CA1075693A - Xanthine derivatives - Google Patents
Xanthine derivativesInfo
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- CA1075693A CA1075693A CA320,438A CA320438A CA1075693A CA 1075693 A CA1075693 A CA 1075693A CA 320438 A CA320438 A CA 320438A CA 1075693 A CA1075693 A CA 1075693A
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- methyl
- xanthine
- oxohexyl
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Abstract
ABSTRACT
This invention relates to a process for the preparation of compounds of general formula (I) wherein R1 is alkyl having from 2 to 4 carbon atoms, R2 is methyl and R3 is a straight-chained 5-oxohexyl group and physiologically acceptable acid addition salts thereof, which comprises a) reacting an alkali metal salt of an 1,3-dialkylxanthine with a substance selected from the group consisting of i) a compound 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 iii) subsequently hydrolysing the product, or b) reacting an alkali metal salt of a 3-methyl-7-oxohexylxanthine 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 the formula (IV) 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 subsequently 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) oxidation of a compound of the formula
This invention relates to a process for the preparation of compounds of general formula (I) wherein R1 is alkyl having from 2 to 4 carbon atoms, R2 is methyl and R3 is a straight-chained 5-oxohexyl group and physiologically acceptable acid addition salts thereof, which comprises a) reacting an alkali metal salt of an 1,3-dialkylxanthine with a substance selected from the group consisting of i) a compound 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 iii) subsequently hydrolysing the product, or b) reacting an alkali metal salt of a 3-methyl-7-oxohexylxanthine 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 the formula (IV) 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 subsequently 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) oxidation of a compound of the formula
Description
~7S~913 This application is a divisional of our copending Canadian Patent Application Serial No. 215,977 filed December 13, 1974.
The invention relates to pharmaceuticals suitable for use in the treatment of diseases involving deficiencies in the blood vascular system.
The pharmaceutical compositions contain certain oxoalkyl-dialkyl-xanthine de-rivatives having in particular vascular dilatory activity and good fibrinolytic action.
l-~Oxoalkyl)-3,7-dimethyl-xanthines and 7-~oxoalkyl)-1,3-dimethyl-xanthines have been prepared. These oxo compounds are readily soluble both in water and in lipoids and have a pronounced vascular dilatory action with a low toxicity.
Medicaments which contain, as active ingredient, xanthine derivatives substituted by identical or different alkyl groups with 1 to 6 carbon atoms, preferably 1 to ~ carbon atoms, in the 1-, 3- and 7-positions, at least one of which alkyl groups carries a hyclrophilic group, preferably OH or COOH, are also already known. The number of hydrophilic groups per alkyl group is generally ~etween 1 and the number of carbon atoms in the given alkyl group and the alkyl group which carries the hydrophilic group preferably contains 1 to ~ carbon i atoms. (Compounds having a hydroxyl substituent on a carbon atom adjacent to a ring nitrogen atom are unstable). The last-mentioned prior art does not disclose, however, that the hydrophilic group may be oxoalkyl group, but there hàve 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. ~urthermore, the only compounds with only one hydrophylic group which have been specifically disclosed are deriva-tives of theobromine and of theophylline.
Pharmaceutical compositions are also known which contain as active .: , , . . ~, ,, . ., . . ,, . . :
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~7~693 ingredient, xanthines having an oxoalky]. group with 6 to 20 carbon atoms in the 1- or 7-position and an alkyl group with 1 or 2 carbon atoms in the other of these two positions and in the 3-position. However no specific oxoalkyl compounds nor the preferred positions of the carbonyl group have been dis-closed in the literature describing these compositions.
According to the present invention we now provide compounds of general formula wherein Rl is alkyl having from 2 to 4 carbon atoms, R2 is methyl and R3 is a straight-chained 5-oxohexyl group and physiologically acceptable acid addi-tion salts thereof.
This invention also relates to a process for the preparation of compounds of general formula R ~ N
wherein Rl is alkyl having from 2 to 4 carbon atoms, R2 is methyl and R3 is a straight-chained 5-oxohexyl group and physiologically acceptable acid addi-tion salts thereof, which comprises a) reacting an alkali metal salt of an 1,3-dialkylxanthine with a . - 2 -.
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~93 substance selected from the group consisting of i) a compound of formula o CH3-C-A-Hal (II[) 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 iii) subsequently hydrolysing the product, or b) reacting an alkali metal salt of a 3-methyl-7-oxohexylxanthine 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 the formula X-Hal Rl-N ~ N' /> (IV) N N
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 subsequently 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 pro-duct formed is isolated per se or reacted with an acid to form a physiological-ly compatible acid addition salt thereof.
In general the new compounds according to the invention have a vas-cular dilatory activity, a good fibrinolytic action and a low toxicity. Cer-tain of the new compounds are soluble in lipoids. They additionally have the effect of improving the circulatory properties of blood and are therefore effective in the treatment of arterial blood flow disturbances. The pharma--- , . . . - . . . . .
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~L~756~3 cological activity spectrum of the new compounds is otherwise substantially similar to that of the previously known oxoalkyl-dimethyl-xanthines (oxoalkyl-theophyllines and oxoalkyl-theobromines).
The following are specific examples of the new compounds according to the invention:
l-n-Propyl-3-methyl-7-~5-oxohexyl)xanthine and l-isobutyl-3-methyl-7-(5-oxohexyl)xanthine.
As indicated above, the compounds of the invention are prepared by one of several reactions.
The reactions are carried out in known manner, generally at tem-peratures of 50 to 150C, preferably 60 to 120C, optionally at elevated or reduced pressure but usually at atmospheric pressure. The various starting materlals may be used in stoichiometric quantities or for economic reasons in nonstoichiometric quantities. In methods a), b) and c), the alkali metal salts are preferably prepared ln situ. Method a), b) and c) are advantageously carried out in a solvent mixture comprising water and an organic solvent. A
strong base can also be prepared. Ketone splitting in method a) is carried -out in the usual manner.
The organic solvents used are preferably those which are miscible with water, particularly monohydric alcohols, e.g. methanol, ethanol, propanol, isopropanol, the various butanols, also comprising ethylene glycol monomethyl ether and monoethyl ether, polyhydric alcohols such as ethylene glycol, aprotic solvents such as acetone, pyridine, formamide and 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.
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. ~ ~ . . ' , ' , , ~ ' ' , ~' i' S~33 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 adminis~ration include for example solutions, emulstions, tabletsJ coated tablets, suppositories, capsules, granulates and sustained release forms. These may be prepared in known manner using the usual auxiliary agents such as excipients, disintegrants, binders, coating substances, swelling agents, lubricants, flavourings, sweeteners, substances to produce a sustained release effect and solubilising agents. Suitable auxiliary agents include for example lactose, mannitol, talcum, lactalbuminJ
startch, 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 in-gredient can be influenced by the addition of larger or smaller ~uantities of extending agents.
Advantageously the new compositions according ot the invention are presented in the form of dosage units, each dosage ~mit being adapted to supply a fixed quantity of active ingredient, preferably 10 to 400 mg of active ingredients.
The compounds of the invention may be administered in an amount of . - ~ - : ,. , : - .
~i~7~3 e.g. 0.1 mg of 125 mg, preferably 1 mg to 50 mg per kg/body weight. The sub-stances 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 methanol and 321 g of water are brought into solution by adding 160 g of 50% sodium hydroxide solution at elevated temperature. The mixture is heated to boiling and 358 g of 1-bromo-hexanone-(5) are then added. The mixture is heated under reflux for 4.5 hours, After cooling, the unreacted 3-methyl-7-propyl-xanthine is separated and the alcohol is distilled off.
The aqueous solution is adjus~ed to p~l 11 with sodium hydroxide solution and extracted wlth methylene chloride. 1-(5-Oxohexyl)-3-methyl-7-propyl-xanthine with a melting point of 69 to 70C 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 25C is about 3.2%. The solubility in ethanol and dimethyl sulphoxide is over 10%.
Example 2 1 26g of a colourless oil is obtained from 131 g of 3-methyl-7-n-hexyl-xanthine? 100 g of water, 60 g of methanol, 20 g of sodium hydroxide and 8~.5 g of 1-bromohexanone-~5) analogously to Example 1. The oil is recrys-tallised by dissolving it in 60 ml of methanol and reprecipitating it from this methanolic solution with 1500 ml of diisopropyl e~her. 1-(5-Oxohexyl)-, :: .
.
.
.
~7S693 3-meth~1-7-n-hexyl-xanthine with a ~elting point of 50 - 52 C is obtained in 90% yield (based on reac~ed 3-methyl-7-n-hexyl-xanthine). The product is only sparingly soluble in water. The solubility in ethanol, dimethyl sulphoxide and dimethylformamide is over 10%.
Example 3 86 g of a crude product is obtained from 92.1 g of 3-methyl-7-isobutyl-xanthine, 80 g of water, 48 g of methanol, 16 g of sodium hydroxide and 71.5 g of 1-bromohexanone-~5) analogously ~o Example 1. After vacuum dis-~tillation (196 - 200 C/0.2 mm) and recrystallisation from diisopropyl ether, 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 dlmethylformamide is over 10%.
Example 4 A suspension of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine in a mixture of 120 g of water and 72 g of methanol is brought into solution by the addition of 18 g of sodium hydroxide at about 60C. 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 distilled off in vacuo. The remaining solution is made alkaline with 4 ml of 50% sodium hydroxide solution and extracted with 350 ml of methylene chloride.
l-n-Propy1-3-methyl-7-~5-oxohexyl)-xanthine with a melting point of 76 - 78C
is obtained in 85% yield from the residue of the methylene chloride solution by recrystallisation from isopropanol. The solutility of the product in ethanol, dimethyl sulphoxide and dimethylformamide is over 10%.
Example 5 A crude product is obtained from 20.4 g of 3-methyl-7-ethyl-xanthine, 24 g of water, 24 g of methanol, 8 g of 50% sodium hydroxide solu-; - 7 -~ - - . ~ . . . . ... . .
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:1~7~i6~3 tion and 17.9 g of 1-bromohexanone-~5) analogously to Example 1. After re-crystallisation from a small quantity of methanol, 1-(5-oxohexyl)-3-methyl-7-ethyl-xanthine with a melting point of 102-103C is obtained in almost quan-titative 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%.
Example 6 110 g of a yellow oil is obtained from 117 g of 3-methyl-7-n-butyl-xanthine, 140 g of water, 85 g of methanol, 20 g of sodium hydroxide and 95 g of 1-bromohexanone-~5) analogously to Example 1. The oil is first distilled in vacuo ~219C/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 80C) is obtained in 60% yield.
Example 7 A mixture of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine, 75 g of water, 75 g of methanol, 18 g of sodium hydroxide and 74.4 g of n-hexyl bromide is boiled under reflux for 4 days and then worked up in a manner analogous to Example 4. 82.9 g of a crude product are obtained from which l-n-hexyl-3-meth~1-7-(5-oxohexyl)-xanthine is obtained in 90% yield after vacuum distillation (230 - 232C/0.3 mm). After recrystallisation rom 500 ml of diisopropyl ether, the melting point is 35 - 38C.
Example 8 A mixture of 106 g of 3-methyl-7-(5-oxohexyl)-xanthine, 100 g of water, 100 g o methanol, 24 g of sodium hydroxide and 82 g of isobutyl bro-mide is ~oiled under reflux for 85 hours and then acidified with 5 ml of con-centrated sulphuric acld. It is then boiled under reflux for a further 1.5 hous and then the unreacted 3-methyl-7-~5-oxohexyl)-xanthine ~58.8 g) is re-moved by filtration. The crude product is worked up in a manner analogous to ' , . : :. . , . :
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~7S6~3 Example 4 to yield 57.7 g of a colourless residue from which 1-isobutyl-3-methyl-7-C5-oxohexyl)-xanthine with a melting point of 96 - 97 C is obtained in 95% ~ield ~based on reacted 3-methyl-7-(5-oxohexyl)-xanthine) by recrys-tallisation from lZ00 ml of diisopropyl ether.
Example 9 80.3 g of 3-methyl-7-n-decyl-xanthine, 140 g of water, 90 g of methanol, 10 g of sodium hydroxide and 44.6 g of 1-bromohexanone-(5) are boiled under reflux for 4 hours. After acidification with 2 ml of concentrat-ed sulphuric acid, the reaction mixture is filtered hot to remove the unreacted 3-meth~1-7-n-decyl-xanthine and the filtrate is worked up as in Example 1.
66.1 g of a crude crystalline product are obtained and are recrystallised from 500 ml of diisopropyl ether. The 1-~5-oxohexyl)-3-methyl-7-n-decyl-xanthine which is obtained in 85% yield melts at 64 - 66C.
~1 0 4.16 g (0.02 mol) of 3-n-butyl xanthine are added to a solution of 5.5 g of water, 4.4 g of methanol and 0.8 g ~0.02 mol) of sodium hydroxide.
The mixture is heated to 70C and stirred for one hour, 3.7 g ~0.0206 mol) of 1-bromo-hexanone-~5) are added at 70C. The solution is then stirred for 5 hours at 70 C. After cooling down to room temperature the crystals are isolat-ed 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 to the but~l xanthine used) melting at 122C.
4.3 g of the crude product are dissolved in 15 ml of water and 0.86 g of sodium hydroxide at 60 C; 0.5 g of active carbon is added thereto, and the mixture is stirred for 15 minutes and then filtered. The filtrate is adjusted with sulphuric acid of 33% strength to pH 9.5 at 60C, and the mix-ture lS then cooled in an ice bath. The precipitated crystals were isolated _ g _ . , , , ,, . , . .
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~7~3 by suction j washed ~Yith water until they ~Yere free from alkali and dried at 100C in the vacuum of a water jet pump.
The yield is 2.6 g (42~5% of the theory, referred to the 3-butyl-xanthine used). The product proves to be uniform on thinlayer chromatography and has a melting point of 134C.
Example 11 166 g ~1 mol) of ~-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 70C and stirred for about one hour.
Then 183 g (1,02 mol) of 1-bromo-hexanone-~5) are dropped at this temperature into the mixture in the course of one hour. After about half an hour a thick pulp is formed which however can still be stirred and is stirred for further 5 hours at 70 C. The pH-value does slightly fall and is at the end of the re-action 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-methy~-7-(5-oxohexyl)-xanthine (=88% of the theory, referred to the reacted 3-methyl-xanthine) are obtained.
205 g of the crude product are dissolved at 60C in 1000 ml of water and ~0 g of sodium hydroxide. 13 g of active carbon are added thereto; the mixture is then stirred for 15 minutes and filtered. The filtrate having a temperature of 60 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 ftlrther hour at 60 C. The crystals precipitated are isolated by suction, washed l~ith 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 ` :~ ' - 1 0 , , , , ', .- ~:. .. .
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1C175~93 theory, referred to the 3-methyl-xanthine used). Melting point 217C.
A 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 and subsequent purification.
After intraduodenal administration to narcotized cats the compound caused a significant and permanent increase in the cerebral blood circulation which is by several times superior to that 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 100 to 1500 mg/kg, while that of ethylenediamine-theophylline is 217 mg/kg only.
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1~75~i~3 Supplementary Disclosure Example 12 104.1 g of 3-n-butylxan~hine are added under stirring to a solution of 20.4 g of sodium hydroxide in 200 ml of water and 200 ml of mcthanol. Then at 70C 83.1 of the the ethylene ketal of 1-chloropentanone-(4) are dropwise added to the clear solution. After stirring for 41 hours a~ 70C the reaction mass is cooled to 20C 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 70C for one hour in 1250 ml of 80% aqueous methanol in the presence of sulfuric acid and at a pH value of 1 to 2. After neutralisa-tion 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 141C
(yield 43.7%, referred to reacted xanthine).
Example 13 24.8 g of 3-n-butyl-7-(4'-oxopentyl)-xanthine are added to a solution of 3.5 g of sodium hydroxide in 80 ml of methanol and water ~1 : 1). After s~irring for 30 minutes at 40C 12.2 g of methyliodide are dropwise added.
After stirring for 50 hours to 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 concen-tration the neutralized ether solution and subsequent distillation at a tem-perature of the mixture of 130C under a pressure of 0.02 mm ~Ig 17.8 of 1-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 solutlon of 15.5 g of sodium hydroxide in 220 ml of a methanol/water mixture (1 : 1). After drop-, :-., , :
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6~3 wise adding 53.7 g of 1-chlorohexanone-~5) to ~he clear solution which has a temperature of 70C the mixture is s~irred at 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 141C ~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 solution having a temperature of 40 C and the mixture is stirred at 4~C for 24 hours. After concentration under reduced pressure the residue is diluted with 300 ml of diethylether and the unreactéd 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 140C temperature of the mixture and 0.02 mmHg 48.5 g of 1-methyl-3-n-butyl-7-(5'oxohexyl)-xanthine are obtained from the ether phase as a viscous oil ~n2D = 1.5320; yield 77.2%, referred to reacted starting xanthine)- 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 under example 15 the following compounds were prepared.
16. 3-n-butyl-7-(6'-oxoheptyl)-xanthine, melting point 110 to 111 C, from 3-n-butylxanthine and 1-chloroheptanone-~6) at 70C temperature of the mixture and under stirring for 43 hours ~yield 80.8%, referred to reacted 3-butylxanthine).
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~75693 17. 3-n-Butyl-7-~7'-oxooctyl)-xanthine, melting point 98.5 to 99 C, from 3-n-butylxanthine and 1-bromooctanone-(7) at a mix~ure temperature of 70C under stirring for 39 hours ~yield: 52.2%, referred to reacted 3-butyl-xanthine).
18. The reaction is performed according to example 21 from 3-n-butyl-7-~6'-oxoheptyl)-xanthine and methyl iodide, but a~ a temperature of the mixture of 50C under stirring for 46 hours. Prior to the distillation at a bath tem-perature of 140C and 0.02 mmHg the product is purified by column chromatogra-phy at silicagel 60 ~Merck) with methylene chloride/acetone ~80 : 2) as eluent.
1-Methyl-3-n-butyl-7-(6'-oxoheptyl)-xanthine was obtained as a viscous oil ~n2D0 = 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% referred to reacted 3-n-butyl-7-~7'-oxooctyl)-xantine.
Example 20 A solutlon of 2.3 g of sodium in 150 ml of absolute ethanol is ad-mixed with 26.4 g of 1,3-dibutylxanthine and 16.6 g of 1-chloro-4-pentanone-ethyleneketal and subsequéntly refluxed under stirring for 26 hours. After heating for one hour with 30 ml of water and 10 ml of 33% sulfuric acid at a temperature of 80C of the mixture and subsequent cooling the reaction mass is neutralized with a saturated solution of sodiumbicarbonate and concentrated under reduced pressure, The residue is adjusted with diluted sodium hydroxyde :~756~3 to a pH value of 13 and repeatedlyextracted with chloroform. The chloroform extracts are combined and after washing with water and drying over sodium sulphate they are concentrated. After colwmn chromatography at silica gel with methylene chloride/acetone in a ratio by volwne 8:1 as the solvent and bulb tube distillation 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-dibutyl-xanthine).
Example 21
The invention relates to pharmaceuticals suitable for use in the treatment of diseases involving deficiencies in the blood vascular system.
The pharmaceutical compositions contain certain oxoalkyl-dialkyl-xanthine de-rivatives having in particular vascular dilatory activity and good fibrinolytic action.
l-~Oxoalkyl)-3,7-dimethyl-xanthines and 7-~oxoalkyl)-1,3-dimethyl-xanthines have been prepared. These oxo compounds are readily soluble both in water and in lipoids and have a pronounced vascular dilatory action with a low toxicity.
Medicaments which contain, as active ingredient, xanthine derivatives substituted by identical or different alkyl groups with 1 to 6 carbon atoms, preferably 1 to ~ carbon atoms, in the 1-, 3- and 7-positions, at least one of which alkyl groups carries a hyclrophilic group, preferably OH or COOH, are also already known. The number of hydrophilic groups per alkyl group is generally ~etween 1 and the number of carbon atoms in the given alkyl group and the alkyl group which carries the hydrophilic group preferably contains 1 to ~ carbon i atoms. (Compounds having a hydroxyl substituent on a carbon atom adjacent to a ring nitrogen atom are unstable). The last-mentioned prior art does not disclose, however, that the hydrophilic group may be oxoalkyl group, but there hàve 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. ~urthermore, the only compounds with only one hydrophylic group which have been specifically disclosed are deriva-tives of theobromine and of theophylline.
Pharmaceutical compositions are also known which contain as active .: , , . . ~, ,, . ., . . ,, . . :
. . : . : .
:; . - : . , . .............................. .. : -: : , ,. : ,:: , :
~7~693 ingredient, xanthines having an oxoalky]. group with 6 to 20 carbon atoms in the 1- or 7-position and an alkyl group with 1 or 2 carbon atoms in the other of these two positions and in the 3-position. However no specific oxoalkyl compounds nor the preferred positions of the carbonyl group have been dis-closed in the literature describing these compositions.
According to the present invention we now provide compounds of general formula wherein Rl is alkyl having from 2 to 4 carbon atoms, R2 is methyl and R3 is a straight-chained 5-oxohexyl group and physiologically acceptable acid addi-tion salts thereof.
This invention also relates to a process for the preparation of compounds of general formula R ~ N
wherein Rl is alkyl having from 2 to 4 carbon atoms, R2 is methyl and R3 is a straight-chained 5-oxohexyl group and physiologically acceptable acid addi-tion salts thereof, which comprises a) reacting an alkali metal salt of an 1,3-dialkylxanthine with a . - 2 -.
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~93 substance selected from the group consisting of i) a compound of formula o CH3-C-A-Hal (II[) 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 iii) subsequently hydrolysing the product, or b) reacting an alkali metal salt of a 3-methyl-7-oxohexylxanthine 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 the formula X-Hal Rl-N ~ N' /> (IV) N N
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 subsequently 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 pro-duct formed is isolated per se or reacted with an acid to form a physiological-ly compatible acid addition salt thereof.
In general the new compounds according to the invention have a vas-cular dilatory activity, a good fibrinolytic action and a low toxicity. Cer-tain of the new compounds are soluble in lipoids. They additionally have the effect of improving the circulatory properties of blood and are therefore effective in the treatment of arterial blood flow disturbances. The pharma--- , . . . - . . . . .
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~L~756~3 cological activity spectrum of the new compounds is otherwise substantially similar to that of the previously known oxoalkyl-dimethyl-xanthines (oxoalkyl-theophyllines and oxoalkyl-theobromines).
The following are specific examples of the new compounds according to the invention:
l-n-Propyl-3-methyl-7-~5-oxohexyl)xanthine and l-isobutyl-3-methyl-7-(5-oxohexyl)xanthine.
As indicated above, the compounds of the invention are prepared by one of several reactions.
The reactions are carried out in known manner, generally at tem-peratures of 50 to 150C, preferably 60 to 120C, optionally at elevated or reduced pressure but usually at atmospheric pressure. The various starting materlals may be used in stoichiometric quantities or for economic reasons in nonstoichiometric quantities. In methods a), b) and c), the alkali metal salts are preferably prepared ln situ. Method a), b) and c) are advantageously carried out in a solvent mixture comprising water and an organic solvent. A
strong base can also be prepared. Ketone splitting in method a) is carried -out in the usual manner.
The organic solvents used are preferably those which are miscible with water, particularly monohydric alcohols, e.g. methanol, ethanol, propanol, isopropanol, the various butanols, also comprising ethylene glycol monomethyl ether and monoethyl ether, polyhydric alcohols such as ethylene glycol, aprotic solvents such as acetone, pyridine, formamide and 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.
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. ~ ~ . . ' , ' , , ~ ' ' , ~' i' S~33 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 adminis~ration include for example solutions, emulstions, tabletsJ coated tablets, suppositories, capsules, granulates and sustained release forms. These may be prepared in known manner using the usual auxiliary agents such as excipients, disintegrants, binders, coating substances, swelling agents, lubricants, flavourings, sweeteners, substances to produce a sustained release effect and solubilising agents. Suitable auxiliary agents include for example lactose, mannitol, talcum, lactalbuminJ
startch, 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 in-gredient can be influenced by the addition of larger or smaller ~uantities of extending agents.
Advantageously the new compositions according ot the invention are presented in the form of dosage units, each dosage ~mit being adapted to supply a fixed quantity of active ingredient, preferably 10 to 400 mg of active ingredients.
The compounds of the invention may be administered in an amount of . - ~ - : ,. , : - .
~i~7~3 e.g. 0.1 mg of 125 mg, preferably 1 mg to 50 mg per kg/body weight. The sub-stances 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 methanol and 321 g of water are brought into solution by adding 160 g of 50% sodium hydroxide solution at elevated temperature. The mixture is heated to boiling and 358 g of 1-bromo-hexanone-(5) are then added. The mixture is heated under reflux for 4.5 hours, After cooling, the unreacted 3-methyl-7-propyl-xanthine is separated and the alcohol is distilled off.
The aqueous solution is adjus~ed to p~l 11 with sodium hydroxide solution and extracted wlth methylene chloride. 1-(5-Oxohexyl)-3-methyl-7-propyl-xanthine with a melting point of 69 to 70C 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 25C is about 3.2%. The solubility in ethanol and dimethyl sulphoxide is over 10%.
Example 2 1 26g of a colourless oil is obtained from 131 g of 3-methyl-7-n-hexyl-xanthine? 100 g of water, 60 g of methanol, 20 g of sodium hydroxide and 8~.5 g of 1-bromohexanone-~5) analogously to Example 1. The oil is recrys-tallised by dissolving it in 60 ml of methanol and reprecipitating it from this methanolic solution with 1500 ml of diisopropyl e~her. 1-(5-Oxohexyl)-, :: .
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.
~7S693 3-meth~1-7-n-hexyl-xanthine with a ~elting point of 50 - 52 C is obtained in 90% yield (based on reac~ed 3-methyl-7-n-hexyl-xanthine). The product is only sparingly soluble in water. The solubility in ethanol, dimethyl sulphoxide and dimethylformamide is over 10%.
Example 3 86 g of a crude product is obtained from 92.1 g of 3-methyl-7-isobutyl-xanthine, 80 g of water, 48 g of methanol, 16 g of sodium hydroxide and 71.5 g of 1-bromohexanone-~5) analogously ~o Example 1. After vacuum dis-~tillation (196 - 200 C/0.2 mm) and recrystallisation from diisopropyl ether, 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 dlmethylformamide is over 10%.
Example 4 A suspension of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine in a mixture of 120 g of water and 72 g of methanol is brought into solution by the addition of 18 g of sodium hydroxide at about 60C. 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 distilled off in vacuo. The remaining solution is made alkaline with 4 ml of 50% sodium hydroxide solution and extracted with 350 ml of methylene chloride.
l-n-Propy1-3-methyl-7-~5-oxohexyl)-xanthine with a melting point of 76 - 78C
is obtained in 85% yield from the residue of the methylene chloride solution by recrystallisation from isopropanol. The solutility of the product in ethanol, dimethyl sulphoxide and dimethylformamide is over 10%.
Example 5 A crude product is obtained from 20.4 g of 3-methyl-7-ethyl-xanthine, 24 g of water, 24 g of methanol, 8 g of 50% sodium hydroxide solu-; - 7 -~ - - . ~ . . . . ... . .
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:1~7~i6~3 tion and 17.9 g of 1-bromohexanone-~5) analogously to Example 1. After re-crystallisation from a small quantity of methanol, 1-(5-oxohexyl)-3-methyl-7-ethyl-xanthine with a melting point of 102-103C is obtained in almost quan-titative 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%.
Example 6 110 g of a yellow oil is obtained from 117 g of 3-methyl-7-n-butyl-xanthine, 140 g of water, 85 g of methanol, 20 g of sodium hydroxide and 95 g of 1-bromohexanone-~5) analogously to Example 1. The oil is first distilled in vacuo ~219C/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 80C) is obtained in 60% yield.
Example 7 A mixture of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine, 75 g of water, 75 g of methanol, 18 g of sodium hydroxide and 74.4 g of n-hexyl bromide is boiled under reflux for 4 days and then worked up in a manner analogous to Example 4. 82.9 g of a crude product are obtained from which l-n-hexyl-3-meth~1-7-(5-oxohexyl)-xanthine is obtained in 90% yield after vacuum distillation (230 - 232C/0.3 mm). After recrystallisation rom 500 ml of diisopropyl ether, the melting point is 35 - 38C.
Example 8 A mixture of 106 g of 3-methyl-7-(5-oxohexyl)-xanthine, 100 g of water, 100 g o methanol, 24 g of sodium hydroxide and 82 g of isobutyl bro-mide is ~oiled under reflux for 85 hours and then acidified with 5 ml of con-centrated sulphuric acld. It is then boiled under reflux for a further 1.5 hous and then the unreacted 3-methyl-7-~5-oxohexyl)-xanthine ~58.8 g) is re-moved by filtration. The crude product is worked up in a manner analogous to ' , . : :. . , . :
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~7S6~3 Example 4 to yield 57.7 g of a colourless residue from which 1-isobutyl-3-methyl-7-C5-oxohexyl)-xanthine with a melting point of 96 - 97 C is obtained in 95% ~ield ~based on reacted 3-methyl-7-(5-oxohexyl)-xanthine) by recrys-tallisation from lZ00 ml of diisopropyl ether.
Example 9 80.3 g of 3-methyl-7-n-decyl-xanthine, 140 g of water, 90 g of methanol, 10 g of sodium hydroxide and 44.6 g of 1-bromohexanone-(5) are boiled under reflux for 4 hours. After acidification with 2 ml of concentrat-ed sulphuric acid, the reaction mixture is filtered hot to remove the unreacted 3-meth~1-7-n-decyl-xanthine and the filtrate is worked up as in Example 1.
66.1 g of a crude crystalline product are obtained and are recrystallised from 500 ml of diisopropyl ether. The 1-~5-oxohexyl)-3-methyl-7-n-decyl-xanthine which is obtained in 85% yield melts at 64 - 66C.
~1 0 4.16 g (0.02 mol) of 3-n-butyl xanthine are added to a solution of 5.5 g of water, 4.4 g of methanol and 0.8 g ~0.02 mol) of sodium hydroxide.
The mixture is heated to 70C and stirred for one hour, 3.7 g ~0.0206 mol) of 1-bromo-hexanone-~5) are added at 70C. The solution is then stirred for 5 hours at 70 C. After cooling down to room temperature the crystals are isolat-ed 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 to the but~l xanthine used) melting at 122C.
4.3 g of the crude product are dissolved in 15 ml of water and 0.86 g of sodium hydroxide at 60 C; 0.5 g of active carbon is added thereto, and the mixture is stirred for 15 minutes and then filtered. The filtrate is adjusted with sulphuric acid of 33% strength to pH 9.5 at 60C, and the mix-ture lS then cooled in an ice bath. The precipitated crystals were isolated _ g _ . , , , ,, . , . .
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~7~3 by suction j washed ~Yith water until they ~Yere free from alkali and dried at 100C in the vacuum of a water jet pump.
The yield is 2.6 g (42~5% of the theory, referred to the 3-butyl-xanthine used). The product proves to be uniform on thinlayer chromatography and has a melting point of 134C.
Example 11 166 g ~1 mol) of ~-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 70C and stirred for about one hour.
Then 183 g (1,02 mol) of 1-bromo-hexanone-~5) are dropped at this temperature into the mixture in the course of one hour. After about half an hour a thick pulp is formed which however can still be stirred and is stirred for further 5 hours at 70 C. The pH-value does slightly fall and is at the end of the re-action 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-methy~-7-(5-oxohexyl)-xanthine (=88% of the theory, referred to the reacted 3-methyl-xanthine) are obtained.
205 g of the crude product are dissolved at 60C in 1000 ml of water and ~0 g of sodium hydroxide. 13 g of active carbon are added thereto; the mixture is then stirred for 15 minutes and filtered. The filtrate having a temperature of 60 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 ftlrther hour at 60 C. The crystals precipitated are isolated by suction, washed l~ith 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 ` :~ ' - 1 0 , , , , ', .- ~:. .. .
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1C175~93 theory, referred to the 3-methyl-xanthine used). Melting point 217C.
A 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 and subsequent purification.
After intraduodenal administration to narcotized cats the compound caused a significant and permanent increase in the cerebral blood circulation which is by several times superior to that 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 100 to 1500 mg/kg, while that of ethylenediamine-theophylline is 217 mg/kg only.
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1~75~i~3 Supplementary Disclosure Example 12 104.1 g of 3-n-butylxan~hine are added under stirring to a solution of 20.4 g of sodium hydroxide in 200 ml of water and 200 ml of mcthanol. Then at 70C 83.1 of the the ethylene ketal of 1-chloropentanone-(4) are dropwise added to the clear solution. After stirring for 41 hours a~ 70C the reaction mass is cooled to 20C 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 70C for one hour in 1250 ml of 80% aqueous methanol in the presence of sulfuric acid and at a pH value of 1 to 2. After neutralisa-tion 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 141C
(yield 43.7%, referred to reacted xanthine).
Example 13 24.8 g of 3-n-butyl-7-(4'-oxopentyl)-xanthine are added to a solution of 3.5 g of sodium hydroxide in 80 ml of methanol and water ~1 : 1). After s~irring for 30 minutes at 40C 12.2 g of methyliodide are dropwise added.
After stirring for 50 hours to 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 concen-tration the neutralized ether solution and subsequent distillation at a tem-perature of the mixture of 130C under a pressure of 0.02 mm ~Ig 17.8 of 1-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 solutlon of 15.5 g of sodium hydroxide in 220 ml of a methanol/water mixture (1 : 1). After drop-, :-., , :
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6~3 wise adding 53.7 g of 1-chlorohexanone-~5) to ~he clear solution which has a temperature of 70C the mixture is s~irred at 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 141C ~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 solution having a temperature of 40 C and the mixture is stirred at 4~C for 24 hours. After concentration under reduced pressure the residue is diluted with 300 ml of diethylether and the unreactéd 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 140C temperature of the mixture and 0.02 mmHg 48.5 g of 1-methyl-3-n-butyl-7-(5'oxohexyl)-xanthine are obtained from the ether phase as a viscous oil ~n2D = 1.5320; yield 77.2%, referred to reacted starting xanthine)- 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 under example 15 the following compounds were prepared.
16. 3-n-butyl-7-(6'-oxoheptyl)-xanthine, melting point 110 to 111 C, from 3-n-butylxanthine and 1-chloroheptanone-~6) at 70C temperature of the mixture and under stirring for 43 hours ~yield 80.8%, referred to reacted 3-butylxanthine).
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~75693 17. 3-n-Butyl-7-~7'-oxooctyl)-xanthine, melting point 98.5 to 99 C, from 3-n-butylxanthine and 1-bromooctanone-(7) at a mix~ure temperature of 70C under stirring for 39 hours ~yield: 52.2%, referred to reacted 3-butyl-xanthine).
18. The reaction is performed according to example 21 from 3-n-butyl-7-~6'-oxoheptyl)-xanthine and methyl iodide, but a~ a temperature of the mixture of 50C under stirring for 46 hours. Prior to the distillation at a bath tem-perature of 140C and 0.02 mmHg the product is purified by column chromatogra-phy at silicagel 60 ~Merck) with methylene chloride/acetone ~80 : 2) as eluent.
1-Methyl-3-n-butyl-7-(6'-oxoheptyl)-xanthine was obtained as a viscous oil ~n2D0 = 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% referred to reacted 3-n-butyl-7-~7'-oxooctyl)-xantine.
Example 20 A solutlon of 2.3 g of sodium in 150 ml of absolute ethanol is ad-mixed with 26.4 g of 1,3-dibutylxanthine and 16.6 g of 1-chloro-4-pentanone-ethyleneketal and subsequéntly refluxed under stirring for 26 hours. After heating for one hour with 30 ml of water and 10 ml of 33% sulfuric acid at a temperature of 80C of the mixture and subsequent cooling the reaction mass is neutralized with a saturated solution of sodiumbicarbonate and concentrated under reduced pressure, The residue is adjusted with diluted sodium hydroxyde :~756~3 to a pH value of 13 and repeatedlyextracted with chloroform. The chloroform extracts are combined and after washing with water and drying over sodium sulphate they are concentrated. After colwmn chromatography at silica gel with methylene chloride/acetone in a ratio by volwne 8:1 as the solvent and bulb tube distillation 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-dibutyl-xanthine).
Example 21
2.1 g of 3-methyl-7-propylxanthine, 0.7 g of l-chloro-heptanone-(6) and 1.4 g of potassiwn carbonate are refluxed in 15 ml of dimethylformamide at 120C under stirring for 7 1/2 hours. After concentration under reduced pres-sure 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 sodiwn 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 melt-ing point of 69 to 70C are obtained in a yield of 76.6%.
Example 22 20.8 g of 3-methyl-7-propylxanthine, 16.9 g of l-chloropentanone-~4)-ethyleneketal and 14.2 g of potassiwm carbonate are stirred in 150 ml of dimethylformamide at 120C for 7 hours and a half. After concentration under reduced pressure the residue is admixed with 250 ml of water and twice extracted with 300 ml of chloroform each. The combined chloroform phases are washed with 100 ml of 1 n-sodiwmhydroxide and water. After concentration the residue is dissolved with 1 1 of methanol/water (8:2), then 15 ml of 33%
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:1~75693 sulphuric acid are added and the mass is heated under stirring for one hour at 70C. After cooling it is neutralised with a saturated solution of sodium ~icarbonate and concentrated to about 100 ml. By three times extraction with 300 ml 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-propy~xanthine having a melting point of 67.5 to 68C are obtained in a yield of ~7.4%.
Example 23 22.2 g of 3-ethyl-7-propylxanthine, 1~.1 g of 1-chlorohexanone-~5) and 14.2 of potassium carbonate in 150 ml of dimethylformamide are stirred at 120C for 8 hours. After concentration under reduced pressure the residue is suspended in 100 ml of water, three times extracted with 200 ml of chloroform each, the combined chloroform extracts are successively treated with 1 n-sodi~lm hydroxide and water and then they are dried over sodium sulphate. The concen-tration residue is submitted to chromatography in a column with silica gel 60 and with chloroform/ethanol (9:1) as a solvent. After recrystallisation of ~ the pure fractions from diisopropylether 12.2 g of 1-(5-oxohexyl)-3-ethyl-7-propylxanthine having a melting point of 81 to 82C are obtained in a yield of 38%.
Example 24 17.1 g of 1-(4-hydroxypentyl)-3-methyl-7-propylxanthine in 25 ml of methylene chloride are dropwise added under stirring at 25C within 10 minutes to 19.4 of~pyrid mium chlorochromate (B.J. Corey and J.W. Suggs, Tetrahedron Letters, Volume 31 ~1975) page 2647 to 2650). Within 20 minutes the tempera-ture Increases to 34C. After three hours stirring and staying over night it is decanted from the greasy precipitate and four times washed with 200 ml . - ., ~756~3 diethylether each. After washing with water and drying over sodium sulphate the combined organic phases are concentrated under reduced pressure. After column chromatography of the residue at silica gel 60 with chloroform/ethanol ~9:1) as a solvent and recrystallisation from diisop-ropylether/acetic ester ~18:1) 14.5 g of 1-~4-oxopentyl)-3-methyl-7-propyl-xanthine having a melting point of 67 to 68C are obtained in a yield of 82.5%.
Example 25 It is worked as in example 24, however, 19.3 g of 1-(6-hydroxy-heptyl)-3-methyl-7-propyl-xanthine are used as starting xanthine substance.
14.1 g of 1-(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%.
Example 26 r It is worked as in example 24, however, 18.5 g of 1-(5-hydroxy-hexyl)-3-methyl-7-propylxanthine are used as starting xanthine substance.
14 g of 1-(5-oxohexyl)-3-methyl-7-propylxanthine are obtained in a yield of 76.3%.
Example 27 It is worked as in example 24, however, 17.7 g of 1-(5-hydroxy-hexyl)-3-methyl-7-ethylxanthine are used as starting xanthine substance.
13.3 g of 1-(5-oxohexyl)-3-me~hyl-7-ethylxanthine are obtained in a yield of 78%.
Example 28 It is worked as in example 24, however, 19.3 g of l-~S-hydroxy-hexyl)-3-methyl-7-butylxanthine are used as starting xanthine substance.
13.7 g of l-~5-oxohexyl)-3-methyl-7-butylxanthine are obtained in a yield of 71.2 %.
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1~5~3 Example 29 It is ~orked as in example 24, however, 19.4 g 1-~5-hydroxyhe~yl~-
Example 22 20.8 g of 3-methyl-7-propylxanthine, 16.9 g of l-chloropentanone-~4)-ethyleneketal and 14.2 g of potassiwm carbonate are stirred in 150 ml of dimethylformamide at 120C for 7 hours and a half. After concentration under reduced pressure the residue is admixed with 250 ml of water and twice extracted with 300 ml of chloroform each. The combined chloroform phases are washed with 100 ml of 1 n-sodiwmhydroxide and water. After concentration the residue is dissolved with 1 1 of methanol/water (8:2), then 15 ml of 33%
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:1~75693 sulphuric acid are added and the mass is heated under stirring for one hour at 70C. After cooling it is neutralised with a saturated solution of sodium ~icarbonate and concentrated to about 100 ml. By three times extraction with 300 ml 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-propy~xanthine having a melting point of 67.5 to 68C are obtained in a yield of ~7.4%.
Example 23 22.2 g of 3-ethyl-7-propylxanthine, 1~.1 g of 1-chlorohexanone-~5) and 14.2 of potassium carbonate in 150 ml of dimethylformamide are stirred at 120C for 8 hours. After concentration under reduced pressure the residue is suspended in 100 ml of water, three times extracted with 200 ml of chloroform each, the combined chloroform extracts are successively treated with 1 n-sodi~lm hydroxide and water and then they are dried over sodium sulphate. The concen-tration residue is submitted to chromatography in a column with silica gel 60 and with chloroform/ethanol (9:1) as a solvent. After recrystallisation of ~ the pure fractions from diisopropylether 12.2 g of 1-(5-oxohexyl)-3-ethyl-7-propylxanthine having a melting point of 81 to 82C are obtained in a yield of 38%.
Example 24 17.1 g of 1-(4-hydroxypentyl)-3-methyl-7-propylxanthine in 25 ml of methylene chloride are dropwise added under stirring at 25C within 10 minutes to 19.4 of~pyrid mium chlorochromate (B.J. Corey and J.W. Suggs, Tetrahedron Letters, Volume 31 ~1975) page 2647 to 2650). Within 20 minutes the tempera-ture Increases to 34C. After three hours stirring and staying over night it is decanted from the greasy precipitate and four times washed with 200 ml . - ., ~756~3 diethylether each. After washing with water and drying over sodium sulphate the combined organic phases are concentrated under reduced pressure. After column chromatography of the residue at silica gel 60 with chloroform/ethanol ~9:1) as a solvent and recrystallisation from diisop-ropylether/acetic ester ~18:1) 14.5 g of 1-~4-oxopentyl)-3-methyl-7-propyl-xanthine having a melting point of 67 to 68C are obtained in a yield of 82.5%.
Example 25 It is worked as in example 24, however, 19.3 g of 1-(6-hydroxy-heptyl)-3-methyl-7-propyl-xanthine are used as starting xanthine substance.
14.1 g of 1-(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%.
Example 26 r It is worked as in example 24, however, 18.5 g of 1-(5-hydroxy-hexyl)-3-methyl-7-propylxanthine are used as starting xanthine substance.
14 g of 1-(5-oxohexyl)-3-methyl-7-propylxanthine are obtained in a yield of 76.3%.
Example 27 It is worked as in example 24, however, 17.7 g of 1-(5-hydroxy-hexyl)-3-methyl-7-ethylxanthine are used as starting xanthine substance.
13.3 g of 1-(5-oxohexyl)-3-me~hyl-7-ethylxanthine are obtained in a yield of 78%.
Example 28 It is worked as in example 24, however, 19.3 g of l-~S-hydroxy-hexyl)-3-methyl-7-butylxanthine are used as starting xanthine substance.
13.7 g of l-~5-oxohexyl)-3-methyl-7-butylxanthine are obtained in a yield of 71.2 %.
' : . . :, , - . . : :~ . . .
., . . :. . - :
:, ,: . .:
- .
1~5~3 Example 29 It is ~orked as in example 24, however, 19.4 g 1-~5-hydroxyhe~yl~-
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%.
Example 30 lt is worked as in example 24, however, 18 g of 1-propyl-3-methyl-7-(5-hydroxyhexyl)-xanthine are used as starting xanthlne substance. 11.6 g Of l-propyl-3-methyl-7-(5-oxohexyl)-xanthine are obtained in a yield of 65%.
Example 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 `
sodlum and 100 ml absolute ethanol. The mixture is refluxed for 2 hours.
After cooling the precipitated crystals are filtered off and the filtrate is evaporated to dryness. The residue is first treated at ambient temperature for 2 hours with 100 ml of 5 percent aqueous sodium hydroxide solution, then acidified with 14 ml of 50 percent sulphuric acid and then boiled for 1 hour.
After standing for 2 days the 3-methyl-7-~5-oxohexyl)-xanthine is filtered off.
The yield is 3.5 g = 50% of theory.
For purification the crude product is dissolved in a little aqueous sodium hydroxide solution and 3-methyl-7-~5-oxohexyl)-xanthine is then obtained by precipitating with aqueous hydrochloric acid in a yield of 40 percent.
Melting point 215 C.
Example 32 ~37.2 g of 3-methyl-7-propylxanthine, suspended in a mixture of 240 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 358 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 `, . ~. . , .. . - .~ . ~
:~07S693 distilled off. The aqueous solution is adjusted with sodium hydroxide to a pH-value of 11 and extracted with methylene chloride. From the residue of the methylene chloride solution and after recrystallisation from 5.2 1 of di-isopropylether 1-~5-oxohexyl)-3-methyl-7-propylxanthine having a melting point of 69 to 70C is obtained in a yield of about 90% ~referred to unreacted 3-methyl-7-propylxanthine). (The solubility in water/25C is about 3.1%, that in ethanol and dimethylsulphoxide above 10%).
Example 33 26.4 g of 1-(5-oxohexyl)-3-methylxanthine, 13.4 g of propylbromide and 13.8 g of potassium carbonate in 100 ml dimethylformamide are heated under stirring to 120C for 3 hours. After distillation off of the solvent under reduced pressure and after addition of 100 ml of water the residue is extracted with methylene chloride. The organic solvent is distilled off under reduced pressure and the residue is recrystallised from diisopropylether. 22 g of 1-~5-oxohexyl)-3-methyl-7-propylxanthine having a melting point of 69 to 70C
are obtained in a yield of 72%.
Example 34 A solution of 2.5 g of sodium in lS0 ml of absolute ethanol is ad-.. . .
mîxed with 14.3 g of acetoacetic acid ethylester and 32.9 g of 1-~3-bromo-propyi)-3-methyl-7-propylxanthine and refluxed for 5 hours. The alcohol is practically distilled off and the residue is refluxed with 150 ml of 5% of sodium hydrox1de for 3 hours. For 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 chlo-ride. After evaporation of the solvent the obtained residue is submitted to chromatography over silica gel with benzene/acetone ~7:3) as a solvent. After recrystallisation of the residue of the main fraction from diisopropylether 1-(5-oxohexyl)-3-methyl-7-propylxanthine having a melting point of 6g to 70C
.
~ - 19 -,,, : , ., . , . ., ~ ,: . , ... .. - .. ~ ., . . ,.., . ., ~ . . . . , . ., ., , . , . .. . :
"
~075~3 is obtained in a yield of 41%.
Example 35 It is worked according to example 33, but in using 12.5 g of 1-~4-oxopentyl)-3-methylxan~hine, 6.8 g of propylbromide cmd 7 g of potassium car-bonate in 100 ml dimethylformamide as starting materials. ll g of 1-(4-oxo-pentyl)-3-methyl-7-propylxanthine having a melting point of 67 to 68C are obtained in a yield of 75% ~recrystallisation from diisopropylether/acetic ester).
Example 36 It is worked as in example 34, but i~ 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-7-propylxanthine. 20 g of a raw product is obtained which is submitted to chromatography at silica gel with chloroform/ethanol (9:1) as a solvent. After recrystallisation 9.2 g 1-(4-oxopentyl)-3-methyl-7-propylxanthine are obtained in a yield of 48%.
Examp]e 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 car-bonate 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 iO C are obtained in a yield of 83%.
Example 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 acetoacetic acid ethylester. 1.7 g of 1-(6-oxoheptyl)-3-methyl-7-propylxanthine are ob-tained.
Example 39 It is worked according to example 32, but in using 117 g of 3-methyl-7-n-buty~lxanthine, 140 g of water, 85 g of methanolJ 20 g of sodium :;, . . ~ : . , :,. : :: ~ , :~7569~
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 (219C/0.5 mm) and then it is crystallised with 700 ml di-isopropylether. In a yield of 60% 1-(S-oxohexyl)-3-methyl-7-n-butylxanthine having a melting point of 79 to 80C is obtained.
Example 40 It is worked as in example 33, but in using 26.4 g 1-(5-oxohexyl)-3-methylxanthine, 10.2 g of n-butylchlorids, 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 80C are ob-tained in a yield of 87%.
Example 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 1-~3-bromopropyl)-3-methyl-7-bu~ylxanthine. 3 g of an oily raw pro-duct 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 melting point of 79C is obtained in a yield of 48%.
Example 42 It is worked according to example 32, but in using 20.4 g of 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 recrystallisa~ion from a little methanol 1-~5-oxohexyl)-3-methyl-7-ethylxanthine having a melting point of 102 to 103C is obtained in a nearly quantitative yleld Example 43 It is worked as in example 33, but in using 13.2 g of 1 ~5-oxohexyl)-:
- 21~-' ' :' .~ . ' . ' ', ' : ' ' ' ' .:
,~ . . . :.:
: . .
:~o~s~ig3 3-me~hylxanthine, 7 g of potassium carbonate and 6.6 g of ethyl bromide in 100 ml of dimethylformamide as starting substances. 10 g of 1-~5-oxohexyl)-3-methyl-7-ethylxanthine are obtained which is recrystallised two times from a little methanol. The final product has a melting point of 103 C.
Example 44 It is worked as in example 34, but in using 15 g of 1-~3-bromo-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-~5-oxohexyl)-3-methyl-7-ethylxanthine having a melting point of 103C are obtained.
Example 45 27.8 g of 1-(5-oxohexyl)-3-ethylxanthine, 8.5 g 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-oxo-hexyl)-3-ethyl-7-propylxanthine having a melting point between 81 and 82 C are obtained in a yield of 75%.
Example 46 3.4 of 1-(3-bromopropyl)-3-ethyl-7-propylxanthineJ 1.3 g of aceto-acetic acid ethyl ester and 0.3 g ofsodium are reacted as in example 34. 1-(5-oxohexyl)-3-ethyl-7-propylxanthine is obtained in a yield of about 20%.
Example 47 A suspension of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine in a mix-ture of 120 g of water and 72 g of methanol is dissolved with 18 g of sodium hydroxide at about 60C and admixed with 55.5 g of n-propylbromide. After refluxing for 24 hours 1 ml of concentrated sulphuric acid is added to the re-action mixture and the mixture is cooled reacted 3-methyl-7-(5-oxohexyl)-xanthine is filtered off and the alcohol is distilled off under reduced pres-sure. The residue is made alkaline with 4 ml of 50% sodium hydroxide and then extracted with 350 ml of methylene chloride. After recrystallisation from - . .
.. . .. . .. .
.. .
- . , :~
:. . . .
.: : , ;
7S~93 isopropanol l-n-propyl-3-methyl-7-~5-oxohexyl)-xanthine having a melting point of 76 to 78C is obtained in a yield of 85% from the residue of the methylene chloride solution. The solubility in ethanol, dimethylsulfoxide and dimethyl-formamide is above 10%.
Example 48 20.8 g of 1-n-propyl-3-methylxanthane and 13.8 g ofpotassium carbonate are heated in 150 ml of dimethylformamide to 120C and 14 g of l-chlorohexanone-~5) are dropwise added during 10 minutes. The reaction mixture 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 extracted with 100 ml of methylene chloride. After washing the organic phase with l-n-sodium hydroxide the solvent is distilled off. After recrystallisation of the residue from di-isopropylether l-n-propyl-3-methyl-7-~5-oxohexyl)-xanthine having a melting point of 53C is obtained in a yield of 25.1 g (= 83%).
Example 49 249 g of 3-methylxanthine and 126 g of sodium bicarbonate are sus-pended in 750 g of dimethylformamide and 210 g of 1-chlorohexanone-5 are por-tionwise added under stirring, wherein the reaction mixture is heated to 75C.
After finished addition the reaction mixture is heated to 130 to 140 C for 2a further 6 hours. Subsequently it is cooled to ambient temperature, the crys-tals are separated by suction and washed with isopropanol. The dried residue is suspended in 1 1 of 90C warm water, the suspension is adjus~ed to a p~l-value of 9.6 with sodium hydroxide and strongly stirred. The suspension 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 219C are obtained in a yield of 62%.
- 23 ~
. .
. .::
.:
, : - , . ~ : . .
.
~56~3 As illustrated in certain of the above examples, the compounds of this invention are prepared by a further process which comprises oxidation of a compound of the formula ~ N ~ (V) wherein Rl and R2 are as defined above and Y is a straight-chained 5-hydroxy-hexyl group; and wherein the product formed is isolated per se or reacted with an acid to form a physiologically compatible acid addition salt thereof. Thus in its broadest form this invention relatcs to a process for the preparation of compounds of general formula ~3 -o ~ ` ~ N >
wherein Rl is alkyl having from 2 to 4 carbon atoms, R2 is methyl and R3 is a straight-chained 5-oxohexyl group and physiologically acceptable acid addi~
tion salts thereof, which comprises a) reacting an alkali me~al salt of an 1,3-dialkylxanthine with a su~stance selected from the group consisting of i) a compound of formula O
1, (III) - 24 - :
..
:
, ~ . . .
~756~3 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 iii) subsequently hydrolys-ing the product, or b) reacting an alkali metal salt of a 3-methyl-7-oxohexylxanthine 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 the formula X-Hal Rl- ~ N' 0 ~ N
R2 - .
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 subsequently 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) oxidation of a compound of the -formula Y
wherein Rl and R2 are as defined above and Y is a straight-chained 5-hydroxy-hexyl group; and wherein the product formed is isolated per se or reacted . .
.
.
with an acid to form a physiologically compatible acid addition salt thereof.
Pharmacological experiments Furthermore with a number of oxoalkyl-xanthines various pharmacolo-gical tests have been performed. The results are evident from the following table 1.
Pharmacological experiments Table 1 ~cf. example No. of the present case~ Pharmacological effects .
Example 30 lt is worked as in example 24, however, 18 g of 1-propyl-3-methyl-7-(5-hydroxyhexyl)-xanthine are used as starting xanthlne substance. 11.6 g Of l-propyl-3-methyl-7-(5-oxohexyl)-xanthine are obtained in a yield of 65%.
Example 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 `
sodlum and 100 ml absolute ethanol. The mixture is refluxed for 2 hours.
After cooling the precipitated crystals are filtered off and the filtrate is evaporated to dryness. The residue is first treated at ambient temperature for 2 hours with 100 ml of 5 percent aqueous sodium hydroxide solution, then acidified with 14 ml of 50 percent sulphuric acid and then boiled for 1 hour.
After standing for 2 days the 3-methyl-7-~5-oxohexyl)-xanthine is filtered off.
The yield is 3.5 g = 50% of theory.
For purification the crude product is dissolved in a little aqueous sodium hydroxide solution and 3-methyl-7-~5-oxohexyl)-xanthine is then obtained by precipitating with aqueous hydrochloric acid in a yield of 40 percent.
Melting point 215 C.
Example 32 ~37.2 g of 3-methyl-7-propylxanthine, suspended in a mixture of 240 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 358 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 `, . ~. . , .. . - .~ . ~
:~07S693 distilled off. The aqueous solution is adjusted with sodium hydroxide to a pH-value of 11 and extracted with methylene chloride. From the residue of the methylene chloride solution and after recrystallisation from 5.2 1 of di-isopropylether 1-~5-oxohexyl)-3-methyl-7-propylxanthine having a melting point of 69 to 70C is obtained in a yield of about 90% ~referred to unreacted 3-methyl-7-propylxanthine). (The solubility in water/25C is about 3.1%, that in ethanol and dimethylsulphoxide above 10%).
Example 33 26.4 g of 1-(5-oxohexyl)-3-methylxanthine, 13.4 g of propylbromide and 13.8 g of potassium carbonate in 100 ml dimethylformamide are heated under stirring to 120C for 3 hours. After distillation off of the solvent under reduced pressure and after addition of 100 ml of water the residue is extracted with methylene chloride. The organic solvent is distilled off under reduced pressure and the residue is recrystallised from diisopropylether. 22 g of 1-~5-oxohexyl)-3-methyl-7-propylxanthine having a melting point of 69 to 70C
are obtained in a yield of 72%.
Example 34 A solution of 2.5 g of sodium in lS0 ml of absolute ethanol is ad-.. . .
mîxed with 14.3 g of acetoacetic acid ethylester and 32.9 g of 1-~3-bromo-propyi)-3-methyl-7-propylxanthine and refluxed for 5 hours. The alcohol is practically distilled off and the residue is refluxed with 150 ml of 5% of sodium hydrox1de for 3 hours. For 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 chlo-ride. After evaporation of the solvent the obtained residue is submitted to chromatography over silica gel with benzene/acetone ~7:3) as a solvent. After recrystallisation of the residue of the main fraction from diisopropylether 1-(5-oxohexyl)-3-methyl-7-propylxanthine having a melting point of 6g to 70C
.
~ - 19 -,,, : , ., . , . ., ~ ,: . , ... .. - .. ~ ., . . ,.., . ., ~ . . . . , . ., ., , . , . .. . :
"
~075~3 is obtained in a yield of 41%.
Example 35 It is worked according to example 33, but in using 12.5 g of 1-~4-oxopentyl)-3-methylxan~hine, 6.8 g of propylbromide cmd 7 g of potassium car-bonate in 100 ml dimethylformamide as starting materials. ll g of 1-(4-oxo-pentyl)-3-methyl-7-propylxanthine having a melting point of 67 to 68C are obtained in a yield of 75% ~recrystallisation from diisopropylether/acetic ester).
Example 36 It is worked as in example 34, but i~ 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-7-propylxanthine. 20 g of a raw product is obtained which is submitted to chromatography at silica gel with chloroform/ethanol (9:1) as a solvent. After recrystallisation 9.2 g 1-(4-oxopentyl)-3-methyl-7-propylxanthine are obtained in a yield of 48%.
Examp]e 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 car-bonate 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 iO C are obtained in a yield of 83%.
Example 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 acetoacetic acid ethylester. 1.7 g of 1-(6-oxoheptyl)-3-methyl-7-propylxanthine are ob-tained.
Example 39 It is worked according to example 32, but in using 117 g of 3-methyl-7-n-buty~lxanthine, 140 g of water, 85 g of methanolJ 20 g of sodium :;, . . ~ : . , :,. : :: ~ , :~7569~
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 (219C/0.5 mm) and then it is crystallised with 700 ml di-isopropylether. In a yield of 60% 1-(S-oxohexyl)-3-methyl-7-n-butylxanthine having a melting point of 79 to 80C is obtained.
Example 40 It is worked as in example 33, but in using 26.4 g 1-(5-oxohexyl)-3-methylxanthine, 10.2 g of n-butylchlorids, 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 80C are ob-tained in a yield of 87%.
Example 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 1-~3-bromopropyl)-3-methyl-7-bu~ylxanthine. 3 g of an oily raw pro-duct 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 melting point of 79C is obtained in a yield of 48%.
Example 42 It is worked according to example 32, but in using 20.4 g of 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 recrystallisa~ion from a little methanol 1-~5-oxohexyl)-3-methyl-7-ethylxanthine having a melting point of 102 to 103C is obtained in a nearly quantitative yleld Example 43 It is worked as in example 33, but in using 13.2 g of 1 ~5-oxohexyl)-:
- 21~-' ' :' .~ . ' . ' ', ' : ' ' ' ' .:
,~ . . . :.:
: . .
:~o~s~ig3 3-me~hylxanthine, 7 g of potassium carbonate and 6.6 g of ethyl bromide in 100 ml of dimethylformamide as starting substances. 10 g of 1-~5-oxohexyl)-3-methyl-7-ethylxanthine are obtained which is recrystallised two times from a little methanol. The final product has a melting point of 103 C.
Example 44 It is worked as in example 34, but in using 15 g of 1-~3-bromo-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-~5-oxohexyl)-3-methyl-7-ethylxanthine having a melting point of 103C are obtained.
Example 45 27.8 g of 1-(5-oxohexyl)-3-ethylxanthine, 8.5 g 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-oxo-hexyl)-3-ethyl-7-propylxanthine having a melting point between 81 and 82 C are obtained in a yield of 75%.
Example 46 3.4 of 1-(3-bromopropyl)-3-ethyl-7-propylxanthineJ 1.3 g of aceto-acetic acid ethyl ester and 0.3 g ofsodium are reacted as in example 34. 1-(5-oxohexyl)-3-ethyl-7-propylxanthine is obtained in a yield of about 20%.
Example 47 A suspension of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine in a mix-ture of 120 g of water and 72 g of methanol is dissolved with 18 g of sodium hydroxide at about 60C and admixed with 55.5 g of n-propylbromide. After refluxing for 24 hours 1 ml of concentrated sulphuric acid is added to the re-action mixture and the mixture is cooled reacted 3-methyl-7-(5-oxohexyl)-xanthine is filtered off and the alcohol is distilled off under reduced pres-sure. The residue is made alkaline with 4 ml of 50% sodium hydroxide and then extracted with 350 ml of methylene chloride. After recrystallisation from - . .
.. . .. . .. .
.. .
- . , :~
:. . . .
.: : , ;
7S~93 isopropanol l-n-propyl-3-methyl-7-~5-oxohexyl)-xanthine having a melting point of 76 to 78C is obtained in a yield of 85% from the residue of the methylene chloride solution. The solubility in ethanol, dimethylsulfoxide and dimethyl-formamide is above 10%.
Example 48 20.8 g of 1-n-propyl-3-methylxanthane and 13.8 g ofpotassium carbonate are heated in 150 ml of dimethylformamide to 120C and 14 g of l-chlorohexanone-~5) are dropwise added during 10 minutes. The reaction mixture 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 extracted with 100 ml of methylene chloride. After washing the organic phase with l-n-sodium hydroxide the solvent is distilled off. After recrystallisation of the residue from di-isopropylether l-n-propyl-3-methyl-7-~5-oxohexyl)-xanthine having a melting point of 53C is obtained in a yield of 25.1 g (= 83%).
Example 49 249 g of 3-methylxanthine and 126 g of sodium bicarbonate are sus-pended in 750 g of dimethylformamide and 210 g of 1-chlorohexanone-5 are por-tionwise added under stirring, wherein the reaction mixture is heated to 75C.
After finished addition the reaction mixture is heated to 130 to 140 C for 2a further 6 hours. Subsequently it is cooled to ambient temperature, the crys-tals are separated by suction and washed with isopropanol. The dried residue is suspended in 1 1 of 90C warm water, the suspension is adjus~ed to a p~l-value of 9.6 with sodium hydroxide and strongly stirred. The suspension 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 219C are obtained in a yield of 62%.
- 23 ~
. .
. .::
.:
, : - , . ~ : . .
.
~56~3 As illustrated in certain of the above examples, the compounds of this invention are prepared by a further process which comprises oxidation of a compound of the formula ~ N ~ (V) wherein Rl and R2 are as defined above and Y is a straight-chained 5-hydroxy-hexyl group; and wherein the product formed is isolated per se or reacted with an acid to form a physiologically compatible acid addition salt thereof. Thus in its broadest form this invention relatcs to a process for the preparation of compounds of general formula ~3 -o ~ ` ~ N >
wherein Rl is alkyl having from 2 to 4 carbon atoms, R2 is methyl and R3 is a straight-chained 5-oxohexyl group and physiologically acceptable acid addi~
tion salts thereof, which comprises a) reacting an alkali me~al salt of an 1,3-dialkylxanthine with a su~stance selected from the group consisting of i) a compound of formula O
1, (III) - 24 - :
..
:
, ~ . . .
~756~3 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 iii) subsequently hydrolys-ing the product, or b) reacting an alkali metal salt of a 3-methyl-7-oxohexylxanthine 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 the formula X-Hal Rl- ~ N' 0 ~ N
R2 - .
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 subsequently 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) oxidation of a compound of the -formula Y
wherein Rl and R2 are as defined above and Y is a straight-chained 5-hydroxy-hexyl group; and wherein the product formed is isolated per se or reacted . .
.
.
with an acid to form a physiologically compatible acid addition salt thereof.
Pharmacological experiments Furthermore with a number of oxoalkyl-xanthines various pharmacolo-gical tests have been performed. The results are evident from the following table 1.
Pharmacological experiments Table 1 ~cf. example No. of the present case~ Pharmacological effects .
4 1-n-Propyl-3-methyl-7-~5-oxohexyl)-xanthine ~melting point 76-78 C): LD50 = 100-250 mg/kg i.p.
~mouse), strong broncholytic effect at the guinea pig to acetylcholien, histamine and serotonine, increase of the cerebral and muscle perfusion at the cat, fibrinolytic effect.
8 1-Isobutyl-3-methyl-7-~5-oxohexyl)-xanthine (melting point 96-97C): LD50 = 250-500 mg/kg i.p.
(mouse), strong broncholytic effect to histamine, phosphodiesterase inhibition at bronchii of cattle about the same as after addition o~ theophylline:
ED50 = 6.1 x 10 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 35-38C): LD50 = 250-500 mg/kg i.p. ~mouse), strong broncholytic effect at the guinea pig to acetylcholine , histamine and serotonine, phospho-.
.
~75693 continuation (cf. example No. of the present case ) _ Pharmacological effect diesterase restriction at bronchii of cattle stronger than that by theophylline : ED50 =
1.95 x 10 4 M ~theophylline ED50 = 7~5 x 10 M).
~mouse), strong broncholytic effect at the guinea pig to acetylcholien, histamine and serotonine, increase of the cerebral and muscle perfusion at the cat, fibrinolytic effect.
8 1-Isobutyl-3-methyl-7-~5-oxohexyl)-xanthine (melting point 96-97C): LD50 = 250-500 mg/kg i.p.
(mouse), strong broncholytic effect to histamine, phosphodiesterase inhibition at bronchii of cattle about the same as after addition o~ theophylline:
ED50 = 6.1 x 10 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 35-38C): LD50 = 250-500 mg/kg i.p. ~mouse), strong broncholytic effect at the guinea pig to acetylcholine , histamine and serotonine, phospho-.
.
~75693 continuation (cf. example No. of the present case ) _ Pharmacological effect diesterase restriction at bronchii of cattle stronger than that by theophylline : ED50 =
1.95 x 10 4 M ~theophylline ED50 = 7~5 x 10 M).
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 isolated tracheal chain in the concentration of 3 x 10 5 strong inhibition ~9~%) of the isoprenaline e~fect which may not be inhibited by propanolol (i.e. it is not caused by a ~2-mimetic e~fect). 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 hanging-clot-test ;
from 25 mmol. At the isolated guinea pig heart from 30 ~ positive inotropic effect.
from 25 mmol. At the isolated guinea pig heart from 30 ~ positive inotropic effect.
6 1-~5-oxohexyl)-3-methyl-7-n-butyl-xanthine (melting point 79-80C): LD50 = 250-500 mg/kg i.p.
~mouse), strong broncholytic effect at the guinea pig to acetylcholine, histamine and serotonine, increase of the cerebral 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, - :
-. . : ~ .. .. .. . . . . . ..
. . , , . . -, . . ~ . :
ILa3~6~3 continuation ~cf. example No. of the present case) Pharmacologicai effect . _ _ ~ _ , increase of the duration of the hexobarbital narcosis.
9 I-~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-ethyl-xanthine (melting point 102-103C): LD50 = 120-200 mg/kg i.v.
~mouse), 250-500 mg/kg i.p. (mouse), strong broncho-lytic effect at the guinea pig to acetylcholine~
histamine and serotonine. Strong and long~lasting improvement of the cerebral blood perfusion at the cat after doses of 1 to 5 mg/kg i.v., increase of the muscular blood perfusion, fibrinoly~ic effect in vitro in hanging-clot-test from 25 mmol.
Comparison of the activities Comparison 1 ~Cl) 1-~5-Oxohexyl)-3-methyl-7-propyl-xanthine; the cerebral blood perfusion was measured at narcotized cats by means of fluvography under administration of doses of 0.3J 1, 2 and 5 mg/kg i.v.. The present compound effects 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 ~as administered in a dose of 3 mg/kg i.v . .
.- ~ . .. . . ..
- ~ . . , ............ -. ', - . :, : . , ~75693 Comparison 2 ~C2) 1-(5-Oxohexyl)-3-methyl-7-ethyl-xanthine: the cerebral blood perfusion at narcotized ca~s was measured by fluvography after administration of doses of 0.3J 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.
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 ~as measured. The results ~ere compared with those of the known substance '~
1-~,5-oxohexyl)-3,7-dimethyl-xanthine and with aminophylline.
The tested compounds are evident from the following table 2.
Table 2 No.
tcf. 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
~mouse), strong broncholytic effect at the guinea pig to acetylcholine, histamine and serotonine, increase of the cerebral 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, - :
-. . : ~ .. .. .. . . . . . ..
. . , , . . -, . . ~ . :
ILa3~6~3 continuation ~cf. example No. of the present case) Pharmacologicai effect . _ _ ~ _ , increase of the duration of the hexobarbital narcosis.
9 I-~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-ethyl-xanthine (melting point 102-103C): LD50 = 120-200 mg/kg i.v.
~mouse), 250-500 mg/kg i.p. (mouse), strong broncho-lytic effect at the guinea pig to acetylcholine~
histamine and serotonine. Strong and long~lasting improvement of the cerebral blood perfusion at the cat after doses of 1 to 5 mg/kg i.v., increase of the muscular blood perfusion, fibrinoly~ic effect in vitro in hanging-clot-test from 25 mmol.
Comparison of the activities Comparison 1 ~Cl) 1-~5-Oxohexyl)-3-methyl-7-propyl-xanthine; the cerebral blood perfusion was measured at narcotized cats by means of fluvography under administration of doses of 0.3J 1, 2 and 5 mg/kg i.v.. The present compound effects 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 ~as administered in a dose of 3 mg/kg i.v . .
.- ~ . .. . . ..
- ~ . . , ............ -. ', - . :, : . , ~75693 Comparison 2 ~C2) 1-(5-Oxohexyl)-3-methyl-7-ethyl-xanthine: the cerebral blood perfusion at narcotized ca~s was measured by fluvography after administration of doses of 0.3J 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.
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 ~as measured. The results ~ere compared with those of the known substance '~
1-~,5-oxohexyl)-3,7-dimethyl-xanthine and with aminophylline.
The tested compounds are evident from the following table 2.
Table 2 No.
tcf. 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-oxohexyl)-xanthine35 - 38 1 1-~5-oxohexyl)-3-methyl-7-propylxanthine 69 - 70 6 l-~5-oxohexyl)-3-methyl-7-n-butylxanthine 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)-3J7-dimethyl-xanthine102 - 105 ~comparison~
C2 aminophylline 270 - 27 (comparison) , ,; ' ,: . . .... : . .
,- , ' ' ' '~ ' - ~' '' ,'' ':
~; - .' , ' . :
Test method The test principle of K.-Golenhofen, H.-Hensel and G.-llildebrandt, "Durchblutungsmessungen mit ~armeleitelementen 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 chlaralose-urethane narcosis ~70 + 200 mg/kg i.p.). The calvaria was opened in the area of the frontal gyrus marginalis or suprasylvicus respectively.
The measurements occured with a modified surface measurement head according to ~ensel ~c. Pflugers Arch. 268 (1959), page 604) which was laid thereon after opening of the dura of the cerebral cortex. The duration of effectivity was registered as half-life-time, the intensity of activity was registered accord-ing to Golenhofen et al as heat transport number ~. The registration was performed by thermosonds over a two-channel fluvograph for the firm Hartmann ~7 Braun, Frankurt on Main. Other circulation parameters registered simul-taneously were conducted to a Helligemore-channel-graph.
Experimental results .
The results obtained at the mentioned experiments are represented ~n the following table 2 as ~ and as half-life-time in minutes. ~ is the change of blood perfusion.
, . , . . .
. . , . . ., : : - :: , ~
: : . . ~: ~: :
- , , ~ : . :
.
1~75~;93 Table 3 Sample change of the cerebral No. dosis mg/kg blood perfusion animals (cf. i.v.half-life-time n example) ~ in minutes ._ . ._ .
1 + 1.85 1.0 2 + 3.45 14.3 2 __ .
1 + 0.97 0.4 3 2 + 1.45 7.0 2 , ~. . . ._ -._ . _ ..
1 + 4.33 4.0 3 1 2 + 6.33 5.8 3 +13.00 14.7 3 ._.__ _ ...
1 + 2.50 1.3 2 6 2 + 2.55 1.3 2 + 2.40 3.0 2 . _ __ . __ 1 -~ 1.40 0.2 1 3 + 2.80 0.5 . _ _ ... __ 1 + 2.46 1.5 5 2 + 5.17 5.0 3 + 8.07 8.2 ~
_ . . ._. . _ . . __._ . Cl 1 + 0.44 0.9 13 (comparison) + 0.86 2.4 40 + 1.15 8.6 33 _ _ _ ..... _........... ___ ... __ C2 1 + 0.19 1.8 7 ~comparison) 2 ~ 0.15 1.8 2 + 0.18 3.3 8 + 0.53 1.7 7 _, _ .__ .. _ ._____ . ~ . , :: ' . . ,: ' . . .
.. .
- . : - - .
. .. , .. , .. . :
- . . . . . . . . .
. .
,, .: ' ' ' . . . .: :
1~5~i~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. C2 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 corresponding 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 six 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-tîme 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 the invention over the substances of the prior art is distinctly proved.
- 3~ -- , : , : . .
. ~ : , . . , . ,, . : : .. . . - .
.
-- ~ .. . . ... . .. : .
~, , .
'' '~ ' ' ,, ' : '' ` '' ' . ' ','~ '.,'".: . ' - , . . .
.
C2 aminophylline 270 - 27 (comparison) , ,; ' ,: . . .... : . .
,- , ' ' ' '~ ' - ~' '' ,'' ':
~; - .' , ' . :
Test method The test principle of K.-Golenhofen, H.-Hensel and G.-llildebrandt, "Durchblutungsmessungen mit ~armeleitelementen 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 chlaralose-urethane narcosis ~70 + 200 mg/kg i.p.). The calvaria was opened in the area of the frontal gyrus marginalis or suprasylvicus respectively.
The measurements occured with a modified surface measurement head according to ~ensel ~c. Pflugers Arch. 268 (1959), page 604) which was laid thereon after opening of the dura of the cerebral cortex. The duration of effectivity was registered as half-life-time, the intensity of activity was registered accord-ing to Golenhofen et al as heat transport number ~. The registration was performed by thermosonds over a two-channel fluvograph for the firm Hartmann ~7 Braun, Frankurt on Main. Other circulation parameters registered simul-taneously were conducted to a Helligemore-channel-graph.
Experimental results .
The results obtained at the mentioned experiments are represented ~n the following table 2 as ~ and as half-life-time in minutes. ~ is the change of blood perfusion.
, . , . . .
. . , . . ., : : - :: , ~
: : . . ~: ~: :
- , , ~ : . :
.
1~75~;93 Table 3 Sample change of the cerebral No. dosis mg/kg blood perfusion animals (cf. i.v.half-life-time n example) ~ in minutes ._ . ._ .
1 + 1.85 1.0 2 + 3.45 14.3 2 __ .
1 + 0.97 0.4 3 2 + 1.45 7.0 2 , ~. . . ._ -._ . _ ..
1 + 4.33 4.0 3 1 2 + 6.33 5.8 3 +13.00 14.7 3 ._.__ _ ...
1 + 2.50 1.3 2 6 2 + 2.55 1.3 2 + 2.40 3.0 2 . _ __ . __ 1 -~ 1.40 0.2 1 3 + 2.80 0.5 . _ _ ... __ 1 + 2.46 1.5 5 2 + 5.17 5.0 3 + 8.07 8.2 ~
_ . . ._. . _ . . __._ . Cl 1 + 0.44 0.9 13 (comparison) + 0.86 2.4 40 + 1.15 8.6 33 _ _ _ ..... _........... ___ ... __ C2 1 + 0.19 1.8 7 ~comparison) 2 ~ 0.15 1.8 2 + 0.18 3.3 8 + 0.53 1.7 7 _, _ .__ .. _ ._____ . ~ . , :: ' . . ,: ' . . .
.. .
- . : - - .
. .. , .. , .. . :
- . . . . . . . . .
. .
,, .: ' ' ' . . . .: :
1~5~i~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. C2 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 corresponding 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 six 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-tîme 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 the invention over the substances of the prior art is distinctly proved.
- 3~ -- , : , : . .
. ~ : , . . , . ,, . : : .. . . - .
.
-- ~ .. . . ... . .. : .
~, , .
'' '~ ' ' ,, ' : '' ` '' ' . ' ','~ '.,'".: . ' - , . . .
.
Claims (19)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of compounds of general formula (IV) wherein R1 is alkyl having from 2 to 4 carbon atoms, R2 is methyl and R3 is a straight-chained 5-oxohexyl group and physiologically acceptable acid addition salts thereof, which comprises a) reacting an alkali metal salt of an 1,3-dialkylxanthine with a substance selected from the group consisting 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 iii) subsequently hydrolys-ing the product, or b) reacting an alkali metal salt of a 3-methyl-7-oxohexylxanthine with an alkylating compound selected from the group consisting of alkyl halides and dialkyl sulphate in the presence of a solvent, or c) reacting a compound of the formula (IV) 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 subsequently 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 formed is isolated per se or reacted with an acid to form a physiolog-ically compatible acid addition salt thereof.
2. A process as claimed in claim 1 wherein the reaction a) or 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 or 3 wherein R1 is n-propyl.
5. A process as claimed in claim 1 or 2 or 3 wherein R1 is isobutyl.
6. A process for the preparation of 1-n-propyl-3-methyl-7-(5-oxohexyl)-xanthine which comprises propylating 3-methyl-7-(5-oxohexyl)xanthine.
7. A process for the preparation of 1-n-propyl-3-methyl-7-(5-oxohexyl)-xanthine which comprises reacting 3-methyl-7-(5-oxohexyl)-xanthine with n-propyl-bromide.
8. A process for the preparation of 1-isobutyl-3-methyl-7-(5-oxohexyl)-xanthine which comprises isobutylating 3-methyl-7-(5-oxohexyl)xanthine.
9. A process for the preparation of 1-isobutyl-3-methyl-7-(5-oxohexyl)-xanthine which comprises reacting 3-methyl-7-(5-oxohexyl)-xanthine with iso-butylbromide.
10. A compound of formula I given in claim 1 or a physiologically ac-ceptable acid addition salt thereof whenever prepared according to the process claimed in claim 1 or 2 or 3 or by an obvious chemical equivalent thereof.
11. 1-n-propyl-3-methyl-7-(5-oxohexyl)-xanthine whenever prepared ac-cording to the process claimed in claim 6 or 7 or by an obvious chemical equivalent thereof.
12. 1-isobutyl-3-methyl-7-(5-oxohexyl)-xanthine whenever prepared ac-cording to the process claimed in claim 8 or 9 or by an obvious chemical equivalent thereof.
Claims supported by the supplementary disclosure
Claims supported by the supplementary disclosure
13. A process for the preparation of compounds of general formula (I) wherein R1 is alkyl having from 2 to 4 carbon atoms, R2 is methyl and R3 is a straight-chained 5-oxohexyl group and physiologically acceptable acid addition salts thereof, which comprises a) reacting an alkali metal salt of an 1,3-dialkylxanthine with a substance selected from the group consisting 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 iii) subsequently hydrolys-ing the product, or b) reacting an alkali metal salt of a 3-methyl-7-oxohexylxanthine 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 the formula (IV) 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 subsequently 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) oxidation of a compound of the formula (V) wherein R1 and R2 are as defined above and Y is a straight-chained 5-hydroxy-hexyl group; and wherein the product formed is isolated per se or reacted with an acid to form a physiologically compatible acid addition salt thereof.
14. A process according to claim 13 for the preparation of compounds of general formula (I) wherein R1 is alkyl having from 2 to 4 carbon atoms, R2 is methyl and R3 is a straight-chained 5-oxohexyl group and physiologically acceptable acid addition salts thereof, which comprises oxidation of a compound of the formula:
(V) wherein R1 and R2 are as defined above and Y is a straight-chained 5-hydroxy-hexyl group; and wherein the product formed is isolated per se or reacted with an acid to form a physiologically compatible acid addition salt thereof.
(V) wherein R1 and R2 are as defined above and Y is a straight-chained 5-hydroxy-hexyl group; and wherein the product formed is isolated per se or reacted with an acid to form a physiologically compatible acid addition salt thereof.
15. A compound of formula (I) as defined in claim l or a physiologically acceptable acid addition salt thereof, whenever prepared according to the pro-cess claimed in claim 13 or by an obvious chemical equivalent thereof.
16. A process for the preparation of 1-propyl-3-methyl-7-(5-oxohexyl) xanthine which comprises oxidising 1-propyl-3-methyl-7-(5-hydroxyhexyl)xanthine.
17. A process according to claim 16 in which the oxidation is effected by reaction with pyridine chlorochromate.
18. A process for the preparation of 1-n-propyl-3-methyl-7-(5-oxohexyl) xanthine which comprises reacting 1-n-propyl-3-methylxanthine with 1-chloro-hexanone-(5).
19. 1-n-Propyl-3-methyl-7-(5-oxohexyl)xanthine whenever prepared by the process of claim 16, 17 or 18 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA320,438A CA1075693A (en) | 1977-12-07 | 1977-12-07 | Xanthine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA320,438A CA1075693A (en) | 1977-12-07 | 1977-12-07 | Xanthine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1075693A true CA1075693A (en) | 1980-04-15 |
Family
ID=4113409
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA320,438A Expired CA1075693A (en) | 1977-12-07 | 1977-12-07 | Xanthine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1075693A (en) |
-
1977
- 1977-12-07 CA CA320,438A patent/CA1075693A/en not_active Expired
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