CA1123435A

CA1123435A - Pharmaceutical compositions, alkenyl xanthins contained therein and process for preparing them

Info

Publication number: CA1123435A
Application number: CA300,333A
Authority: CA
Inventors: Harald Furrer; Alfons Soder; Jaromir Komarek; Heinz-Joachim Hinze; Gerhard Munch
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1977-04-02
Filing date: 1978-04-03
Publication date: 1982-05-11
Also published as: NL188620C; DE2714953A1; FR2420346A1; IT7821900A0; BE865601A; NL7803504A; DE2714953C2; IT1094052B; NL188620B; CH639849A5; ZA781876B; GB1580782A; FR2420346B1; AU3467278A; AU523125B2; JPS53149998A; JPS5649886B2

Abstract

ABSTRACT OF THE DISCLOSURE

Xanthine derivatives of the formula

Description

l~Z39,35 This invention relates to novel pharmac,eutical compositions comprising xanthine derivative~ , ~o novel xanthine derivatives and to a process ~or preparing them, - A process for the hydration of (~-l)-alkenyl-xanthine derivatives of general formula ~ . R

\ ~ ~ N /

O ~ N 1 N :~
R2 , .

in the presence of a catalyst to form corresponding (~-l)-hydrox,ralkyl-xanthines is known, In the above formula one of R , R and R represents an (~-l)-alkenyl group having from 4 to 8-carbon atoms and the remainder of Rl, R2 and R3, which may be the same or different, - each represents a straight-chained or branched alkyl group having from 1 to 12 carbon atoms~and Rl and/or R3 may also represent hydrogen atoms, with the proviso .. .... ~ .... . ,. . ~

1~23435 however that at least one of Rl, R2 and R3 has at least 5 carbon atoms. (w~ Hydroxyalkyl-xanthines are suitable for use in medicine, especially for the treatment of circulation disorders of blood in the brain We have now found that corresponding alkenyl-xanthines, and especially (~-l)-alkenyl-xanthines, exhibit interesting pharmacological properties and in particular a vascular circulation-assisting activityl an activity of pro-moting blood perfusion, especially in the cerebrovascular reEion.

According to one aspect of the present invention there is provided a pharmaceutical composition comprising as active ingredient at least one compound of formula Q R

O ~ ~ N ~

~.
(wherein Rl represents a hydrogen atom, an alkyl group 3.~23~35 having from 1 to 12 carbon atoms or an alkenyl group having from 4 to 8 carbon atoms; and R2 and R3, which may be the same or different, each represents an alkyl group having from 1 to 12 carbon atoms or an aIkenyl group having from 4 to 8 c æ~on atoms; with the proviso that at least one of Rl, R and R represents an alkenyl group having from 4 to 8 c æ bon atcms) in association with a pharmaceutical OE rier or excipient. Any of the alkyl and alkenyl groups may be straight-chained or branched.
Preferred cumpositions are those comprising compounds of formula I in which at least one alkenyl group is an (~-l)-alkenyl group.
Also preferred æ e those comp~sitions containing compounds of formula I in which one of Rl, R2 and R3 is an (w~ alkenyl radical with 4 to 8 carbon atoms in which the carbon atom of the double bond is separated from the xanthine nucleus by at least one saturated carbon atom and both of the other groups are ~.ethyl, ~ ~-ever Rl may also be a hydrogen aton, but R2 always represents a methyl or an alkenyl group. One of R , R and R3 in the campound of formula I is preferably a straight chained ..

' !, ,: . ' ' : ., '` ., :
~, `' ~'.".. `, '`''' ' '.`;
" .,: '' . ,. ,, :"

LZ343~

(~-l)-alkenyl radical with 5 to 8 carbon atoms Advanta-geously one of R and R is a straight-chained ~
alkenyl group having from 4 to 8 carbon atoms and the other is a methyl group According toa further feature of the invention there are provided compounds of general formula \ ~N

wherein Rl represents a hydrogen atom, an alkyl group ;
having from 1 to 12 carbon atoms or an alkenyl group ;
having from 4 to 8 carbon atoms; and R and R , which may be the same or different, each represents an alkyl group having from 1 to 12 carbon atoms or an alkenyl group having from 4 to 8 carbon atoms; with the provisos that at least one of Rl~ R2 and R represents an alkenyl group having from 4 to 8 carbon atoms, Rl is other than a but-3-enyl, pent-4-enyl or 2-methyl-~1239L3S

but-3-enyl group when R2 and R both represent methyl groups, Rl is other than a hex-5-enyl group when R
represents a methyl group and R represents a methyl, ethyl, propyl, butyl, isobutyl, decyl or hex-5-enyl group~ Rl is other than a methyl group when R2 is a methyl group and R is a 2-methyl-but-3-enyl, but-3-enyl, pent-4-enyl, hex-5-enyl or hept-6-enyl group, Rl is other than a hydrogen atom when R2 is a methyl group and R is hex-5-enyl group , and R is other than a propyl, isobutyl, pentyl or hexyl group when R2 is a methyl group and R3 is a hex-5-enyl group Preferred compounds of formula I' are those in which R is an alkenyl group having from 4 to 8 carbon atoms or an alkyl group having form 1 to 12 carbon atoms, and when R2 is methyl and Rl or R3 is an (~-l)-alkenyl group unbranchedin(~-l)-position, the sum of the carbon atoms of the alkyl substituents Rl and R2 is, however, greater than 7 or the sum of the carbon atoms of the alkyl substituents R2 and R is greater than 11 1~23~3S

E~pecially preferred com~ounds of the invention are those in ~rhich at least one of the r~dicals Rl, R2 and R3 represents an ~lkyl group having Yrom 2 to 12 carbon atoms and at least on Or them represen~s an alkenyl group~ R
beinæ alkyl, alkenyl or even hydrogen and one of the radicals possibly being methyl. Also espeOEially preferred are compounds in which more than one of the groups ~ , R2 and R3 are alkenyl groups in ~hich the double bon~preferably is in the (~-l)-position, Another preferred embodiment relates to compounds in which the double bond is in a position other than the (~-l)-position, ~:
According to a stili further aspect of the present invention there are provided the following processes for the preparation of the novel alkenyl-xanthines of~
formula I ~-a) reacting a compound of formula I'in which at least one of Rl, R2 and R is hydrogen and the remainder of these groups is an alkyl and/or alkenyl group, optionally in the pres~nce of a base or in the form of their salts, with a compound of formula, ' . - . ' ' : . . ,,: . . : . -R ~ X ;~

in which X represents a halogen, preferably a chIorine or bromine atom or a sulphonic acid ester or phosphoric acid ester group and R represents an alkenyl group having from 4 to 8 carbon atoms (for the introduction of one or more alkenyl groups) or an alkyl group having from 1 to 12 carbon atoms (for the intro-- duction of one or more alkyl groups).
Thus, unsubstituted xanthine; 1-, 3- or 7-monoalkyl-xanthines or monoalkenyl-xanthines; or 1,3-, 1,7- or 3,7~dialkyl- or dialkenyl-xanthines or a corres-ponding monoalkyl-monoalkenyl-xanthine are used in this process The alkyl and alkenyl groups may be straight-chained or branched, as desired.
The xanthine derivatives used in this process are preferably in the form oftheir alkali metal or alkaline-earth metal salts, This process may be carried out in conventional m~.nner, generally at a temperature of from 20 to 160C, preferably from 35 to 125C, and optionally at an elevated ~:lZ3435 or reduced pressure, but usually at atmospheric pressure The individual starting materials may be usPd in stoichiometric or, for economic reasons, in non-stoichio-metric quantities, The reaction time is, of course, generally dependent on the temperature The reaction may be completed after one hour, although the reaction time - generally amounts to more than 6 hours The reaction is conveniently effected in the presence of an inorganic base such as, for example, an alkali metal or alkaline earth metal hydroxide, carbonate, hydride or alcoholate, or an organic base such as triethylamine or tributylamine Alkali metal or alkaline-earth metal salts of the starting xanthines are advantageously produced in situ.
The above process is conveniently effected in the presence of a solvent, Convenient solvents are those ~.
which are miscible with water, and may be used in admixture with water, e g methanol, ethanol, propanol, isopropanol, the various butanols, acetone, pyridine, polyhydric _ g _ -~ - - . ... .... .. . . .

ur~
~;
~1~3435 . -~,`.
..
alcohols such as ethylene glycol and ethylene glycol `:. monomethyl or ethyl ether. Aprotic dipolar solvents .~ such as formamide, dimethyl.formamide, dimethylacetamide, ~, N-methylpyrrolidone, tetramethyl-urea, hexamethylphosphoric acid trisamide and dimethylsulphoxide may also be used ';-~ In addition, hydrocarbon solvents such as benzene, toluene ~i~
or xylene, as well as mixtures of the said solvents, if they are mutually miscible are also suitable, This process enables the same or different alkenyl and/or alkyl substituents to be introduced in succession r or several similar substituents can be linked to the ! . xanthine nucleus without isolationg any intermediate product in a coupled reaction :
b) reacting an appropriate oxoalkyl-xanthines with ..,~
,~ an olefinising agent, whereby the number of carbon atoms .i in the oxoalkyl group and in the group introduced with the olefinising agent is in total from 4 to 8 carbon atoms; or c) dehydrating an appropriate hydroxyalkyl-xanthine .

.

L23~3S

in which the hydroxyalkyl group has from 4 to 8 earkon atams.
Process b) may be effeeted by the eonventional olefinising reaetions, for example, according(~to Wittig-Horner (IIouben-Weyl volume 5/1 b (1972), 383 et seq.). Oxaalkyl-xanthines may be converted into corresponding alkenyl-xanthines according to the invention in solvents such as dioxan, dimethylformamide or dimethylsulphoxide, generally at temFeratures of fram 20 to 160C, preferably of fram 20 to 80C, by reaetion, for example, with a suitable phosphinyl alkylene. Branch-chained xanthine derivatives may also be obtained by this process.
Dehydration of hydroxyalkyl-xanthines into alkenyl-xanthines aocording to process e) may ke earried out by conventional techniques, for example, in the presenee of acid catalysts, e.g. _-toluenesulphonic aeid.
If 1,3,7-trisubstituted-hydroxyalkyl-xanthines are used in process e), the Tsehugaeff xanthate method is advantageously adopted, that is eonverting the hydroxyalkyl-~ Z 3 ~3S

xanthines preferably ~,in benzene, ether or toluene solution via their alkali metal s~lts, preferably their sodium salts, by reaction with carbon disulphide and methyl iodide into methyl xanthates which are transformed at temperatures of 110 to 230C intOcorresponding alkenyl-xanthines The processes according to the invention ena~le - those alkenyl-xanthines to be prepared in which the ,C=C~ :
grouping of the alkenyl group is bound directly to a nitrogen atom and also those in which thP ~ C=C~ grouping is separated by at least one, preferably 2 to 6 carbon atoms from the xanthine nucleus.
Examples of particular substances according to the invention which may be incorporated into the compositions according to the invention are:-1,3-dimethyl-7-(but-3-enyl)-xanthine;
1,3,-dimethyl-7-(pent-4-enyl)-xanthine;
1,3-dimethyl-7-(hex-5-enyl)-xanthine;
l-(-but-3-enyl)-3,7-dimethyl-xanthine;
l-(pent-4-enyl)~3,7-dimethyl-xanthine;

: .. . . . . .

~35 l~(but-3-enyl)~3-methyl-7-n-propyl-xanthine;
l-(but-3-enyl) 3-methyl.-7-n-hexyl-xanthine;
l-(-hex-S-enyl)-3-methyl-7-n-propyl-xanthine;
l-(hex-S-enyl)-3-methyl-7-n-hexyl-xanthine;

l-(hex-S-enyi) -3-me thyl-7-n-decyl-xanthine;
l-ethyl-3-methyl-7-(hex-5-enyl)-xanthine;
l-n-propyl-3-methyl-7-(but-3-enyl)-xanthine;
l-n-hexyl-3-methyl-7-(but-3-enyl)-xanthine;
l-n-hexyl-3-methyl-7-(pent-4-enyl)-xanthine;
l-n-decyl-3-methyl-7-(but-3-enyl)-xanthine;
ethy~1~3-ethyl-7-(hex-5-enyl)-xanthine;
1,3-diethyl-7-(pent-4-enyl)-xanthine;
1,3-diethyl-7-(hex-5-enyl)-xanthine;
1,3-di-(n-butyl)-7-(but-3-eny ~xanthine;
3-Methyl~7-(but-3-enyl)-xanthine;
3-Methyl-7-(pent-4-enyl)xanthine;
3-Methyl-7-(hex-S-enyl)-xanthine;
3-ethyl-7-(but-3-enyl)-xanthine;
3-ethyl-7-(hex-5-enyl)-xanthine;

, , . , ~, , .

~1 2 3 43~

1~7-di-(but-3 enyl)-3-ethyl-xanthine;
l-(but-3-enyl)-3-ethyl-7-(hex-5-eny:~-xanthine i_n_hexyl_3 methyl~7-(hex-5-enyl)xanthine;
1,3-dimethyl-7 (S-methyl-hex-5-enyl)-xanthine;
1,3-dimethyl-7-(hex-4-enyl)-xanthine;
l-methyl-3-n butyl-7-(oct-7-enyl)-xanthine;
3~7-di-(pent-4-enyl)-xanthine;
1,3,7-tri-(pent-4-enyl)-xanthine;
l-n-propyl-3-(hex 5-enyl)-7-n-hexyl-xanthine;
methyl-3-ethyl-7-(hept-6-enyl)-xanthine;
1,7-dimethyl-3-(pent-4-enyl)-xanthine;
1~3-di-(n-hexyl)-7-(but-3-enyl)-xanthine;
1,3-di-(n-butyl)-7-(hex-5-enyl)-xanthine;
1-(2-methyl-but-3-enyl)-3~7-dimethyl-xanthine;
l-(hex-S-enyl)- 3-methyl-7-butyl and 7-isobutyl-xanthine;
1,3-di-methyl-7-(2 methyl-but-3-enyl)~xanthine;
1,3-dimethyl-7-(hept-6-enyi)-xanthine;
l-propyl-, l-isobutyl-~ and l-pentyl-3-methyl-7 ~ I4 -.. , ~ , . . ....... .. , ,, ~

, ~ . . ~ . ., ,,,, .;; , ~ ., l:~LZ3435 (hex-5-enyl)-xanthine; and 1,7-di-(hex-5-enyl)-3-methyl-xanthine.
The compositions according to the invention have interesting physiological properties. They may be conveniently administered orally or rectally, e.g. in solid or dissolved forms. If the particular xanthine derivative according to the invention desired is readily soluble in water, it may also be administered parenterally.
If desired the compositions according to the invention may additionally comprise one or more further ingredients being pharmacodynamically active, such as for example vitamins.
Suitable forms of administration of the compositions of the invention are, for example, solutions, emulsions, tablets, coated tablets, capsules, mic~ocapsules, powders, syrups, suppositories, granulates or forms adapted to provide a sustained release of active ingredient, and these may be prepared in a manner known per se using excipients conventional therefor such :

~Z3~35 as, for example, carriers; disintegrants;binders; coatings;
swelling, sliding or lubri~ating agents; flavourings;
sweetners; agents providing a sustained release effect; and solubilising agents Examples of such additives are lactose,mannitol, talcum, milk protein, starch, gelatin, cellulose or its derivatives such a~ methyl c~llulose, hydroxyethyl cellulose or suitable swelling or non-swelling copolymers, By the use of extenders, which can be used in lesser or greater amounts,the decomposition of the preparation and, as a result the re].ease of the active ingredient, may be controlled, The compositions of the present invention may be presented in the form of injectible solutions of compounds Or general ~ormula I in sterile water, e,g, in double distilled water, As indicated above they may also be in a solid form preferably in dosage unit form, if desired in a form giving delayed release of the active ~ -ingredient(s) Dosage unit formulations o~ the compositions preferably contain, according to the particular degree of activity, from 10 to 1000 mgt generally up to 400 mg and especially up to 200 mg, of the active ingredient of formula I, Thus, the average quantity of the compounds of forrrula I- administered is in the range of 0,2 to 20 mg per kg of body weight, Dosage units may be administered once or more -times daily, the number of administrations depending on the particular content of active ingredient and on the type of administration, More frequent administration is recommended if for example the dosage unit has only a small contet~t of active substance; but on the other hand if the content is relatively high, the compositions may be administered only for example once a day, If, further, the composition is supplied in sustained release form, administration may be restricted to at least once a day, The length of time over which administration may be effected during treatment may range from one to several weeks, although if necessary and/or desired the compositions rnay be administered over much longer periods, - 17 - .

, , , .
. .

~1~3~35 The compositions of the invention have interesting physiological properties `, in par'icular a blood circulation-assisting activity, ~nd also a low toxicity. Thuq the compositions are of value for increasing cerebrovascular .i;
circulationO

Investi~ation of brain c rculation in cats A heat-conduction prove was used to measure local `- brain circulation(in the cortex), The method necessary to measure heat conduction was adopted in detail from the experiments described by Betz et al, in (1) Betz et al,: Pflugers Arch, ges, Physiol. 288, 389 (.1966), ,

(2) Priebe, L, et al,: Pflugers Arch. ges, Physiol, 294, 3, 26 (1967), `(3) Betz, E,: Symposium der Dtsch, Ges, f, Angiologie, 6, Jahrestagung, ~unich (1968), (4) Betz, E,: Pflugers ~rch, ges, Physiol, 284, 3, 278 (1965), :' . ' , ~lZ39L3~

(5) setz, E.: Acta Neurol. Scand., Suppl. 14, 29 (1965), (6) setz, E.: Physiological Rev. 52, 3 (1972).
The tests were conducted on anaesthetised cats (sodium pentabarbital 35 mg/kg body weight i.p.). Blood pressure was measured in a femoral artery using a Statham device.
Table 1 indicates for some of the alkenyl-xanthines according to the invention prepared, the duration of activity as a half-value time (HVT) and the intensity of activity as the difference in the heat-conduction number ~ (Q~= ~after ~~before) in comparison with corresponding values for the vasotherapeutic product aminophylline. The results indicate that the substances contained in the compositions according to the invention have a superiority both in the intensity of the effect and in the duration of activity from fluvographic measurement of brain circulation in cats.

, .. .:: . :
. ... : . , . :
- . ~ .. :-. : . -, . . " ."

~;~39~35 Table 1:
Activity of various alkenyl xanthines and amino-phyllin on brain circulation in cats . . . __ Substance Dose in Change in blood perru- .;
mg/kg i.v. ~ ~ æion HVT~mi-n . _ , .
Example 1 2 + 3 0.5 - . 5 + 4,5 2 ;
. Example 2 5 + 4,5 2 .

Example 3 52 + 2,2 10 Example 4 2 + 7~3 5 + 7~5 3 Il:
Example 5 2 + 3 7 5 ~.~
. .~ . ,~.
Aminophylline 1 . + 0~19 1~8 :~
(Comparison) 2 + 0015 1~8 . .
+ 0,18 3~3 + 0,53 1,.7 . _ _ , ~ :.

, ::

- , . : . , ; , .. . .

liZ343S

The following Examples serve to illustrate the pre~
paration of compounds according to the invention, In these Examples the ratios relate to volume ratios~
Example 1: 1~3-Dimethyl-7~but-3-enyl)-xanthine - 13,9 g of 4-bromo-but-l-en~'- are reacted with 20,2 g of sodium theophylline in 200 ml of dimethyl-formamide at 120C with stirring for approximately 6 to 8 hours until the reaction is complete as indicated by thin-layer chromatography, The solvent is then removed under reduced pressure, The residue is dissolved at 200C in lO0 ml of methylen~ chloride, separated from insoluble sodium bromide and purified through a column packed with neutral aluminium oxide to remove small quantities of dark-coloured accompanying substances~ Melting point: 110C (acetone); yield:
21,6 g (91% of theory relative to the starting material used), After thin-layer chromatography on Merck DC
finished plates of silica gel 60 F254 with benzene/
acetone (6:4) as eluent, the product has an Rf ~ 21 - .

~Z3435 value of 0.54; and wi-th nitromethane/benzene/pyridine (20:10:3) as eluent, an Rf value of 0.65. Ultra-violet light was used as indicator after the pyridine of the eluent had, however, been removed at 50C under reduced pressure because of its property -to extinguish fluoresence.
Examples 2 to 5 The following compounds are prepared analogously to Example 1 from the corresponding dimethyl compounds:

2, 1,3-Dimethyl-7-(pent-4-enyl-xanthine

3, 1,3-Dimethyl-7-(hex-5-enyl)-xanthine

4, 1-(But-3-enyl)-3,7-dimethyl-xanthine

5, 1-(Pent-4-enyl)-3,7-dimethyl-xanthine The physical data of these compounds are set out in Table 2, Example 6: 1-(But-3-enyl)-3-methyl-7-n-propyl-xanthine 20.8 g of 3-methyl-7-propyl-xanthine, 13.8 g of anhydrous potassium carbonate and 13.5 g of 4-bromo-but-1-ene are refluxed for 8 hours in 150 ml of , `' ':
. ~

l~Z39L35 dimethylfo.~mamide, and the solvent is~hen removed under reduced pressure, The residue is then dissolved in 150 ml of l-N sodium hydroxide solution and the alkaline solution ls extracted with methylene chloride, The - residue obtained ater separation and evaporation of the methylene chloride is triturated with 100 ml of diisopropyl ether and unreacted 3-methyl-7-propyl- ~
xanthine is removed, 15,6 g (70% of theory) of the :.
title compound of melting point 480C (from n-hexane) are obtained from the filtrate, Examples 7 to 10, The following compounds are prepared analogously to Example 6 from the corresponding dialkyl-xanthine compounds:

7. ~- (But-3-enyl)-3-methyl~7-hexyl-xanthine (Hex-5-enyl~ -3-methyl-7 -propy;l-xanthine 1 ~(Hex-S-enyl~-3-methyl-7-hexyl-xanthine I0. ~ lex-5-enyl~-3-methyl-7-dec~l-xanthine The physical data of the compounds are set out in Ta~le 2.
' -;

... . ... .

~llZ~435 Example 11: 1-Ethyl-3-methyl-7-(hex-5~enyl)-xanthine 20 g of 3- methyl~7-(hex-5-enyl)-xanthine (see Example 22) are added to a solution of approximately 3,3 g of NaOH in 70 ml of methanol/water (1:1) and subsequently 9 g of ethyl bromide are added thereto, The mixture is kept at 400C under a nitrogen atmosphere for 40 hours, The solvent is then removed under reduced pressure, the residue dissolved in diethyl ether and the pH of the solution is adjusted with aqueous sodium hydroxide solution to a ~H-value of 13,5 to remove unreacted 3-methyl-7-(hex-5-enyl)-xanthine, 1-Ethyl-3-methyl-7 (hex-5-enyl)-xanthine is then obtained from the ether phase as a colourless oil by column chromatography using sili.ca gel with methylene chloride/acetone (8:2) ::
as eluent followed by distillation under reduced pressure, Yield: 11,2 g (81,3% of theory) of the title compound, nD = 1,5415, Example 12: 1-Propy~3-methyl-7-(but-3-enyl)~xanthine The title compound is prepared ana.logously to ~23435 Example 11 from 3-methyl-7-(bult-3-enyl)-xanthine (see Example 20), but with the difference that the reaction temperature is 70OC, Example 13_and 14: _ 1-Hexyl-3-methyl-7-(but-3 enyl)_xanthine and l-Hexyl-3-methyl-7-~pent-4-e ~ t_ ne are prepared analogously to Example 1, Example 15;~ D ~ -methyl-7-(but-3-enyl)-xanthine is , .' prepared analogously to Example 12, E ample 16; 1-Methyl-3-eth~1-7-(hex-5-enyl~-xanthine is prepared analogously to Example 11 ~rorn 3-ethyl-7 (hex-5-enyl)-xanthine (see Example 24 ?, Example ~ 3-Dieth~1-7-(pent-4-enyl)-xanthine is prepared analogously to Example 12 from 1,3-diethyl-xanthine and 5-bromopent-1-ene: the yield relative to the starting material used is given Table 2. . `
Example 18: 1,3-Diethyl-7-(hex ~ )-xanthine is prepared analogously to Example 12 from 1,3-diethyl~
xanthine; the yield relative to the starting materi.al used is given in Table 2, - , , - -~

llZ3~3S

.. .
Exam~le 19: 1,3-Di-n-butyl-7~(but-3-enyl)-xanthin2 38,9 g of 1,3~ n-butyl-xanthine are added at ;~
250C to a solution of 3,4 g of sodium in 200 ml of absolute ethanol, 20,5 g of 4-bromobut~l ene are then a~ded at 500C, After stirring for 46 hours under a nitroger. atmosphere at 70C the reaction mixture is cooled to 200C, precipitated sodium bromide is filtered off and the filtrate is then evaporated under reduced pressure, The residue obtained is trea-ted with chloro-form and ' l-N sodium hydroxide solution to remove 1,3-di-n-butyl-xanthine, From the chloroform phase there.is obtained a yellow oily residue which after column chromatography on silica gel with methylene chloride/
acetone (8:2) as eluent and after distillation under reduced pressure yields 29,7 g (78,8% of theory) .
of the title compound with a melting point of 41 to 42C, Example 20: 3-Methyl-7-(but-3-enyl)-xanthine ;.
41~5 g of 3-methyl-xanthine are added with stirring at 700C to a solution of 10,2 g of NaOII in 400 ml - , .

~23~35 of methanol/water (1:1), After mixing with 35,1 g of 4-bromobut-1-ene the mixture is stirred under a nitrogen atmosphere for 27 hours at 700C, The reaction mixture is then cooled to 200C and the precipitate formed is fil~ered off, By re--precipitation from alkaline solution (pH 13,5) and acidification with dilute sulphuric acid to pH 10,29,6 g (89~7a/o of theory) of the title compound of melting point 245 to 2460C are obtained after drying, Example 21. 3-Methyl-7-(pent-4-enyl)-xanthine is prepared analogously to Example 1, Examples 22 to 24: 3-Methyl-7-(hex-S-enyl)~xanthine, 3-Ethyl-7~ but-3-enyl)-xanthine and 3-Ethyl~7-(hex-5-enyl)-xanthine are prepared analogously to Example 20 from the corresponding alkyl-xanthines, Example 25: 1,7-Dimethyl-3-(hex-5-enyl)-xanthine is prepared analogously to Exam~le 6 from 1,7-dimethylxanthine and

6-bromo-hex-1-~ne. : .

Example 26: 1,7-Di-(but-3-enyl)-3-ethyl-xanthine is prepared analogously to Example 12 from a) 1 mol of 3-ethyl-7~(but-3-enyl)-xanthine and 1 mol o~ 4-bromobut-1-ene (yield: 83% of theory relative to reacted 3-ethyl-7-(but-3-enyl)-xanthine); and : - ~ - .

.

~2 3 ~35 b) 1 mol of 3-ethyl xanthine and 2 mol of 4-bromobut-l-ene (yield: 39% of theory relative to reacted3-ethyl-xanthine), Example 27: 1-(But-3-enyl)-3-ethyl-7-(hex-5-enyl)-xanthine is prepared analogously to Example 12 from 3-ethyl-7-(hex-5-enyl)-xanthine and 4-bromobut-1-ene (yield: 71,6% of theory relative to reacted 3-ethyl-7-(hex-5-enyl)-xanthine), Example 28: l-He ~ -7-(hex-S-enyl)-xanthine is prepared analogously to Example 1, Exa ple 29: 1,3-Dimethyl-7-(5-methyl-hex-5-enyl)-xanthine m 0,5 g of sodium hydride in 15 ml of anhydrous dim~thyl-sulphoxide are reacted under a nitrogen atmosphere with stirring at 80OC and cooled to 15C after 25 minutes, To prepare triphenyl-methylene-phosphorane, 8,1 g of methyl-tri~ènyl phosphonium iodide in 20 ml of anhydrous dimethylsulphoxide are added to this solution~ :
After stirring for 10 minutes at room temperature, 5,6 g of 1,3-dimethyl-7-(5-oxohexyl)-xanthine in 10 ml of dimethylsulphoxide are added dropwise over 1~343S

10 minutes, and the temperature is not allowed to exceed 200C, After standing overnight, the mixture is dissolved in water, extracted with ether and the ether phase is separated and dried over Na2S0~, The product obtained after evaporation at reduced pressure is in the form of an oil following purification by colutnn chromatography on silica gel with methylene chloride/acetone (1:1) as eluent and distillation under reduced pressure, Yield: 3,5 g ~63,3% of theory relative to the starting product used); refractive index: n20 1,5445, Example 30: 1,3-Dimethyl-7-(hex-4-enyl)-xanthine

7 g of 1,3-dimethyl-7-(5 hydroxyhexyl)-xanthine and 9,5 g of p-toluene sulphonic acid are refluxed in 100 ml of toluene for 12 hours with continuous separation of the water formed in the reaction, After cooling to room temperature the reaction mixture is mixed with 100 ml of ether, washed with sodium bicarbonate solution and water ~mtil neutral and the organic phase ~L~Z3435 is separated, dried over sodium sulphate and eYaporated under reduced pressure. After column chromatography on silica gel with methylene chloride/acetone (1:1) as eluent and distillation under reduced pressure the residue gives a product which still contains a few percent of isomeric 1,3-dimethyl-7-(hex-5-enyl)-xanthine (as shown by the n.m.r. spectrum). Yield: 4.3 g (65.5~ of theory relative to the starting product used).
Melting point: 58-64C.

Example 31: 1-(Hex-5-enyl)-3,7-dimethyl-xanthine is prepared analogously to Example 1.
Examples 32 and 33: 1-(Hex-5-enyl)-3-ethyl-7-methyl-xanthine and l-(Pent-4-enyl)-3-ethyl-7-methyl-xanthine are prepared analogously to Example 12.
Example 34: 1,3-Dimethyl-7-(2-methyl-pent-2-enyl)-xanthine is prepared analogously to Example 29.
Example 35: Preparation of the medicament: For the preparation of 1000 coated tablets 100 g of 1,3-dimethyl-7-(5'-hexenyl)-xanthines, 20 g of lactose, 30 g of maize starch, 8.5 g of talc, 0.5 g of colloidal silicic acid and 1 g of magnesium stearate are mixed and pressed into coated tablet cores weighing 160 mg.
For the tablet coating mixture 44.57 g of cane sugar, 23.4 g -, .
- , ` .
, - ~L12343S

of talc, 8 g of cellulose acetate ~hthalate, 2.24 g Or castor oil and very small additions OL wax, titanium dioxide and gum arabic are used in such a way that the final weight Or the coated tablets is 240 mg.

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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OF PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the manufacture of a xanthine derivative of the formula I

(I) wherein one to three of the radicals R1, R2 and R3 represent alkenyl having from 4 to 8 carbon atoms, the other radicals are alkyl having from 1 to 12 carbon atoms, and R1 may also be hydrogen, with the proviso that R1, R2 and R3 together have a meaning other than 1-(3'butenyl)-, 1-(4'-pentenyl)-, 1-(5'-hexenyl)-, 1-(2'-methyl-3'butenyl)-3,7-dimethyl; 1-(5'-hexenyl)-3-methyl-7-ethyl, -7-propyl, -7-butyl, -7-isobutyl, -7-decyl; 1,3-dimethyl-7-(2'-methyl-3'-butenyl), -7-(3'-butenyl), -7-(4'pentenyl), -7-(5'-hexenyl), -7-(6'-heptenyl); 3-methyl-7-(5-hexenyl); 1-propyl-, 1-isobutyl-, 1-pentyl-, 1-hexyl-3-methyl-7-(5'-hexenyl) and 1,7-di-(5'-hexenyl)-3-methyl; which process comprises:
(a) reacting a xanthine of formula I in which, however, at least one of R1, R2 and R3 is hydrogen, per se or as a salt or in the presence of a basic agent with a compound of the formula R-X in which X is halogen or a sulfonic ester or phosphoric ester group and in which for the introduction of alkenyl R is an alkenyl having from 4 to 8 carbon atoms and for the introduction of alkyl R is alkyl having from 1 to 12 carbon atoms; or (b) reacting a xanthine of formula I wherein at least one of R1, R2 and R3 is oxoalkyl with an olefinising agent whereby the number of the carbon atoms in the oxoalkyl and in the group introducted with the olefinising agent is in total from 4 to 8 carbon atoms; or (c) dehydrating a xanthine of formula I wherein at least one of R1, R2 and R3 is hydroxyalkyl with 4 to 8 carbon atoms.

2. A process according to claim 1 (a) wherein the xanthine derivative is reacted in form of an alkali or alkaline earth metal salt.

3. A process according to claim 1 (a) or 1 (b) which is performed at a temperature in the range from 20 to 160°C.

4. A process according to claim 1 (c) wherein the olefinis-ing agent is an alkylidene phosphorane.

5. A xanthine derivative of the formula I of claim 1, when-ever prepared by any process of claim 1 or by an obvious chemical equivalent thereof.

6. A process according to claim 1 wherein R2 is alkenyl hav-ing from 4 to 8 carbon atoms or alkyl having from 1 to 12 carbon atoms and wherein, if R2 is methyl and R1 or R3 is an (.omega.-1)-alkenyl radical being unbranched in (.omega.-1)-position, the sum of the carbon atoms of the alkyls R1 and R2 is higher than 7 and the sum of the carbon atoms of the alkyl R2 and R3 is higher than 11.

7. A xanthine derivative of the formula I of claim 1 wherein R2 is alkenyl having from 4 to 8 carbon atoms or alkyl having from 1 to 12 carbon atoms and wherein, if R2 is methyl and R1 or R3 is an (.omega.-1)-alkenyl radical being unbranched in (.omega.-1)-position, the sum of the carbon atoms of the alkyls R1 and R2 is higher than 7 and the sum of the carbon atoms of the alkyl R2 and R3 is higher than 11, whenever prepared by a process of claim 6 or by an obvious chemi-cal equivalent thereof.

8. A process according to claim 1 wherein more than one of the radicals R1, R2 and R3 is alkenyl.

9. A xanthine derivative of the formula I of claim 1 wherein more than one of the radicals R1, R2 and R3 is alkenyl.

10. A process according to claim 1 wherein at least one of the radicals R1, R2 and R3 is alkyl having from 2 to 12 carbon atoms and at least one is alkenyl, R1 being said alkyl, alkenyl or hydrogen and wherein one of R1, R2 and R3 may also be methyl.

11. A xanthine derivative of the formula I of claim 1 wherein at least one of the radicals R1, R2 and R3 is alkyl having from 2 to 12 carbon atoms and at least one is alkenyl, R1 being said alkyl, alkenyl or hydrogen and wherein one of R1, R2 and R3 may also be methyl, whenever prepared by a process of claim 10 or by an obvious chemical equivalent thereof.

12. A process according to claim 1 wherein the alkenyl group double bond is in a position other than (.omega.-1).

13. A xanthine derivative of the formula I of claim 1 where-in the alkenyl group double bond is in a position other than (.omega.-1) whenever prepared by a process of claim 12 or by an obvious chemical equivalent thereof.