CA1263387A - Medicaments, vicinal dihydroxyalkylxanthines contained therein, process for the preparation of these xanthine compounds and intermediate products suitable for these - Google Patents
Medicaments, vicinal dihydroxyalkylxanthines contained therein, process for the preparation of these xanthine compounds and intermediate products suitable for theseInfo
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- CA1263387A CA1263387A CA000529856A CA529856A CA1263387A CA 1263387 A CA1263387 A CA 1263387A CA 000529856 A CA000529856 A CA 000529856A CA 529856 A CA529856 A CA 529856A CA 1263387 A CA1263387 A CA 1263387A
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Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to the preparation of xanthine derivatives of the formula I
(I) in which one of the radicals R1, R2 and R3 represents a group of the formula IV
(IV) or IX
The invention relates to the preparation of xanthine derivatives of the formula I
(I) in which one of the radicals R1, R2 and R3 represents a group of the formula IV
(IV) or IX
Description
~633~7 - This Application is a Divisional of Canadian P~tent Application Serial Nu~ber 412,172, Filed September 24, 19820 The invention relates to new medicaments which are sultable, in particular, for the treatment of obstructive diseases of the respiratory tract, the uharmacologically active vicinal dihydroxyalkylxanth-ines contained in them, processes for the preparationo~ these xanthine derivatives and intermediate products for this purpose.
m e xarthine compounds, which act as phospho-diesterase inhibitors, have a pre-eminent position among 10 the bronchospasmolytic agents hitherto known (c~. B.
Hellwlg; M~d~rne Ar~neimittel (Mode~n D~ugs)~S~att~art 1980, page 1,274)S since they have no ~2-sympatho~imetic activity and are thus particularly suitable for the long-term therapy ~hich is always necessary for chronlc 15 obstructive disorders of the respiratory tract. 0~
this group o~ substances, the naturally occurring xan-thine derivativetheophylline (1,~-dimethylxanthine), has been the undisputed agent of choice in asthma ther-apy for several decades now. Its activity, which is 20 clinically well established, is, however, contras'ed by the disadvantages of its very narrow therapeutic range, its serious gastrointestinal, cardiovascular and renal side-eLfects, as well as those.in the central nervous sys~em, and the fact that it can onl~ be used enterally 25 due to its lack.o~ water solubility, and these ~6;~38'7 disadvantages are the basis for the desire OL clinicians for, and the pharmaceutical research directed at find-ingS products having a greater ther~peutic safety.
It has in fact been possible, by t}e prepara-tion of water-soluble salts or addition compounds, such as, for example, theophylline ethylenediamine (amino-ph~rlline), to obtain formulations of theopkylline which can also be administered parenterally, but bhese ~re not associated with a significant increase in the thera-10 peutic range or a decrease in the abovementionedundesired side-effects; especially since the ethylene-diamine itself, which functions as a solubilizer in am~inophylline, exerts a deleterious effect on the cardio-vaccular system.
Thus~ there haYe been many attempts to obtain, by va.riations in the structure of the theophylline mole-cule, better tolerated compounds having5 if possible, a greater bronchospasmolytic activity.
e only synthetic theophylline derivative which 20 has found a certain therapeutic use is diphyllinc [ 7-(2,3-dihydro~ypropyl)-1,3-dimethylxa.nthine]. The 2r3-dihydroxypropyl group in the 7-position does confer a good water solubility on this product, so that the un~lesired use of solubilizers ~or parenteral administra-25 tion is no longer nec.essary and the int.erferingtheophylline-like side-effects are much less pronounced, but these advantages are, at the same time, paid for by a drastic decrease in the bronchospasmolytic activity co~pared to that of theophylline.
.~
.
... ,. i . ~; ... . . .
In systematic continuatlon of these investiga- -tions, the .~o methyl groups in the 1- and 3-positions hàve been exchanged ~or longer alkyl groups, while retaining the 2,3-dihydroxypropyl radical in the 5 7-position of the xanthine skeleton. This led to 7-~2,3-dihydrox~-propyl)-1,3-dipropylxanthine, which is .
described in Canadian Patent 1, 082,184 and which is a compound readily soluble in water, which is said alnlost to reach the bronchospasmolytic activity of 10 theophylline and, at the same time, to have a lower acute toxicity and fewer disadvantageous side-effects.
Nevertheless, this product has not hitherto found acceptance in ast~ma therapy. Further~ore, according to the abovementicned Offenlegurgsschrift, it induces }5 stimulation of -the centra3. nervous system~ although this is markedly weaker than that of theophylline, which can lead to restlessness and sleep disturbances.
Accordingly, water-soluble xanthine compounds, which are superior to theophylline in respect of strength of action and therapeutic range and which induce no sig-nificant side-effectsS in particular no.stimulation o~
the cen-tral nervous system, would still represent a genu.ine enrichmellt o~ the the~apy of obstructive dis-orders of the respira-tory tract.
~5 . It has now been found, surprisingly., that increasing the length of the dihydroxypropyl radical, which has not hitherto been investigated~ irrespective of i-ts posi~tion on the xanthiné skeleton, leads to com-pounds which fulfil these stric.-t therapeutic demands.
~;33~7 _ 5 _ It is true that ~rc xanthine derivatives of this type, namely l-(5,6-dihydroxyhexyl)-3 7 7-dimethylxanthine and 1-~4j5-dihydroxyhexyl)-3 7--dimethylxanthine in the threo and erythro forms, have already been described in ~ne literature (Arzneimittelforschung (Drug Res.) 22, 1,151 (1972)), but these compounds were merely isolated and identified as metabolites of the vasof,hera-peutic agent pentoxifylline. Accordingly, there are no da-ta on their pharmacological properties in this 0 pu~lication.
us, the present invention relates to medica-~ents which contain vicinal dihydroxyalkylxanthines of the general formula I
K
R~
~/~3 ~ /> (I) .
R
wherein one of the radicals Rl, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and ~Q vicinal hydroxyl groups in the ~,~-1 or ~ 2 posltlons and the two other radlcals represent straighL-- chain or branched al~yl groups having up to 12 C atoms in the position of Rl and R3 and up to 4 C atoms in the posit:lon of R2, the total of C atoms in these two alkyl ~bstituents belng a maximum of 14.
In this context~ those medicaments are pre-ferred whlch contain compo~mds of the formula I ln which ~3;3 ~7 - Rlor R2 represents zn (w,~ dihydroxyall~1 radical having5 or 6C atoms and the two alkyl substituents R2 and R3 or ~1 and R3 together comprise 3 to 6 C atoms.
R fur~her preferred embodiment of the invention relates to medicaments which contain those compounds of . the formula I in which R3 denotesan (~,w~ dihydroxy-alkyl group having 4 to 7 C atoms or a 4,5-dihydroxy~
hexyl group, and the total of C atoms in the two alkyl radicals R1 and ~2 is 3 to 7. Among these medlcaments, those in turn are particularly preferred which contain those compounds o~ the formula I in which R3 represents a 5,6~dikydroxyhexy1 radical, such asf for example, in 3-ethyl-7-(5,6-dihydroxyhexyl)-1-propyl--xant.hine.
A fur~her particular embodiment of the invention comprises the compounds of the,formula I not being a~ministered per se, but in the form of a prodrug, from which the dihydroxyalkylxanthines, having bronchospasmo-lytic activity; with their substituen-ts Rl, R2 and R3
m e xarthine compounds, which act as phospho-diesterase inhibitors, have a pre-eminent position among 10 the bronchospasmolytic agents hitherto known (c~. B.
Hellwlg; M~d~rne Ar~neimittel (Mode~n D~ugs)~S~att~art 1980, page 1,274)S since they have no ~2-sympatho~imetic activity and are thus particularly suitable for the long-term therapy ~hich is always necessary for chronlc 15 obstructive disorders of the respiratory tract. 0~
this group o~ substances, the naturally occurring xan-thine derivativetheophylline (1,~-dimethylxanthine), has been the undisputed agent of choice in asthma ther-apy for several decades now. Its activity, which is 20 clinically well established, is, however, contras'ed by the disadvantages of its very narrow therapeutic range, its serious gastrointestinal, cardiovascular and renal side-eLfects, as well as those.in the central nervous sys~em, and the fact that it can onl~ be used enterally 25 due to its lack.o~ water solubility, and these ~6;~38'7 disadvantages are the basis for the desire OL clinicians for, and the pharmaceutical research directed at find-ingS products having a greater ther~peutic safety.
It has in fact been possible, by t}e prepara-tion of water-soluble salts or addition compounds, such as, for example, theophylline ethylenediamine (amino-ph~rlline), to obtain formulations of theopkylline which can also be administered parenterally, but bhese ~re not associated with a significant increase in the thera-10 peutic range or a decrease in the abovementionedundesired side-effects; especially since the ethylene-diamine itself, which functions as a solubilizer in am~inophylline, exerts a deleterious effect on the cardio-vaccular system.
Thus~ there haYe been many attempts to obtain, by va.riations in the structure of the theophylline mole-cule, better tolerated compounds having5 if possible, a greater bronchospasmolytic activity.
e only synthetic theophylline derivative which 20 has found a certain therapeutic use is diphyllinc [ 7-(2,3-dihydro~ypropyl)-1,3-dimethylxa.nthine]. The 2r3-dihydroxypropyl group in the 7-position does confer a good water solubility on this product, so that the un~lesired use of solubilizers ~or parenteral administra-25 tion is no longer nec.essary and the int.erferingtheophylline-like side-effects are much less pronounced, but these advantages are, at the same time, paid for by a drastic decrease in the bronchospasmolytic activity co~pared to that of theophylline.
.~
.
... ,. i . ~; ... . . .
In systematic continuatlon of these investiga- -tions, the .~o methyl groups in the 1- and 3-positions hàve been exchanged ~or longer alkyl groups, while retaining the 2,3-dihydroxypropyl radical in the 5 7-position of the xanthine skeleton. This led to 7-~2,3-dihydrox~-propyl)-1,3-dipropylxanthine, which is .
described in Canadian Patent 1, 082,184 and which is a compound readily soluble in water, which is said alnlost to reach the bronchospasmolytic activity of 10 theophylline and, at the same time, to have a lower acute toxicity and fewer disadvantageous side-effects.
Nevertheless, this product has not hitherto found acceptance in ast~ma therapy. Further~ore, according to the abovementicned Offenlegurgsschrift, it induces }5 stimulation of -the centra3. nervous system~ although this is markedly weaker than that of theophylline, which can lead to restlessness and sleep disturbances.
Accordingly, water-soluble xanthine compounds, which are superior to theophylline in respect of strength of action and therapeutic range and which induce no sig-nificant side-effectsS in particular no.stimulation o~
the cen-tral nervous system, would still represent a genu.ine enrichmellt o~ the the~apy of obstructive dis-orders of the respira-tory tract.
~5 . It has now been found, surprisingly., that increasing the length of the dihydroxypropyl radical, which has not hitherto been investigated~ irrespective of i-ts posi~tion on the xanthiné skeleton, leads to com-pounds which fulfil these stric.-t therapeutic demands.
~;33~7 _ 5 _ It is true that ~rc xanthine derivatives of this type, namely l-(5,6-dihydroxyhexyl)-3 7 7-dimethylxanthine and 1-~4j5-dihydroxyhexyl)-3 7--dimethylxanthine in the threo and erythro forms, have already been described in ~ne literature (Arzneimittelforschung (Drug Res.) 22, 1,151 (1972)), but these compounds were merely isolated and identified as metabolites of the vasof,hera-peutic agent pentoxifylline. Accordingly, there are no da-ta on their pharmacological properties in this 0 pu~lication.
us, the present invention relates to medica-~ents which contain vicinal dihydroxyalkylxanthines of the general formula I
K
R~
~/~3 ~ /> (I) .
R
wherein one of the radicals Rl, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and ~Q vicinal hydroxyl groups in the ~,~-1 or ~ 2 posltlons and the two other radlcals represent straighL-- chain or branched al~yl groups having up to 12 C atoms in the position of Rl and R3 and up to 4 C atoms in the posit:lon of R2, the total of C atoms in these two alkyl ~bstituents belng a maximum of 14.
In this context~ those medicaments are pre-ferred whlch contain compo~mds of the formula I ln which ~3;3 ~7 - Rlor R2 represents zn (w,~ dihydroxyall~1 radical having5 or 6C atoms and the two alkyl substituents R2 and R3 or ~1 and R3 together comprise 3 to 6 C atoms.
R fur~her preferred embodiment of the invention relates to medicaments which contain those compounds of . the formula I in which R3 denotesan (~,w~ dihydroxy-alkyl group having 4 to 7 C atoms or a 4,5-dihydroxy~
hexyl group, and the total of C atoms in the two alkyl radicals R1 and ~2 is 3 to 7. Among these medlcaments, those in turn are particularly preferred which contain those compounds o~ the formula I in which R3 represents a 5,6~dikydroxyhexy1 radical, such asf for example, in 3-ethyl-7-(5,6-dihydroxyhexyl)-1-propyl--xant.hine.
A fur~her particular embodiment of the invention comprises the compounds of the,formula I not being a~ministered per se, but in the form of a prodrug, from which the dihydroxyalkylxanthines, having bronchospasmo-lytic activity; with their substituen-ts Rl, R2 and R3
2~ defined in the foregoing, can only be liberated by bio-transformation in the organism. For this purpose, for example, the epoxides having the structural element of the for~ula IV and, in particular, the acetals ` havin~-the structural element of the formula IX, when these &recompletely alkylated, which are dealt with below as intermediate products in the preparation process, are - suitable.
The invention also relates to new vicinal ,, .~ . .
~L2633~7 - dihydroxyalkylxanthines of the formula I, in which one of the radicals Rl, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in ~,w-l or w~ -2 positions and 5 the ~wo other radicals represent straight-chain or branched alkyl groups havillg up to 12 C atoms in the position of Rl and R3 and up to 4 C atoms in the posi~-tion of R2, the tota- of C atoms in these ~o a7ky substituents being, however, a maximwm of 14 and R and R3 not both being methyl, when Rl represents a 4,5- or 5,6-dihydroxyhe~yl radical.
In this context, particularly suitable compounds are those in which Rl or R2 represents an (w,~-l)-di-hydroxyalkyl radical having 5 or 6 C atoms and the two alkyl substituents R2 and R3 or R1 and R3 together con-taln 3 to 6 C atoms, and also those ~herein R3 denotes ~n(~,~-l)-dihydroxyal~yl group having 4 to 7 C atoms or a 4,5-dihydroxyhe~yl group, and the two alkyl radicals Rl and R2 together contain 3 to 7 C atoms. Amongst the 20 compol~ds mentioned latterly, the 7-(5,6-dihydroxyhexyl)-1,3-dialkylxanthines having a total of 3 to 7 C atoms in the two alkyl radicals R1 and R2, s~ch as, for example,
The invention also relates to new vicinal ,, .~ . .
~L2633~7 - dihydroxyalkylxanthines of the formula I, in which one of the radicals Rl, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in ~,w-l or w~ -2 positions and 5 the ~wo other radicals represent straight-chain or branched alkyl groups havillg up to 12 C atoms in the position of Rl and R3 and up to 4 C atoms in the posi~-tion of R2, the tota- of C atoms in these ~o a7ky substituents being, however, a maximwm of 14 and R and R3 not both being methyl, when Rl represents a 4,5- or 5,6-dihydroxyhe~yl radical.
In this context, particularly suitable compounds are those in which Rl or R2 represents an (w,~-l)-di-hydroxyalkyl radical having 5 or 6 C atoms and the two alkyl substituents R2 and R3 or R1 and R3 together con-taln 3 to 6 C atoms, and also those ~herein R3 denotes ~n(~,~-l)-dihydroxyal~yl group having 4 to 7 C atoms or a 4,5-dihydroxyhe~yl group, and the two alkyl radicals Rl and R2 together contain 3 to 7 C atoms. Amongst the 20 compol~ds mentioned latterly, the 7-(5,6-dihydroxyhexyl)-1,3-dialkylxanthines having a total of 3 to 7 C atoms in the two alkyl radicals R1 and R2, s~ch as, for example,
3-ethyl-7-(5,6-dihydroxyhexyl)-1-propylxan-thine 9 in turn represent particularly preferred compo~ds accord-25 ing to formula I.
The invention further relates to processes forthe preparation of the vicinal dihydroxyalkylxanthines according to formula I.
An example of a process comprises starting with ~6~3~7 xanthines of the formula II
. ~ ~3' R
0~1 ' R
in which one of theradicals Rl, R2 or R3 is an (~-1?- or (w-2)-alkenyl group of the formula III
-(CH2)n-CX=CH-R4 (III), having 4 to 8 C atoms, R4 denoting hy~rogen or methyl, and -the other two substituents represent hydrogen or alkyl as defined in formula Is and a) reacting them on the olefinic double bond with suit-10 able oxidizing agents to give n~w epoxyalkylxanthines -having the structural element of the formula IV
-(CH2)n-CH-CH-R4 (IV), '\G( and hydrolytically opening their oxir2ne ring with forma-tion of dihydroxyalkylxanthines having the structural 15 unit o~ the formula V
--( CH2 )1l-CH-CH-R4 (V ) OH OH
or b~ dihydro~ylating on the olefinic double bond with customa~y oxidizing agen-ts to give direc-tly the dihyd-20 roxyalkylxantnines having the structural elementcharac-terized by formula V, .
~ 6 ~3 ~7 _ g .
and then alkylating those diols obtained according to a) or b), which still car~ hydrogen in the positions of Rl, R2 and/or R3~ optionally in the presence of basic agents or in the form of their salts, with alkylating 5 agents of the formula VI
R5-X (~I), In which X denotes halogen, preferably c~lorine or bro -mi~e, o.r a sulfonaie or phosphate grouping and R5 derotes the alkyl radicals defined. for formula I to 10 give the compounds of the formula I.
~ he alkenyl-, monoalkyl- and dialkyl-alkenyl-xanthines of ~he formula II used as starting ma+erials in this process are known, inter alia, from Canadian - Patents 1,123,435 and 1,12~,083.
~xamples of suitable oxidizing agents for the epoxidation of the olefini.c side-chain according to formula III are chromium(VI) oxideS preferably.in acetic anhydride and carbon disulfide or carbon tetrachloride;
or compounds containing peroxide groups, such as potas-siu~ peroxomonosulfate in the presence of ketones, preferably acetone, in a homogeneous phase or in a ~wo-phase system with phase-transfer catalysis, perox~
boranes,.which are advantageously produced in situ from boric acid or its derivatives and hydroperoxides; -tri-25 phenylsilyl hydroperoxide; hydrogen peroxide in thepresence of coreact.~nts, such as, for example~ aliphatic or aromatic carbonitriles (for example acetonitr le or benzonitrile), optionally substituted cyanamide or .
. ~2633~7 -- ~o -- .
isocyanates (for e~ample phenyl isocyanate); hydrogen peroxide or al~yl or ara~yl hydroperoxides, such as, for example, tert.-butyl hydroperoxide, l-phenylethyl hydroperoxide and cumene hydroperoxide, in the presence 5 of either basic agents or, pre~erably, particular cata-lysts, such as, for example, tungstic acid, vanadium(V) oxide, molybdenum hexacarbonyl and vanadium or molyb-denu~ acety~acetonates; and, in particular, percarbo~ylic acids, such as, for example, performic, peracetic, tri 10 fluoroperacetic, monopermaleic, monopersuccinic, per-benzoic, 4-nitroperbenzoic and, preferably, 3-chloro perber.zoic and monoperphthalic acid.
Epoxid2tion with the aid of percarboxylic acids (Prileschajew reactlon) is advantageously carried out in .
a solvent or distributing agent which is inert towards the reactants and which has been found to exe~t a con-siderable effect on the rate of reaction. Since solvents which can form hydrogen bonds with the per-carboxylic acids generally decrease the rate of reac-tiOll, aromatic hydrocarbons, such as benzene or toluene,arld halogenai:ed hydroca~bons, such as dich]olomethane, chloroform or carbon tetrachloride, are frequently pre-ferred to ethers, such as diethyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether, alco 25 ~-hols, esters and carbo~lic acids. The reaction is customarily carried out at temperatures between -10 and +40C, preferably at room temperature~ the reaction time varying from a few minutes up to several hours.
The percarboxylic acids are usually employed for ~L~633~7 the reaction in an-isolated form, but they can also be produced in situ in the reaction mixture from, for examples the corresponding carboxylic acid and hydrogen peroxide.
On using peracids of strong carboxylic acids, -such asp for example, trifluoroperacetic acid, it is advisable to decrease the acid concentration by working in a heterogeneous system or bytne addition ol~buf~er sub-stances~ such as sodium carbonaté, sodiunt bicarb~nate or disodium hydrogen phosphate, in order to suppress undes-- ired secondary reactions of the carbo~ylic acid, which is produced in the reaction, with the initially formed epoxide.
The epoxyalkylxanthines according to form~la II
hav ng the ~truc~t~ral ~nit of the fûi~u'a I~ cân, hG~
ever, also be obtained by base-catalyzed dehydrohalo-- . genation of corresponding ~alogenohydrins, which in curn can be obtained, for example, by adding hypohalous aci~s, such as, for example, hypochlorous acids9 to the olefinic double bond of the alKellylxanthine~ accord-ing-to formulae II and IlI. The reaction:of these olefins with N-halogenostlccinimides, such as N-bromo- -succinimide, or chloramine ~ in water or mixtures of solvents containing water also leads to the nalogeno-hydrins. The basic dehydrohalogenating agents usuallyused are alkali metal or alkaline eartll me-tal hydrox-ides or carbonates, prcferably sodium potassitlm or calcillm nydroxide or soditLm or potassium carbonate, but organic bases or other oxiranes~ such as ethylene oxide 33 ~7 or 1,2-epox~propane, can also be employed successfullyO
m e eFoxyalkylx~nthlnes can ~ither De isolated in the pure form or further processed ~s crude productsO
The hydrolytic clea~age of the epoxyalkylxan-. _ .. . ....
thines to give the ~iGinal diols having the structuralelement of the formula ~ is carried out in an aqueous medium, to which, if necessary to increase ~he solu-bility, an organic so]vent which is miscible with ~iater i's added, for example tetrahydrofuran7 dioxane or eth~1 ene glycol dimethy' ether, advantageously in the presence of acid catalysts~ preferably weakly nucleo- -philic acids, such as sulfuric, perchloric or p-toluene-sulfonic acid, or strongly acid cation exchanger resins (~or e~ample Nafion-H)~ at tempe-atur~s be-~een 20 and 15 100C, bui preferably at room temper~ture, by stirring for several hours. However, in principle, the oxi.ralle ring opening is also possihle under neutral or alkaline conditions.
Customary oxidizing agents for the direct vici-20 nal dihydrox~rlation o~ the alkenylxanthines according to formulae II and III to give the dihyd-oxyalkylxan-thines char~cterlzed by the structural unit of formula V9 are represented byl for example, hydrogen peroxide in the presenc.e of form.ic acid or glacial acetic acid, ~5 chromyl chloride, potassium permanganate~ triphenyl~
methylphosphonium permanganate, iodine in the presence of silver carboxylates or thallium(l) carboxyla-ces, such as, for e;~ample, thallium(I) acetate, seleniùm dioxide, molybderum(VI) oxide and, i.n par~icularg osmium * denotes trade mark.
33~7 ~etroxide. .
When using osmi.wm ~tetroxide as the oxidizing agent~..the reagen~ can eil~her be employed in the stoi-chiometric amo~nt or in catalytic amounts with the addition of a secondary oxidizing agent, which regener~
ates the osmium ~etroxide from ~he initially produced cyclic esters, with oxidati~e hydrolysis to give the diols.
,' Xn the non-catalytic dihydroxylation of the ole-finic double bond with stoichiometric amounts of osmium -~etroxide, the process is advantageously carried out n sol~e1lts not having a reducing action, preferably ethers, . such as diethy] ether, tetrahydrofuran and dioxane, or hydrocalbons, such as benzene, cyclopentane or cyclo-hexane, optionally with the addition of a tertiaryamine, such as, in particular, p-~rldine or qu.inoline, - isoquinoline, 3- or 4-picoline, at temperatures be~een 0C and the bolling point of the particular solvent, preferably at room temperature, it being possible .,or the reaction times to be from a few minutes to several hours. Then the osmium(~rI) ester complexes, which are produced as intermediates in this process, are advan-tageously reductively hydrolyzed, the use of sodium or potass~um sulfite or bisul~ite, hydrogen sul,ide, lith-ium aluminum hydride or catecllol or alkaline mannitol~olution in a4ueous or aqueous-alcoholic medium having been found particularly useful. However, oxida-ti.ve hydrolysis of the complexes is 21so possible; but it is ad~Tisable, in this case, to carry out the .
~2633~7
The invention further relates to processes forthe preparation of the vicinal dihydroxyalkylxanthines according to formula I.
An example of a process comprises starting with ~6~3~7 xanthines of the formula II
. ~ ~3' R
0~1 ' R
in which one of theradicals Rl, R2 or R3 is an (~-1?- or (w-2)-alkenyl group of the formula III
-(CH2)n-CX=CH-R4 (III), having 4 to 8 C atoms, R4 denoting hy~rogen or methyl, and -the other two substituents represent hydrogen or alkyl as defined in formula Is and a) reacting them on the olefinic double bond with suit-10 able oxidizing agents to give n~w epoxyalkylxanthines -having the structural element of the formula IV
-(CH2)n-CH-CH-R4 (IV), '\G( and hydrolytically opening their oxir2ne ring with forma-tion of dihydroxyalkylxanthines having the structural 15 unit o~ the formula V
--( CH2 )1l-CH-CH-R4 (V ) OH OH
or b~ dihydro~ylating on the olefinic double bond with customa~y oxidizing agen-ts to give direc-tly the dihyd-20 roxyalkylxantnines having the structural elementcharac-terized by formula V, .
~ 6 ~3 ~7 _ g .
and then alkylating those diols obtained according to a) or b), which still car~ hydrogen in the positions of Rl, R2 and/or R3~ optionally in the presence of basic agents or in the form of their salts, with alkylating 5 agents of the formula VI
R5-X (~I), In which X denotes halogen, preferably c~lorine or bro -mi~e, o.r a sulfonaie or phosphate grouping and R5 derotes the alkyl radicals defined. for formula I to 10 give the compounds of the formula I.
~ he alkenyl-, monoalkyl- and dialkyl-alkenyl-xanthines of ~he formula II used as starting ma+erials in this process are known, inter alia, from Canadian - Patents 1,123,435 and 1,12~,083.
~xamples of suitable oxidizing agents for the epoxidation of the olefini.c side-chain according to formula III are chromium(VI) oxideS preferably.in acetic anhydride and carbon disulfide or carbon tetrachloride;
or compounds containing peroxide groups, such as potas-siu~ peroxomonosulfate in the presence of ketones, preferably acetone, in a homogeneous phase or in a ~wo-phase system with phase-transfer catalysis, perox~
boranes,.which are advantageously produced in situ from boric acid or its derivatives and hydroperoxides; -tri-25 phenylsilyl hydroperoxide; hydrogen peroxide in thepresence of coreact.~nts, such as, for example~ aliphatic or aromatic carbonitriles (for example acetonitr le or benzonitrile), optionally substituted cyanamide or .
. ~2633~7 -- ~o -- .
isocyanates (for e~ample phenyl isocyanate); hydrogen peroxide or al~yl or ara~yl hydroperoxides, such as, for example, tert.-butyl hydroperoxide, l-phenylethyl hydroperoxide and cumene hydroperoxide, in the presence 5 of either basic agents or, pre~erably, particular cata-lysts, such as, for example, tungstic acid, vanadium(V) oxide, molybdenum hexacarbonyl and vanadium or molyb-denu~ acety~acetonates; and, in particular, percarbo~ylic acids, such as, for example, performic, peracetic, tri 10 fluoroperacetic, monopermaleic, monopersuccinic, per-benzoic, 4-nitroperbenzoic and, preferably, 3-chloro perber.zoic and monoperphthalic acid.
Epoxid2tion with the aid of percarboxylic acids (Prileschajew reactlon) is advantageously carried out in .
a solvent or distributing agent which is inert towards the reactants and which has been found to exe~t a con-siderable effect on the rate of reaction. Since solvents which can form hydrogen bonds with the per-carboxylic acids generally decrease the rate of reac-tiOll, aromatic hydrocarbons, such as benzene or toluene,arld halogenai:ed hydroca~bons, such as dich]olomethane, chloroform or carbon tetrachloride, are frequently pre-ferred to ethers, such as diethyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether, alco 25 ~-hols, esters and carbo~lic acids. The reaction is customarily carried out at temperatures between -10 and +40C, preferably at room temperature~ the reaction time varying from a few minutes up to several hours.
The percarboxylic acids are usually employed for ~L~633~7 the reaction in an-isolated form, but they can also be produced in situ in the reaction mixture from, for examples the corresponding carboxylic acid and hydrogen peroxide.
On using peracids of strong carboxylic acids, -such asp for example, trifluoroperacetic acid, it is advisable to decrease the acid concentration by working in a heterogeneous system or bytne addition ol~buf~er sub-stances~ such as sodium carbonaté, sodiunt bicarb~nate or disodium hydrogen phosphate, in order to suppress undes-- ired secondary reactions of the carbo~ylic acid, which is produced in the reaction, with the initially formed epoxide.
The epoxyalkylxanthines according to form~la II
hav ng the ~truc~t~ral ~nit of the fûi~u'a I~ cân, hG~
ever, also be obtained by base-catalyzed dehydrohalo-- . genation of corresponding ~alogenohydrins, which in curn can be obtained, for example, by adding hypohalous aci~s, such as, for example, hypochlorous acids9 to the olefinic double bond of the alKellylxanthine~ accord-ing-to formulae II and IlI. The reaction:of these olefins with N-halogenostlccinimides, such as N-bromo- -succinimide, or chloramine ~ in water or mixtures of solvents containing water also leads to the nalogeno-hydrins. The basic dehydrohalogenating agents usuallyused are alkali metal or alkaline eartll me-tal hydrox-ides or carbonates, prcferably sodium potassitlm or calcillm nydroxide or soditLm or potassium carbonate, but organic bases or other oxiranes~ such as ethylene oxide 33 ~7 or 1,2-epox~propane, can also be employed successfullyO
m e eFoxyalkylx~nthlnes can ~ither De isolated in the pure form or further processed ~s crude productsO
The hydrolytic clea~age of the epoxyalkylxan-. _ .. . ....
thines to give the ~iGinal diols having the structuralelement of the formula ~ is carried out in an aqueous medium, to which, if necessary to increase ~he solu-bility, an organic so]vent which is miscible with ~iater i's added, for example tetrahydrofuran7 dioxane or eth~1 ene glycol dimethy' ether, advantageously in the presence of acid catalysts~ preferably weakly nucleo- -philic acids, such as sulfuric, perchloric or p-toluene-sulfonic acid, or strongly acid cation exchanger resins (~or e~ample Nafion-H)~ at tempe-atur~s be-~een 20 and 15 100C, bui preferably at room temper~ture, by stirring for several hours. However, in principle, the oxi.ralle ring opening is also possihle under neutral or alkaline conditions.
Customary oxidizing agents for the direct vici-20 nal dihydrox~rlation o~ the alkenylxanthines according to formulae II and III to give the dihyd-oxyalkylxan-thines char~cterlzed by the structural unit of formula V9 are represented byl for example, hydrogen peroxide in the presenc.e of form.ic acid or glacial acetic acid, ~5 chromyl chloride, potassium permanganate~ triphenyl~
methylphosphonium permanganate, iodine in the presence of silver carboxylates or thallium(l) carboxyla-ces, such as, for e;~ample, thallium(I) acetate, seleniùm dioxide, molybderum(VI) oxide and, i.n par~icularg osmium * denotes trade mark.
33~7 ~etroxide. .
When using osmi.wm ~tetroxide as the oxidizing agent~..the reagen~ can eil~her be employed in the stoi-chiometric amo~nt or in catalytic amounts with the addition of a secondary oxidizing agent, which regener~
ates the osmium ~etroxide from ~he initially produced cyclic esters, with oxidati~e hydrolysis to give the diols.
,' Xn the non-catalytic dihydroxylation of the ole-finic double bond with stoichiometric amounts of osmium -~etroxide, the process is advantageously carried out n sol~e1lts not having a reducing action, preferably ethers, . such as diethy] ether, tetrahydrofuran and dioxane, or hydrocalbons, such as benzene, cyclopentane or cyclo-hexane, optionally with the addition of a tertiaryamine, such as, in particular, p-~rldine or qu.inoline, - isoquinoline, 3- or 4-picoline, at temperatures be~een 0C and the bolling point of the particular solvent, preferably at room temperature, it being possible .,or the reaction times to be from a few minutes to several hours. Then the osmium(~rI) ester complexes, which are produced as intermediates in this process, are advan-tageously reductively hydrolyzed, the use of sodium or potass~um sulfite or bisul~ite, hydrogen sul,ide, lith-ium aluminum hydride or catecllol or alkaline mannitol~olution in a4ueous or aqueous-alcoholic medium having been found particularly useful. However, oxida-ti.ve hydrolysis of the complexes is 21so possible; but it is ad~Tisable, in this case, to carry out the .
~2633~7
4 --dihydroxylation at t~.e outset with cataly~ic amounts of osmium tetroxide in the presence of secondary oxidiz-ing agents, such as, for example, hydrogen peroxide, metal chlorates (for example sodium or potassium and, i~ particul~r, silver or barium chlorate)~ sodium per-chlorate, oxygen, sodium perlodate or hypochlorit~ and, in particular, tert.-butyl hydropero~ide or trialkyl-; amine N-oxides (for example ~-methylmorpholi.ne .~I~o~ide, trlmethylamine N-oxide or triethylamine N-oxide).
The alkylation of the dihydroxyalkylxanthines ~ith the compounds of the formula VI is usually carried out in a distribu-ting agent or solvent which is inert towards the reactants. Dipolar aprolic solvents, Io..
example formamide5 dimethylformamide, dimethylacetamide~
~5 ~-m~thylpyrrolidone, tetramethylureaf hexamethylphosp}loric triamide, dimethyl sulfoxide, acetone or butanone are particularly suitable; ho~;ever, alcohols, such as metha-nol, ethylene glycol and its ethers, ethanol, propanol~
is~propanol and the various butanols; hydrocarbons, such as benzene, toluene or xylenes; halogenated hydro oarbons,suchas dichloromethane or chloroform; pyridine and mixlures of the solvents mentioned or their mix-tures with water can also find use.
1'he reactions are advantageollsly carried out in the presence of a basic condensing agent. Examples o~
suitable agents for this purpose are al~ali metal or alkaline earth metal hydroxides, carbonates, hydrides, alcoholates or organic bases, such as trialkylamines - (for example triethylamine or tributylamine), quaternary :~ ~63~Y~7 - ammonit~m or phosphcrium hydroxides and crosslinked resir.s having fixed ammoniunt or phosphonium groups, which are optionally substi~uted.
However, the xanthine derivatives can also be employed directly in the al~ylation reaction in the form of their salts pre~ared separately, such as the alkali metal, alkaline earth metal or optionally sub-stituted ammonium or phosphoniu~ sal~s. Furthermore, the dihydroxyalkylxallthines and their monoalkylated 10 derivatives can be readily all~ylated both in the pre-sence of the abovementioned inorganic condensing agents and also in the fo~m of their alkali metal or alkaline earth metal salts, with the assistance of so-called phase-.rans~er catalystss for ex~mple ter-tiary amines, ]5 ~udte,na-i~ a~o~ m ur ph~sphoIlium salts or crown ethers, preferably in a t~o-phase sys-tem under the conditions of phase-transfer catalysis.
In the introduction of the alkyl radicals by ~le prooedures describe~ in the foregoing, the reaction 20 is generally carried out at a lemperature between 0C and the boi]ing point of the reaction meditLm used in each case~ preferably bet~een 20 and 130C, if appropriate tmder elevated or reduced pressure, but usually under atmospheric pressure, it being possible for the reac-tion time to be from less -than orle hour to several hours~
In -this process for those dihydroxyalkylxanthines, into which ~o all~yl radicals are still to be introduce~, eicher ldentical or different substituents can be at-tached consecuti~ely or t~ro similar alkyl g~roups can .2633~37 be at~cached with the xanthine skeleton without isola-tion of in~e~ediate products in a one-pot reaction.
A further process for the preparation of com-pounds of the formula I, which is like~ise preferred, comprises reacting xanthines of the formula VII
. .
~ R
0 ~ (VII)~
R
in~.rllich amaximum oftwo ofthe substituents Rl to R3 rep-resent the alkyl àefined for formula I and a formula of t~ro of these radicals denote hydrogen, optionally in the presence ol basic agents or in tne form of their salts a) with alkylating agen-ts.of the formula VIII
X - (CH23n - CH - CH - R4 \ / (YIII), ~ \ 7 in which the alkyl chain has a total of 4 t.o 8 C atoms and R4 denotes hydrogen or methyl, R6 ~nd R7, independ-encly of one another, denote hydrogen, lower alkyl preferably having up to ~ C atoms, phenylalkyl having up to 2 C atoms in the alkyl moiety or optlonally su~-sti~uted phenyl and X denotes halogen, preferably 33~37 chlorine or bromine, or a sulfonate or phosphate group~
ing,to give new dialkylated or trialXylated xanthines having the structural element of the formula IX
~~C~2)n ~ IH ~ IH ~
O \ f (IX) ~6/ ~ ~7
The alkylation of the dihydroxyalkylxanthines ~ith the compounds of the formula VI is usually carried out in a distribu-ting agent or solvent which is inert towards the reactants. Dipolar aprolic solvents, Io..
example formamide5 dimethylformamide, dimethylacetamide~
~5 ~-m~thylpyrrolidone, tetramethylureaf hexamethylphosp}loric triamide, dimethyl sulfoxide, acetone or butanone are particularly suitable; ho~;ever, alcohols, such as metha-nol, ethylene glycol and its ethers, ethanol, propanol~
is~propanol and the various butanols; hydrocarbons, such as benzene, toluene or xylenes; halogenated hydro oarbons,suchas dichloromethane or chloroform; pyridine and mixlures of the solvents mentioned or their mix-tures with water can also find use.
1'he reactions are advantageollsly carried out in the presence of a basic condensing agent. Examples o~
suitable agents for this purpose are al~ali metal or alkaline earth metal hydroxides, carbonates, hydrides, alcoholates or organic bases, such as trialkylamines - (for example triethylamine or tributylamine), quaternary :~ ~63~Y~7 - ammonit~m or phosphcrium hydroxides and crosslinked resir.s having fixed ammoniunt or phosphonium groups, which are optionally substi~uted.
However, the xanthine derivatives can also be employed directly in the al~ylation reaction in the form of their salts pre~ared separately, such as the alkali metal, alkaline earth metal or optionally sub-stituted ammonium or phosphoniu~ sal~s. Furthermore, the dihydroxyalkylxallthines and their monoalkylated 10 derivatives can be readily all~ylated both in the pre-sence of the abovementioned inorganic condensing agents and also in the fo~m of their alkali metal or alkaline earth metal salts, with the assistance of so-called phase-.rans~er catalystss for ex~mple ter-tiary amines, ]5 ~udte,na-i~ a~o~ m ur ph~sphoIlium salts or crown ethers, preferably in a t~o-phase sys-tem under the conditions of phase-transfer catalysis.
In the introduction of the alkyl radicals by ~le prooedures describe~ in the foregoing, the reaction 20 is generally carried out at a lemperature between 0C and the boi]ing point of the reaction meditLm used in each case~ preferably bet~een 20 and 130C, if appropriate tmder elevated or reduced pressure, but usually under atmospheric pressure, it being possible for the reac-tion time to be from less -than orle hour to several hours~
In -this process for those dihydroxyalkylxanthines, into which ~o all~yl radicals are still to be introduce~, eicher ldentical or different substituents can be at-tached consecuti~ely or t~ro similar alkyl g~roups can .2633~37 be at~cached with the xanthine skeleton without isola-tion of in~e~ediate products in a one-pot reaction.
A further process for the preparation of com-pounds of the formula I, which is like~ise preferred, comprises reacting xanthines of the formula VII
. .
~ R
0 ~ (VII)~
R
in~.rllich amaximum oftwo ofthe substituents Rl to R3 rep-resent the alkyl àefined for formula I and a formula of t~ro of these radicals denote hydrogen, optionally in the presence ol basic agents or in tne form of their salts a) with alkylating agen-ts.of the formula VIII
X - (CH23n - CH - CH - R4 \ / (YIII), ~ \ 7 in which the alkyl chain has a total of 4 t.o 8 C atoms and R4 denotes hydrogen or methyl, R6 ~nd R7, independ-encly of one another, denote hydrogen, lower alkyl preferably having up to ~ C atoms, phenylalkyl having up to 2 C atoms in the alkyl moiety or optlonally su~-sti~uted phenyl and X denotes halogen, preferably 33~37 chlorine or bromine, or a sulfonate or phosphate group~
ing,to give new dialkylated or trialXylated xanthines having the structural element of the formula IX
~~C~2)n ~ IH ~ IH ~
O \ f (IX) ~6/ ~ ~7
5 and opening their 1,3-d~oxolane ring hydrolytically, split~ing off R6-Co-R7 and forming dihydro~yalkyl-xanthines having the structural unit of the formula V
-~CH2)n - ~ CIi -o~ OH
or b) ~lith alkylating agents of the Lormula X
Y~ - (C~I2) n ~ fI~ - IH R (Y.) OH OH
in which the alkyl chain has a total of 4 to 8 C a-toms and- ~4 and X have the meanings indicated for formula VIII, directly to gi~e the dihydroxyal'l~ylxanth mes, having tne structural element characterized by fo~mula V, and then reactirlg the monoall;yldihydroxyalkylxanthines obtained according to a) or b), ~hich still carry a hydrogen atom in the position of Rl, R2 or R3, op~tion-ally in the presence cf basic agents or in tlle form of ~ ~633~7 their salts with alkyiating agents of the formula VI
P.5 X (VI) in rh-ch X and R5 have the meanings defined for formula Yl in claim 12, to give the compounds of the formula or initially alkylating the dialkylated xanthines pre-pared according to a), having the structura- element .of.~he ~ormula IXs with ~le compounds of the formula ~5~ (VI) and then hydrolytically cleaving the di~
oxolane rin~ with forma~ion ofthe dihydroxyalkylxantll-ines according to formula I.
m e monoalkylxanthines or dialkyl~anthines of the formula ~rII and the alkylating agents OI the for-m~lae VIII and X used as starting materials in this process are lar~ely k~o~.m or can easily be prepared by methods kno~n from the literature.
~ hus, the compounds of the formula VIII, ~or example, can be obtained from the triols of the formula XI
~Q -- ( cu ) -- C!I -- C~ -- R
2 n ~ I (XI ) 0~1 01~
by reaction of the two vicinal hydroYyl groups with alde-- hydes or ketones or with their acetals, ~Yith proton catalvsis, and subseqlent replacement of the isolated terminal hydro~l function with halogen using inorganic acid halides, or its est.erification ~r-th sulfonyl or phospho.nyl halides or al~lydrides, advantageously in the ~ ~6 ~3 ~7 - presence of basic agents, from which in turn the com-pounds of the formula X can be prepared by acid hydroly-sis of the l,~-dioxolane ring. The alkenyl halides of the formula XII
Hal-(CH2)n-CH=CH-R4 (XII) can also serve as starting materials for the prepara-tion of compounds of the formulae VIII and X, ei ~her by subjecting them, as described for the alkenylxanthines9 to epoxidation on the olefinic double bond and then 10 hydrolyzing the oxirane ring with acid or by oxidizing in a one-step reaction directly to the dihydroxyalkyl hal.ides of the formula X and converting these, if appro-priateS ~ith aldehydes or ketones.or their acetals into 1,3-dioxolanes o~ the formula ~III.
m e reactions of the xanthine derivatives with the alkylating agents of the formulae VI, VIII and X
are advantageously carried out under the reaction con-ditlons already described in detail for the alk~lation of the dihydroxyalkylxanthines and monoalkyldihydroxy-alkylxanthines with the compounds of the formula VI.
~Iowever, if the compounds of the formula X are used to introduce the dihydroxyalkyl radical, those hav,ng a total of either 6 to 8 C atoms, when R4 has the meaning o~ hydrogen, or 7 or 8 C atoms, when R4 denotes a 25 methyl group, in the alkyl chain are preferred, since the diols of the formula X having shorter chains have a par-~icular tendenc-y to ~orm tetrahydrofuran derivatives under the alkaline conditions of the alkylation reac tion, which can lead to a noti.ceable reduction in the 2633t~3 yields of desired alkylation product~.
m e hydrolytic cleavage of the 1~3-dioxolane ring in the xanthines of the formula V~I having the structural element of the formula IX to give the d~hyd-5 roxyalkylxanthines characterized by the structural ~nitof the formula V is normally carried out in an aaueous medium, optionally with the addition of a solubilizer, such as tetrahydrofuran, dioxane or ethylene glycol din~ethyl ether, advantageously in the presence of acids, 10 for example formic, oxalic, ~a~taric, citric, sulfuric, perchloric, phosphoric or p-toluenesulfonic acid, or an a id ion exchanger (for example Nafion H)s at tempera-tures between 20C and the boiling point of the reaction mixture, preferably 50 and 100C5 it being possib~e 15 ~G-' the -eaction time to be f~om several ~inu-tes to a few hours. ~oist silica gel, having a water content up to 10%, is also a reagent which can be used for the deacetalization, the reaction preferably belng carried out in optionaily halogenated hydrocarbons, such as 20 benzene, toluene, dichloromethane or chlorofolm, at room temperature.
A further method for preparing the xanthines of the formula VII with the structural element of the for-mula IX containing the dioxolane ring comprises adding 25 carbonyl compounds of the formula R~-Co-R7 onto the oxirane ring of the epoxyalkylxanthines according to ~ormula II, having the struc~ural unit of the ~or-mula IV. m is reaction is advantageously carried out in the presence of acid catalysts, ~referably Le~is acids, Z~33~ .
such as boron trifluoride, zinc(II) chloride~tin(IV) chloride or copper(II) sulfate, at temperatures between 0 and 60C. However, quaternary ~onium salts, for example tetraethylammonium halides, are also able to catalyze the addition reaction to give the cyclic .
acetals.
The vicinal dihydroxyalkylxanthines of the for~
mula I have either one or two asymmetric C atoms~
depending on the position of the two hydro~rl groups in 10 the side chain according ~o formula V, and can thus be present in stereoisomeric forms. lThe invention thus relates both ~ the pure scereoisomeric compounds and also to their mixtures~
The medicamerts acoording to the invention can be a.tnin stered orally, ~ec'.al3;, parentela'ly VL as an a.erosol.
Examples of suitabie solid or llauld galenic formulations are granules, powders, tablet~ 5 coated tab-lets, (micro)capsules, suppositories~ syrups5 emulsions, suspensions, aerosols, drops or injectable solutions as well as ~ormulations ~ith protracted release ol the act-ive compo~d5 in the preparation of which, auxiliaries, such as vehicles, disintegrants, binders, coating agents, swelling agents, lubricants or emollients, flavoring materials 5 sweetening agents or solubilizers are used. ~xamples of frequently used auxiliaries which may be mentioned are lactose, mannitol and other sugars, talc, lactal~umin, gelatin, starch, cellulose and its derivatives~ animal and vegetable oils, polyethylene
-~CH2)n - ~ CIi -o~ OH
or b) ~lith alkylating agents of the Lormula X
Y~ - (C~I2) n ~ fI~ - IH R (Y.) OH OH
in which the alkyl chain has a total of 4 to 8 C a-toms and- ~4 and X have the meanings indicated for formula VIII, directly to gi~e the dihydroxyal'l~ylxanth mes, having tne structural element characterized by fo~mula V, and then reactirlg the monoall;yldihydroxyalkylxanthines obtained according to a) or b), ~hich still carry a hydrogen atom in the position of Rl, R2 or R3, op~tion-ally in the presence cf basic agents or in tlle form of ~ ~633~7 their salts with alkyiating agents of the formula VI
P.5 X (VI) in rh-ch X and R5 have the meanings defined for formula Yl in claim 12, to give the compounds of the formula or initially alkylating the dialkylated xanthines pre-pared according to a), having the structura- element .of.~he ~ormula IXs with ~le compounds of the formula ~5~ (VI) and then hydrolytically cleaving the di~
oxolane rin~ with forma~ion ofthe dihydroxyalkylxantll-ines according to formula I.
m e monoalkylxanthines or dialkyl~anthines of the formula ~rII and the alkylating agents OI the for-m~lae VIII and X used as starting materials in this process are lar~ely k~o~.m or can easily be prepared by methods kno~n from the literature.
~ hus, the compounds of the formula VIII, ~or example, can be obtained from the triols of the formula XI
~Q -- ( cu ) -- C!I -- C~ -- R
2 n ~ I (XI ) 0~1 01~
by reaction of the two vicinal hydroYyl groups with alde-- hydes or ketones or with their acetals, ~Yith proton catalvsis, and subseqlent replacement of the isolated terminal hydro~l function with halogen using inorganic acid halides, or its est.erification ~r-th sulfonyl or phospho.nyl halides or al~lydrides, advantageously in the ~ ~6 ~3 ~7 - presence of basic agents, from which in turn the com-pounds of the formula X can be prepared by acid hydroly-sis of the l,~-dioxolane ring. The alkenyl halides of the formula XII
Hal-(CH2)n-CH=CH-R4 (XII) can also serve as starting materials for the prepara-tion of compounds of the formulae VIII and X, ei ~her by subjecting them, as described for the alkenylxanthines9 to epoxidation on the olefinic double bond and then 10 hydrolyzing the oxirane ring with acid or by oxidizing in a one-step reaction directly to the dihydroxyalkyl hal.ides of the formula X and converting these, if appro-priateS ~ith aldehydes or ketones.or their acetals into 1,3-dioxolanes o~ the formula ~III.
m e reactions of the xanthine derivatives with the alkylating agents of the formulae VI, VIII and X
are advantageously carried out under the reaction con-ditlons already described in detail for the alk~lation of the dihydroxyalkylxanthines and monoalkyldihydroxy-alkylxanthines with the compounds of the formula VI.
~Iowever, if the compounds of the formula X are used to introduce the dihydroxyalkyl radical, those hav,ng a total of either 6 to 8 C atoms, when R4 has the meaning o~ hydrogen, or 7 or 8 C atoms, when R4 denotes a 25 methyl group, in the alkyl chain are preferred, since the diols of the formula X having shorter chains have a par-~icular tendenc-y to ~orm tetrahydrofuran derivatives under the alkaline conditions of the alkylation reac tion, which can lead to a noti.ceable reduction in the 2633t~3 yields of desired alkylation product~.
m e hydrolytic cleavage of the 1~3-dioxolane ring in the xanthines of the formula V~I having the structural element of the formula IX to give the d~hyd-5 roxyalkylxanthines characterized by the structural ~nitof the formula V is normally carried out in an aaueous medium, optionally with the addition of a solubilizer, such as tetrahydrofuran, dioxane or ethylene glycol din~ethyl ether, advantageously in the presence of acids, 10 for example formic, oxalic, ~a~taric, citric, sulfuric, perchloric, phosphoric or p-toluenesulfonic acid, or an a id ion exchanger (for example Nafion H)s at tempera-tures between 20C and the boiling point of the reaction mixture, preferably 50 and 100C5 it being possib~e 15 ~G-' the -eaction time to be f~om several ~inu-tes to a few hours. ~oist silica gel, having a water content up to 10%, is also a reagent which can be used for the deacetalization, the reaction preferably belng carried out in optionaily halogenated hydrocarbons, such as 20 benzene, toluene, dichloromethane or chlorofolm, at room temperature.
A further method for preparing the xanthines of the formula VII with the structural element of the for-mula IX containing the dioxolane ring comprises adding 25 carbonyl compounds of the formula R~-Co-R7 onto the oxirane ring of the epoxyalkylxanthines according to ~ormula II, having the struc~ural unit of the ~or-mula IV. m is reaction is advantageously carried out in the presence of acid catalysts, ~referably Le~is acids, Z~33~ .
such as boron trifluoride, zinc(II) chloride~tin(IV) chloride or copper(II) sulfate, at temperatures between 0 and 60C. However, quaternary ~onium salts, for example tetraethylammonium halides, are also able to catalyze the addition reaction to give the cyclic .
acetals.
The vicinal dihydroxyalkylxanthines of the for~
mula I have either one or two asymmetric C atoms~
depending on the position of the two hydro~rl groups in 10 the side chain according ~o formula V, and can thus be present in stereoisomeric forms. lThe invention thus relates both ~ the pure scereoisomeric compounds and also to their mixtures~
The medicamerts acoording to the invention can be a.tnin stered orally, ~ec'.al3;, parentela'ly VL as an a.erosol.
Examples of suitabie solid or llauld galenic formulations are granules, powders, tablet~ 5 coated tab-lets, (micro)capsules, suppositories~ syrups5 emulsions, suspensions, aerosols, drops or injectable solutions as well as ~ormulations ~ith protracted release ol the act-ive compo~d5 in the preparation of which, auxiliaries, such as vehicles, disintegrants, binders, coating agents, swelling agents, lubricants or emollients, flavoring materials 5 sweetening agents or solubilizers are used. ~xamples of frequently used auxiliaries which may be mentioned are lactose, mannitol and other sugars, talc, lactal~umin, gelatin, starch, cellulose and its derivatives~ animal and vegetable oils, polyethylene
6;~3~7 -- 22 -- ;
glycols and solvents, such as, for example, sterile water.
'~he for.mulations are preferably produced and administered as dosage units, each unit containing a sp~cified dose of active substance according to ~ormula I. m is dose can be up to 1,000 mg,.but preferably 5G
to 300 mg~ for fixed dosage units, such as tablets, cap--sules and suppositories, and can be up to 200 mg, but p~eferably 20 to 100 mg, for injection solutions in 10 vials.
For the treatment of an adult pat-ent suffering from bronchial obstruction, daily doses of 100 to 500 mg o~ active compound, preferably 200 to 300 mg, on oral administratior. and of 20 to 150 mg~ preferably 40 to ~0 5 mg, on intravenous a~inistratio- arc in~ioatcd, depend~
i~g on the effectiveness of the compounds according to formula I in humans. In certain circumstances, however, higher or lower daily doses can also be approprlate.
The administration of the daily dose can be carried out - 20 either by a single administration in the form o~ a single dosage unit or of several smaller dosage units 5 or by several a~ministralions of sub-divided doses at specified intervals.
Finallys in the preparation of the abovementioned 25 galenic formulationsS the xanthine der vatives of the formula I can also be formulatedtogether with other suit-able active compounds~ for example antiallergic and ailtitussive agents, expectorants, sédatives, peripheral vasotherapeutic agents, antihistamines and also other ~6 3~'87 . - 23 -bronchospasmolrticagents, such as ~2-sympathomimetic agents or parasympatholytics.
Exam~les ~he structure of,all tne compounds described in 5 the follo~Ying text was confirmed by elementary analy~
sis and IR and lH I~R spectra.
Exam~le 1 Ethyl--7-(5,6-dihvdroxs~hexvl~ ro~ lYanthine~
a) ~=~ydroxy-5,6-isopro~vlidened~o~yhexane H0 (C~2)4-lH ~2 O\ O
.,/\
~3C: C~3 - ~ ml of 98~'strength sulfuric &cid were added ' drop~.~ise in the course of 5 minutes to a mixture of 830 g of 1,236-hexanetriol (97~0 pure) and 828 ml of 2,2-dimethoxypropane (98% pure) at room temperature.
Af-ter stirring for a further hour at 25C, 30 g o~
potassium carbonate ~ere added~ the mixture was stirred another hour and then vacuum-distilled over a 10 c~
packed colu~n.
Yield: 897 g (86% of theory) Boiling point (0.5 mbar) 83 - 87C
Re:Eractiv~ index nD =1.4452 .
~33~7 -- 2~ --- b) l~Chloro-5,6-iso~ro~lidenedloxyhexane Cl - (CH2)4 - IH I~2 \~
~ C/ \CH
.
77 ml ofthionyl chloride were added dropwise with stirring in the course of ~ hours to a solution of 5 176.4 g of 1-hydroY~y-5,6 isopropylidenedioxyhexane and 155 ml of triethylamine in 1,300 ml of toluene at 5 - 7C internal temperature. After stirring at 2~ - 25C for a further half an hour, the mixture was heated at 70C until evolutiorl of S02 was complete (about 4 hours~. m e mixture was then cooled do~m and t~e precipi~ate whicll s~para~ed out ~ras flilered off ~Jith suct on. After washing ~rIth 100 ml of toluene, the toluene phases were combined, washed to neutrality, dried and evaporated under reduced pressure. 15 g of potassiws carbonate ~rere added to the residue and this ~ras distilled in vacuo over a packed colwnn.
Yield: 149.6 g (77.6S' of theory) Boiling ~point (0.15 mbar) 4~ - 50C
Re~ractive index I~8 = 1.44&2 c) 3-EthY] ~ 6-lso~ropylidenedioxyhexyl)Yanthirle ~ . .
o ( f H 2 ) ~ f 12 Cl~2-C~I3 :
.
3 ~7 A mixture of 360.4 g of 3-ethylxanth~nej 40902 g o~ l-chloro-5,6-isopropylidenedio~xyhexane and 284.7 g of potassium carbonate in 3 1 of dimethylformamide was heated at 100C ~ith stirring for 2 hours. After evaporation of tne suspension under reduced pressure, the residue was taken up with 1.1 1 of 2N sodium hyd-roxide solu~ion and thoroughly extracted with methylene chloride. The collected me~hylene chloride phases were washed again with 2N sodium hydroxide solulioIl, therl washed with water to neutrality, dried and evapor-ated under reduced pressure. 94.5 g o~ crude 3-ethyl 1,~-bis(5,6-isopropylidenedioh~hexyl)xanthine were obtained as a by-product. The combined aqueous phases, which were alkaline with sodium hydroxide, were treated dro~ e with 33% s-trenOth sulfllric acid at room temperature, with stirring, ~ntil pH 10 was reached.
The precipitate ~laS filtered off with suction, washed to neutrali~y and dried at 100C in vacuo.
Yield: 508 g ~75.5~ o~ t~leory); 9 Melting poir.t: 123 - 124C
C16H24N404 (~Y - 336-4) Ana]vs~s: calculated: C 57.13% H 7.19% N 16.66%
found: C 56.92% H 7.21% N 16.68%
dj 3-Ethyl-7-(5;6-dihvdrox~hexvl)-l-Prop-~lxanthine ( I 112 ] ,~ . CEI2 H3C-C~2-CH ~ ~ ~ OE~ OH
Cli2 -Cli 3 .
33~7 ~ 336.4 g of 3-ethyl-7-(5,6-isopropylidenedioxy-hexyl)xanthine, 151 g of l-bromopropane and 138 g of potassit~t carbonate in 1.5 1 of dimethylformamide were stirred for 48 hours at an internal temperature of 70C.
After removal of the solvent under reduced pressure, the residue ws taken up with methylene ch-oride, ~ashed with dilute soditlm hydroxide solution and the neutIal i7ed and dried methylene chloride phase was evaporatedO
~he residue was heated in 1 1 of sulfuric acid, at a pH
10Of 0.5~ for 2 hours at 100C. After cooling down, the mixture was neutrali ed, evaporat~d t~tder reduced pres-sure and the residue was taken up wi~h me-thylene cllloride. The methylene chloride phase was washed with dilute sodit~t hydr?xide solution and with water, dried 15 and evaporated t~lder reduce~~piessure.
The crude product ~as recrystallized from metlly-lene chloride/diethyl ether.
Yield: 259 g (76.5~/o of theory~
Melting point: 96 - 98C
Cl~H26N404 (I~l = 338-4) ~alysis: calculated: C 56.79% H 7.74~o N 16.56%
~ found: C 56.86% H 7.56% N 16.60,,~
Exa~le 2:
..
, 3-D~l~=b~lhine ( CH 2) 4 - f ~ ClH 2 ~13C-cH~ . OH H
~6331~7 ~ A) A mix'cure of 62.5 g of 1,3-diethylxanthine, 62.7 g of 1-chloro-5,6-isopropylidenedioxyhexane, 42~7 g of potassium carbonate and 450 ml of dimethylformamide was stirred at 120C for 10 hours. A~ter evaporation under reduced pressure, the residue was taken up with 300 ml of lN sodium hydroxide solution and extracted with methylene chloride. The methylene chloride phase was washed with dilute sodium hydroxide solution, washed to neutrality, dried and evaporated under reduced pres-sure. The crude product was distilled under 0.027 mbarand at a bath temperature of 1~0 - 150C in a thin-la~er evaporator, and 107.2 g were obtained.
3-Diethyl-7-(5,6-iso~rG~lidenedioxyhexyl~xar.lhinG
O ~ 4 - fH ~ ~H2 ~3C-C~
C~2-CH3 ~le latter was taken up in 1.~ 1 of methanol and 353 ml of water and, after the addition of 1.5 ml of perchlorlc acid (7~% strength), was stirred at 70~
for 1 hour. After cooling dol.~n to room temperature, the mixture was neutralized with sodium bicarbonate solution and evaporated co dryness under reduced pressul~e.
T~e residue was ext~iac'~edwlth 1.5 1 of methylene chloride and the extrac-t was evaporated. 92.5 g (95% of theory) of crude product were obtained, which, after recrystal-lization twice fro~ mechylene chloride/diethyl ether ~;~63387 (~olume ratio 2 : 3), gave 1,3-diethyl-7-(5,6-dihydroxy-he~yl)xanthine, which was pure by thin-layer chromatography.
Yield: 81.7 g (83.9% of theory) Melting point: 94 - 95C
~ 15H24N44 (~1 = 324.4) Analysis: calculated: C 55.54/~ H 7.46% N 17~27%
found: C 55.52% H 7.52yo N 17.02%
B) The above product was also obtained by hydroly-sis o~ 1,3-diethvl-7-(5,6-e~oxyllexyl~xarlthine (melting point: 58 - 59C) !15C~/ ~2)4-C\~-~C-~2 . C,2~5 .
in analogy to Example 3.
C) The same compound was also obtained by hydroxyla-tion of ~ ethyl-7-(5-hexenyl)xanthine 5C~12) ,~~C~l=C~2 C2~s with os~ium tetroxide: 0.73 g of ,3-diethyl-7-(5-hex-enyl)xanthine in 11 ml of diethyl ether was added drop-wise with stirring in 5 minutes to 0~65 g of osmiumtetroxide in 11 ml of diethyl ether at room temperature.
.. . .
,.
.......... ... .
i33~37 After standing overnight, the precipitate (lr2 g) was filter~d off with suction. This was stirred under reflux in a mixture of 55 ml OI water, 15 ml of ethanol ar.d 11.2 g of sodium sulfite heptahydrate for 3 5 hours. After coolin~; down, the precipitate formed was separated off and the filtra',e was extracted with methy-lene chloride. After drying ancl evaporating the col-lected methylene chloride phases under reduced pressure, 0.6 g of crude product ~as ob~tained, which gave - 10 ~.3-diethyl-7-(5,6-d hydro~he~rl)xanthine as the mono- -hydrate after recrystallization from diethyl ether.
Yield: 0.47 g (57.7% of theo~y) Melting point: 77 - 78C (monoh~,-drate) C15H24N44-H2~ r = 342.4) 15Aralysis: calculated: C 52.62% H 7.65~o N 16.35/~
found: C 52.480/o H 7.69% N 16.2Q%
xamp] e 3:
l ~im. ethvl -7 - (~L6-d ihydro~h exSTl ~ xanth in e a) 1 ~-Dimethyl-7- ( 5, 6-e~o~hexyl ) xanthine ( I H 2 ) 4 ~ C\ / ~ 2 20~3C~
A solution of 31 g OI 1, 3--dimethyl-7-(5-hexenyl) xanthine and ~4.9 g of m-chloxoperbenzoic acid (70%
pure) in 700 ~11 of chloroform was stirred at room te.nperature for 48 hours. The mix-ture was: shaken with 25 lO~o s trength sodium di thionite solution until the test ~63~37 ~o - with starch-iodide-paper was negative, and washed with sodium bicarbonate solutioIl and then with water to neutrality, dried and evaporated under reduced pressure.
Purification of the crude product was ~y means of column chromatography on silica gel (mobile phase:
methylene chloride/acetone, volume ratio 7/3) and by recrystallization from petroleum ether.
Yield: 20.8 g (63.20~o of theory), melting point ! 59 - 6~C
y~calculated: C 56 10~ H 6.52% N 20.13%
found: C 55.87% H 6.51% N 19.91%
b) 1,3-Dimethyl~-7~ 6-dih-~droxyhexYl~.Yanthine )4_lH_IH~
~3C-~ ~ ~ OH OH
0024 ml of perchloric acid (70,' strength) was added dropwise with stirring in 5 minutes to a solution o~ 3.6 g of 1,3-dimetllyl-7-(5,6-epox~hexyl)xanthine in 280 ml OL a mixture of ethylene glycol dimethyl ether and ~Jater (volume ratio 3 : 2) at roo~ temperature.
A~ter s~irring at room tempera~ture for 16 hours, the mixture W3.S neutralized with sodium bicarbonate solu-tion and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (mobile phase: chlorofor,~/ethanol~ volume ratio 8/2) and recrystallization from ethyl acetate , ~G3387 Yield: 3 g (7& . ~qb o f theory) Melting point: 98 - 100C
Cl3H20N404 (~J = 2~6.3) Analy~: calculaied: C 52.69% H 6.80~o N 18.91%
found: C 52.39% H 6.7~6 N 18.83%
Bo~th the reaction of l,3-dimethyl-7-(5-hex-enyl)xanthine ~rith osmium tetroxide in analogy to Example 2 C) and also the alkylation of 1,3-dimethyl-xanthine with l-chloro-5,6-isopropylidenedioxyhexane and subsequ~n'L, acid hyd~lysis of the dioxolane ring according to ~xample 1 o'r 2 A) led to the s~me compound.
Example 4 Dibutvl-7-(~,4--dihydrox~-butvl)xantlline a) l~ Dibutyl--7-(3,4-e~oxvbvt,yl ~ e f CH~-C~I2--~, H2 il3C-(C~)3 ~ ~ o ) -C~
39,4 g of m-chloroperbenzoic aci.d (70~0 pure) were added to a solution of 42.7 g of 1,3-dibutyl-7-(3--butenyl)xarlthine in 900 ml of chloroform within l~
~,ir,utes, with stirring. hfter.stirring at room -tempera-ture for 27 hoursj the ~.ix-ture was washed with 10,b ~trength sodi~.~ dithionite solution, saturated sodium bicar~onate .solution and waterj dried and evaporated under reduced pressure. The res:idue was cnroma+ographed on a'silic~a gel column with a mixture of methylene ~;33~37 c~iloride/aceto~e (7 : ~, v: v) and recrystallized from petroleum ether.
Yield: 19 g (42.4~ of theor~7) Melting point: 52 - 53C
C17H26N43 (~Y = 334.4) Ana~yxis: calculated: C 61.06~o H 7~84~ N 16.755' __ found: C 61.01% H 7.89% ~ 16.74 b) 1,3-Dibut~1-7 (3,4-dlh~droxvbutvl)xanthine ~C~2)2- CH ~H2 H3C-(CH2)3 ~ ~ OH OH
lC~ )3-C~3 0.~ ~1 of perchlo:^ic acid (70% strength) was added clrop~rise ~Yith stirring in 5 minutes to a solution of 7 g of 1,3--dibutyl-~-(3,4-epox~butyl)xanthine in 300 ml of a mi~ture of ethylene glycol dimethyl ether/water (volume ratio 3 : 2) at room temperature. After stir-ring at room temperature for 45 hours5 ~he mixture was neutralized with sodium bicarbonate and the solution was evaporated. The re,sidue was t~ken up with methylene chloride and purified by column chromatography on silica gel wi-th a mixture of chlorofcrm and ethanol (volume r~-tio 8 : 2) as the mobile phase and by recrystalliza-tion from methylene chloride/petrolellm ether.
Y ld: 4.8 g (65,b of theory) ~leltin~ point: 92 - 93C
Cl~H28N404 (~n~ = 352.4), ~63~3~37 nalysis: calculated: C 57.946 H 8.00% N 15.90,b fo~d: C 58.06% H 8.060~o N 15.77%
Alternatively, this diol can be obtained by a one-step oxidation of 1,3-dibutyl-7-(3-butenyl)xanthine with osmium tetroxide in analogy to Example 2 C) or by alkylation of 1,3-dibutylxanthine with the l-halogeno-~,4 isopropylidenedioxybutanes known from the litera~ure (for example Tetrahedron ~4 (1978), pages 2,873 -2,878) and subsequent acid hydrolysis of the dioxolane ring in analogy to Example 1.
EY.am~le 5 ~3-Diethyl-7-(6,7-dihydrox~heptyl)xanthine a) l-Bromo-6~7-ePoxyhe~tane 2 ~ \ / 2 . ` ' O
37.~ g of 1-bromo-5-heptene were added dropwise within 40 minutes, with stirring and flushing with nitrogen, to 50.~ g of m-chloroperbenzoic acid (~5~
pure) in 300 ml of methylene chloride at room temperature.
After standing overnight, the precipitate was ~iltered off with suction and the filtrate was washed with 10% strength Na2S204 solution, with saturated sodium bicarbonate solution and with wat2r and (after-drying) evaporated under reduced pressure. 42.2 g of crude l-bromo-697-epoxyheptane were obtained.
~ b) l-Bromo-6,7-dihvdroxy~ptane OH OH
Br-(Ci~2)5-CH-CH2 42 g of 1-bromo-6,7-epoxyheptane were introduced into ~ mixture of 400 ml of tetrahydrofuran and 235 ml of wacer, which had been adjusted to pH 2 with per-chloric acid, at rocm temperature. After stirring at room temperat~re for ~ hours, the mixt~re ~Yas neutral-ized, evaporated under reduced pressure and the residue was extracted with methylene chloride. A~ter removal of the solvent~ 41 5 ~ of crude 1-bromo-6,7-dihydrox~-heptane were o~tained.
_~ .
c) l-Bromo-6,7-isopropvlidenedio~vhe~tane \ /
.
~ O
Br-(CII2)5-CH CH2 0.1 ml of concentrated sulfuric acid was added, 15 wi-th stirring under nitro~en,-to 41 g of 1-bromo-6,7-di-hydroxyheptane and 22.2 g of 2,2-dimethoxypropane in 100 ml of acetone at room tempera-ture. After 4 hours, 0 6 g of sodium bicarbonate was added. After s-'cirring for a ~urther one hovr, the solid was filtered off, the filtrate was evaporated under reduced pressure and the residue was subjected to fractional vacuum distillation.
.
, ,, ,:~ ,~, .. . .
~633~'7 Yie-d: 38 g (77.9YO cf theory~ -Boiling poin~ (0.4 ~bar) 73 - 76C
Refractive index n20 = 1.4556 d) 1,3-Diethyl-7-(6,7-dihydrox~he~tYl~xanthine .
- (CH2)s~ H2 ~5C2 ~ OH OII
I C~H5 1~.9 g of l,~-diethylxanthine, 18 g of l-bromo-6,7-isopropylidenedioxyheptane and 9.5 g OL potassium carbonate in 100 ml OL d~methylformamide ~lere ileated at 100C with stirring for 7 hours. After evaporation under reduced pressure, dilute sodium hydroxide solu-tion was added to the residue and this was extracted -several times with methylene chlorlde. The collected methylene chloride phases were washed with water, dried and evaporated. The residue was distilled in a bulb-1~ tube apparatus under OoOl mbar and at a bath tempera-ture of 100 - 1]5C. 17 g of 1,3-diethyl-7-(6~7-iso-~____ edioxvhe~-tvl ~aothine were obtained, which . . .
were ta~enup in 70 ml of sul~uric acid at a pH o. 0.5 and heated under reflux for 2 hours After cooling, the m:ixture was neutralized~ evaporated ~mder reduced pres-sure and the residue was recrystallized ~rom methylene chloride/diethyl ether.
" ~ , ,, .,. . , ~., ~.
33~37 _ 36 --~ Yield: 13.8 g (61~i% of theory) Meltin~ point 105C
C16H26N404 (~IW = 338 . 4) Analysis: calculated: C 55.79% H 7.74% N 16.56~o 5found: C 56.83% H 7.70% N 16.67%
m e l-bromo-6,7-dihydroxyheptane prepared in step b) can also be employed directly for ~he alkyla-tion of the 1,3-diethylxanthine in step d) without previous reaction with 2, 2-dime ~oxypropane to giv~ tne dioxolane derivative.
xample 6 .
~,7-Diethyl-1-(4,5-dihydrox~hexyl) anthine a) l-Chloro-4-hexene Cl-(CH2)3-CH=CH-CH~ ~
476 g ~4 moles) of thionyl chloride were added from a dropping funnel to a solution of 330 g (3.3 moles) of 4-hexen-1-ol (Organic Syntheses, Vol. 55, page 62 et seq.) in 400 ml of pyridine, with stirring and cooling in ice, in such a manner that the reaction temperature did not exceed 55C. The mixture was then heated at 80C for 1 hour. Thereaiter, the mixture was allowed to cool down slowly~ water was added and the mixtvre was extracted several times with diethyl ether~
m e combined ether extracts were ex.tracted by shaking with saturated sodivm bicarbona-te solu-tion, washed with water to neutrality, dried over sodiv~ sulfate and evaporated vnder norma pressure. l-Chloro-4-hexene, ~rhich was pure by gas chromatography, was obtained by ~L2633~7 - . . -- 37 --- fractional distillation of the residue under reduced pressure.
Yield: 196.2 g (50.1% of theory) Boiling point (]40 mbar) 80C
Refractive index n21 = 1.4400 b) ~s7-Diethyl~ 4,5-dihvdrox~rhexyl~xanthine CH3-~H-IH-(cH2)3 ~ ~
20.8 g (0~1 mole) of 3,7-diethylxanthine, 15.2 g (0.11 mole) of potassium carbonate and 13.0 g (0.11 mole) of 1-chloro-4-hexene in 600 ml o~ dimethylforma-mide were stirred at 110C ~or 18 hours. After cooling down, the mixture was filtered, th filtrate was evapor-ated ~nder reduced pressure and the residue was taken ~p in chloroform. lhe ~nreacted 3,7-diethylxanthine was removed b-y- extracting with lN sodium hydroxide solution by shaking, the organic phase was washed to neutrality with water, dried over sodium sulfat;e and the solven-t was distilled off in a rotary evaporator. After dryin~ the solid residue from evaporationS 27.5 g (94.7%
of theory) of crude ~,7-di thyl-1-(4~hexenyl)xanthine were ob~ained, ~ ~633~7 ;
~H3-Cu=c~-(cl~2)3 ~
.. .
which,after dissolving in 350 ml of chloroform and add-ing 23.1 g (0.114 mole) of 3-chloroperbenzoic acid (85%
pure)~ras stirred under a nitrogen atmosphere at room temperature ~or 48 hours. The mixt~re was then initi-ally e~tracted by shaking with 10,' strength sodium dithionite solution until the iodine-starch reaction disappeared, and then with 10% strength sodium bicarbon-ate solution, and the solution was washed with water until neutral and free of salt9 dried 2nd evaporated under reduced pressure. 29.0 g (100% of theory) of c~lde 3,7-diethyl-1-(4,5-epoxvhex~l)xanthine were .
obtained CH -C~l-\H-(CH~)3 ~ 15 ~2~5 which, af-ter beir~g taken up in a solvent mixture com-posed of ~50 ml of tetrahydrofuran and 100 ml of water and addition of 0.46 ml of perchloric acid (70% strength), was stirred at room temperature for 90 hours. The mix-ture was then neutralized ~ith saturated so~ium bicarbon- .
ate solution, the solven-t was dlstilled orf under reduced .
.:
.
~LZ6~ 7 pressure and the residue was chromatographed on silica gel with chloroform as the mobile phase. This produced 26.4 g (86% of theory) of a ~rystalline product, which was recrystallized from ethyl acetate/petroleum ether~
and wilich was almost pure by thin-layer ch~omatographyO
Yield: 21.5 g (70% of theory) Melting point 91 - 93C
C15H24N404 (i~ = 324.4) ~nalvsis: calculated: C 55.54~ H.7.46g~ N 17 27 found: C 55.54% H 7 . 59% N 16 . 97~o m e same compound was obtained by a one-step oxidation of 3,7-diethyl-1-(4--hexenyl)xanthine with osmium tetroxide in analogy to ~xample 2 C).
Exam~le 7 3-But~l-1=~4,5-dihydroxyPen~yl)-7-methylxanthine ~ CH3 0~ ON ~ ~
(CH2~3 3 33.3 g (0.15 mole) of 3-butyl-7-methylxanthine, 24.3 g (0.16 mole) o~ 1-bromo-4-pentene and 22.1 g (0.16 mole) oi potassium carbonate in 500 ml of dimethyl-formamide were heated with stirring at 100C ~or 15 hours. A~ter cooling down, the reaction mixture was evaporated under reduced pressure, the residue was taken up in methylene ehloride, filtered and the filtrate was extracted by sha.king with lN sodium hydrcxide solution, -` ~L~33~37 the organic phase was washed with water to neutrali~y, dried over sodium sulfate and solvent was removed in a rotary evaporator. m is produced 42.2 g (97% of the-ory) of crude, crystalline 3-butvl-7-methyl-1-(~-pe~lt-en~l~xanthine CH2=~-~C~)3- ~ ~
(C~2'3-C~3 which was dissolved in 550 ml of chloroform, 35.6 g (0.175 mole)of 3-chloroperbenzoic acid (85% pure) were added and the mixture, a~ter covering with an atmos~
phere o~ nitrogen? was stirred at room temperature for 67 hours. Extraction by shaXing wi~h 10% stren~th sodium dithionite solution until disappearance of the iodine-starch reaction, washing, i~itially with 10%
strength sodium bicarbonate solution and then with water, drying over sodium sulfate and evaporation under reduced pressure provided 37.7 g (84.7y of theory) of crude 3 bu-tyl~ ,5~e~ OJYYPent ~ -7-m~ __ hine, .
which was subjected to hydrolytic opening of the oxirane ring without intermediate puri~ication. For this purpose~
2633~37 the 37.7 g of epoxide was dissolved in a mixture of 200 ml of tetrahydroIuran and 135 ml of water, and 0.61 ml of perchloric acid (70% strength) was added dropwise with stirring within about lO minutes at room temperature. After stirring at room temperature for 14 hours~ the mixture was neutralized with saturated sodium bicarbonate solution and evaporated under reduced pressure. The remaining oily crude product (100% of theory) could be purified by column chromatog-raphy on silica gel with chloroform/meth~nol (volumeratio lO/1) as the eluting agent and subsequent recrys~
tallizat~on from ethyl acetate with the addition o~
petroleum ether at the boiling poir.t until cloudy.
Yi~ld: 29D2 g (73.2yQ of theory) l~ lvieiting point 76 - 78C
C15H24NL~04 (~*.'i = 324-4) Anal~Tsis: calculated: C 55.54% H 7.46% N 17.27%
found: C 55.38% H 7.450,6 N 17.625'.
The same compound was obtained by direc-t dihydroxylation of the C=C double boIld of 3-butyl-
glycols and solvents, such as, for example, sterile water.
'~he for.mulations are preferably produced and administered as dosage units, each unit containing a sp~cified dose of active substance according to ~ormula I. m is dose can be up to 1,000 mg,.but preferably 5G
to 300 mg~ for fixed dosage units, such as tablets, cap--sules and suppositories, and can be up to 200 mg, but p~eferably 20 to 100 mg, for injection solutions in 10 vials.
For the treatment of an adult pat-ent suffering from bronchial obstruction, daily doses of 100 to 500 mg o~ active compound, preferably 200 to 300 mg, on oral administratior. and of 20 to 150 mg~ preferably 40 to ~0 5 mg, on intravenous a~inistratio- arc in~ioatcd, depend~
i~g on the effectiveness of the compounds according to formula I in humans. In certain circumstances, however, higher or lower daily doses can also be approprlate.
The administration of the daily dose can be carried out - 20 either by a single administration in the form o~ a single dosage unit or of several smaller dosage units 5 or by several a~ministralions of sub-divided doses at specified intervals.
Finallys in the preparation of the abovementioned 25 galenic formulationsS the xanthine der vatives of the formula I can also be formulatedtogether with other suit-able active compounds~ for example antiallergic and ailtitussive agents, expectorants, sédatives, peripheral vasotherapeutic agents, antihistamines and also other ~6 3~'87 . - 23 -bronchospasmolrticagents, such as ~2-sympathomimetic agents or parasympatholytics.
Exam~les ~he structure of,all tne compounds described in 5 the follo~Ying text was confirmed by elementary analy~
sis and IR and lH I~R spectra.
Exam~le 1 Ethyl--7-(5,6-dihvdroxs~hexvl~ ro~ lYanthine~
a) ~=~ydroxy-5,6-isopro~vlidened~o~yhexane H0 (C~2)4-lH ~2 O\ O
.,/\
~3C: C~3 - ~ ml of 98~'strength sulfuric &cid were added ' drop~.~ise in the course of 5 minutes to a mixture of 830 g of 1,236-hexanetriol (97~0 pure) and 828 ml of 2,2-dimethoxypropane (98% pure) at room temperature.
Af-ter stirring for a further hour at 25C, 30 g o~
potassium carbonate ~ere added~ the mixture was stirred another hour and then vacuum-distilled over a 10 c~
packed colu~n.
Yield: 897 g (86% of theory) Boiling point (0.5 mbar) 83 - 87C
Re:Eractiv~ index nD =1.4452 .
~33~7 -- 2~ --- b) l~Chloro-5,6-iso~ro~lidenedloxyhexane Cl - (CH2)4 - IH I~2 \~
~ C/ \CH
.
77 ml ofthionyl chloride were added dropwise with stirring in the course of ~ hours to a solution of 5 176.4 g of 1-hydroY~y-5,6 isopropylidenedioxyhexane and 155 ml of triethylamine in 1,300 ml of toluene at 5 - 7C internal temperature. After stirring at 2~ - 25C for a further half an hour, the mixture was heated at 70C until evolutiorl of S02 was complete (about 4 hours~. m e mixture was then cooled do~m and t~e precipi~ate whicll s~para~ed out ~ras flilered off ~Jith suct on. After washing ~rIth 100 ml of toluene, the toluene phases were combined, washed to neutrality, dried and evaporated under reduced pressure. 15 g of potassiws carbonate ~rere added to the residue and this ~ras distilled in vacuo over a packed colwnn.
Yield: 149.6 g (77.6S' of theory) Boiling ~point (0.15 mbar) 4~ - 50C
Re~ractive index I~8 = 1.44&2 c) 3-EthY] ~ 6-lso~ropylidenedioxyhexyl)Yanthirle ~ . .
o ( f H 2 ) ~ f 12 Cl~2-C~I3 :
.
3 ~7 A mixture of 360.4 g of 3-ethylxanth~nej 40902 g o~ l-chloro-5,6-isopropylidenedio~xyhexane and 284.7 g of potassium carbonate in 3 1 of dimethylformamide was heated at 100C ~ith stirring for 2 hours. After evaporation of tne suspension under reduced pressure, the residue was taken up with 1.1 1 of 2N sodium hyd-roxide solu~ion and thoroughly extracted with methylene chloride. The collected me~hylene chloride phases were washed again with 2N sodium hydroxide solulioIl, therl washed with water to neutrality, dried and evapor-ated under reduced pressure. 94.5 g o~ crude 3-ethyl 1,~-bis(5,6-isopropylidenedioh~hexyl)xanthine were obtained as a by-product. The combined aqueous phases, which were alkaline with sodium hydroxide, were treated dro~ e with 33% s-trenOth sulfllric acid at room temperature, with stirring, ~ntil pH 10 was reached.
The precipitate ~laS filtered off with suction, washed to neutrali~y and dried at 100C in vacuo.
Yield: 508 g ~75.5~ o~ t~leory); 9 Melting poir.t: 123 - 124C
C16H24N404 (~Y - 336-4) Ana]vs~s: calculated: C 57.13% H 7.19% N 16.66%
found: C 56.92% H 7.21% N 16.68%
dj 3-Ethyl-7-(5;6-dihvdrox~hexvl)-l-Prop-~lxanthine ( I 112 ] ,~ . CEI2 H3C-C~2-CH ~ ~ ~ OE~ OH
Cli2 -Cli 3 .
33~7 ~ 336.4 g of 3-ethyl-7-(5,6-isopropylidenedioxy-hexyl)xanthine, 151 g of l-bromopropane and 138 g of potassit~t carbonate in 1.5 1 of dimethylformamide were stirred for 48 hours at an internal temperature of 70C.
After removal of the solvent under reduced pressure, the residue ws taken up with methylene ch-oride, ~ashed with dilute soditlm hydroxide solution and the neutIal i7ed and dried methylene chloride phase was evaporatedO
~he residue was heated in 1 1 of sulfuric acid, at a pH
10Of 0.5~ for 2 hours at 100C. After cooling down, the mixture was neutrali ed, evaporat~d t~tder reduced pres-sure and the residue was taken up wi~h me-thylene cllloride. The methylene chloride phase was washed with dilute sodit~t hydr?xide solution and with water, dried 15 and evaporated t~lder reduce~~piessure.
The crude product ~as recrystallized from metlly-lene chloride/diethyl ether.
Yield: 259 g (76.5~/o of theory~
Melting point: 96 - 98C
Cl~H26N404 (I~l = 338-4) ~alysis: calculated: C 56.79% H 7.74~o N 16.56%
~ found: C 56.86% H 7.56% N 16.60,,~
Exa~le 2:
..
, 3-D~l~=b~lhine ( CH 2) 4 - f ~ ClH 2 ~13C-cH~ . OH H
~6331~7 ~ A) A mix'cure of 62.5 g of 1,3-diethylxanthine, 62.7 g of 1-chloro-5,6-isopropylidenedioxyhexane, 42~7 g of potassium carbonate and 450 ml of dimethylformamide was stirred at 120C for 10 hours. A~ter evaporation under reduced pressure, the residue was taken up with 300 ml of lN sodium hydroxide solution and extracted with methylene chloride. The methylene chloride phase was washed with dilute sodium hydroxide solution, washed to neutrality, dried and evaporated under reduced pres-sure. The crude product was distilled under 0.027 mbarand at a bath temperature of 1~0 - 150C in a thin-la~er evaporator, and 107.2 g were obtained.
3-Diethyl-7-(5,6-iso~rG~lidenedioxyhexyl~xar.lhinG
O ~ 4 - fH ~ ~H2 ~3C-C~
C~2-CH3 ~le latter was taken up in 1.~ 1 of methanol and 353 ml of water and, after the addition of 1.5 ml of perchlorlc acid (7~% strength), was stirred at 70~
for 1 hour. After cooling dol.~n to room temperature, the mixture was neutralized with sodium bicarbonate solution and evaporated co dryness under reduced pressul~e.
T~e residue was ext~iac'~edwlth 1.5 1 of methylene chloride and the extrac-t was evaporated. 92.5 g (95% of theory) of crude product were obtained, which, after recrystal-lization twice fro~ mechylene chloride/diethyl ether ~;~63387 (~olume ratio 2 : 3), gave 1,3-diethyl-7-(5,6-dihydroxy-he~yl)xanthine, which was pure by thin-layer chromatography.
Yield: 81.7 g (83.9% of theory) Melting point: 94 - 95C
~ 15H24N44 (~1 = 324.4) Analysis: calculated: C 55.54/~ H 7.46% N 17~27%
found: C 55.52% H 7.52yo N 17.02%
B) The above product was also obtained by hydroly-sis o~ 1,3-diethvl-7-(5,6-e~oxyllexyl~xarlthine (melting point: 58 - 59C) !15C~/ ~2)4-C\~-~C-~2 . C,2~5 .
in analogy to Example 3.
C) The same compound was also obtained by hydroxyla-tion of ~ ethyl-7-(5-hexenyl)xanthine 5C~12) ,~~C~l=C~2 C2~s with os~ium tetroxide: 0.73 g of ,3-diethyl-7-(5-hex-enyl)xanthine in 11 ml of diethyl ether was added drop-wise with stirring in 5 minutes to 0~65 g of osmiumtetroxide in 11 ml of diethyl ether at room temperature.
.. . .
,.
.......... ... .
i33~37 After standing overnight, the precipitate (lr2 g) was filter~d off with suction. This was stirred under reflux in a mixture of 55 ml OI water, 15 ml of ethanol ar.d 11.2 g of sodium sulfite heptahydrate for 3 5 hours. After coolin~; down, the precipitate formed was separated off and the filtra',e was extracted with methy-lene chloride. After drying ancl evaporating the col-lected methylene chloride phases under reduced pressure, 0.6 g of crude product ~as ob~tained, which gave - 10 ~.3-diethyl-7-(5,6-d hydro~he~rl)xanthine as the mono- -hydrate after recrystallization from diethyl ether.
Yield: 0.47 g (57.7% of theo~y) Melting point: 77 - 78C (monoh~,-drate) C15H24N44-H2~ r = 342.4) 15Aralysis: calculated: C 52.62% H 7.65~o N 16.35/~
found: C 52.480/o H 7.69% N 16.2Q%
xamp] e 3:
l ~im. ethvl -7 - (~L6-d ihydro~h exSTl ~ xanth in e a) 1 ~-Dimethyl-7- ( 5, 6-e~o~hexyl ) xanthine ( I H 2 ) 4 ~ C\ / ~ 2 20~3C~
A solution of 31 g OI 1, 3--dimethyl-7-(5-hexenyl) xanthine and ~4.9 g of m-chloxoperbenzoic acid (70%
pure) in 700 ~11 of chloroform was stirred at room te.nperature for 48 hours. The mix-ture was: shaken with 25 lO~o s trength sodium di thionite solution until the test ~63~37 ~o - with starch-iodide-paper was negative, and washed with sodium bicarbonate solutioIl and then with water to neutrality, dried and evaporated under reduced pressure.
Purification of the crude product was ~y means of column chromatography on silica gel (mobile phase:
methylene chloride/acetone, volume ratio 7/3) and by recrystallization from petroleum ether.
Yield: 20.8 g (63.20~o of theory), melting point ! 59 - 6~C
y~calculated: C 56 10~ H 6.52% N 20.13%
found: C 55.87% H 6.51% N 19.91%
b) 1,3-Dimethyl~-7~ 6-dih-~droxyhexYl~.Yanthine )4_lH_IH~
~3C-~ ~ ~ OH OH
0024 ml of perchloric acid (70,' strength) was added dropwise with stirring in 5 minutes to a solution o~ 3.6 g of 1,3-dimetllyl-7-(5,6-epox~hexyl)xanthine in 280 ml OL a mixture of ethylene glycol dimethyl ether and ~Jater (volume ratio 3 : 2) at roo~ temperature.
A~ter s~irring at room tempera~ture for 16 hours, the mixture W3.S neutralized with sodium bicarbonate solu-tion and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (mobile phase: chlorofor,~/ethanol~ volume ratio 8/2) and recrystallization from ethyl acetate , ~G3387 Yield: 3 g (7& . ~qb o f theory) Melting point: 98 - 100C
Cl3H20N404 (~J = 2~6.3) Analy~: calculaied: C 52.69% H 6.80~o N 18.91%
found: C 52.39% H 6.7~6 N 18.83%
Bo~th the reaction of l,3-dimethyl-7-(5-hex-enyl)xanthine ~rith osmium tetroxide in analogy to Example 2 C) and also the alkylation of 1,3-dimethyl-xanthine with l-chloro-5,6-isopropylidenedioxyhexane and subsequ~n'L, acid hyd~lysis of the dioxolane ring according to ~xample 1 o'r 2 A) led to the s~me compound.
Example 4 Dibutvl-7-(~,4--dihydrox~-butvl)xantlline a) l~ Dibutyl--7-(3,4-e~oxvbvt,yl ~ e f CH~-C~I2--~, H2 il3C-(C~)3 ~ ~ o ) -C~
39,4 g of m-chloroperbenzoic aci.d (70~0 pure) were added to a solution of 42.7 g of 1,3-dibutyl-7-(3--butenyl)xarlthine in 900 ml of chloroform within l~
~,ir,utes, with stirring. hfter.stirring at room -tempera-ture for 27 hoursj the ~.ix-ture was washed with 10,b ~trength sodi~.~ dithionite solution, saturated sodium bicar~onate .solution and waterj dried and evaporated under reduced pressure. The res:idue was cnroma+ographed on a'silic~a gel column with a mixture of methylene ~;33~37 c~iloride/aceto~e (7 : ~, v: v) and recrystallized from petroleum ether.
Yield: 19 g (42.4~ of theor~7) Melting point: 52 - 53C
C17H26N43 (~Y = 334.4) Ana~yxis: calculated: C 61.06~o H 7~84~ N 16.755' __ found: C 61.01% H 7.89% ~ 16.74 b) 1,3-Dibut~1-7 (3,4-dlh~droxvbutvl)xanthine ~C~2)2- CH ~H2 H3C-(CH2)3 ~ ~ OH OH
lC~ )3-C~3 0.~ ~1 of perchlo:^ic acid (70% strength) was added clrop~rise ~Yith stirring in 5 minutes to a solution of 7 g of 1,3--dibutyl-~-(3,4-epox~butyl)xanthine in 300 ml of a mi~ture of ethylene glycol dimethyl ether/water (volume ratio 3 : 2) at room temperature. After stir-ring at room temperature for 45 hours5 ~he mixture was neutralized with sodium bicarbonate and the solution was evaporated. The re,sidue was t~ken up with methylene chloride and purified by column chromatography on silica gel wi-th a mixture of chlorofcrm and ethanol (volume r~-tio 8 : 2) as the mobile phase and by recrystalliza-tion from methylene chloride/petrolellm ether.
Y ld: 4.8 g (65,b of theory) ~leltin~ point: 92 - 93C
Cl~H28N404 (~n~ = 352.4), ~63~3~37 nalysis: calculated: C 57.946 H 8.00% N 15.90,b fo~d: C 58.06% H 8.060~o N 15.77%
Alternatively, this diol can be obtained by a one-step oxidation of 1,3-dibutyl-7-(3-butenyl)xanthine with osmium tetroxide in analogy to Example 2 C) or by alkylation of 1,3-dibutylxanthine with the l-halogeno-~,4 isopropylidenedioxybutanes known from the litera~ure (for example Tetrahedron ~4 (1978), pages 2,873 -2,878) and subsequent acid hydrolysis of the dioxolane ring in analogy to Example 1.
EY.am~le 5 ~3-Diethyl-7-(6,7-dihydrox~heptyl)xanthine a) l-Bromo-6~7-ePoxyhe~tane 2 ~ \ / 2 . ` ' O
37.~ g of 1-bromo-5-heptene were added dropwise within 40 minutes, with stirring and flushing with nitrogen, to 50.~ g of m-chloroperbenzoic acid (~5~
pure) in 300 ml of methylene chloride at room temperature.
After standing overnight, the precipitate was ~iltered off with suction and the filtrate was washed with 10% strength Na2S204 solution, with saturated sodium bicarbonate solution and with wat2r and (after-drying) evaporated under reduced pressure. 42.2 g of crude l-bromo-697-epoxyheptane were obtained.
~ b) l-Bromo-6,7-dihvdroxy~ptane OH OH
Br-(Ci~2)5-CH-CH2 42 g of 1-bromo-6,7-epoxyheptane were introduced into ~ mixture of 400 ml of tetrahydrofuran and 235 ml of wacer, which had been adjusted to pH 2 with per-chloric acid, at rocm temperature. After stirring at room temperat~re for ~ hours, the mixt~re ~Yas neutral-ized, evaporated under reduced pressure and the residue was extracted with methylene chloride. A~ter removal of the solvent~ 41 5 ~ of crude 1-bromo-6,7-dihydrox~-heptane were o~tained.
_~ .
c) l-Bromo-6,7-isopropvlidenedio~vhe~tane \ /
.
~ O
Br-(CII2)5-CH CH2 0.1 ml of concentrated sulfuric acid was added, 15 wi-th stirring under nitro~en,-to 41 g of 1-bromo-6,7-di-hydroxyheptane and 22.2 g of 2,2-dimethoxypropane in 100 ml of acetone at room tempera-ture. After 4 hours, 0 6 g of sodium bicarbonate was added. After s-'cirring for a ~urther one hovr, the solid was filtered off, the filtrate was evaporated under reduced pressure and the residue was subjected to fractional vacuum distillation.
.
, ,, ,:~ ,~, .. . .
~633~'7 Yie-d: 38 g (77.9YO cf theory~ -Boiling poin~ (0.4 ~bar) 73 - 76C
Refractive index n20 = 1.4556 d) 1,3-Diethyl-7-(6,7-dihydrox~he~tYl~xanthine .
- (CH2)s~ H2 ~5C2 ~ OH OII
I C~H5 1~.9 g of l,~-diethylxanthine, 18 g of l-bromo-6,7-isopropylidenedioxyheptane and 9.5 g OL potassium carbonate in 100 ml OL d~methylformamide ~lere ileated at 100C with stirring for 7 hours. After evaporation under reduced pressure, dilute sodium hydroxide solu-tion was added to the residue and this was extracted -several times with methylene chlorlde. The collected methylene chloride phases were washed with water, dried and evaporated. The residue was distilled in a bulb-1~ tube apparatus under OoOl mbar and at a bath tempera-ture of 100 - 1]5C. 17 g of 1,3-diethyl-7-(6~7-iso-~____ edioxvhe~-tvl ~aothine were obtained, which . . .
were ta~enup in 70 ml of sul~uric acid at a pH o. 0.5 and heated under reflux for 2 hours After cooling, the m:ixture was neutralized~ evaporated ~mder reduced pres-sure and the residue was recrystallized ~rom methylene chloride/diethyl ether.
" ~ , ,, .,. . , ~., ~.
33~37 _ 36 --~ Yield: 13.8 g (61~i% of theory) Meltin~ point 105C
C16H26N404 (~IW = 338 . 4) Analysis: calculated: C 55.79% H 7.74% N 16.56~o 5found: C 56.83% H 7.70% N 16.67%
m e l-bromo-6,7-dihydroxyheptane prepared in step b) can also be employed directly for ~he alkyla-tion of the 1,3-diethylxanthine in step d) without previous reaction with 2, 2-dime ~oxypropane to giv~ tne dioxolane derivative.
xample 6 .
~,7-Diethyl-1-(4,5-dihydrox~hexyl) anthine a) l-Chloro-4-hexene Cl-(CH2)3-CH=CH-CH~ ~
476 g ~4 moles) of thionyl chloride were added from a dropping funnel to a solution of 330 g (3.3 moles) of 4-hexen-1-ol (Organic Syntheses, Vol. 55, page 62 et seq.) in 400 ml of pyridine, with stirring and cooling in ice, in such a manner that the reaction temperature did not exceed 55C. The mixture was then heated at 80C for 1 hour. Thereaiter, the mixture was allowed to cool down slowly~ water was added and the mixtvre was extracted several times with diethyl ether~
m e combined ether extracts were ex.tracted by shaking with saturated sodivm bicarbona-te solu-tion, washed with water to neutrality, dried over sodiv~ sulfate and evaporated vnder norma pressure. l-Chloro-4-hexene, ~rhich was pure by gas chromatography, was obtained by ~L2633~7 - . . -- 37 --- fractional distillation of the residue under reduced pressure.
Yield: 196.2 g (50.1% of theory) Boiling point (]40 mbar) 80C
Refractive index n21 = 1.4400 b) ~s7-Diethyl~ 4,5-dihvdrox~rhexyl~xanthine CH3-~H-IH-(cH2)3 ~ ~
20.8 g (0~1 mole) of 3,7-diethylxanthine, 15.2 g (0.11 mole) of potassium carbonate and 13.0 g (0.11 mole) of 1-chloro-4-hexene in 600 ml o~ dimethylforma-mide were stirred at 110C ~or 18 hours. After cooling down, the mixture was filtered, th filtrate was evapor-ated ~nder reduced pressure and the residue was taken ~p in chloroform. lhe ~nreacted 3,7-diethylxanthine was removed b-y- extracting with lN sodium hydroxide solution by shaking, the organic phase was washed to neutrality with water, dried over sodium sulfat;e and the solven-t was distilled off in a rotary evaporator. After dryin~ the solid residue from evaporationS 27.5 g (94.7%
of theory) of crude ~,7-di thyl-1-(4~hexenyl)xanthine were ob~ained, ~ ~633~7 ;
~H3-Cu=c~-(cl~2)3 ~
.. .
which,after dissolving in 350 ml of chloroform and add-ing 23.1 g (0.114 mole) of 3-chloroperbenzoic acid (85%
pure)~ras stirred under a nitrogen atmosphere at room temperature ~or 48 hours. The mixt~re was then initi-ally e~tracted by shaking with 10,' strength sodium dithionite solution until the iodine-starch reaction disappeared, and then with 10% strength sodium bicarbon-ate solution, and the solution was washed with water until neutral and free of salt9 dried 2nd evaporated under reduced pressure. 29.0 g (100% of theory) of c~lde 3,7-diethyl-1-(4,5-epoxvhex~l)xanthine were .
obtained CH -C~l-\H-(CH~)3 ~ 15 ~2~5 which, af-ter beir~g taken up in a solvent mixture com-posed of ~50 ml of tetrahydrofuran and 100 ml of water and addition of 0.46 ml of perchloric acid (70% strength), was stirred at room temperature for 90 hours. The mix-ture was then neutralized ~ith saturated so~ium bicarbon- .
ate solution, the solven-t was dlstilled orf under reduced .
.:
.
~LZ6~ 7 pressure and the residue was chromatographed on silica gel with chloroform as the mobile phase. This produced 26.4 g (86% of theory) of a ~rystalline product, which was recrystallized from ethyl acetate/petroleum ether~
and wilich was almost pure by thin-layer ch~omatographyO
Yield: 21.5 g (70% of theory) Melting point 91 - 93C
C15H24N404 (i~ = 324.4) ~nalvsis: calculated: C 55.54~ H.7.46g~ N 17 27 found: C 55.54% H 7 . 59% N 16 . 97~o m e same compound was obtained by a one-step oxidation of 3,7-diethyl-1-(4--hexenyl)xanthine with osmium tetroxide in analogy to ~xample 2 C).
Exam~le 7 3-But~l-1=~4,5-dihydroxyPen~yl)-7-methylxanthine ~ CH3 0~ ON ~ ~
(CH2~3 3 33.3 g (0.15 mole) of 3-butyl-7-methylxanthine, 24.3 g (0.16 mole) o~ 1-bromo-4-pentene and 22.1 g (0.16 mole) oi potassium carbonate in 500 ml of dimethyl-formamide were heated with stirring at 100C ~or 15 hours. A~ter cooling down, the reaction mixture was evaporated under reduced pressure, the residue was taken up in methylene ehloride, filtered and the filtrate was extracted by sha.king with lN sodium hydrcxide solution, -` ~L~33~37 the organic phase was washed with water to neutrali~y, dried over sodium sulfate and solvent was removed in a rotary evaporator. m is produced 42.2 g (97% of the-ory) of crude, crystalline 3-butvl-7-methyl-1-(~-pe~lt-en~l~xanthine CH2=~-~C~)3- ~ ~
(C~2'3-C~3 which was dissolved in 550 ml of chloroform, 35.6 g (0.175 mole)of 3-chloroperbenzoic acid (85% pure) were added and the mixture, a~ter covering with an atmos~
phere o~ nitrogen? was stirred at room temperature for 67 hours. Extraction by shaXing wi~h 10% stren~th sodium dithionite solution until disappearance of the iodine-starch reaction, washing, i~itially with 10%
strength sodium bicarbonate solution and then with water, drying over sodium sulfate and evaporation under reduced pressure provided 37.7 g (84.7y of theory) of crude 3 bu-tyl~ ,5~e~ OJYYPent ~ -7-m~ __ hine, .
which was subjected to hydrolytic opening of the oxirane ring without intermediate puri~ication. For this purpose~
2633~37 the 37.7 g of epoxide was dissolved in a mixture of 200 ml of tetrahydroIuran and 135 ml of water, and 0.61 ml of perchloric acid (70% strength) was added dropwise with stirring within about lO minutes at room temperature. After stirring at room temperature for 14 hours~ the mixture was neutralized with saturated sodium bicarbonate solution and evaporated under reduced pressure. The remaining oily crude product (100% of theory) could be purified by column chromatog-raphy on silica gel with chloroform/meth~nol (volumeratio lO/1) as the eluting agent and subsequent recrys~
tallizat~on from ethyl acetate with the addition o~
petroleum ether at the boiling poir.t until cloudy.
Yi~ld: 29D2 g (73.2yQ of theory) l~ lvieiting point 76 - 78C
C15H24NL~04 (~*.'i = 324-4) Anal~Tsis: calculated: C 55.54% H 7.46% N 17.27%
found: C 55.38% H 7.450,6 N 17.625'.
The same compound was obtained by direc-t dihydroxylation of the C=C double boIld of 3-butyl-
7-methy]-l (4-pentenyl)xanthine with OSI~iUm tetroxi~e in analogy to Example 2 C).
Exam~le 8 1,7-Diethyl-3-(~,5~dihydroY~yh a) 1.7-Diethylxar.th1ne ~ i2~5 ~sC2~
Exam~le 8 1,7-Diethyl-3-(~,5~dihydroY~yh a) 1.7-Diethylxar.th1ne ~ i2~5 ~sC2~
8~7 18 g of 3-benzyl-1,7-diethylxanthine (mel~ing point 119C? in 1,500 ml OL glacial acetic acid were hydrogenated in the presence of 2.5 g of 10% palladium on active charcoal at 80C and under ~.4 bar while shaking for 47 hours. After cooling down, the mixture was covered with an atmosphere of nitrogen while the catalyst was filtered off and the filtrate was evapor-- ated under reduced pressure. ~le residue was dissolved in a mixture of 250 ml of methylene chloride and lG0 ml ~f lN sodium hydroxide solution. .4fter washing the methylene chloride phase again with lN sodiu~ ~lydroxide solution, the combined aqueou~ phases were adjusted to pH 6 by addlng 33% streng~h sulfuric acid dropwise ~rith stirring. After washing to neutrality and drying the precipitate produced, 8.1 g ~54.~% of theory) of ls7~di~
ethylxanthine, of melting point 204 - 205C, were obtained.
4.6 g of 3-benzyl-1,7-diethylxanthine were recovered from the methylene chloride phase.
b) 1,7-Diethyl--3-(5^6-dihy~o~yhexYI)xanthine ~ IC2~5 0~ 0~
.
A mixtul-e of 7 g of 1,7-diethylxanthine, 7.2 of l-chloro-5,G-isopropylidenedioxy~lexane, 5 g of ~L~633 potassium carbonate and 50 ml o~ dimethylformamide was stirred at 120C for 8 hours. After evaporation under reduced pressure, the residue was taken up with 50 ml of lN sodium hydroxide solution and e~tracted with methylene chloride. The methylene chloride phase was washed again with dilute sodi~ hydroxide solution, washed to neutral-ity, dried and evaporated under reduced pressure. The residue was distilled under 0.01 to 0.02 mbar and-at a bath temperature of 120 - 150C in a thin-layer evapora-tor and 11.5 g of 1,7-diethyl-3-(5,6-isopropylidene-dioxyhexvl)xanthine were obtained This was taXen up with 325 ml o~ methanol and 80 ml of ~ater and, after the addition of 0.4 ml o~ perchloric acid (70,~ strength), stirred at 70C for 1 hour. After cooling down to room temperature, the mixture was neutralize~ with sodium bicarbonate solution and evaporated to dryness under reduGed pressure. The residue was taken up with 200 ml of methylene chloride and the e~tract ~ras evaporated.
m e residue was purified by column chromatog raphy on silica gel with methylene chloride/ethanol (volume ratio 8!2) as the mobile phase and by sub-sequent recrystalli2ation from nethylene chloride/
diethyl ether.
Yield: 7.9 ~ (72.5,6 of theory) Melting point: 115 - 116C
j~ C15H24N44 (M~J = 324-4~
Ana~ calculated: C 55. 54,6 H 7 . 46/o N 17 .27%
found: C 55-37% H 7 . 51% N 17 . 08%
:,~
, . ~ .
i33 This diol was also obtained by reaction of 1,7-diethyl-3-~5-hexenyl)xanthine with osmium tetroxide in analogy to Example 2 C) or by epoxidation of the foregoing xanthine compound, followed by acid hydroly~
sis of the epoxide ring in analogy to Examples 3, 4 and 7.
Example 9 7~( ?,3-DihvdroxvbutYl)-1,3-di~ropylxanthine a ) Chloro-2, ,3--e~oxybutane ' ~O
Cl-CH2-CH-CH-CH3 ' 93.4 g of crotyl chloride (97% pure) were added dropwise with stirring ~rithin one hour to a solution of 244 g of 3-chloroperbenzoic acid (850~6 pure) in 1.5 1 o~
chloroform while cooling in ice. After stirring for a further 70 hours at room temperature, the precipitate wa~ filtered off with suction, and the filtrate was washed with 10% strength sodium dithionite solution (until the starch-iodine test was negative), with satur-ated sodi-lm bicarbonate solution and with ~rater. After drying over sodium sulfate, the soîution was fraction-ally distilled over a paGke~ column.
Yield: 58 g (54.30,6 of theory) Boiling point (133 mbar) 70 - 73G
Refractive index n20 = 1.4327 C4H7C10 (I~ = 106.55) Analysis: calculat:ed: C 45.09% H 6.62% Cl 33.27%
found: C 45.28% H 6. 78Q~o Cl 33 . 30%
~2~ 8~.
b) l-Chloro-2,3-dih~rdroxybutane . . .
Cl-C~2-CH-~ CH~
0~ OH
57 g of 1-chloro-2S3-epo~,rbutane were stirred in a mixture of 500 ml of water, 800 ml of tetrahydro-~uran and 1.2 ml of perchloric acid (70% strength) atroom temperature for 7 days. After neutralization with sodium bicarbonate solution, the mixture was evaporated to d~yness under reduced pressure and the residue was taken up with 2 1 o die~lyl ether. The ethereal solu-tion was dried and evapcra~ed under reduced pressure.
Yield: 54 g (81~o of theory) c) l-Chlcro-213-isoproP-ylidenedioxybutane f . O\ O
~ .
~Er3 3 1 ml oX perchloric acid (70% strength) was added dropwise witll stirring within 6 minutes to a solution of 53 g of 1--chloro-2$3-dihydroxybu-tane in 50 ml of acetone and 71 g of 2f2-dimethoxypropane under an atmosphere of nitrogen at room temperature After stirring at room temperature for a further hour, 5 g of finely powdered sodium bicarbonate was added, the mixture was stirred for half an hour, filtered and the filtrate was dislilled over a packed colu~n. - .
~63~87 Yield: 36.8 g (52.5~ of theory) Boiling point (6.5 mbar) 49 - 53C
d) 7-(2,3-Dihvdroxybutvl)-l.3-di~lo-G~lxanthine ¦H2~1H_f~_CH3 3 ~ ~ OH 01 A mixture of 47.2 g of l,3-dipropylxanthi1le, ~3.6 g of l-chloro-2,3-isopropylidenedioxybutane, 28.2 g of potassium carbonate and 300 ml of dimethylformamide was stirred at 120C for 8 hours. The mixtvre was evaporated under reduced pressure and the residue was take~ up with 250 ml of lN sodium hydroxi.de solution and 500 ml of methylene chloride. After washing the aqueou~ pha~e again Wi~l methylene chloride, the com-bined methylene chloride phases were washed with lN
~: sodi~ hydroxide solution and water, dried and evapor-ated under red~lced pressure. The residue was distilled in a bulb-tube apparatus under 0.03 - 0.07 mbar and at a bath temperature of 90C. 26.8 g of 7-(2S3-isopropyl-idenedioxybutyl)~l,3-dipropylxanthirle (91.5~ o~ +heory relative to reacted l,3~dipropylxanthine) wer.e obtained, ~ C~2 - fH ~ ~ C~3 H7C3 ~ ~ 3 C~3 c3~7 ~6 33 ich was s~irred in a mixture of 700 ml of tetrahydro~
furan, 100 ml of water and 0.8 ml of perchloric acid (70% strength) at 70C ~or 1 hour. After neutral'za-tion with sodium bicarbonate solution7 the mixture was e~aporated under reduced pressure, the residue was taken up with 800 ml of methylene chlori~e, and the solution was dried and eva~orated under reduced pressure. The residue was purified by recrystallization from methylene chloride~diethyl ether.
ield: 20~9 g (87.6% of theory) Melting point: 99 - 101C
C15H24N404 ( ~1 = 324 . 39 ) ~alysis: calculated: C 55.54% H 7.46% N 17.27~o found~ C 55049% H 7.49~ N 17.18%
~5 ~ne compounds afo-em~ntioned and those prepared in an analogous ~anner are complled in Table 1.
.
i33~37 `.- ~ ~o i .~ ____ ~ ~
~ . ~ ~ .. ,., . ~ ~
CD ~ ~ P~ P. ~ P~
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.j, _ . ___ ~_ __ _ Table 2: Int2~ediate products ha-~ing a structural element ol the formula IY (arrangement of the - radical~ Rl, R2 ard R3 as ~or formula I) Co~- ~ R~ R3 Melting pol~d point~
C
~ . . .. .
1~ ~ 2~3 ~ / 2 C2H5 3 76-7~
O
2a n C~Hg CH3 ( Example Y.~I C H C H
2 3 ~0/ 3 2 5 ~ 5 (E~ample ~C~2) 4 ~ / 2 3 ~3 5d F;~-s O U
G2 CH3 C1~3 ~ (CH2~ 4~ 59 ~ ~?
72 C~ET5 CZ~S ~ 2 3 ~ /-2 ~8 - 5 ~b 8~ C21~5 C2H5 ,~ (Cq ) ~ C 58 ~ 59 Sd C4Hg C~ 9 ~CH2~ 2 C~ 2 ~2 ~ 5 3 $~3~
able 3: Inter~.ediate prGducts havlng a s~ruc~ural element of the formula IX (R6 = Cn39 ~4, R7 and n: see table, arran~emen-t o~ Rl~ R2 and R3 as for ~crmula I) Com Rl R2 R3 Bulb-~ube~istillalion Meltin PO1~rAd ~C mbar ~oint ~C
_ _ . . _ ~
1b ~ a~ n=4, ~4=~ 3 .7-188 R7 = ~3 Zb ~ c2~;ts n=4, R-=R 146 =H
3b E ~2H5n;4, R =H 123-124 R = GI3 . ~ . . . ~
4}~ CE~3 C2~ 0 o, 0?
. . . _ ~
5b ~5 c2~5 " 130-150 0,027 *
., n;5, ~4 ~ , 1 0C- 1 15 0, 0 1 R = Cff3 7b " C3~7 n;4, R4=ETr 150-160 0,02 R = CH3 ~b C~,.TI7 2 5 135--1~10 0,Ql ~ ..
g~ n ~I n=5, R4=H, 130 0,02 R7 = C~13 lOb " C3,-17 n--4, Rds= H 140-150 0,05 R = CH3 11b -- " n=1, R4= CH3 90 0, G3-0, 07 R7 = C~3 12b C~ 3 C2H, n-4, P~ = H 17.0-130 0,03 R = CH3 13b ~5E~ T 1l 13;)-140 0,03 14b " C2H5 " 130-140 0,02 --r!--~---r-- ___ ____ ~ b C~EI5 R7~'~`EI3 ~ O, 02*
?6!:) n-~ RG- C ''i C3~7 140-1rl? 0,2 ~ _ 17b . ~3~7 ~3 ~ ~,2 ~Th..i~-lay~r e-~apor~to~
33.~3 Example 52 Medicamerlt formulation: For the production of 1,000 coated tablets, 100 g of 3--ethyi-7- ~ -dihydroxy~
hexvl,~- -pr ~Ylxanthine (eompound acco~ding to Example 1), 20 g OI lactose, 30 g of corn starch, 8.5 g of talc~
005 g of ccllloidal silicic acld and 1 g of magnesium stearate we~e mixed and compressed to form tablet cores weighing 160 mg, ~Ihich were then trea1ed with a coating mixt~re eomposed of 40 g of sucrose~ 23.5 g of t21e and very small a~ounts of wax 9 titanium dioxide and gum arabie added so that f~he final weight o~ each o:~ the ~oated tablets was 225 mg.
Example 5~
TIe_icament formulaflon: For the production of 1,000 coated tablets. ll:L.8 g of 3-eth~1-7-(5,~-iso-prop~-licenediox~,rle~yl~ pro~vlxanthlne (from Example 1J, 20 g of lactose, 30 g of corn starchg 8.5 g of talc~
0.5 g of eolloidal silicic acid and 1 g of magnes um stearate were mixed and compressed to form tablet cores weighing 171.8 mg, which were then-treated with a coat-ing mixture composed oî 40 g of ~ucros~, 2305 g of talc a~d very small amounts o:f waxS titanium dioxide and arabic ackled so tllat the final weight of each of the coated tablets was 240 m~.
Z5 ~Yample ~
Medicament form~ ation: For the productiorl of 1,000 coated tablets, 100 g cf 1,3-di~y~ ,6-c-~oxy-hexyl)xanthine (from Example 2 B)), 20 g of lacto~e 30 g o~ corn ~tarch~ 8.5 g of talc5 0.5 g of colloidal 33sQ~ -_ 50 --silicic acid and 1 g of ma~nesium stearate were mixed and compressed to form tablet cores weighing 160 mg, ~hich were then treated with a coatin~ mi;{ture composed o~ l~o g of sucrose, 23.5 g of talc and very small ~mounts of wax9 tita~ium dioxide and gum arabic added so that the final weight of each ol the coated tablets was 225 mg.
~3~L~aoææL~ testin~ and results ____ __ 1.' Bronchos~asmo]ytic activity ~le co~pounds according to the invention were tested ~or bronchospasmolytic activity essentially using the experimental design described by H. Konzett and . Rossler (Arch~ e~p. Path. u. Pharmak. 195 (1940) 75), comparing Wit'l the stanc'ard therapeutic agent, theo-'5 ~lly-lliln~-e-thyle~îe~iamill~9 an~ ith ~he t~o ~,~-d~lyd ox~r-.
propyl compour.ds already known diphylline[ 7-( 2,3-di-hyAroxypropyl)-1~3-~imethylxanthine] ~nd 7-(2~3-di-hydro~Jprop~,rl)-1,3-diprop~lxanthine. In this method, the inhibition of experimontal bronchspasms - induced by intravenous admin~stration of amines havl~g spasmo-~enic activi-t~9 such as acetylcholine, histamine and - serotonine - in guiIlea-pigs of bo-th sexes urder ure-thaneallaestrlesia (1.25 g/kg i.p~) i.s i~:vestigated~
m e test substances were ad~irlistered in aque-ou5 solution elther intravenously (i.v.) or intra~duodeIIally (i.d.). Ihe ED~o values~ which represent 1,hat dose in mg/kg at w.lich tne experimen~ally produced spasm -is decreased by one ha'lf compared -to tnat in untreated animals9 Je~e de-termined ~raphlcally ~'ro~ the dose-activit,v cu~ves .
. 2. Acute toxicity .
Determination of the LD5~ values was by the st~ndard method of the mortality occurring within 7 days amongI~ I mice after a single intravenous (i~Vo ) illtraperitoneal ~i.p.) or oral ~p.o.) administra-tion.
m e results of these investigations 3 which demonstrate the superiority of the compounds according to the invention corresponding to ~or~ula I compared to the standard prod~ct theo~hylline-ethylenedi2mine and the two oth~r comparj-son substances (particularly taking into accol~nt the more favorable ratio of LD50 to ED50), are compiled in the following Table 4-.
.
.
;33Y~
C~
~; ~rl~
.. . . . _. _ __ .
o,i . ~ X
~ ~ o u- O O O O O O ~ r_ ~ r~ o ~ , :~ X ~ ~ c~J o o u~ o o o o .5 ~ .D O
~ ~ ~, ~ ~ r~ ~ ~D ~ ~ r~ , ~ ~ r~ ~
~ ~ o E~ ~ . f~ ~\ ~ J~ O
'X ~ > O- ::~' o Q > ~ .
Ei h . . . . . . . . . . . . . . ~
E~ O ~_ Q ,_ ._ ., ~_ .~ ~_ .. ,_ .~ ., .~ ~
1~o 1 n- l ~ I
~H O I _ ¦ r O ¦ O ¦ O O ~ U~ O O .n ¦ O
~1 o h l o I u~ C~J I c~ I ~ o I I ~D ~ I ~ ~ C ¦ ~
+ ~,~I I ! ! ~ _ ,1 ~ o E; ~ ~ 1 ~ N I o ~ o ~ Ln ~n ~ o o ~ L~ ~ O ¦ O O ~ O ~ ~
it~5 1 ~ i ~
~ I O X I a~ I I I I
I~ 11 I ~ ~O I I~ Ic I~ I n Io, I~
4 1 ~ T
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U~ 1 1 1 1 11 1 1 1 1 I CH t~
O ~ D ~ tq ~ O ~ I I I I I '-~ I I I I (~ I I I I +) h Q ~,~ ~ o I o I o I ~ ~, o ~ F ~F ~ m~ ~ O '1-!
Ht~ I> I~ I> I ~ r~
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s~" I h ~ I ~
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O ~ ~ S~l tD I ~ I ~_ ~ O ~ r~ ¦ ~~
t~ I o h ~' 1 1 1 1 1 1 1 1 15~ -1 S~ I I ~ h E~ l I r~ ~ r_~ I I I I I I I I I E~ ~ a.) I ~ I ~~ .~ S 4 ;~1 Q~ I ~Y *' ~6;~3 -- 64 _ The unequivocal superiority of the compounds ac~ording to the invention, e~pecially compared to the xanthine derivative which is most frequently emplo~Jed for the therapy of obstruc,ive respirctory -tract dis eases, theophylline-ethylenediamine (aminophylline), was also impressively confir~ed in further specific experiment~:
Since it is regarded as proven that, apart from the biogenic amines, acet~-lcholine3 histamine and sero-tonineS listed in Table 49 bladykinin also plays an impor~ant part as a mediator substance in the provoca~
tion of asthma attacks, the inhibito~y effect on the b~onchospas~ induced in ~linea-~igs with-bre~d~kinin was investigated~ In ~liS test, lor exa~ple5 the compound 15 from EXa~ .e 15 0~ intravenous ~ ) acl~inistration, ~as found to ha~ean ED50 of 1 - 3 mg/kg and~ after intra-duocleIlal (i.d.) ad~inistration5 an ED50 of 4.0 - 6.3 mg/kg and thus ~ras abollt 3 times and about 6 times respectively more effective than theophylline-ethylenedia~ine, for ~.rhic~ the corresponcling total ~50 values ~ere .~ound to ~e ~ - lO mg/kg i.v. and 25 - 40 mg/kg i.d.
The compounds of the foImlla I also e ert a strcnF ir~ib-~ory e~fect ol1 tile broncho.spasm incluced with ovalb-l~ir~ cg/k~ i~v~ 3 in ~the presensltized ~uirlea-pig~
~hich is hardly c~fected by th~ cus-toma~y~ xantline derivatives. rm1~ for e:~ample~ -tne E~50 val~ for the cGm~o-~ncl of Exa~ple 1 is be~een 6 and 12 ~Ig/kg i.v.~
w~ilst theophyl e-e-thylenediamine shows no effect in tnis desic;n of e ~eriment ~ th doses up to 12 mg/kg.
31~'7 ~5 ~ ke superior bronchospasmolytic activity of the x2nthines according to formula I was finally demonstrat~d - in ~he pulmona-y ~unc tion test on the anaesthetized dog usi~g the ir~ibition of the bronchospastic reactlons induced with aerosols of acetylcholine, hista-.~ine and asG2ris extract.
mus, for e~a~ple, the co~pound ln Example 1 already sho-led a siGnificant inhibitory effect at 12 mgfkg i . v., ~lhilst theophylline , in dos es up to 20 mg/kg 10 i.v~, proved to have no e~fect~ .
As has already been mentioned in -the introduction9 th~ bronchospasmolytic effect o~ theophylline which is clinically well established9 is con-trcsted by the considerable dlsadvantage of a very nar-5 ~ nerapcu-~ic ran~e combined with ~erious si~e-e~tects, particularly ir the cardiovascular system (hypotensive activi~y ~ decre~se in cerebr-11 blood flow) and in the central nervous system (lor example restlessness, in.~omnia an~ ~rertigo!. ~ne stimulatior of the central nervous ~0 sys em is regarded by pa-tien-ts and clinlcians as being particularly disturbiIlg, since it fre~uently leads to ~-lsomnia and thus has a persisterlt; adv-erse effe^-t on the ge~leral stclte ci' heal-th o~ the asthmatic patient. A
e~pression o~ this sti~ulation of tne cent~al nelvous 25 sys~em is the inc.ease iin spcrltaneous mc,tility of male w~i~e mice by 186% over a perlod of 7 hours after oral ad~i~istration of ;~0 m~r~lg o~ theo~hylline-ethylene-di~.ine. According to Canadian Patent 1,082,184, the otller ti;o comparisorl proc.uct.s dvphyllin ~ ,,6;33~
and 7-(2,3-dihydro~ypropyl)-1,3-dipropylxanthine also bring about a stimulation of the central nervous system in mic~, although these effects are markedly less pro nounced than for theophylline. In contrastg the 5 compounds of the formula I according to the invention have no component stimulating the central nervous sys~
~em, but, on the contrary7 e~ert a slight depressant ~ffect on the central nervous sys-tem which is assessed to be particularly advantageous from the the~apeutic 10 point of view. ~hus, the spontaneous motility of mice~
~or e~ample~ is decreased by 53Q,~ for a period of 11 hours after oral administration of 50 mg/k~ of the com pou~d from E~ample 1~
m e inves-tigations o~ the circulatory system carriecl ou-t on rats and do~s 9 comparing ~,rith theophylline-ethylellediamine, have sho~rn -that the compo~nds of the formula I have a hypotensive activity, ifany at all, which is ~arl;edly lo~-er and that tbey ca~JSe no decrease in cerebral blQod flow.
ethylxanthine, of melting point 204 - 205C, were obtained.
4.6 g of 3-benzyl-1,7-diethylxanthine were recovered from the methylene chloride phase.
b) 1,7-Diethyl--3-(5^6-dihy~o~yhexYI)xanthine ~ IC2~5 0~ 0~
.
A mixtul-e of 7 g of 1,7-diethylxanthine, 7.2 of l-chloro-5,G-isopropylidenedioxy~lexane, 5 g of ~L~633 potassium carbonate and 50 ml o~ dimethylformamide was stirred at 120C for 8 hours. After evaporation under reduced pressure, the residue was taken up with 50 ml of lN sodium hydroxide solution and e~tracted with methylene chloride. The methylene chloride phase was washed again with dilute sodi~ hydroxide solution, washed to neutral-ity, dried and evaporated under reduced pressure. The residue was distilled under 0.01 to 0.02 mbar and-at a bath temperature of 120 - 150C in a thin-layer evapora-tor and 11.5 g of 1,7-diethyl-3-(5,6-isopropylidene-dioxyhexvl)xanthine were obtained This was taXen up with 325 ml o~ methanol and 80 ml of ~ater and, after the addition of 0.4 ml o~ perchloric acid (70,~ strength), stirred at 70C for 1 hour. After cooling down to room temperature, the mixture was neutralize~ with sodium bicarbonate solution and evaporated to dryness under reduGed pressure. The residue was taken up with 200 ml of methylene chloride and the e~tract ~ras evaporated.
m e residue was purified by column chromatog raphy on silica gel with methylene chloride/ethanol (volume ratio 8!2) as the mobile phase and by sub-sequent recrystalli2ation from nethylene chloride/
diethyl ether.
Yield: 7.9 ~ (72.5,6 of theory) Melting point: 115 - 116C
j~ C15H24N44 (M~J = 324-4~
Ana~ calculated: C 55. 54,6 H 7 . 46/o N 17 .27%
found: C 55-37% H 7 . 51% N 17 . 08%
:,~
, . ~ .
i33 This diol was also obtained by reaction of 1,7-diethyl-3-~5-hexenyl)xanthine with osmium tetroxide in analogy to Example 2 C) or by epoxidation of the foregoing xanthine compound, followed by acid hydroly~
sis of the epoxide ring in analogy to Examples 3, 4 and 7.
Example 9 7~( ?,3-DihvdroxvbutYl)-1,3-di~ropylxanthine a ) Chloro-2, ,3--e~oxybutane ' ~O
Cl-CH2-CH-CH-CH3 ' 93.4 g of crotyl chloride (97% pure) were added dropwise with stirring ~rithin one hour to a solution of 244 g of 3-chloroperbenzoic acid (850~6 pure) in 1.5 1 o~
chloroform while cooling in ice. After stirring for a further 70 hours at room temperature, the precipitate wa~ filtered off with suction, and the filtrate was washed with 10% strength sodium dithionite solution (until the starch-iodine test was negative), with satur-ated sodi-lm bicarbonate solution and with ~rater. After drying over sodium sulfate, the soîution was fraction-ally distilled over a paGke~ column.
Yield: 58 g (54.30,6 of theory) Boiling point (133 mbar) 70 - 73G
Refractive index n20 = 1.4327 C4H7C10 (I~ = 106.55) Analysis: calculat:ed: C 45.09% H 6.62% Cl 33.27%
found: C 45.28% H 6. 78Q~o Cl 33 . 30%
~2~ 8~.
b) l-Chloro-2,3-dih~rdroxybutane . . .
Cl-C~2-CH-~ CH~
0~ OH
57 g of 1-chloro-2S3-epo~,rbutane were stirred in a mixture of 500 ml of water, 800 ml of tetrahydro-~uran and 1.2 ml of perchloric acid (70% strength) atroom temperature for 7 days. After neutralization with sodium bicarbonate solution, the mixture was evaporated to d~yness under reduced pressure and the residue was taken up with 2 1 o die~lyl ether. The ethereal solu-tion was dried and evapcra~ed under reduced pressure.
Yield: 54 g (81~o of theory) c) l-Chlcro-213-isoproP-ylidenedioxybutane f . O\ O
~ .
~Er3 3 1 ml oX perchloric acid (70% strength) was added dropwise witll stirring within 6 minutes to a solution of 53 g of 1--chloro-2$3-dihydroxybu-tane in 50 ml of acetone and 71 g of 2f2-dimethoxypropane under an atmosphere of nitrogen at room temperature After stirring at room temperature for a further hour, 5 g of finely powdered sodium bicarbonate was added, the mixture was stirred for half an hour, filtered and the filtrate was dislilled over a packed colu~n. - .
~63~87 Yield: 36.8 g (52.5~ of theory) Boiling point (6.5 mbar) 49 - 53C
d) 7-(2,3-Dihvdroxybutvl)-l.3-di~lo-G~lxanthine ¦H2~1H_f~_CH3 3 ~ ~ OH 01 A mixture of 47.2 g of l,3-dipropylxanthi1le, ~3.6 g of l-chloro-2,3-isopropylidenedioxybutane, 28.2 g of potassium carbonate and 300 ml of dimethylformamide was stirred at 120C for 8 hours. The mixtvre was evaporated under reduced pressure and the residue was take~ up with 250 ml of lN sodium hydroxi.de solution and 500 ml of methylene chloride. After washing the aqueou~ pha~e again Wi~l methylene chloride, the com-bined methylene chloride phases were washed with lN
~: sodi~ hydroxide solution and water, dried and evapor-ated under red~lced pressure. The residue was distilled in a bulb-tube apparatus under 0.03 - 0.07 mbar and at a bath temperature of 90C. 26.8 g of 7-(2S3-isopropyl-idenedioxybutyl)~l,3-dipropylxanthirle (91.5~ o~ +heory relative to reacted l,3~dipropylxanthine) wer.e obtained, ~ C~2 - fH ~ ~ C~3 H7C3 ~ ~ 3 C~3 c3~7 ~6 33 ich was s~irred in a mixture of 700 ml of tetrahydro~
furan, 100 ml of water and 0.8 ml of perchloric acid (70% strength) at 70C ~or 1 hour. After neutral'za-tion with sodium bicarbonate solution7 the mixture was e~aporated under reduced pressure, the residue was taken up with 800 ml of methylene chlori~e, and the solution was dried and eva~orated under reduced pressure. The residue was purified by recrystallization from methylene chloride~diethyl ether.
ield: 20~9 g (87.6% of theory) Melting point: 99 - 101C
C15H24N404 ( ~1 = 324 . 39 ) ~alysis: calculated: C 55.54% H 7.46% N 17.27~o found~ C 55049% H 7.49~ N 17.18%
~5 ~ne compounds afo-em~ntioned and those prepared in an analogous ~anner are complled in Table 1.
.
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tl~ td ~d l tD u~ tD u~ tD u3 ~ u~ G) v~
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.j, _ . ___ ~_ __ _ Table 2: Int2~ediate products ha-~ing a structural element ol the formula IY (arrangement of the - radical~ Rl, R2 ard R3 as ~or formula I) Co~- ~ R~ R3 Melting pol~d point~
C
~ . . .. .
1~ ~ 2~3 ~ / 2 C2H5 3 76-7~
O
2a n C~Hg CH3 ( Example Y.~I C H C H
2 3 ~0/ 3 2 5 ~ 5 (E~ample ~C~2) 4 ~ / 2 3 ~3 5d F;~-s O U
G2 CH3 C1~3 ~ (CH2~ 4~ 59 ~ ~?
72 C~ET5 CZ~S ~ 2 3 ~ /-2 ~8 - 5 ~b 8~ C21~5 C2H5 ,~ (Cq ) ~ C 58 ~ 59 Sd C4Hg C~ 9 ~CH2~ 2 C~ 2 ~2 ~ 5 3 $~3~
able 3: Inter~.ediate prGducts havlng a s~ruc~ural element of the formula IX (R6 = Cn39 ~4, R7 and n: see table, arran~emen-t o~ Rl~ R2 and R3 as for ~crmula I) Com Rl R2 R3 Bulb-~ube~istillalion Meltin PO1~rAd ~C mbar ~oint ~C
_ _ . . _ ~
1b ~ a~ n=4, ~4=~ 3 .7-188 R7 = ~3 Zb ~ c2~;ts n=4, R-=R 146 =H
3b E ~2H5n;4, R =H 123-124 R = GI3 . ~ . . . ~
4}~ CE~3 C2~ 0 o, 0?
. . . _ ~
5b ~5 c2~5 " 130-150 0,027 *
., n;5, ~4 ~ , 1 0C- 1 15 0, 0 1 R = Cff3 7b " C3~7 n;4, R4=ETr 150-160 0,02 R = CH3 ~b C~,.TI7 2 5 135--1~10 0,Ql ~ ..
g~ n ~I n=5, R4=H, 130 0,02 R7 = C~13 lOb " C3,-17 n--4, Rds= H 140-150 0,05 R = CH3 11b -- " n=1, R4= CH3 90 0, G3-0, 07 R7 = C~3 12b C~ 3 C2H, n-4, P~ = H 17.0-130 0,03 R = CH3 13b ~5E~ T 1l 13;)-140 0,03 14b " C2H5 " 130-140 0,02 --r!--~---r-- ___ ____ ~ b C~EI5 R7~'~`EI3 ~ O, 02*
?6!:) n-~ RG- C ''i C3~7 140-1rl? 0,2 ~ _ 17b . ~3~7 ~3 ~ ~,2 ~Th..i~-lay~r e-~apor~to~
33.~3 Example 52 Medicamerlt formulation: For the production of 1,000 coated tablets, 100 g of 3--ethyi-7- ~ -dihydroxy~
hexvl,~- -pr ~Ylxanthine (eompound acco~ding to Example 1), 20 g OI lactose, 30 g of corn starch, 8.5 g of talc~
005 g of ccllloidal silicic acld and 1 g of magnesium stearate we~e mixed and compressed to form tablet cores weighing 160 mg, ~Ihich were then trea1ed with a coating mixt~re eomposed of 40 g of sucrose~ 23.5 g of t21e and very small a~ounts of wax 9 titanium dioxide and gum arabie added so that f~he final weight o~ each o:~ the ~oated tablets was 225 mg.
Example 5~
TIe_icament formulaflon: For the production of 1,000 coated tablets. ll:L.8 g of 3-eth~1-7-(5,~-iso-prop~-licenediox~,rle~yl~ pro~vlxanthlne (from Example 1J, 20 g of lactose, 30 g of corn starchg 8.5 g of talc~
0.5 g of eolloidal silicic acid and 1 g of magnes um stearate were mixed and compressed to form tablet cores weighing 171.8 mg, which were then-treated with a coat-ing mixture composed oî 40 g of ~ucros~, 2305 g of talc a~d very small amounts o:f waxS titanium dioxide and arabic ackled so tllat the final weight of each of the coated tablets was 240 m~.
Z5 ~Yample ~
Medicament form~ ation: For the productiorl of 1,000 coated tablets, 100 g cf 1,3-di~y~ ,6-c-~oxy-hexyl)xanthine (from Example 2 B)), 20 g of lacto~e 30 g o~ corn ~tarch~ 8.5 g of talc5 0.5 g of colloidal 33sQ~ -_ 50 --silicic acid and 1 g of ma~nesium stearate were mixed and compressed to form tablet cores weighing 160 mg, ~hich were then treated with a coatin~ mi;{ture composed o~ l~o g of sucrose, 23.5 g of talc and very small ~mounts of wax9 tita~ium dioxide and gum arabic added so that the final weight of each ol the coated tablets was 225 mg.
~3~L~aoææL~ testin~ and results ____ __ 1.' Bronchos~asmo]ytic activity ~le co~pounds according to the invention were tested ~or bronchospasmolytic activity essentially using the experimental design described by H. Konzett and . Rossler (Arch~ e~p. Path. u. Pharmak. 195 (1940) 75), comparing Wit'l the stanc'ard therapeutic agent, theo-'5 ~lly-lliln~-e-thyle~îe~iamill~9 an~ ith ~he t~o ~,~-d~lyd ox~r-.
propyl compour.ds already known diphylline[ 7-( 2,3-di-hyAroxypropyl)-1~3-~imethylxanthine] ~nd 7-(2~3-di-hydro~Jprop~,rl)-1,3-diprop~lxanthine. In this method, the inhibition of experimontal bronchspasms - induced by intravenous admin~stration of amines havl~g spasmo-~enic activi-t~9 such as acetylcholine, histamine and - serotonine - in guiIlea-pigs of bo-th sexes urder ure-thaneallaestrlesia (1.25 g/kg i.p~) i.s i~:vestigated~
m e test substances were ad~irlistered in aque-ou5 solution elther intravenously (i.v.) or intra~duodeIIally (i.d.). Ihe ED~o values~ which represent 1,hat dose in mg/kg at w.lich tne experimen~ally produced spasm -is decreased by one ha'lf compared -to tnat in untreated animals9 Je~e de-termined ~raphlcally ~'ro~ the dose-activit,v cu~ves .
. 2. Acute toxicity .
Determination of the LD5~ values was by the st~ndard method of the mortality occurring within 7 days amongI~ I mice after a single intravenous (i~Vo ) illtraperitoneal ~i.p.) or oral ~p.o.) administra-tion.
m e results of these investigations 3 which demonstrate the superiority of the compounds according to the invention corresponding to ~or~ula I compared to the standard prod~ct theo~hylline-ethylenedi2mine and the two oth~r comparj-son substances (particularly taking into accol~nt the more favorable ratio of LD50 to ED50), are compiled in the following Table 4-.
.
.
;33Y~
C~
~; ~rl~
.. . . . _. _ __ .
o,i . ~ X
~ ~ o u- O O O O O O ~ r_ ~ r~ o ~ , :~ X ~ ~ c~J o o u~ o o o o .5 ~ .D O
~ ~ ~, ~ ~ r~ ~ ~D ~ ~ r~ , ~ ~ r~ ~
~ ~ o E~ ~ . f~ ~\ ~ J~ O
'X ~ > O- ::~' o Q > ~ .
Ei h . . . . . . . . . . . . . . ~
E~ O ~_ Q ,_ ._ ., ~_ .~ ~_ .. ,_ .~ ., .~ ~
1~o 1 n- l ~ I
~H O I _ ¦ r O ¦ O ¦ O O ~ U~ O O .n ¦ O
~1 o h l o I u~ C~J I c~ I ~ o I I ~D ~ I ~ ~ C ¦ ~
+ ~,~I I ! ! ~ _ ,1 ~ o E; ~ ~ 1 ~ N I o ~ o ~ Ln ~n ~ o o ~ L~ ~ O ¦ O O ~ O ~ ~
it~5 1 ~ i ~
~ I O X I a~ I I I I
I~ 11 I ~ ~O I I~ Ic I~ I n Io, I~
4 1 ~ T
o I h ~ > I ~ ¦ > ~ ¦ > ¦ > ~
1 ~ L ~- `
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. a~
t~
. ' ~ O C c `D ~ a~ .~ O ~ C~J O C~J
a) ~ ~ _ ~, r~ ~n ~ ~ ~ , ~ ~
~ ~ ~ ~ i~ \~ ~ \l ~!
~ a~
. ~ , __ . _ O T O n O O O O ~n O ' ~ # O
-:1 . O O O L-') o o c,~ Ln 0 c:2 3~ D ~_ C~ C~J C~l ~ ~ _ ~> c~ c~
,~ T~ /~ A c :~ ~ l > o ~ > , ~.
_ ~... _. ___ ......
o ~ . ~_ ~ ~ o~ o o ~ o o o . l ..
C) ~ 1, ~ o I ~ ~ , o o o ~ o I ,. ~ ~ ~ X o q~ h h i l . ~ . O
a~, Ul l . i . r~
~ ~ o ~l~o ~
r,q bO ,S~ 1 S~
U~ 1 1 1 1 11 1 1 1 1 I CH t~
O ~ D ~ tq ~ O ~ I I I I I '-~ I I I I (~ I I I I +) h Q ~,~ ~ o I o I o I ~ ~, o ~ F ~F ~ m~ ~ O '1-!
Ht~ I> I~ I> I ~ r~
Ll ~ $
s~" I h ~ I ~
tl) I I Ll~ I t J I ! t~- l ~. 1 1~ I r-l I ~ S~ D C) r~ t!) ~ ~ r-l r~ O
O ~ ~ S~l tD I ~ I ~_ ~ O ~ r~ ¦ ~~
t~ I o h ~' 1 1 1 1 1 1 1 1 15~ -1 S~ I I ~ h E~ l I r~ ~ r_~ I I I I I I I I I E~ ~ a.) I ~ I ~~ .~ S 4 ;~1 Q~ I ~Y *' ~6;~3 -- 64 _ The unequivocal superiority of the compounds ac~ording to the invention, e~pecially compared to the xanthine derivative which is most frequently emplo~Jed for the therapy of obstruc,ive respirctory -tract dis eases, theophylline-ethylenediamine (aminophylline), was also impressively confir~ed in further specific experiment~:
Since it is regarded as proven that, apart from the biogenic amines, acet~-lcholine3 histamine and sero-tonineS listed in Table 49 bladykinin also plays an impor~ant part as a mediator substance in the provoca~
tion of asthma attacks, the inhibito~y effect on the b~onchospas~ induced in ~linea-~igs with-bre~d~kinin was investigated~ In ~liS test, lor exa~ple5 the compound 15 from EXa~ .e 15 0~ intravenous ~ ) acl~inistration, ~as found to ha~ean ED50 of 1 - 3 mg/kg and~ after intra-duocleIlal (i.d.) ad~inistration5 an ED50 of 4.0 - 6.3 mg/kg and thus ~ras abollt 3 times and about 6 times respectively more effective than theophylline-ethylenedia~ine, for ~.rhic~ the corresponcling total ~50 values ~ere .~ound to ~e ~ - lO mg/kg i.v. and 25 - 40 mg/kg i.d.
The compounds of the foImlla I also e ert a strcnF ir~ib-~ory e~fect ol1 tile broncho.spasm incluced with ovalb-l~ir~ cg/k~ i~v~ 3 in ~the presensltized ~uirlea-pig~
~hich is hardly c~fected by th~ cus-toma~y~ xantline derivatives. rm1~ for e:~ample~ -tne E~50 val~ for the cGm~o-~ncl of Exa~ple 1 is be~een 6 and 12 ~Ig/kg i.v.~
w~ilst theophyl e-e-thylenediamine shows no effect in tnis desic;n of e ~eriment ~ th doses up to 12 mg/kg.
31~'7 ~5 ~ ke superior bronchospasmolytic activity of the x2nthines according to formula I was finally demonstrat~d - in ~he pulmona-y ~unc tion test on the anaesthetized dog usi~g the ir~ibition of the bronchospastic reactlons induced with aerosols of acetylcholine, hista-.~ine and asG2ris extract.
mus, for e~a~ple, the co~pound ln Example 1 already sho-led a siGnificant inhibitory effect at 12 mgfkg i . v., ~lhilst theophylline , in dos es up to 20 mg/kg 10 i.v~, proved to have no e~fect~ .
As has already been mentioned in -the introduction9 th~ bronchospasmolytic effect o~ theophylline which is clinically well established9 is con-trcsted by the considerable dlsadvantage of a very nar-5 ~ nerapcu-~ic ran~e combined with ~erious si~e-e~tects, particularly ir the cardiovascular system (hypotensive activi~y ~ decre~se in cerebr-11 blood flow) and in the central nervous system (lor example restlessness, in.~omnia an~ ~rertigo!. ~ne stimulatior of the central nervous ~0 sys em is regarded by pa-tien-ts and clinlcians as being particularly disturbiIlg, since it fre~uently leads to ~-lsomnia and thus has a persisterlt; adv-erse effe^-t on the ge~leral stclte ci' heal-th o~ the asthmatic patient. A
e~pression o~ this sti~ulation of tne cent~al nelvous 25 sys~em is the inc.ease iin spcrltaneous mc,tility of male w~i~e mice by 186% over a perlod of 7 hours after oral ad~i~istration of ;~0 m~r~lg o~ theo~hylline-ethylene-di~.ine. According to Canadian Patent 1,082,184, the otller ti;o comparisorl proc.uct.s dvphyllin ~ ,,6;33~
and 7-(2,3-dihydro~ypropyl)-1,3-dipropylxanthine also bring about a stimulation of the central nervous system in mic~, although these effects are markedly less pro nounced than for theophylline. In contrastg the 5 compounds of the formula I according to the invention have no component stimulating the central nervous sys~
~em, but, on the contrary7 e~ert a slight depressant ~ffect on the central nervous sys-tem which is assessed to be particularly advantageous from the the~apeutic 10 point of view. ~hus, the spontaneous motility of mice~
~or e~ample~ is decreased by 53Q,~ for a period of 11 hours after oral administration of 50 mg/k~ of the com pou~d from E~ample 1~
m e inves-tigations o~ the circulatory system carriecl ou-t on rats and do~s 9 comparing ~,rith theophylline-ethylellediamine, have sho~rn -that the compo~nds of the formula I have a hypotensive activity, ifany at all, which is ~arl;edly lo~-er and that tbey ca~JSe no decrease in cerebral blQod flow.
Claims (18)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a xanthine derivative of the formula I
(I) in which one of the radicals R1, R2 and R3 represents a group of the formula IV
(IV) or IX
(IX) R4 denoting hydrogen or methyl, R6 and R7, independently of one another, being hydrogen, lower alkyl, phenyl or phenyl-alkyl having up to 2 C atoms in the alkyl moiety and n, when R4 is hydrogen, denoting 2 to 6 and when R4 is methyl, denoting 1 to 5, the rest of the radicals R1, R2 and R3, independently of one another, denote hydrogen or alkyl having 1 to 12 C
atoms in the positions R1 and R3 and having 1 to 4 C atoms in the position R2, and the total of carbon atoms in these two radicals, being a maximum of 14 which comprises reacting a) a xanthine of the formula II
(II), which one of theradicals R1', R2' or R3' is'an (.omega.-1)- or (.omega.-2)-alkenyl group of the formula III
-(CH2)n-CH=CH-R4 (III), having 4 to 8 C atoms, R4 denoting hydrogen or methyl, and the other two substituents represent hydrogen or alkyl as defined in formula I, on the olefinic double bond with an oxidizing agent to yield a compound of the formula I having the structural element of the formula IV, b) converting a xanthine of the formula II to a halogeno-hydrin which is then dehydrohalogenated to yield a compound of the formula I, containing the group IV, or c) a xanthine of the formula VII
(VII), in which a maximum of two of the substituents R1'' to R3'' re-present the alkyl defined for formula I and one or two of these radicals denote hydrogen, in the absence or presence of basic agents or in the form of their salts, with an alkylating agent of the formula VIII
(VIII), in which the alkyl chain has a total of 4 to 8 C atoms and R4 denotes hydrogen or methyl, R6 and R7, independ-entry of one another denote hydrogen, lower alkyl having up to 4 C atoms, phenylalkyl having up to 2 C atoms in the alkyl moiety or unsubstituted phenyl and x denotes halogen or a sulfonate or phosphate grouping, to give new dialkylated or trialkylated xanthines having the structural element of the formula IX
(IX) or d) reacting a dialkylated xanthine prepared according to c), having the structural element of the formula IX and still carrying hydrogen in a position of R1'', R2'' or R3'', in the absence or presence of a basic agent or in the form of a salt, with an alkylating agent of the formula R5-X (VI) in which X denotes halogen or a sulfonate or phosphate grouping and R5 denotes the alkyl radical defined for formula I, to give a compound of the formula I
or e) reacting a compound of the formula I, having the structural unit of the formula IV with a carbonyl com-pound of the formula R6-CO-R7, in which R6 and R7, in-dependently of one another, are hydrogen, lower alkyl having up to 4 carbon atoms, phenylalkyl having up to 2 C atoms in the alkyl moiety or unsubstituted phenyl, to give a compound of the formula I with the structural element of the formula IX.
(I) in which one of the radicals R1, R2 and R3 represents a group of the formula IV
(IV) or IX
(IX) R4 denoting hydrogen or methyl, R6 and R7, independently of one another, being hydrogen, lower alkyl, phenyl or phenyl-alkyl having up to 2 C atoms in the alkyl moiety and n, when R4 is hydrogen, denoting 2 to 6 and when R4 is methyl, denoting 1 to 5, the rest of the radicals R1, R2 and R3, independently of one another, denote hydrogen or alkyl having 1 to 12 C
atoms in the positions R1 and R3 and having 1 to 4 C atoms in the position R2, and the total of carbon atoms in these two radicals, being a maximum of 14 which comprises reacting a) a xanthine of the formula II
(II), which one of theradicals R1', R2' or R3' is'an (.omega.-1)- or (.omega.-2)-alkenyl group of the formula III
-(CH2)n-CH=CH-R4 (III), having 4 to 8 C atoms, R4 denoting hydrogen or methyl, and the other two substituents represent hydrogen or alkyl as defined in formula I, on the olefinic double bond with an oxidizing agent to yield a compound of the formula I having the structural element of the formula IV, b) converting a xanthine of the formula II to a halogeno-hydrin which is then dehydrohalogenated to yield a compound of the formula I, containing the group IV, or c) a xanthine of the formula VII
(VII), in which a maximum of two of the substituents R1'' to R3'' re-present the alkyl defined for formula I and one or two of these radicals denote hydrogen, in the absence or presence of basic agents or in the form of their salts, with an alkylating agent of the formula VIII
(VIII), in which the alkyl chain has a total of 4 to 8 C atoms and R4 denotes hydrogen or methyl, R6 and R7, independ-entry of one another denote hydrogen, lower alkyl having up to 4 C atoms, phenylalkyl having up to 2 C atoms in the alkyl moiety or unsubstituted phenyl and x denotes halogen or a sulfonate or phosphate grouping, to give new dialkylated or trialkylated xanthines having the structural element of the formula IX
(IX) or d) reacting a dialkylated xanthine prepared according to c), having the structural element of the formula IX and still carrying hydrogen in a position of R1'', R2'' or R3'', in the absence or presence of a basic agent or in the form of a salt, with an alkylating agent of the formula R5-X (VI) in which X denotes halogen or a sulfonate or phosphate grouping and R5 denotes the alkyl radical defined for formula I, to give a compound of the formula I
or e) reacting a compound of the formula I, having the structural unit of the formula IV with a carbonyl com-pound of the formula R6-CO-R7, in which R6 and R7, in-dependently of one another, are hydrogen, lower alkyl having up to 4 carbon atoms, phenylalkyl having up to 2 C atoms in the alkyl moiety or unsubstituted phenyl, to give a compound of the formula I with the structural element of the formula IX.
2. A process as claimed in claim 1, wherein a compound of the formula II is used, in which one of the radicals R1' and R3' is the radical of the formula III
-(CH2)n-CH=CH-R4 (III) or is a halogenohydrin derived therefrom, and the other radicals, independently of one another, are alkyl having 1 to 4 C atoms.
-(CH2)n-CH=CH-R4 (III) or is a halogenohydrin derived therefrom, and the other radicals, independently of one another, are alkyl having 1 to 4 C atoms.
3. A process as claimed in claim 1, wherein in formula VII a maximum of two of the substituents R1'' to R3'' re-present alkyl and one or two of these radicals denote hydrogen, with the proviso that an alkyl in R1 -position has from 1 to 5 C atoms and an alkyl in R2'' and R3'' has, independently of one another, 1 to 3 C atoms, and this compound is reacted with an alkylating agent of the formula VIII according to embodiment c) of claim 1 or subsequently further reacted according to embodiment of d) of claim 1.
4. A process as claimed in claim 1, wherein in formula VII R1'' is hydrogen or alkyl having 1 to 5 C atoms and R2'' and R3'', independently of one another, are hydrogen or alkyl having 1 to 3 C atoms, at least one of R1'' to R3'' being hydrogen.
5. A process as claimed in claim 1, wherein in formula II R1' or R2' and in formula VII R1'' and R2'' represent hydrogen and the two alkyl substituents R2' and R3' or R1' and R3' in formula II or R2'' and R3'' or R1'' and R3'' together con-tain 3 to 6 carbon atoms and wherein the (.omega.-1)alkenyl group of the formula III and the compound of the formula VIII con-tains, in addition to any R6 and R7 groups, 5 or 6 C atoms and in which R4 each is hydrogen.
6. A process as claimed in claim 1; wherein in formula II
R3' and in formula VII R3'' represents hydrogen and the two alkyl substituents R1' and R2', or R1'' and R2'' respectively, together contain 3 to 7 C atoms and wherein the (.omega.-1)alkenyl group of the formula III and the compound of the formula VIII
contains, in addition to any R6 and R7 groups 4 to 7 C atoms and in which R4 each is hydrogen.
R3' and in formula VII R3'' represents hydrogen and the two alkyl substituents R1' and R2', or R1'' and R2'' respectively, together contain 3 to 7 C atoms and wherein the (.omega.-1)alkenyl group of the formula III and the compound of the formula VIII
contains, in addition to any R6 and R7 groups 4 to 7 C atoms and in which R4 each is hydrogen.
7. A process as claimed in claim 1, wherein in formula II R3' and in formula VII R3'' represents hydrogen and the two alkyl substituents R1' and R2' , or R1'' and R2'' respectively, together contain 3 to 7 C atoms and wherein the (.omega.-2)alkenyl group of the formula III and the compound of the formula VIII
contains, in addition to any R6 and R groups, 6 C atoms and in which R4 each is methyl.
contains, in addition to any R6 and R groups, 6 C atoms and in which R4 each is methyl.
8. A process as claimed in claim 1, wherein in formula II R3' and in formula VII R3'' represents hydrogen and the two alkyl substituents R1' and R2' , or R1'' and R2'' respectively, together contain 3 to 7 C atoms and wherein the (.omega.-1)alkenyl group of the formula III and the compound of the formula VIII
contains, in addition to any R6 and R7 groups, 6 C atoms and in which R4 is hydrogen.
contains, in addition to any R6 and R7 groups, 6 C atoms and in which R4 is hydrogen.
9. A compound of the formula (I) in which one of the radicals R1, R2 and R3 represents a group of the formula IV
(IV) or IX
(IX), R4 denoting hydrogen or methyl, R6 and R7, independently of one another, being hydrogen, lower alkyl, phenyl or phenyl-alkyl having up to 2 C atoms in the alkyl moiety and n, when R4 is hydrogen, denoting 2 to 6 and when R4 is methyl, denoting 1 to 5, the rest of the radicals R1, R2 and R3, independently of one another, denote hydrogen or alkyl having 1 to 12 C atoms in the positions R1 and R3 and having 1 to 4 C atoms in the position R2, the total of carbon atoms in these two radicals being a maximum of 14.
(IV) or IX
(IX), R4 denoting hydrogen or methyl, R6 and R7, independently of one another, being hydrogen, lower alkyl, phenyl or phenyl-alkyl having up to 2 C atoms in the alkyl moiety and n, when R4 is hydrogen, denoting 2 to 6 and when R4 is methyl, denoting 1 to 5, the rest of the radicals R1, R2 and R3, independently of one another, denote hydrogen or alkyl having 1 to 12 C atoms in the positions R1 and R3 and having 1 to 4 C atoms in the position R2, the total of carbon atoms in these two radicals being a maximum of 14.
10. A compound of the formula I as defined in claim 9, wherein R1 or R3 is the radical of the formula IV and the other radicals, independently of one another, are alkyl having 1 to 4 C atoms
11. A compound of the formula I as defined in claim X, wherein a maximum of two of the substituents R1 to R3 re-present alkyl and at most one of these radicals denotes hydrogen with the proviso that an alkyl in R1-position has from 1 to 5 C atoms and an alkyl in R2- and R3-position has, independently of one another 1 to 3 C atoms, and wherein at least one of the remaining positions has a group of the formula IX.
12. A compound of the formula I as defined in claim 9, wherein R1 is hydrogen or alkyl having 1 to 5 C atoms or a radical of the formula IX and R2 and R3, independently of one another, are alkyl having 1 to 3 C atoms or hydrogen or a radical of the formula IX, at most one of R1 to R3 being hydrogen.
13. A compound of the formula I as defined in claim 9, wherein R1 or R2 represents the group of the formula IV or IX
having 5 to 6 C atoms in addition to any R6 and R7 groups, but wherein R4 each is hydrogen, and the two alkyl substituents R2 and R3 or R1 and R3 together contain 3 to 6 C atoms.
having 5 to 6 C atoms in addition to any R6 and R7 groups, but wherein R4 each is hydrogen, and the two alkyl substituents R2 and R3 or R1 and R3 together contain 3 to 6 C atoms.
14. A compound of the formula I as defined in claim 9, wherein R3 represents a group of the formula IV or IX having 4 to 7 C atoms in addition to any R6 and R7 groups, but in which R4 is hydrogen, and the two alkyl radicals R1 and R2 together contain 3 to 7 C atoms.
15. A compound of the formula I as defined in claim 9, wherein R3 represents a group of the formula IV or IX having a total of 6 C atoms in addition to any R6 and R7 groups, but wherein R4 each is methyl, and the two alkyl radicals R1 and R2 together contain 3 to 7 C atoms.
16. A compound of the formula I as defined in claim 9, wherein R3 represents a group of the formula IV or IX having a total of 6 C atoms, but wherein R4 each is hydrogen, and the two alkyl radicals R1 and R2 together contain 3 to 7 C atoms.
17. Use of a compound of the formula I as defined in claim 1, for use as a pro-drug in the treatment of obstructive respiratory tract diseases.
18. The compound of the formula I as defined in claim 1 for use as a pro-drug in the treatment of obstructive respiratory tract diseases.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000529856A CA1263387A (en) | 1981-09-26 | 1987-02-16 | Medicaments, vicinal dihydroxyalkylxanthines contained therein, process for the preparation of these xanthine compounds and intermediate products suitable for these |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813138397 DE3138397A1 (en) | 1981-09-26 | 1981-09-26 | "MEDICINAL PRODUCTS CONTAINING VICINALS OF DIHYDROXYALKYLXANTHINE AND PRODUCTION METHOD FOR THESE XANTHINE COMPOUNDS" |
| DEP3138397.1 | 1981-09-26 | ||
| CA000412172A CA1286292C (en) | 1981-09-26 | 1982-09-24 | Medicaments, vicinal dihydroxyalkylxanthines contained therein, process for the preparation of these xanthine compounds and intermediate products suitable for these |
| CA000529856A CA1263387A (en) | 1981-09-26 | 1987-02-16 | Medicaments, vicinal dihydroxyalkylxanthines contained therein, process for the preparation of these xanthine compounds and intermediate products suitable for these |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000412172A Division CA1286292C (en) | 1981-09-26 | 1982-09-24 | Medicaments, vicinal dihydroxyalkylxanthines contained therein, process for the preparation of these xanthine compounds and intermediate products suitable for these |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1263387A true CA1263387A (en) | 1989-11-28 |
Family
ID=25669818
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000529856A Expired CA1263387A (en) | 1981-09-26 | 1987-02-16 | Medicaments, vicinal dihydroxyalkylxanthines contained therein, process for the preparation of these xanthine compounds and intermediate products suitable for these |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1263387A (en) |
-
1987
- 1987-02-16 CA CA000529856A patent/CA1263387A/en not_active Expired
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