% sodium hyd-roxide and then extracted with 350 ml of methylene chloride. After recrystal-lisation from isopropanol l-n-propyl-3-methyl-7-(5-oxohexyl)-xanthine having a melting point of 76 to 78 C is obtained in a yield of 85% from the residue of the methylene chloride solution. The solubility in ethanol, dimethyl-sulfoxide and dimethylformamide is above 10%~
48. 20.8 g of 1-n-propy]-3-methylxanthine and 13.8 of potassium car-bonate are heated in 150 ml of dimethylformamide to 120 C and 14 g of 1-29 chlorohexanone-(5) are dropwise added during 10 minutes. The reaction mix-~ 0i756~
ture is stirred for one hour, then the solvent is distilled off under reduced pressure and the cooled residue is admixed with 100 ml of water and extractecl with 100 ml of methylene chloride. After washing the organic phase with 1-n-sodium hydroxide the solvent is distilled off. After recrystallisation of the residue from diisopropylether l-n-propyl-3-methyl-7-(5-oxohexyl)-xanthine having a melting point of 53 C is obtained in a yield of 25.1 g (=83%).
49.249 g of 3-methylxanthine and 126 g of sodium bicarbonate are suspended in 750 g of dimethylformamide and 210 g of 1-chlorohexanone-5 are portionwise added under stirring, wherein the reaction mixture is heated to 75 C. After finished addition the reaction mixture is heated to 130 to 140 C
for further 6 hours. Subsequently it is cooled to ~nbient temperature, the crystals are separated by suction and washed with iso~propanol. The dried residue is suspended in 1 1 of 90 C warm water, the suspension is adjusted to a pH-value of 9.6 with sodium hydroxide and strongly stirred. The sus-pension is cooled and after one day of staying the crystals are separated by suction. After washing with water and drying 325 g of 3-methyl-7-(5-oxohexyl) -xanthine having a melting point of 219 C are obtained in a yield of 62%.
Pharmacological experiments Furthermore with a number of oxoalkyl-xanthines various pharmaco-logical tests have been performed. m e results are evident from the following table 1.
~ .
Table 1 (cf. example No. of the present Pharmacological effects case)_ _ _ ~ _ _ _ 4 1-n-Propyl-3-methyl-7-~5-oxohexyl)-xanthine (melting point 76-78 C3: LD50 = 100-250 mg/kg i.p.
29 (mouse), strong broncholytic effect at the guinea pig to -23- ;
~s~
(cf. example No. of the present Pharmacological effects case) acetylcholine, histamine and serotonine, increase of the cerebral and muscle perfusion at the cat, fibrinolytic effect.
8 1-Isobutyl-3-methyl-7-(5-oxohex~l)-xanthine (melting point 96-97 C): ID50 = 250-500 mg/kg i.p. (mouse), strong broncholytic effect to histamine, phosphodiester-ase inhibition at bronchii of cattle about the same as after addition of theophylline: ED50 = 6.1 x 10 4 M
(theophylline ED50 = 7 5 - 10 M), increase of the cerebral blood perfusion at the cat.
7 1-Hexyl-3-methyl-7-(5-oxohexyl)-xanthine (melting point 35-38 C): LD50 = 250-500 mg/kg i.p. (mouse), strong bron-cholytic effect at the guinea pig to acetylcholine, his- ;
tamine and serotonine, phosphodiesterase restriction at bronchii of cattle stronger than that by theophylline:
ED50 = l.9S x 10 4 M (theophylline ED50 = 7.5 x 10 M).
1 1-(5-oxohexyl)-3-methyl-7-propyl-xanthine (melting point 69-70 C): LD50 = 107 mg/kg i.v. (mouse), 860 mg/kg per os (mouse), strong broncholytic effect at the guinea pig to acetylcholine, histamine and serotonine; at the iso- -lated tracheal chain in the concentration of 3 x 10 strong inhibition ~94%) of the isoprenaline effect which may not be inhibited by propanolol (i.e. it is not caused by a R2-mimetic effect~. Long-lasting increase of the cerebral blood perfusion at the cat after a dosis between 1 and 5 mg/kg i.v.. Fibrinolytic effect in vitro in 29 hanging-clot-test from 2S mmol. At the isolated guinea ~75~
(cf. example No. of the present Pharmacological effect case) pig heart from 30 ~ positive inotropic efEect.
6 1-(5-oxohexyl)-3-methyl-7--n-butyl-xanthine (melting point 79-80 C): LD50 = 250-500 mg/kg i.p. (mouse), strong broncholytic effect at the guinea pig to acetyl-choline, histamine and serotonine, increase of the cere-bral blood perfusion.
3 1-(5-oxohexyl)-3-methyl-7-isobutyl_xanthine (melting point 75-76 C): LD50 = 500-700 mg/kg i.p. (mouse), fibrinolytic effect in vitro from 20 mmol, increase of the duration of the hexobarbital narcosis~
9 1-(5-oxohexyl)-3-methyl-7-decyl-xanthine (melting point 64-66 C): LD50 = 500 mg/kg i.p~ (mouse), broncholytic effect at the guinea pig to acetylcholine, histamine and serotonine, increase of cerebral blood perfusion at the cat.
1-(5-oxohexyl)-3~methyl-7-ekhyl-xanthine (melting point 102-103 C): LD50 = 120-200 mg/kg i.v. (mouse~, 250-500 mg/kg i.p. (mouse), strong broncholytic effect at the guinea pig to acetylcholine, histamine and serotonine.
Strong and long-las~ing improvement of the cerebral blood perfusion at the cak after doses of 1 to 5 mg/kg i.v., increase of the muscular blood perfusion, fibrinolytic effect in vitro in hanging-clot-test from 25 mmol.
' 9~ ' Comparison 1 (Cl) 1-(5-Oxohexyl)-3-methyl-7-propyl-xanthine, the cerebral b]ood per-29 fusion was measured at narcotized cats by means of fluvography under admini-, :
S~i~3~ ~
stration of doses of 0.3, 1, 2 and 5 mg/kg i.v.. The present compound efIects a long-lasting increase of the cerebral blood perfusion being dependent on the dosis. The effect was superior to that of the 1-(5-oxohexyl)-3,7-dimethyl -xanthine which was administered in a dose of 3 mg/kg i.v..
Gomparison 2 (C2) 1-(5-Oxohexyl)-3-methyl-7-ethyl-xanthine: the cerebral blood perfusion at narcotized cats was measured by fluvography af~er administration of doses of 0.3, 1, 2 and 5 mg/kg i.v.. The present compounds effected a distinct increase of the cerebral blood perfusion being dependent on the dose.
10 It proved to be more effective than 1-~5-oxohexyl)-3,7-dimethyl-xanthine which was used for comparison and which had been administered in a dosis of 3 mg/kg i.v............................................................ ,~
Comparison tests for cerebral blood perfusion Several experiments were performed with various oxoalkyl-xanthine derivatives wherein the increase of the cerebral blood perfusion at the cat was measured. The results were compared with those of the known subst-ance 1-(5-oxohexyl)-3,7-dimethyl-xan~hine and with aminophylline.
The tested compounds are evident from the following table 2.
Table 2 20 No.
(cf. example) Substance Melting point C
4 1-propyl-3-methyl-7-(5-oxohexyl)-xanthine 76-78 8 1-isobutyl-3-methyl-7 (5-oxohexyl)-xanthine 96-97 7 1-hexyl-3-methyl-7-(5-oxohe~yl)-xanthine35-38 1-(5-oxohexyl)-3-methyl-7-propylxanthine 69-70 6 1-(5-oxohexyl)-3-methyl 7-n-butylYanthine 79-80 4 1-(5-oxohexyl)-3-methyl-7-decyl-xanthine64-66 1-(5-oxohexyl)-3-methyl-7-ethyl-xanthine102-103 ;
Cl 1-~5-oxohexyl)-3,7-dimethyl-xanthine102-105 (comparison) 29 C2 aminophylline 270-274 ~comparison) .- :. . . ,, ,., . , ., . , . :
.. . . . .
Test method The test principle of K.~Golenhofen, H.-Hensel and G.-Hildebrandt, "Durchblutungsmessungen mit Warmeleitelementen in Forschung und Klinik"
(="blood perfusion measurements with heat conducting elements in research and clinics", Thieme edition Stuttgart 1963) was used. The -test animals were cats in chloralose-urethane narcosis (70 + 200 mg/kg i.p.). The calvaria was opened in the area of the frontal gyrus marginalis or suprasylvicus res-pectively. The measurements occured with a modified surface measurement head according to Hensel (cf. Pflugers Arch. 268 (1959), page 60~) which was laid thereon after opening of the dura of the cerebral cortexO The duration of effectivity was registered as half-life~ime, the intensity of activity was registered according to Golenhofen et al as heat transport number A.
The registration was performed by thermosonds over a two-channel fluvograph of the firm Hartmann ~ Braun, Frankfurt on Main. Other circulation parameters registered simultaneously were conducted to a Helligemore-channel-graph.
Experimental results . , .
The results obtained at the mentioned experiments are represented in the following table 2 as~ ~ and as half-life-time in minutes. ~ ~ is the change of blood perfusion.
. .
:
~ ..................... . .
1~7~6~0 Table 3 _ _ Sample dosis mg/kg change of the cerebral animals No. i.v. blood perfusion n (cf. A ~ half-life--time exam le~ ~\ tl in minutes _P~ __ ___ ~, 8 1 ~ 1~85 1.0 2 _ 5 ~ 3.45 1~.3 _ _2 _ 7 1 + 0.97 0.4 3 2 + 1.45 _0 _ _ _2 1 1 ~ 4.33 4.0 3 2 -~ 6.33 5.8 3 ~3.00_ _1~.7 3 6 1 -~ 2.50 1.3 2 2 + 2.55 1.3 2 _ _ 5 _+ 2.40 __ 3.0 4 1 + 1.40 0.2 1 _ 3 -~ 2.80 0.5 _ 1 1 -~ 2.46 1.5 5 2 + S.17 5.0 3 -~ 8 07 8 2 3 _ . . _ ~:
Cl 1 ~ 0.44 0.9 13 (comparison) 5 -~ 0.86 2.4 40 -~ 1.15 8.6 33 _ _20 _ _~ _ _ . ___ __ C2 1 ~ 0.19 1.~ 7 (comparison) 2 + 0.15 1.8 2 ~ 0.1~ 3,3 8 _ ~ _ _ 10 + 0.53 1.7 _ .
:;
~ 137569~3 Discussion of the results As it is evident from table 3 above sample No. 8 shows a stronger and more extended cerebral blood perfusion. Thus, a dose of 5 mg has an effect being four times stronger and a half-life-time being five times longer than those of the comparison sample No. Cl. In a dose of 2 mg/kg of sample No. 7 the effect is about double so strong and the half life-time about three times so long as the corresponding effects of the comparison substance No. G2 but with a higher dose of 5 mg/kg of the comparison substance. In all doses of sample No. 1 an essential (i.e. more than ten times) stronger and longer cerebral blood perfusion is obtained compared with the correspond:ing dosages of the comparison substance No. Cl. Sample No. 6 effects an increase of cerebral blood perfusion compared with a comparison substance No. Cl. Thus, at a dose of 1 mg/kg the cerebral blood perfusion is about si~ times higher and at a dose of 5 mg/kg it is about three times higher than that of the substance No. Cl. An improvement over substance No. Cl is also shown at sample No. 5 wherein the cerebral blood perfusion at a dose of 1 mg/kg is about five times higher and at a dose of 5 mg/kg it is about nine times ! higher than that of the comparison substance. At a dose of 1 mg/kg the half-life_time is 1.5 times longer and at a dose of 5 mg/kg it is more than three times longer than that of the comparison substance No. Cl.
There is also a distinct improvement of the effectivity of cerebral blood perfusion over the comparison substance aminophylline.
The technical advance of khe invention over the substances of the prior art is distinctly proved.
.. ..
45. 27.8 g of 1-(5-oxohexyl)-3-ethylxanthine, 8.5 f of propylbromide, 13.8 g of potassium carbonate in 150 ml of dimethylformamide are reacted as in example 33. After recrystallisation from diisopropylether 24 g of 1-(5-oxohexyl)-3-ethyl-7-propylxanthine having a melting point between 81 and 82 C
are obtained in a yield of 75%.
46. 3.4 of 1-(3-bromopropyl)-3-ethyl-7-propylxanthine, 1.3 g of aceto-acetic acid ethyl ester and 0.3 of sodium are reacted as in example 34.
1-(5-oxohexyl)-3-ethyl-7-propylxanthine is obtained in a yield of about 20%.
47. 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 dissolved with 18 g of sodium hydroxide at about ~0 C and admixed with 55.5 g of n-propylbromide.
After refluxing for 24 hours 1 ml of concentrated sulphuric acid is added ko the reaction mixture and the mixture is cooled reacted 3-methyl-7-(5-oxo-hexyl)-xanthine is filtered off and the alcohol is distilled off under reduced pressure. me residue is made alkaline with 4 ml of 50% sodium hyd-roxide and then extracted with 350 ml of methylene chloride. After recrystal-lisation from isopropanol l-n-propyl-3-methyl-7-(5-oxohexyl)-xanthine having a melting point of 76 to 78 C is obtained in a yield of 85% from the residue of the methylene chloride solution. The solubility in ethanol, dimethyl-sulfoxide and dimethylformamide is above 10%~
48. 20.8 g of 1-n-propy]-3-methylxanthine and 13.8 of potassium car-bonate are heated in 150 ml of dimethylformamide to 120 C and 14 g of 1-29 chlorohexanone-(5) are dropwise added during 10 minutes. The reaction mix-~ 0i756~
ture is stirred for one hour, then the solvent is distilled off under reduced pressure and the cooled residue is admixed with 100 ml of water and extractecl with 100 ml of methylene chloride. After washing the organic phase with 1-n-sodium hydroxide the solvent is distilled off. After recrystallisation of the residue from diisopropylether l-n-propyl-3-methyl-7-(5-oxohexyl)-xanthine having a melting point of 53 C is obtained in a yield of 25.1 g (=83%).
49.249 g of 3-methylxanthine and 126 g of sodium bicarbonate are suspended in 750 g of dimethylformamide and 210 g of 1-chlorohexanone-5 are portionwise added under stirring, wherein the reaction mixture is heated to 75 C. After finished addition the reaction mixture is heated to 130 to 140 C
for further 6 hours. Subsequently it is cooled to ~nbient temperature, the crystals are separated by suction and washed with iso~propanol. The dried residue is suspended in 1 1 of 90 C warm water, the suspension is adjusted to a pH-value of 9.6 with sodium hydroxide and strongly stirred. The sus-pension is cooled and after one day of staying the crystals are separated by suction. After washing with water and drying 325 g of 3-methyl-7-(5-oxohexyl) -xanthine having a melting point of 219 C are obtained in a yield of 62%.
Pharmacological experiments Furthermore with a number of oxoalkyl-xanthines various pharmaco-logical tests have been performed. m e results are evident from the following table 1.
~ .
Table 1 (cf. example No. of the present Pharmacological effects case)_ _ _ ~ _ _ _ 4 1-n-Propyl-3-methyl-7-~5-oxohexyl)-xanthine (melting point 76-78 C3: LD50 = 100-250 mg/kg i.p.
29 (mouse), strong broncholytic effect at the guinea pig to -23- ;
~s~
(cf. example No. of the present Pharmacological effects case) acetylcholine, histamine and serotonine, increase of the cerebral and muscle perfusion at the cat, fibrinolytic effect.
8 1-Isobutyl-3-methyl-7-(5-oxohex~l)-xanthine (melting point 96-97 C): ID50 = 250-500 mg/kg i.p. (mouse), strong broncholytic effect to histamine, phosphodiester-ase inhibition at bronchii of cattle about the same as after addition of theophylline: ED50 = 6.1 x 10 4 M
(theophylline ED50 = 7 5 - 10 M), increase of the cerebral blood perfusion at the cat.
7 1-Hexyl-3-methyl-7-(5-oxohexyl)-xanthine (melting point 35-38 C): LD50 = 250-500 mg/kg i.p. (mouse), strong bron-cholytic effect at the guinea pig to acetylcholine, his- ;
tamine and serotonine, phosphodiesterase restriction at bronchii of cattle stronger than that by theophylline:
ED50 = l.9S x 10 4 M (theophylline ED50 = 7.5 x 10 M).
1 1-(5-oxohexyl)-3-methyl-7-propyl-xanthine (melting point 69-70 C): LD50 = 107 mg/kg i.v. (mouse), 860 mg/kg per os (mouse), strong broncholytic effect at the guinea pig to acetylcholine, histamine and serotonine; at the iso- -lated tracheal chain in the concentration of 3 x 10 strong inhibition ~94%) of the isoprenaline effect which may not be inhibited by propanolol (i.e. it is not caused by a R2-mimetic effect~. Long-lasting increase of the cerebral blood perfusion at the cat after a dosis between 1 and 5 mg/kg i.v.. Fibrinolytic effect in vitro in 29 hanging-clot-test from 2S mmol. At the isolated guinea ~75~
(cf. example No. of the present Pharmacological effect case) pig heart from 30 ~ positive inotropic efEect.
6 1-(5-oxohexyl)-3-methyl-7--n-butyl-xanthine (melting point 79-80 C): LD50 = 250-500 mg/kg i.p. (mouse), strong broncholytic effect at the guinea pig to acetyl-choline, histamine and serotonine, increase of the cere-bral blood perfusion.
3 1-(5-oxohexyl)-3-methyl-7-isobutyl_xanthine (melting point 75-76 C): LD50 = 500-700 mg/kg i.p. (mouse), fibrinolytic effect in vitro from 20 mmol, increase of the duration of the hexobarbital narcosis~
9 1-(5-oxohexyl)-3-methyl-7-decyl-xanthine (melting point 64-66 C): LD50 = 500 mg/kg i.p~ (mouse), broncholytic effect at the guinea pig to acetylcholine, histamine and serotonine, increase of cerebral blood perfusion at the cat.
1-(5-oxohexyl)-3~methyl-7-ekhyl-xanthine (melting point 102-103 C): LD50 = 120-200 mg/kg i.v. (mouse~, 250-500 mg/kg i.p. (mouse), strong broncholytic effect at the guinea pig to acetylcholine, histamine and serotonine.
Strong and long-las~ing improvement of the cerebral blood perfusion at the cak after doses of 1 to 5 mg/kg i.v., increase of the muscular blood perfusion, fibrinolytic effect in vitro in hanging-clot-test from 25 mmol.
' 9~ ' Comparison 1 (Cl) 1-(5-Oxohexyl)-3-methyl-7-propyl-xanthine, the cerebral b]ood per-29 fusion was measured at narcotized cats by means of fluvography under admini-, :
S~i~3~ ~
stration of doses of 0.3, 1, 2 and 5 mg/kg i.v.. The present compound efIects a long-lasting increase of the cerebral blood perfusion being dependent on the dosis. The effect was superior to that of the 1-(5-oxohexyl)-3,7-dimethyl -xanthine which was administered in a dose of 3 mg/kg i.v..
Gomparison 2 (C2) 1-(5-Oxohexyl)-3-methyl-7-ethyl-xanthine: the cerebral blood perfusion at narcotized cats was measured by fluvography af~er administration of doses of 0.3, 1, 2 and 5 mg/kg i.v.. The present compounds effected a distinct increase of the cerebral blood perfusion being dependent on the dose.
10 It proved to be more effective than 1-~5-oxohexyl)-3,7-dimethyl-xanthine which was used for comparison and which had been administered in a dosis of 3 mg/kg i.v............................................................ ,~
Comparison tests for cerebral blood perfusion Several experiments were performed with various oxoalkyl-xanthine derivatives wherein the increase of the cerebral blood perfusion at the cat was measured. The results were compared with those of the known subst-ance 1-(5-oxohexyl)-3,7-dimethyl-xan~hine and with aminophylline.
The tested compounds are evident from the following table 2.
Table 2 20 No.
(cf. example) Substance Melting point C
4 1-propyl-3-methyl-7-(5-oxohexyl)-xanthine 76-78 8 1-isobutyl-3-methyl-7 (5-oxohexyl)-xanthine 96-97 7 1-hexyl-3-methyl-7-(5-oxohe~yl)-xanthine35-38 1-(5-oxohexyl)-3-methyl-7-propylxanthine 69-70 6 1-(5-oxohexyl)-3-methyl 7-n-butylYanthine 79-80 4 1-(5-oxohexyl)-3-methyl-7-decyl-xanthine64-66 1-(5-oxohexyl)-3-methyl-7-ethyl-xanthine102-103 ;
Cl 1-~5-oxohexyl)-3,7-dimethyl-xanthine102-105 (comparison) 29 C2 aminophylline 270-274 ~comparison) .- :. . . ,, ,., . , ., . , . :
.. . . . .
Test method The test principle of K.~Golenhofen, H.-Hensel and G.-Hildebrandt, "Durchblutungsmessungen mit Warmeleitelementen in Forschung und Klinik"
(="blood perfusion measurements with heat conducting elements in research and clinics", Thieme edition Stuttgart 1963) was used. The -test animals were cats in chloralose-urethane narcosis (70 + 200 mg/kg i.p.). The calvaria was opened in the area of the frontal gyrus marginalis or suprasylvicus res-pectively. The measurements occured with a modified surface measurement head according to Hensel (cf. Pflugers Arch. 268 (1959), page 60~) which was laid thereon after opening of the dura of the cerebral cortexO The duration of effectivity was registered as half-life~ime, the intensity of activity was registered according to Golenhofen et al as heat transport number A.
The registration was performed by thermosonds over a two-channel fluvograph of the firm Hartmann ~ Braun, Frankfurt on Main. Other circulation parameters registered simultaneously were conducted to a Helligemore-channel-graph.
Experimental results . , .
The results obtained at the mentioned experiments are represented in the following table 2 as~ ~ and as half-life-time in minutes. ~ ~ is the change of blood perfusion.
. .
:
~ ..................... . .
1~7~6~0 Table 3 _ _ Sample dosis mg/kg change of the cerebral animals No. i.v. blood perfusion n (cf. A ~ half-life--time exam le~ ~\ tl in minutes _P~ __ ___ ~, 8 1 ~ 1~85 1.0 2 _ 5 ~ 3.45 1~.3 _ _2 _ 7 1 + 0.97 0.4 3 2 + 1.45 _0 _ _ _2 1 1 ~ 4.33 4.0 3 2 -~ 6.33 5.8 3 ~3.00_ _1~.7 3 6 1 -~ 2.50 1.3 2 2 + 2.55 1.3 2 _ _ 5 _+ 2.40 __ 3.0 4 1 + 1.40 0.2 1 _ 3 -~ 2.80 0.5 _ 1 1 -~ 2.46 1.5 5 2 + S.17 5.0 3 -~ 8 07 8 2 3 _ . . _ ~:
Cl 1 ~ 0.44 0.9 13 (comparison) 5 -~ 0.86 2.4 40 -~ 1.15 8.6 33 _ _20 _ _~ _ _ . ___ __ C2 1 ~ 0.19 1.~ 7 (comparison) 2 + 0.15 1.8 2 ~ 0.1~ 3,3 8 _ ~ _ _ 10 + 0.53 1.7 _ .
:;
~ 137569~3 Discussion of the results As it is evident from table 3 above sample No. 8 shows a stronger and more extended cerebral blood perfusion. Thus, a dose of 5 mg has an effect being four times stronger and a half-life-time being five times longer than those of the comparison sample No. Cl. In a dose of 2 mg/kg of sample No. 7 the effect is about double so strong and the half life-time about three times so long as the corresponding effects of the comparison substance No. G2 but with a higher dose of 5 mg/kg of the comparison substance. In all doses of sample No. 1 an essential (i.e. more than ten times) stronger and longer cerebral blood perfusion is obtained compared with the correspond:ing dosages of the comparison substance No. Cl. Sample No. 6 effects an increase of cerebral blood perfusion compared with a comparison substance No. Cl. Thus, at a dose of 1 mg/kg the cerebral blood perfusion is about si~ times higher and at a dose of 5 mg/kg it is about three times higher than that of the substance No. Cl. An improvement over substance No. Cl is also shown at sample No. 5 wherein the cerebral blood perfusion at a dose of 1 mg/kg is about five times higher and at a dose of 5 mg/kg it is about nine times ! higher than that of the comparison substance. At a dose of 1 mg/kg the half-life_time is 1.5 times longer and at a dose of 5 mg/kg it is more than three times longer than that of the comparison substance No. Cl.
There is also a distinct improvement of the effectivity of cerebral blood perfusion over the comparison substance aminophylline.
The technical advance of khe invention over the substances of the prior art is distinctly proved.
.. ..
Claims
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of compounds of general formula (I) wherein one of the groups R1and R3 is a straight-chain (w-1)-oxoalkyl group containing from 5 to 8 carbon atoms and the other one of groups R1 and R3 is a straight-chain alkyl group containing from 6 to 10 carbon atoms or hydrogen and R2 is methyl or butyl or wherein R1 is methyl, R2 is butyl and R3 is a straight chain (W-1) oxoalkyl group and physiologically acceptable acid addi-tion salts thereof which comprises a) reacting an alkali metal salt of a 3-monoalkylxanthine or of a 1,3-or 3,7-dialkyl-xanthine with a substance selected from the group consisting of i) a compound of formula (III) wherein A is an allcylene group containing from 3 to 6 carbon atoms and Hal is a halogen atom; ii) a ketal therefrom and in case ii) subsequently hydrolysing the product, or b) reacting an alkali metal salt of one of the substances 1-oxoalkyl -3-alkyl-xanthine and 3-alkyl-7-oxoalkyl-xanthine with an alkylating compound selected from the group consisting of alkyl halides and a dialkyl sulphate in the presence of a solvent, or c) reacting a compound of one of the formulae (IV) and wherein X is an alkylene group containing from 2 to 5 carbon atoms and Hal is a halogen atom with an alkali metal salt of an acetoacetate and subsequent-ly subjecting the reaction product to ketone splitting to obtain a product of general formula I as defined above in which there are at least 3 carbon atoms between the carbonyl group and the nearest nitrogen atom, and wherein the product obtained is isolated per se or reacted with an acid to form a physiologically compatible acid addition salt thereof.
2. A process as claimed in claim 1 wherein the reaction a) and b) is effected at temperatures from 50 to 150°C.
3. A process as claimed in claim 1 wherein in reaction a) the alkali metal salt of the xanthine compound to be reacted is prepared in situ.
4. A process as claimed in claim 1 or 2 wherein R1 is n-hexyl-, R2 is methyl and R3 is 5-oxohexyl.
5. A process as claimed in claim 1 in which 1-n-hexyl-3-methyl-7-(5-oxohexyl)-xanthine is prepared by reacting 3-methyl-7-(5-oxohexyl)-xanthine with n-hexylbromide.
6. A process as claimed in claim 1 or 2 wherein R1 is 5-oxohexyl, R2 is methyl and R3 is n-decyl.
7. A process as claimed in claim 1 in which 1-(5-oxohexyl)-3-methyl-7-n-decyl-xanthine is prepared by reacting 3-methyl-7-n-decyl-xanthine with 1-bromohexanone-(5).
8. A process as claimed in claim 1 or 2 wherein R1 is hydrogen, R2 is n-butyl and R3 is 5-oxohexyl.
9. A process as claimed in claim 1 in which 3-n-butyl-7-(5-oxohexyl)-xanthine is prepared by reacting 3-n-butyl-xanthine with 1-bromohexanone-(5).
10. A compound of formula I as defined in claim 1 or a physiologically acceptable acid addition salt thereof whenever prepared according to the process claimed in claim 1 or 2 or by an obvious chemical equivalent thereof.
11. 1-n-hexyl-3-methyl-7-(5-oxohexyl)-xanthine whenever prepared according to the process claimed in claim 5 or by an obvlous chemical equi-valent thereof.
12. 1-(5-oxohexyl)-3-methyl-7-n-decyl-xanthine whenever prepared according to the process claimed in claim 7 or by an obvious chemical equi-valent thereof.
13. 3-n-butyl-7-(5-oxohexyl)-xanthine whenever prepared according to the process claimed in claim 9 or by an obvious chemical equivalent there-of.
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
14. A process for the preparation of compounds of general formula (I) wherein one of the groups R1 and R3 is a straight-chain (.omega.-1)-oxoalkyl group containing from 5 to 8 carbon atoms and the other one of groups R1 and R3 is a straight-chain alkyl group containing from 6 to 10 carbon atoms or hydrogen and R2 is methyl or butyl or wherein R1 is methyl, R2 is butyl and R3 is a straight chain (.omega.-1) oxoalkyl group and physiologically acceptable acid addition salts thereof which comprises a) reacting an alkali metal salt of a 3-monoalkylxanthine or of a 1,3- or 3,7-dialkyl-xanthine with a substance selected from the group consist-ing of i) a compound of formula (III) wherein A is an alkylene group containing from 3 to 6 carbon atoms and Hal is a halogen atom; ii) a ketal therefrom and in case ii) subsequently hydro-lysing the product, or b) reacting an alkali metal salt of one of the substances 1-oxoalkyl -3-alkyl-xanthine and 3-alkyl-7-oxoalkyl-xanthine with an alkylating compound selected from the group consisting of alkyl halides and a dialkyl sulphate in the presence of a solvent, or c) reacting a compound of one of the formulae (IV) and wherein X is an alkylene group containing from 2 to 5 carbon atoms and Hal is a halogen atom with an alkali metal salt of an acetoacetate and subsequent-ly subjecting the reaction product to ketone splitting to obtain a product of general formula I as defined above in which there are at least 3 carbon atoms between the carbonyl group and the nearest nitrogen atom, or d) reacting an alkali metal salt of a 3-monoalkyl-xanthine with a compound of formula (III) wherein A is an alkylene group containing from 3 to 6 carbon atoms and Hal is a halogen atom in a water-free medium, and wherein the product obtained is isolated per se or reacted with an acid to form a physiologically compatible acid addition salt thereof.
15. A process as claimed in claim 1 or 14 wherein R1 is methyl, R2 is n-butyl and R3 is 6-oxoheptyl or 7-oxooctyl.
16. A process as claimed in claim 14 wherein 1-methyl-3-n-butyl-7-(6-oxoheptyl)-xanthine or 1-methyl-3-n-butyl-7-(7-oxooctyl)-xanthine is prepared by reacting 3-n-butyl-7-(6-oxoheptyl)-xanthine or 3-n-butyl-7-(7-oxooctyl)-xanthine with methyl iodide.
17. A process as claimed in claim 1 or 14 wherein R1 is hydrogen, R2 is methyl and R3 is 5-oxohexyl.
18. A process as claimed in claim 14 wherein 3-methyl-7-(5-oxohexyl)-xanthine is prepared by reacting 3-methyl-7-bromo-propyl-xanthine with acetoacetic acid ester.
19. A compound of the formula I as defined in claim 14 or a physiolo-gically acceptable acid addition salt thereof whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.
20. 1-methyl-3-n-butyl-7-(6-oxoheptyl)-xanthine whenever prepared according to the process claimed in claim 16 or by an obvious chemical equi-valent thereof.
1. 21. 1-methyl-3-n-butyl-7-(7-oxooctyl)-xanthine whenever prepared according to the process claimed in claim 16 or by an obvious chemical equi-valent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA215,977A CA1075690A (en) | 1974-12-13 | 1974-12-13 | Xanthine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA215,977A CA1075690A (en) | 1974-12-13 | 1974-12-13 | Xanthine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1075690A true CA1075690A (en) | 1980-04-15 |
Family
ID=4101847
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA215,977A Expired CA1075690A (en) | 1974-12-13 | 1974-12-13 | Xanthine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1075690A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4833146A (en) * | 1985-07-19 | 1989-05-23 | Hoechst Aktiengesellschaft | Tertiary hydroxyalkylxanthines, medicaments containing them and their use |
| US4845102A (en) * | 1986-10-06 | 1989-07-04 | Hoechst Japan Limited | Therapeutic agent for the treatment of peptic ulcer disease |
| US5795897A (en) * | 1992-11-18 | 1998-08-18 | Cell Therapeutics, Inc. | Oxohexyl methylxanthine compounds |
-
1974
- 1974-12-13 CA CA215,977A patent/CA1075690A/en not_active Expired
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4833146A (en) * | 1985-07-19 | 1989-05-23 | Hoechst Aktiengesellschaft | Tertiary hydroxyalkylxanthines, medicaments containing them and their use |
| US4845102A (en) * | 1986-10-06 | 1989-07-04 | Hoechst Japan Limited | Therapeutic agent for the treatment of peptic ulcer disease |
| AU595379B2 (en) * | 1986-10-06 | 1990-03-29 | Hoechst Japan Limited | Therapeutic agent for the treatment of peptic ulcer disease |
| US5795897A (en) * | 1992-11-18 | 1998-08-18 | Cell Therapeutics, Inc. | Oxohexyl methylxanthine compounds |
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