CA1286292C - 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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- CA1286292C CA1286292C CA000412172A CA412172A CA1286292C CA 1286292 C CA1286292 C CA 1286292C CA 000412172 A CA000412172 A CA 000412172A CA 412172 A CA412172 A CA 412172A CA 1286292 C CA1286292 C CA 1286292C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/10—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C31/34—Halogenated alcohols
- C07C31/42—Polyhydroxylic acyclic alcohols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/20—Free hydroxyl or mercaptan
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
Abstract
Abstract of the Disclosure:
Compounds of the formula
Compounds of the formula
Description
9~
, .
~ ne inven-tion relates to new medicaments which are sui~able, in particular, ~or -the treatment o~
obstructive diseases of the respiratory tract, the pharmacologically active vicinal dihydroxyalkylxanth-ines contained in -them, processes for the preparation of these xanthine derivatives and intermediate products ~or this purpose.
The xanthine compounds, which act as phospho-dies~terase inhibitors, have a pre-eminent position among 10 the bronchospasmolytic agents hither-to known (cf. B.
He~ ri~; Mode~e A-7neimittel (Modern "rugs~S~utt5art 1980, page 1,27~), since they have no ~2~sympathomimetic activity and are thus particularly suitable for the long-term therapy ~rhich is always necessary for chronic 15 obstructive disorders of the respiratory -tract. Of this group o~ substances, the naturally occurring xan-thine deriva~ivetheophylline (1,3-dimethylxanthine), has been the undisputed agent o~ choice in asthna ther-apy for several decades now. Its activity, ~Yhich is 20 clinically well es~tablished, is, however, con,;rasted by -the disadvantages o:~ its very narro~Y therapeutic range, its serious gastrointes-tinal, cardiovascular and renal side-effects, as well as those in the central nervous sys~eril, al~d tile fac-t that i-t can only be used en-terally 25 due -to its lac~ of water solubility, and these . - 3 -disadvantages are the basis for the desire of clinicians for, and the pharmaceutical research directed at find-ing, products having a greater therapeutic safety.
I~ has in fact been poss~ble~ by the prepara-tion of water-soluble salts or addition compounds, such as, for example, theophylline-ethylenediamine (amino-ph~lline), to obtain formulations of theophylline which ca~ also be administered parenterally, but these are no~ associated with a significant increase in the thera-10 peutic range or a decrease in t~e abovementioned undesired side-effects; especially since the ethylene-diamine iteelf, which f~nctions as a solubilizer in ~m~nophylline, exerts a deleterious e~fect on the cardio-vascular syste~. . ' ~hus, there have been many at~empts to obtair, by variations in the structure of the theophylline mole-cule, better tolerated compounds having, if possible, a greater bronchospasmolytic activity.
The only synthetic'theophylline derivative which 20 has ~ound a certain 'therapeutic use is diphylline [ 7-(2~3-dihydroxypropyl)-1,3-dime~hylxa.nthine]. m e 2~3-dihydroxypropyl group in.the 7-position does confer a good water solubility on this product, so that the undesired use of solubilizers ~or parenteral admLnistra-25 ti~n is no longer necessary and ~he interferingt~eophylline-like side-~ffects are much less pronounced, but these advantages are, at the same time, paid ~or by '.
a drastic decrease in the bronchospasmolytic activity compared to that of theophylline.
. .. .
128~29~, I~ systematic continuation of these investiga-tions, the two methyl groups in the l- and 3-positions have been exchanged for longer alkyl groups, Yhile re~aining the 2,3-dihydroxypropyl radical in the 5 7-position of the xanthine skeleton. This led to 7-(2,3-dihydrox~ropyl)-l,3-dipropylxanthine, which is described in Canadian Patent 1~82~184 and wnich ~s a comnound readily soluble in watèr, which is said almost to reach the bro~chospasmolytic activity of lO ~heophylline and, at ~he same time, to have a lower acute toxici-ty and fewer disadvantageous side-ef~ects~
Neverl~heless, this product ~as no~ hither-to found acceptance in asthma therapy. Further~ore, according to ~1~ abovementicned Offenle~ur.gsschrift, it induces 15 s~imulation of the central nervous sys-tem, althoug11 this is mar~edly wea~er than that o~ theophylline, which can lead to restlessness and sleep disturbances.
Accord~ngly, water-soluble xanthine compounds, which are superior to theophylline in respect o~ s-trength of 2~ action and therapeutic range and which induce no sig-nificant side-effects5 in par-ticular no stimulation of ~e central nervous system, ~ould still represent a genuine enric~ment ol the therap~r of obstructive dis-orders of the respiratory tract.
It has now been found, surprisingly, that increasing the length of the dihydroxypropyl radical, which has not hitherto been investigate~15 irrespective o~ its position on the xanthine skeleton, leads ~o com~
pounds which fulf`il these stri.t therapeutic demands.
62~2 _ 5 ~
It is true -that two xanthine derivatives o~ this type, namely 1-(5,6-dihydroxyhe~Jl)-~,7-dimethylxan-thine and 1-(4,5-dihydrox~rhexyl)-3,7-dimethylxanthine in the threo and e~ytkro fo~ns, have already been described in -the literature ~Arzneimittelforschung ~Drug Res.) 22, 1,144 - 1,151 (1972)), but these com~ounds were merely isolated and identified as metabolites of the vasothera-peutic agent pentoxifyll;ne. Accordingly, there are no data on their pharmacological properties in this publication.
Thus~ the present invention relates to medica~
ments which contain vicinal dihydroxyalkylxanthines of ~he general fo~nula I
O R-R~
7/> (I) x2 1~ wherein one of th~ radicals Rl, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and ~Yo vicinal hydroxyl groups in the ~ 1 or ~ -2 positions and the two other radicals represent s-traight-c~ain or branched alkyl grGups having up to 12 C a-toms 2~ in the posi-tion o~ Rl and R3 and up to ~ C ato~s in the posi-tion of R2, the to-tal of C atoms in these t~o alkyl s~lbs-tituents being a maximum of 14.
In -tllis conte~:t, those medicclmen-ts are pre-ferred which contain compounds o~ the :Eormula X in ~hich - ~2~i29X
, or R~ represents an (~,w~ dihydrox~all~l radicalha~ing 5 or 6 C atoms and the two alkyl substituents R2 and R3 or d R3 together comprise 3 to 6 C atoms.
R fur~her preferred embodiment of the invention rela~es to medicaments which contain those compounds of ~e formula I in which R3 denotesan (~ dihydroxy all~yl group having 4 to ~ C atoms or a 4,5-dihydro~y~ -hexyl groupS and the total o~ ~ atoms in the t~o alkyl radicals Rl and R2 is 3 to 7. Among these med~camentss those in turn are particularly preferred which contain those compounds o~ the formula I in which R~ represents a 5,6-dikydroxyhexyl radical, such as, for example, in ~-eihyl-7-(5,6-dihydroxyhexyl)-l-propyl-xa~thine.
A fur~her particular embodiment of the invention comprises the compounds o~ the formula I not being adm~nistered per se, but in the form of a prodrug, from which the dihydroxyalkylxanthines, having bronchospasmo-ly-tic activity, with their substituents Rl, R2 and R3 defined in the fore~oing, can only be liberated by bio-traA~sformation in the organism. For this pu~pose, for e~ample, the epoxides having the structural element of the for~ula IV and, in particular, the acetals ` havin~
2~ the structural element of the formula IX, when these are completely alkylated, which are dealt with below as inter~ediate products in the preparation process, are suitable.
The invention also relates to new vicinal , ~ ........... . ........ .. ..
, . ~. .
~2~3~29 dihydrox~al~ylxanthines of the formula I, in which one of the r~dicals Rl, R2 or R3 deno-tes a straigh-t-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in ~,w-l or~-l,w-2 positio~s and 5 the two oth~r radicals represent straigh-t-chain or branched alkyl groups having up to 12 G atoms in the position of Rl and R3 and up to 4 C atoms in the posi-tion o~ R2, the total of C atoms in these t~Yo alkyl substituents being, however, a maximum of 14 and R2 and 10 R3 not both being methyl, when Rl represents a 4,5- or dihydrox~-hexyl radical.
In ~his context, particul~rly suitable compounds are those in which Rl or R2 represents an (~ di-hydroxyalkyl radical having 5 or 6 C atoms and the two aI~yl substi~uen~s R' and R3 or Rl and R3 together con-tain 3 to 6 C atoms~ and also those wherein. R3 deno~es an(~ dihydroxyalkyl group having 4 to 7 C atoms or a 4,5-dihydroxyhex~rl group, and the two alkyl radicals Rl and R2 together contain 3 to 7 C atoms. Amongst the 20 compounds mentioned latterly, the 7-(5,6-dihydroxyhex~
1,3-dialkylxanthines having a total of 3 to 7 C a-toms in the two alkyl radicals Rl and R29 such as, for example, 3-e-thyl-7-(5,6-dihydrox~rhexyl)-1-propylxan-thille, in turn represent par-ticulclrly pre~erred compo~ds accord-25 i~g to ~ormula I. -, m e i.nvention ~ur-th~r rela-tes -to processes fo1 th~ preparation o.~ the ~ic.i~al dihydroxyalkylx~nthines accordin~ to fornu~a I.
An e};amp:le o~ a ~xocess comprises starting .ril;h 12~6Z9 " . -- 8 ---- xan~hines of the formula II
. ~ ~3' Rl 12~ .
in ~hich one o~ theradicals Rl, R2 or R3 is an (~-1)- or (~-2)-alkenyl group of the formula III
-(CH~)r-C~=CH-R4 (III), .
- having 4 to 8 C atoms, R4 denoting hycLrogen or methyl, and the other ~o substi~uents represent hydrogen or alkyl as de~ined in formula I~ and a) reacting them o~ t~e ol~finic double bond wi~h suit~
10 able oxid~zing agents to give new epoxyalkylxanihines ha~ing the st~uctural element of the formula IV
' -(CH2)n-CH~H-R4 tIV) s a.-d hydrolytically opening their oxir~.ne ring with forma-tion o~ dihydro,xyalkylxanthines having the structural 15 unit of the formula V
- ( CH2 )1l-CH-CH-R4 (V ) OH OH
or b) dihydrox-rlating on the olefinic double bond with customary oxicLizing agents to give direc-tly the dihyd-20 roxyalkylxanthines having the structural element characterized b~r ~ormula V, `~
.
: . :
~2~6292 _ g -~ and then alk~latin~r those diols obtained according to a) or b), which still car~y hyd~ogen in the positions o~ Rl, R2 and/or R3, optionally in the presence of basic age~nts or in the form of their salts,with alkylating 5 a~nts of ~he formula VI
R5-X (YI3, in which X denotes halogenJ preferably chlorine or bro-~ine, or a sulfonaie or phosphate grouping and R5 der.otes Mle a~kyl radicals defined.for formula I to ~0 give the compounds of the formula I.
~ h~ alkenyl-, monoaI~yl- and dialkyl-alkenyl-xanthines of ,~he lormula II used as starting ma+erials in this process are known, in,~er alia, from Canadian ~ Patents 1,123,435 and 1,12~,083.
Examples of suitable oxidizinOc agents for the epoxidation of t~e olefinic side-chain according to ~ormula III are chromium(VI) oxides preferably in acetic ~nhydride and carbon disulfide or carbon tetrachloride;
or compounds containing pero~ide g~oups, such as potas-20 sium peroxomonosulfate in the presence of ke'ones, preferably acetone, in a homogeneous phase or in a two-~hase system with phase-transfer catalysis; perox~7-boranes, which are advantageously produced in situ from boric acid or its derivatives and hydroperoxides; -tri-25 phenylsilyl hydroperoxi~e; hydrogen peroxide in thepresence of coreact.~nts, such as, for example, aliphatic or aromatic carbonitriles (for example acetonitrile or benzonitrile), optionally substi.tuted cyanamide or .
- - lZ~6`~9~ .
- isoc~-anates (for eY~mple phenyl isocyanate); ~ydrogen peroxide or alXyl or ara~yl hydroperoxides, such as, for example, tert.-butyl hydroperoxide, l-phenylethyl hydroperoxide and cumene hydroperoxide, in the presence 5 o~ either basic agents or, preferably, particular cata-lysts, such as, ~or e.ample, t.~gstic acid, vanadium(V) oxide, molybdenum hexacarbonyl and vanadium or molyb-den~m acetylaceionates; and, in particular, percarboxylic acids, such as, ~or example, perfo~mic, peracetic, tri 10 fluoroperacetic~ monopermaleic, monopersuccinic9 per-benzoic~ 4-nitroperben~oic ard, preferably, 3-chioro-perber.zoic a~d monoperphthalic acid.
` E~oxidation with the aid of ~ercarboxylic acids (Prileschajew reaction) is advantageously carried out in 1~ a sol~reri o~ disiributing agren~ which is inert towards the reactants and which has been found to exert a con-siderable effe^t on the rate of reaction. Since solvents which can form hydrogen bonds with the per-carboxylic acids generally decrease the rate of reac-tion, aromatic hydrocarbons, such as benzene or toluene~ -æna halogen~ked hydroca~bons, such as dich]oromethane, chloroform or carbon tetracl~loride, are fr~equently pre-~erred to ethers, such as diethyl ether, dioxæne~
tetrahydro~uran or ethylene glycol dimethyl ether, alco-25 -h~ls, esters and carbo~lic acids. ~he reaction is customarily carried out at temperatures between -10 and ~40C, preferabl~r at room temperature, the reaction time varying :from a ~ew minutes up to several hours.
The percarboxylic acids are usually employed for .
~2~6~92 the reaction ill an isolated ~orm, but they can also be produced in situ in the reaction mixtu~e from, for example, the corresponding carboxylic acid and hydrogen peroxide.
On using peracids of strong carbox~lic acids, suc~ as, ~or example, trifluoroperacetic acidS it is advisable to decrease the acid concentration by working in a heterogeneous system or bythe addition ofbu~fer sub-~tances~ such as sodium carbonate, sod.ium bicarbonate or disod.ium hydrogen phosphate, in order to suppress undes-ired secondary reactions of ~he carboxylic acid, which is produced.in the reaction, with the initiall~r formed epoxide.
The epoxyalkylxanthines according to formula II
vi rl~ tho S+l uc t~ral -~nit ol the ~o~mula T~ ca~, how-ever, also be ohtained by base-catalyzed dehydrohalo-- . gena-tion of corresponding ~alogenohydrins, ~ ich in ~ n can be obtained, for example, by adding hy~ohalous aci~s, such as, for examp'.e, hypochlorous acids7 to the ole~inic double bond of the al~enylxanth.ines accord-illg-to ~ormulae II and III. The reaction:of these olefins ~rith N-halogenosuccininides, such as N-bromo-succinimide, or cllloramine T in water or mix-tures of solvents conk~ining water also leads -to -the halogeno-hydrins. m e basic dehydrohalogenating agents usuallyused are al~ali ~.etal or alkaline ear-th me-tal hydrox-ides or carbona+ves, pre~-erably sodium, potassium or calcium hy~3ro~.ide or sodium or potassium carbonate, bu-t organic bases or o-ther oxiranes, such .tS eth~rlene oxide ~2~629~
-- or 1,2-epox~propane? can also be employed successfully.
m e epoxyalkylx~thines can either be isolated in t~.e pure ~orm or f~rther processed as crude products.
The hydrolytic cleavage of the epoxyalkylxan-. _ . . . ~ . . .
thines to give the ~icinal diols having the s~ructural element of the formula ~T iS carried out in an aqueo~ls medium, ~o which, if necessary to increase ~he solu-- bility, an organic solvent whiGh is miscible with water is added, for example tetrahydrofuran7 dioxan~ or ethyl-e~e glycol dime~kyl ether, cdvanta~eously in the - pr~sence of acid caia ys~s~ pre~e~ably weakly nucleo philic acids, such as sulfuric, perchloric or p-toluene-sul~onic acid, or strQngly acid cation exchanger resins (~or exa~ple Nalion-H)y at tempe~atur~s bet~een 20 and l~ 100C? bui preferGbly at room +e~perature? by stirring for several hours. Ho~ever, in principleJ the oxiralle ring opening is also possihle under neutral or alkaline co~ditions.
Customary oxidi ing agents for the direct vici- -20 nal dihydrox~ation of the ali~enylxanthines according ~o formulae II and ITI to give the dihyd~ox~alkylxan-thines char~c-ter7zed by the struciural unit of formula ~Tg are represented bys for example, hydrogen peroxide in the presence of formic acid or glacial acetic acidJ
chromyl chloride, potas~ium perma~ganate~ triphenyl~
metlvlphosphoniu~ permanganate, iodine in the presence of sllver carboxylates or thalliu~(I) carboxylates, such as, ~or ~:~ample, thallium(I) acetate, seleniùm dioxide, molybderum(VI) oxide and, in particular~ osmiwm * denotes trade mark.
- 13 - i - tetroxide ` ~
When using osrr.ium tetro~ide as the oxidizing agent,.the reagent can ei~er be employed in the stoi-- ¦
chiometric amount or in catalytic amounts with the addition of a secondary oxidizi.ng agent, which regener-ates the osmium te-troxide ~rom the inltially produced cyclic esters, with oxidative hydrolysis to give the diols.
In the non-catalytic dihydroxylation of the ole-~0 ~inic double bond with stoichiome-tric amo~mts of osmium tetroxide, the process is advantageously cal~ried out in solvents not having a reducin~ action, preferably ethers, such as die-thyl ether, tetrahydro~u~an and dioxane, or hydrocar~ons$ such as benzene, cyclopen-tane or cyclo-15 hexane, optionally ~rith the addition of a tertiaryamineS such as, in particular, pyridine or auinoline, - isoquinoline, ~- or 4-picoline, at temperatures be~een 0C and t~e bolling point of the particula~ solvent, - prelerably at roor~ lemperclture7 i-t being possible for the reaction times to be from a ~ew minutes to several hours. Then the osrnium(VI) ester complexes, which are produced as intermediates in this process~ are advan-tageously reductively hydrolyzed~ -the use of sodiurn or potassium sulfi-te or b:isulfite, hydrogen sulfide, llth-~5 iu~ aluminurn hydride or catechol or all~aline~ malmi-tol solu~ion .in aqueous or aqueous-alcoholic mediu~ havin~
heen found par-t.icula.ly useful . Ho~Yever, oxi.dative hydrolysis ol the~ cornple~es is ~lso possibl~; but i-t is ~dvis~l~le, in thi.s case~ to car~y O~IC the ~286~:9 _ 14 --- ~ihydroYylation at the outset with catalytic amounts of osm~um tetroxide in the presence of secondary oxidiz-in~ agents, such as, ~or example, hydrogen peroxide, metal chlorates (for example sodium or potassium and, in particular, silver or barium chlorate)~ sodium per- -chlorate, o.Y~rgeIl, sodium perio~ate or hypochlorite and, in particular, tert.-butyl hydroperoxide or trialkyl-amine N-oxides (for example N-methylmorpholine ~-oxide, trimethylamine N-oxide or triethylamine N-oxide).
m e alkylation of the ~ihydroxyalkylxanthines wi~h the compounds of the for~ula VI is usually carried ouc in a distributing agent or solvent ~ihich is inert towards the reactants. Dipolar aprotic solvents, for e~:ample formamide, dimethyl~ormamideS dime-thylacetamide, i~ ~-methylpyrrolidone, tetramethylurea, hexamethylphosphoric triamide, dimethyl sulfoxide, acetone or butanone are par-ticularly suitabl~; however, alcohols, such as metha--nol, ethylen~ col and iis ethers, ethanol, propanol~
isopropanol and the various bu-tanols; hydrocarborlsg su~ll as benzene, toluene or xylenes; halogenatecl hydro- -:
carbons,such as dichlorome-thane or chloroform; pyricline and mix-tures o~ the .solvents mentioned or ~heir mix-~ur~s with ~;ter can also find use.
me reaC-tJ ons are aclvan-tageollsly carrièd out in ~ presei-lce of a bas:ic conclensing agen-t. Examples o~
~uitable a~en-ts for t;his purpos~ are alkali mecal or alkaline ear-th me-tal hydro~ides, carbona-tes, hydricles 9 al~nholates or organic base.s, su^h as tria].kylarnines t~or e~am~le ~rie-thylam.ine or -tributylam:ine), ~ua-ternary ~L2~
ammonium or phosphonium hydroxicles and crosslini~ed resins having fi~ed am~!onium o~; phosphonium groups, ~hich are optionally substituted.
However, ~he ~a.nthine deri~atives c.an also be employed directly in the alkylat.ion reacti.on in the form of their salts prepared separately, such as ~the alkali metal, alkaline earth me~tal or optionally sub-stituted ammoni~m or phosphonium saltsr Further~ore, the dihydro~yalkylxanthines and their monoalkylated 10 derivatives can be readily a Xylated both in the pre-sence of the abovementioned inorganic condensing age.n-ts ar.d also in the form of ~heir alkali metal or alkaline earth me-tal salts, with -the assistance of so-called phase-transler catalysts~ for example tertiary am~nes, ~ua-~ a"~uniu~ u~ u}~ p}~ iU~ leI'~ ?
prèferably in a -~o-p}iase system under the conditions of phase-transfer catalysis.
In the in-troduction of -the allcyl radicals by the procedures described in the foregoing, -the reaction 20 is generally carried out a-t a temperature between 0C and the boiling poin-t of the react.ion medil~ used in each ~ase, preferably bet~/een 20 and. 13~C, if appropria-te under elevated or reduced pressure, but usually under atmospheric pressure, i-t being poss.i.bl~ for -the reac-tion time -to ~e ~rom less -than one hour to several hours In -this process ~or -those clihydro~alkylxan-thines~
in-to ~Yhich two all~yl radicals are slill -to be introduced:
~ither identi.cal or di.f~eren-t substi-tuents can be attached consecu-tively or t~o similar all~yl groups can 1 2 ~ ~2 92 be atcached with the xanthine skeleton without isola-tion of in~ermediate products in a one-pot reaction.
A ~urther process for the preparation of com-pounds of the formula I, which is likewise pre~erred, co~prises reacting xanthines of the formula VII
- R1 ~ ~3"
O ~ (YII), l2~-in w~ich a maximum oftwo of ~he s-ubstituents Rl to R3 rep-rese~t the alkyl defin~d for formula I and a formula of ~lO of these radicals denote hydrogen, optionally in ~h~ presence o~ basic agents or in tne form o~ ~heir sa~ts ~) with 21 kylating agents.of the formula VIII
X - (CH2)n - CH - CN - R
\ (VIII), C~
in which the alkyl chain has a total of 4 to 8 C atoms and R4 denotes hydrogen or methyl, R6 and R7, independ--ently of one another, denote hydrogen, lower alkyl preferably h~v.ing up to 4 C atoms, phenylalkyl having up to 2 C atoms in the alkyl moiety or optionally sub~
sti~ute~ phenyl and X denotes halo~en, pre~erably G
;292 c~lorine or bromine, or a sulfonate or phosphate group~
ing~to give new dialkylated or triaL~-lated xanthines having the ~tructural element of the forml~la IX
-tC~;2)n - IH ~ R
,f~ X) . ~6/ ~7 .
5 and ope~ing theil 1,3-dioxolane ring hydrolytically, spli~ing off R6-Co-R7 and forming dihydroxyalkyl-xanthines having the struc~ural uni~ of the fo~mula V
~ 2)n ~ - R~
0~ o~ ~
or lQ b) with alkyla-ting agents of the formula X
X - (C~ cH - CH - R4 OH OH
in which the alkyl chain has a total of 4 -to 8 C a-t~ms and ~4 and X have the meanings indicated for ~or~ula VIII, directly to gi~e the di7nydroxyall,~ylxant~lines, having the st~uctural element charact~ri~ed by fo~mula V, al`ld then reacting the monoal~;yldihydroxyalkylxar.thines obtained acco:rding to a) or b), ~hich still carry a hydr~gen atom in the position of Rl, ~2 or R3, option-all~ in the p:resence of basic agents or in the ~orm of .
B~iZ9 -- 18 --their salts with alkylating agents of the formula VI
. R5-X ~VI) Ln ~hich X and R5 have -the meanings defin~d for for~ula VI in claim 12, ~o give the compounds of the formula or initially alkylating the dialkylated xanthines pre-pareci ac ording to a), having t,h~ s-tructural element o~ the ~or~ula IX; with the compo~tlas of the formula R5-X (VI) and then ~lydrolyiically cleaving -the di-~
oxolane rin~ with formati.on ofthe dihydrox~alk~rlxanth-i~es according to formula I.
r~he monoalkylxanthines or dial~ylxanthines of the ~ormula VII and the al~ylating agents OI' the for-~ulae VIII and X used as startin~ materials in -this ~rocess are Largely ~no~.~ or can`easily be prepared by methocls kno.rn fro~ the li..erature.
l'hus~ the com~ounds of -the formula VI~I, for e~ample~ can be obt.ained from the -triols of -the formula XI
~!0 - ~CH.) - Cl~ - CH - R
~ n l l (~I) 013 0~1 by react.ion o:E the -~ro vicinal hydro~yl groups ~Yi-th alde-hydes or k~tones or ~rith -their acet~-lls, ~ith proton catalysis, ancl subs~quent replacemento~-the isolated terminaJ. hydroxyl :~unction wi.th halogen Usillg inorganic acid ha:lr,.cles, or .i-ts esteri~ica-tion wi-th sul.fonyl or p~osijhon~ ha:Licles or ar~ycirides~ advanta~eou;-,ly in -the ~X~3~29~
presence of basic agentsS from which in turn the com-po~ds o~ the formula X can be prepared by acid hydroly~
sis of the 1,3-dioxol~ne ring. m e 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 o.~ the formulae VIII and X~ either by subjecting them, a~ described for the alkenylxanthi.nes, to epoxidation on the ole~inic double bond and then 10 hydrolyzing the oxirane ring with acid or by oxidizing in a one-step reaction direc-tly to the dihydlox~alkyl halides of the formula X and converting -these~ if a~pro-priate, with aldehydes or ketones.or their acetals into 1,3-dioxolai~es of the formula VIII. .
~ne reactions of the xanthine derivatlves ~Yith the alkylating agents o~ the formulae VI, VIII and X
are advantag~eously carried out under the reaction con-di-tions already described in detail for the alkylation of the dihydro -yalk~lxanthines and monoalkyldiny-droxy--20 alkylxanthines ~Yith the compo~ds of the formula VI.
HoweverJ il the compounds of -the formula X are ~sed to introduce -the clihydroxyalkyl radical, those havino a -total of either 6 to ~ C atoms, when R~ has -the meaning of hydro~en, or 7 or 8 C atoms, ~Yhen R4 denotes a 25 methyl ~roup, in the alkyl chain are preferred, since the diols of -the ~ormula X having shorter chains have a p?~rt.icular -tendency -to .~orm te-tra.hydrof~lran dcrivatives under tho alha'.ine condi-tions o.~ the alkylation reac-tion, which can lead to a noticeahle reduction i.n -the 1~629 yields of desired alkylation product.' The hydroly~ic cleavage of the l,~-dioxolane ring in the xanthi.nes of the formula Y~I having the structural element of the formula IX to give the dihyd-5 roxyalk~lxanthines characterized by the structural unit.
of the formula V is normally carried out in an aqueous medium, optionally with the addition of a solubilizer~
such as tetrah~drofuran$ dioxane or ethylene glycol dimethyl ether, advantageously in t.he presence of acids, 10 for example ~ormic, oxalic, tartaric~ citric~ sulfuric, perchloric, phosphoric or p-toluenesulfonic acid, or an `
acid ion exchanger (for example Nafion-H)~ at tempera-tures be~/een 20C and the boiling point of the reaction mixture, pre~erably 50~ and 100C~ it being possible 1, ~vr ~hc reac~ioii ~i~e tû '~e fro~ several minuies to 2 ~ew hours. Moist silica gels having a water conten-t up to 10~, is also a reagent which can be used for the deace~talization, the reaction ~referably belng carried out in optionally halogenat~d hydrocarbonss sush as 20 benzeneS toluene, dichloromethane or chloroform, at room t.cmperature.
A further methG~ for prepari.ng the xan-~hines of the ~ormula ~rII ~ith the structural element of thé T`or-mula IX containing the ~io~olane ring comprises adding 25 carbonyl co~pounds o~ the formula R -Co-R7 onto the oxirane ring o~ the epox~ralkyl~anthi.n.es according t;o ~ormula II, having t.he structural unit of the ~or-~ula I~i. Thi~; reaction is advantageously carried ou-t .i.n ~he ~resence o.~ clC.i~ catalysts, prelerabl~ L~w:is acicls~
~ 2 9 - such as boron trifluoride, 2inc(II) chloride)tin(lV) chloride or copper(II) sulfate, at temperatures bet~een 0 and 60C. However, quaternary ammonium salts, for example tetraetnylammonium halides, are also able to catalyze the addition reaction to give the cyclic acetals.
~ le vicinal dihydroxya~;yl;anthines of the ~or-mula I have either one or two asymmetric C atoms, depending on the position of the two hydroxyl groups in 10 the side chain according to formula V, and can thus be present in stereoisomeric forms. ~he invention thus relates both t~ the pure stereoisomeric compounds and also to thei~ mixtures. : -m e medicaments according to the invention canbc a~ is'e~ed o-al y, rGc'ally, parGnte ally or as an aerosol.
Examples of suitable solid or ll~uld galenic for~ulations are gra~ules, po~ders, table-ts, coa~ed tab-lets, (micro)ca~sules, suppositories, Syl~lps~ emulsions~
suspensions, aerosols, drops or injectable solutions as well as fo-rmulations wi-th protrac~ed release of the act-ive compound, in the prepara-tion of ~hich, auxiliaries, such as vehicles, disi~ltegran-ts,`binders, coating agents~ swelliIlg agen~ts, lubricants or emollien-ts, flavQrinO materialss s~leetening agents or solubilizers are used. Examples of frequen-tly used au~iliariev ~hich n~ay be ~entioned are ~actose, manni-tol and o-tller sugars, talc~ laclalbumin, gelatin, starch, cel]ulose and its ~eriv~tives, animal and vegetab~e oils, polyethylene `- ~Z~6Z92 -- 22 -- ;
glycols and solventsS such as, ~or example9 sterile ~ater.
Thc? fG~mulations a~e preferably produced and adminis-tered as dosage units, each ~it containing a specified dose of active substance according to formula I. This dose can be up to 1,000 mg,.but pre~erably 50 to 300 mg, for fixed dosage units, such as tablets, cap-sules and suppositories, an~ can be up to 200 mg, but preferably 20 to 100 mg, for injection solutions in lC) YialsO
For the treatment of an adult patient suffering ` from bronchial obstruction~ daily doses o~ 100 -to 500 mg - o, active compound~ pre~erably 200 to 300 mg, on oral administration a~d o~ 20 to 150 mg, preferably 40 to 80 mO; on in-tra~.~er~o-ls a~ministra-tiol~ arc nd.icatcd, depe.ld--ing on the ef~ective~ess of the compounds acccrding to formula I .in hu~ans. In certain circurnstances, however, h~gher cr lo~er daily doses can also be appropriate~
m e administration of the daily dose can be carried out ~0 either by a single administra-tion in the form of a sin~- e dosage unit or of several smaller dosage units, or b~r several adminis-trations o~ sub--div~ded doses at sp~cified i~tervals.
Finally, in -the prepa:ration o.~ the abovemen-tionecl 25 ~alenic ~ormulations, the xanthine derivat.ives of -the formula ~ can also be ~ormulatedtoge-ther wi-th o-ther suit-able active compoullds, for example antiallergic and an-l:it~l3si~e ag entsS e~pectorants 9 sedatives, peliphc-r~l va~otherapeut:ic agentsJ antihistamines and also other Z9~ , brollchosp2smolyticaOents,su^h as ~2-sympa~homime~ic agents or parasympatholytics.
Exam~les ~he struc~lre o~ all tne compounds described in 5 ~le following text was confirmed by elementary analy-sis and IR and lH I~ spectra.
Exam~~e 1 3-Ethyl--7-(5~6-dih~droxvhexvl~ ro~vlxanthin~
a) ~ o~ro~vliden&d~o~yhexane Ho-(c~2)4-~H ~2 O\ O
3 ml o~ 98~', strength sulfuric acid ~ere added drop;rise in the course of 5 minutes to a ~ixture of 830 g o~ 1,2,6-hexanetriol (97~ p-lre) and 828 ml of 2,2-dimethoxypropane (98~ pure) at room temperature.
A~ter stirring for a ~ur'her hour at 25C, 30 g of potassium carbonate ~ere added, the ~ixture was stirred anotber hour and then vacuum-distilled over a 10 cm packed column.
Yield: 897 g (8~5~ of theory) BoilinO~ ~oin~ (0.5 mbar) 83 - 87C
Re~ractive ir.dex nD =1.4452 .~ .,; .
2~6292 - b) l-Chloro-5~6-isopropylidenedio~yhexane Cl - tCH2)4 IH 1~2 O\ ,~
77 nl ofthionyl chlorlde were added drop~Jise wi~h stirringr in the course o~ 3 hours to a solution of 5 176.4 g of 1-hydroxy-5,6-isopropylidenedioxyhexane and 155 ml o~ triethylamine in 1,300 ml of toluene at 5 - 7C internal tempe.ature. After stirring at 20 - 25C ~or a further hal~ an hour, the mixture was heated at 70~ until evolu1ion o~ S02 was complete (about 4 hours). rne mixture w-as then coo]ed do~.rn and ~LL.hr pl'eCipi~.dt,e -~Y-i-li.C.il ~;epa~ e;i Uuc ~YaS îiltered OI~
wit-h suc~ion. After t~raxhing with 100 ml of ~oluene, the toluene phases were combined5 washed to neutrali-ty, dried and evapora-ted under reduced pressure. 15 g o~
p~tassium carbona~e-~ere added ~o the residue and this was distilled in vacuo over a packed column.
Yield: 149.6 ~ (77.693 of theory) Boiling point (0.15 mbar) ~ - 50C
Refractive index nl8 = 1.4482 c) 3-~thyl-'7- ~ 6-isop~ y~denediox~hex~rl~xant;hine ( (`'H 2 ) ~ f EI 2 ~*,X ~ ~ C/ CE~3 C~2 il3 A mixture of 360.4 g of 3-ethylxanthinej 409.2 g of l-chloro-5,6-isopropylid~nedioxyhexane ~nd 284.7 g of potassium carbonate in 3 1 of dimethylformamide was heated at 100C with stirring for 2 hours. After evaporation of the suspension under reduced pressure, ~he residue was taken up with 1.1 1 of 2N sodium hyd-- roxide solution an~ thoroughly extracted with methylene chloride. m e collected meihylene chloride phases were washed again with 2N sodium hydroxide solution, then washed with water to neutrality, dried and evapor-ated under reduced pressure. 94.5 g of crude 3-ethyl-1,7-bis(5,6-isopropylidenedioxyhexyl)xanthine were obtained as a by-product. The combined aqueous phases, which were alkaline with sodium hydroxide, were treated ~5 ~r!)pT,'~SC' ~ h 33b c~rQn~oth s~ ric ~d ~t ro~
temperature, with stirring, until pH 10 was reached.
The precipitate was filtered off with suction, washed to neutrality and dried at 100C in vacuo.
Yield: 508 g (75.5% of theory);
Melting point: 123 - 124C
C16H24N404 (~ = 336.4) Anal~sis: calculated: C 57.13% H 7.19% N 16.66%
~ound: C 56.92% H 7.21% N 16.68%
;~ d) 3-~thyl-7-(5,6-dJhydrox~he ~ lxanthine O
25 ~l3F'-C~2-C~ 0~1 0~1 G
~2~29?.
3~5.4 g of 3-ethyl-7-(5,6-isopropylidenedioxy-he~l)xanthin~, 151 g of l-bromopropane and 138 g of potassiu~ carbonate in 1.5 1 o* dimethylformamide were stirred for 48 hours at an internal temperature of 70C.
5 A~ter remo~ral of the solvent under reduced pressure, the residue was -t~en up with mel~hylene chloride, washed with dilute sodium hydro~ide solut~on and the neutral-ized and dried methylene chloride phase was evaporated.
~he residue was heated in 1 1 of sulfuric acid, at a pH
of 0.5, for 2 hours at 100C. After cooling do~l, the ~ixture was r.eu-tralized~ evaporated under reduced pres-sure and the residue ~ras taken up wi-th methylene chloride. m e methylene chloride phase was washed with ~ilute sodilum hydro~ide solution and with wa-ter~ dried .L5 and e~aporated ~nder reduc~d pressure.
m e crude ploduct ~las recrystallized from methy-lene chloride/diethyl ether.
Y~eld: 259 g (75.5% of theory) Mel-ting point: 95 - 98C
C16H26~404 (~ = 33~ 4) hnalysi.s: calculated: C 56.79% H 7.74% N 16.56~o founrl: C 56.85% H 7.56S~ N 16.60~b Example 2:
____ ~ Diet.h~l 7-55,6-dihydro_y~ h: e ~ (Cl~-l2)~ - f~ 2 Tl3C~ . 0}l E~
C~2 ~l3 h) A mixi~e of 62.5 g Q~ 1,3-diethylxanthille, 62~7 g of 1-chloro-5,6-isopropylidenedioxyhexane, 42.7 g of potassium carbonate and 450 ml of dimethylformamide was stirr~d at 120G for 10 hours. After evaporation under reduced pressure, the residue was taken up with 300 ml of lN sodium hydroxide solution and extracted with mèthylene chloride. The ~ethylene chloride phase was washed ~Yi-~h dilute sodium .~ydroxide solution, washed ltO neutrality, dried and evapora-ted under reduced pres-sure. The c~ude product was distilled ~nder 0.027 mbar~nd at a bath temperature of 13Q - 150C in a t~in-layer evapora-tor, and 107.2 g were obtained.
Die ~i~vl-7~ 6-iso~rop~. l idenedio~cvh ~ IH2 ) 4 -- ICH fH2 H3C C~I2~ \C/O
~7 N H3C~/ CH3 .. C~l2 CH3 T~e latter was taken up in 1.~ 1 of me-thanol and 350 ml of ~a-ter and, after the addition of 1.'-, ml of perchloric acid (70j' s-t~ength), was s-tirred at 70C
for 1 hnur. After (:ool.i.ng do~rl-to room temperQture~
.he mixtu~ as neu-trali.zed with sodiuM bicarbonal;e solution and evaporated ~oc~ryn2ss under reduced pressure.
T.he r~si.due ~las extr~ct~d ~ithl.5 ~ o~ methylene chlnride and t;he e~tr~c-' was evapora-ted 92.5 ~ (95~o of -theory) o~ crude. prodllct; were ob-t:ained, ~lhich, after recrys~al~
~ ation t~lce from methylene chloride/diet;h~l ether `q2~62~
- ~volume ratio 2 : 3), gave 1,3-diethyl-7-(5,6-dihydro~y-hex~rl)xanthi~e, which w~s pure by thiIl-layer chromatography.
Yield: 81.7 g (83.95~ of theory) ~Ielting point: 94 - 95C
C15H24~44 (MW = 324-4) Analysis: calculated: C 55.5~yO H 7.46% N 17.276 found: C 55.52~ H 7.52% N 17.02%
B) ~he above product l.ras also obtained by hydroly-sis of 1,3-diethvl-7- ~~6-ep?x~hex~rl)xanthine (melting poin-t: 58 - 59C) o (C~2)4 - ~ CH2 C
C~1~5 i~ analogy to Exa~ple 3.
C) m e same compound was also obtained by ~Iydro~Yyla~
-~ion of 1,~-diethyl-7--(5-hexen~l)xaQth ne (C1~2) 4~ CH2 C~I5 with osmium tetroxide: 0.73 g of 1,3-diethyl-7-(5-he}~-~nyl)xanthine ln 11 ml o~ diethyl ether was add~d drop-2(~ wise with stirring in 5 m;nlltes -to n,6s g oI` osmium -t~troxicle in 11 ml of dietllyl e-ther at room terllpera*ure.
~28~i29~ 1 -- 29 -- i After standing overnight, the precipitate (1.2 g) was filtered off with suction. m is was stirre~
under reflux in a mixture of 55 ml of water, 1~ ml of ethanol and 11.2 g of sodium sulfite heptahydrate for 3 - 5 hours. After cooling do~rn, the precipitate formed was separated off and the ~iltrate was extracted with methy lene chloride. After drying and ev~porat~ng the col-lected methylene chloride phases under reduced pressure, 0.6 g of crude product was obtained, which gave 1,3-diethyl-7-(5,6-dih~droxyhexvl~xanthine as the mono-hydr~te after recrystallization from diethyl ether.
Yie~d: 0.47 g (57~7% o~ theory) Melting point: 77 - 78C (~onohydrate) ClsH~ 4o4-H2o (~r:.~ = 342.~) ~nalysis: calculated: C 52.620,~ H 7.65~' N 16.3~%
found: C 52./r850 H 7.69% N 16. 20~Q
Example 3:
~Dim~l_7_~ ~!~hine a) 1.3 Dim~th 1-7-(5~ ~ rl)xanthine 1~ ~7~2) ~'! C\ ~ 2 A solution o~ 31 g o~ 153-dirnethyl-7-(5-hexen~rl) xanthine and 34.9 g of m-cl~loroperberlzolc acid (70%
pure) in 700 ml of clllorof:orm ~as s-tlrred a-t rOoI~
tempera-t~-re ~or lS houls. 11~e mix-~re ~/as shaken wi-th 1OSQ strength sodium d:i-t~ionite solu-tion un-til the tes-t ~ 2c~6Z9~
-- ~o -- .
with starch-iodide paper was negative, and washed with sodium bicarbonate solution and then ~Yith water to neutrality; dried and evaporated under reduced pressure.
Purification o~ -the crude product was by means of column chromato~raphy on si:lica gel (mobile phase:
methylene chloride/acetone9 ~-o:Lume ratio 7/3) and by recrystallization from petroleum ether.
Yield: 20.8 g (63.2~ of t.heory), melting point ! 59 - 60C
C13H18N403 (i~W = 278.3 Anal~sis: calculated: C 56.10S6 H 6~52% N 20.13%
found: C 55 87% H 6.51% N 19.~1 b) 1,3-~imethyl-7-(5~6-d ~ i_ I, (C~I., ) "--CH--C~I,, ~
. 3 0.24 ml o~ perchlorlc acid (70% strengtl~ as added drop~ise with s-tirring in 5 n~inutes -to a solution of 3 6 g oi 1,3-dime-thyl-7~-(5,6-epoxyhexyl)xan-th:ine in 28~ ml o~ a mixtul7e of ethylene g~ycol dime-thyl ether and water (volu~e ratio 3 : 2) at roorn ternperature~
~ter sti.r.ling at roorn -tempera~ture ~or 16 hours, ~he mixture was neu-trall~e~cl ~.rith sodiv.m bicarbona-te solu-tiOll and evaporatc-cl ~n~ler red-lced press-lre. l~e residue was purifiecl by column chrcmato~,raphy on silica gel (mobile ph~se: chl OI o~orrn~ethanol5 vo~.urne ra-t:io 8/2) ~5 a~d r~crystallizatio.rl ~roM e-thyl ~cetate.
2~i292 - Yield: 3 g (78.3~ of theory) Melting point: 9~ - 100C
13 20N404 (~W 296.3) Analy~is: calculated: C 52.6~ H 6.80% N 18.~1~
foun~: C ~2.39% H 6.72% N 18.83%
Bo-th the reaction of 1,3-dimethyl-7-(5-hex-enyl)xanthine with osmium tetrox-de in analogy to Example 2 C) and also the alkylation of 1,3-dim~thyl-xanthine with l-chloro-5,6-isopropylidenedioxyhexane ~d subsequent acid h~drolysis of the dioxolane ring accordin~ to Example 1 or 2 A) led to the same compound.
EXamPle 4 .
1,3-Dibut,v~1-7-(~?4-dih~,~droxYbu!~l)xanthine a~ -Dibutyl-7-~4-epoxy~ hine - I ` c~I2-CEt2 ~H-CH2 ~3C-~C-32)3-N ~ ~ o (CE~3-CH3 .4 g of m-chloroperbenzoic acid (70~ pure) ~ere added t~ a solution o~ 42.7 g o~ 1,3-dibu-tyl-7--(3-butenyl)~an-thine in 9~0 ml o~ cl-lloro~orm ~ritn~n 15 minutes, with s-cirrin~. A:~ter stirring at room ternpera-.
2~ ture ~or 27 hours, the rnixture was was~led w:it~ lO~bstrength sodium dit:hionit~ solll-tion, sa-turat;ed sodium bicarbonate sol~!tion and ~terj dried and t~vaporated der rcduced ~ress~lre. The resid~le ~as chroma-tograplled o~ a silica ~el column wi-'-h a mix-hlre o~` mechylene g~, - ~2 -chloride/acetone (7 : ~, v~ v) and recrystallized ~rom petroleum ether.
Yield: 19 g (42.4~o of theory) Melting point: 52 - 53C
17 26 4 3 ( 334.4~
Analysi~: c~lculated: C 61.06% H 7~84% N 16.75%
found: C 61.01% H 7.89% ~ 16~74%
b) 1,3-Dibutyl-7 ~ r~utyl ~anthille ~ ~CH2)2- CH CH2 3~ (CH2)3 ~ ~ ~ OH OH
ln 0.4 ~1 of perc}-loric ~cid ~70% streng~h) was a~de~ dropwise with stirring in 5 minutes -to a solution o~ 7 g of 1~3~dibutyl-7-(3,4~epoxybutyl)xan~thine in 300 ml of a mixture of e-thylene glycol dimethyl ether/la1er (~olume ra~tio 3 : 2) at room temperature. hfter stir-ring at room temperature for 45 hours, the mix-ture ~as neu-tralized with s~dium bioarbonate and the solu-tion was evapo~ated. '~ne residue was taken up with me-thylene chloride and purified by cGlumn chromatography on sil:ica gel with a mixture ol chloro:~orm ancle-thanol (volume ratio 8 : 2) as -the mobile phase and by recrys-talliza-tion from m~thylene chloride~petrQleu~n e~ler~
,Y ld: 4~8 g (65~ of theory) ~el t:ill~ point: 9~ - 9~C' ~iH2~3N~iO~ T ~2 ., ~i ~
~286~92 - ~3 4nalysis: calculated: C 57.94% H 8.00% N 15.90%
- found~ C 58.06% H 8.06% N 15.77~
Alternatively, this diol can be obtained by a one-step oxidation of 1,3~dibu-tyl-7-(~-butenyl)xanthine 5 with osmium tetroxide in analcgy to Example 2 C) or by alkylation of 1,3~dibutylxanthine with the l~halogeno-3,4-isopropylidenedioxybutanes kno~n from the literature (for example Tetrahedron 34 (1~378), pages 2,873 -2,878) and subsequent acid hydrolysis o~ the dioxolane ring in analog~ to ~xample 1.
Æxam?le 5 1~3-Diethyl-7-(b,7-dih~droYyhe~tyl)xanthine a) l-Bromo-6,7 e~ox~heptane Br-(CH2)~-C\--~H2 . ` O
37 3 g of 1-bromo-6-hep-tene were added dropwis~`
wi~hin 40 ~inutes, with stirrin~ and flushing wi-th nitrog~r., to 50.~ ~ of m-chlorQperbenzoic acid (~5%
pu~e) in 300 ~1 of methylene chlor:ide at room t~mperature.
A~ter standing overnight, the plecipi-tate was ~`iltered o~f with suction and -the :filtrate was washed ~ith lO~o st.rength Na2S20~ solution, wi-th saturated sodium bica.bonate solu-ion ancl ~lith wa-ter alld (a:f-ter drying) e~aporated under recluced pressure. 42.2 g of cl~de 1-bromo-6,7-e~o~yyhep-tane ~tere obtainecl.
b) l-Bromo-6,?-dihYdrox~he~-tane OH OH
~r-(CH2)5-cf~-c~
42 ~ of 1-bromo-6~7-epox~rheptane were introduced into a mixture of 400 ml of tetrah~rdrofuran and 235 ml of water, lr~hich had been adjus~ted to pH 2 with per-chloric acid, a-t room temperature. After stirring at ~oom ~er~perature for 8 hours, the mix-ture was neutral-ized, evaporated under reduced pressure and the residue was ex-tracted with methylene chloride. After removal ol -t~e solve~t, 41.~ t~ ~7-dihydro~-h~ptane were obtaine~.
c) l-~rom~-6,7-iso~ro~Yl id enedloxyheptane H3C C~3 - \C/
Br-(Cil2)5-Cll ~ C~I2 .
0.1 ml of concentrated sulfuric acid was added, ~riih s-tirrin~ under ni-trogen~ -to ~] g of 1-bro~o-6,7-di-h~rdroxyheptane and 22.2 g of 2,2-dimetho~rpropane in 100 ml o~ acetone a-t room tempera-ture. After 4 hours~
o.6 g of sodium bicarbonate was added. A:~ter ~tirring for a ~urther one houIs the solid ~as ~il-tered o.f:~, the fil-trat~ was e~raporated under reduced pr~ssure and tllc ~esi~lu~ wa.C; sllbjected to fractional vacuum di~-til:La-tion - . . .
12~6292 Yield: 38 g (77.9y of theory) Boiling point (0.4 mbar) 73 - 76C
Refractive lndex n20 = 1.4656 d) 1,3-Diethyl-7-(6.7-dihydro~yhe~tyl)xanthine R ~IH2)5~l}~ 2 ~5C2-N~ ~ ~ OH 0~l ~ I
., C2H5 13.9 g of 1~3-die+~hylxanthine, 18 g of l-bromo-- 6,7-isopropylidenedioxyheptane and 9.5 g oi` potassium carbonate in 100 ml o.~ dimethylIormamide were heated at 100C with stirring i`or 7 hours. Ai.`ter evaporation - 10 un~er reduced pressllre~ dilute sodi~tm llydroxide solu-tion was added to the residue and thi.s was extracted several times with methylene chloride. The collec-t~
methylene chloride phases ~rere washed with water~ dried and evaporated-. The residue was dis~tilled in a `oulb~
~ub~ app~.ra-tus under 0.01 mbar and at a bath tempera-ture of 100 - 115C. 17 g of _ -7-(6~Z~=so~
propylidene~iox~hep-tvl~xant~ ne were obtained, ~h:ich were'takenup in 70 3nl of sul~uric acid a-t a pH o:~ 0.5 and hea-ted ~der rei.'lux for 2 }lours. A~ter coolin~ the ~ix-t~lre was neutralized, evapo.a~ted under r'~duced pres--sure ancl the residue was recx~tallized fro~ methylene ch'loride/diethyl etht?r.
-` 12~292 ~ 36 --Yield: 13.8 g (61.1% of theory) Melting point 105C
Cl6H26N44 (~r = 3~8.4) Analysis: calculated: C 56.79~ H 7.74% N 16.56%
5fou-nd: C 56.8~% H 7.70~ N 16.67%
The l-bromo-6,7-dihydroxyheptane prepared in step b) can also be e~ployed directly ~or the alkyla-tion of the 1,3-diethylxan-thine in step d) without previous rea~.~ion with 2,2-dimethoxypropane to give the ~ioxolane deriva-tive.
Example 6 ~,7-Diethyl~1-(4,5-dihyclroxyhe~yllxanthine a) l-Chloro-4-hexene - Gl-(CX2)3-CH=~H-~H3 .
47~ g (4 moles) of thiony]. chloride were added ~rom a ~rcpping f~l-nel -to a ~olution of 330 g (3.3 moles) of 4-~exen-1-ol (Organic Syni,heses, Vnl. 55, page 62 et se~-.) in 400 ml o~ pyridine, with stirring and cooling in ice, in such a ma~ner tha-t the reaction t.empera-ture did not exceed 55C. ~ne mixtul-e was then hea~te~l a-t; 80C :~or 1 hour~ Therea:~ter 9 -the mixture was allowed to cool do~n slo-rly~ water ~a.s addecl and the mixiure was extrac-ted se~reral time3 wi-th ~i.eth~rl ether~
~ne coIr,bined ether extracks werc ex~,rac-ted by shal~ing with saturated sodiurn bicarbona-te solut.ion, washcd with wa~;e~ to ne-~tralii.y; dried over socl.ium sul~a-te and e~l~poral;cd Imder norrnal pressure. l-Chloro-4--hexei-le~
whic~l was ~?ure by gas chro;nato~ra~hy, was obtained by ~2~6292 ~ractional distillation of the residue under reduced pressure.
Yield: 196.2 g (50.1% of theory) Boiling point (140 mbar) 80G
Refractive index nDl = 1.4400 b) ~s7-Dietllyl-l- ~ c~-dihvdro~exyl)xanthine CH3-fH-fH-(C~2~3 OH OH
CH2~ 3 20.8 g (0.1 mole) of ~,7-diethylxanthine, 15.2 g (0.11 mole) of potassium carbonate and 13.0 g (0.11 mole) of 1-chloro-4-hexe~e in 600 ml o~ dimethylforma-. mide ~rere stirr~d at 110C i~or 18 hours. After cooling do~m, the mixture was filtered, the filtrate was evapor-ate~ under reduced pressure an~ the residue was taken ~p in.chlorofor~. ~.he ~nreacted 3,7-die-thylxanthine ~as removed by ex~rac-ting wi~h lN sodium hydroxide solution by shaking, the organic ph.a~e was washed to nel--trality with water, dried over sodium sulfa"e and the solven-t was distillod off in a rotaly evaporator. After dryinO the solid residue from evaporation~ 27.5 g (94.7%
o~ theory) o~ crude ~,7-diethy'-i-(4-hex_l ~ nthine were ob-tained, . ' ' .
.li,, ~
- 12~2 -3~ --. 0 C~H5 H3 C~=CH-(C~
~ .
which~after dissolving in 350 ml of chLoroform and add-ing 23.1 g (0.114 mole) of 3-chloroperbenzoic acid (85%
pure), was s-tirred under a ni+rogen atmosphere at room temperat,ure for 48 hours. ~ne mixture was then initi-ally ex-tracted by shakinG wi-th lO~o st,~ength sodium dithionite solution until the iodine-starch reaction - disappeared~ ar.d then with 10~ sirength sodium b'carbon-~t~ solution9 ~nd th~ solution .as washed wi-th ~Yater ~ntil neutra]. and free of salt, dricd and evapora~ted under reduced pressure. ~9.0 g (100% ol theory~ of crud~ ~ ~,JL~_anthine were obtained C}13-C~-\c~l-(c~2 ~15 whicll, af-ter beillg takell up i.n a solvent mlxt,ure com-posed o~ 150 ml ol te-trahydro~uran and 100 ml of wa-i;er antl adtiltion o 0.4G ~:L of perch:Loric ac:;d ('/0~ s-treng-th)~
was s-~ red at room -temperclt~ o fol~ 90 hou.rs. l~e mix t~lre ~a.~ th~n nel.ll;ral.i~.ed w.ii;h sa~urc~teti sod.iurn bicarbon~
a~ solu-tion, t.he so:l.vent wac; di.,ti~.led o~f undel~ reduced -` 12~629~
pressur~ and the residue was chromato~raphed on silica gel with chloroform as the mobile phase. This produced 26.4 g (85% of theory) of a crystalline product, which was recrystallized from ethyl acetate/petroleum ether, and wnich was almost pure by thin~layer chromatography.
Yield: 21.5 g (70% of theory) Melting point 91 - 9~C
C15H2~44 (~ = 324-4) alysis: calculated: C 55.54~ H 7.46% N 17.27%
~ound: C 55.54~6 H 7.5~j' N 16.97%
m e san~e compound ~as obtained by a one-step oxid~tion of 3,7-diethy~ exenyl)xan~thine ~ith osmiu~ te-troxide in analogy to Example 2 C).
E~a~P~ ?
3-But~ 4,5~ rox~elltyl)-7-meth~lx_n hine C~l2~ C~2)3 ~
(CH2)3~C~3 33.3 g (~.15 ~ole) ol 3-butyl-7-met.hylxcn-thine, 24.3 g (0.16 mole) of 1-b~omo-4--pentene and 22.1 g ` (0.16 molc) of po-tassium carbo~la-t~ in 500 ml of dimethyl-~ormamid~ wc~re he~~ted wi-th stirring a~t 100C for 15 hours. After cooling do~m~ the reac-tion mixture was evapoxa-ted ullder reducfd pressure, the residue was talie up in me-thy7.e~f! chlori~le~ f:i.lkered and the fil-tra-te was e~-trclci,ed ~y shaki.ng with lN sodium hydroxide so~.ut:ion~
c~6Z92 _ 40 --the organic p~lase was washed with water to neu-trali~y~
dried o~er sodium sulfate and solvent was removed in rotary evaporator. m is produced 42.2 g (97y o~ the-ory) of crude, crystalline ~butyl-7-methyl-1- ~ t-~l)xanthine .
C112-CH- (CH2) j~
~l2)3 CH3 ~Yhich w~s dissolved in 550 ml of chloroform, ~5.6 g ~0.175 mole)of 3-chloroperbenzoic acid (85~ pure) were ra~ded ~nd the mixture, after covering with an atmos-phere o~ nitrogen, was stirred at room temperature for 67 ~louls. ~x~~rac-~ioll by sh~Xing with 10,' strength sodium di-thionite solution unt~l disappearance of the iodine-s.arch reaction, ~ashing, ini-tially with 106 streng-th sodiu~ blcarbona-te solu-tio;q and then wlth ~rater9 drying over SOdiWII sullate and evaporation under reduceci pressure pro~ided 37.7 g ~r . 7% of theory) of crude ~ en~ a " ~rp~
~ fl~3 C\2r~CH-(~H2) O
2~3~C~13 ~.nich Iras subjectecl -to hydroly-ti.c Ope~ling of ~the oxirarlr-~
~ing ~r~ out interl~edi.a-te pu-:i Fication,. For -t.his purpose9 the 37.7 g of epoxide was dissolved in a mix~lre o~
200 ml of tetrahydrofuran and 1~5 ~1 of water, and 0.61 ml of perchloric acid (70% strength) was added dropwise with stirring within about 10 minutes at room temperature. After stirring at room tempera~ure for 14 hoursA the mix~ure was neutrali~ed 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 or silica gel with chloroform/meth~nol (volume ratio 10/1) as the eluting agent and subsequen~ recrys-iallization from ethyl acetate with the addition o~
petroleum ether at the boiling poir.t until cloudy.
Yield: 29.2 g (73O2~o of theory) iel~n~ point 7O - 7~C
C15H24N404 (~,~, = 324.4) Analysis: calculated: C 55.54% H 7.46% N 17.27,h - fo~nd: C 55.38S~ H 7.45,~ N 17.52 The same compound ~as obtained by direc-t dihydroxylation OI the C=C double b^nd o~ 3 butyl-7-methyl-1-(4-pentenyl)xanthine with osmium tetroxide in anals~y to Example 2 c!.
Exam~le 8 ,7-Diethyl-3-(5,5-dihydro,~x~he~vl);-an~hi e a) 1~7-Dieth~rlxar.tline 1 2~I5 12~292 18 g of ~-benzyl-1,7-diethylxanthine (mel-ti.ng point 119C? in 1,500 ml of glacial acetic acid were hydrogenated in the presence of 2.5 g of 10% palladium on active charcoal at 80C and under 3.4 bar while shaking for 47 hours. After cooling do~n, the mixtur~
was covered with an atmosphere of nitrogen ~hile the catalyst was filtered off and the filtrate ~as evapor-- ated under reduced pressure. The residue was dissolved in a mixture of 250 ml of methylene chloride and 100 ml 1~ of lN sodium hydroxide solution. After washing the methylene chloride phase again with lN sodium hydro~ide - solution, the combined a~ueous phases were adjusted to pH 6 by add ng 335S s-trength sulfuric aci.d dropwise with siirrin~. After washing to neut.rali-ty and drying the preoipital~ produc~d~ ~.l.g (~4.5~0 of theory) of lr7~di--e-thylxanthi;1e~ of melting point 204 - 205C 3 WQre o~tailled ~
~ ne inven-tion relates to new medicaments which are sui~able, in particular, ~or -the treatment o~
obstructive diseases of the respiratory tract, the pharmacologically active vicinal dihydroxyalkylxanth-ines contained in -them, processes for the preparation of these xanthine derivatives and intermediate products ~or this purpose.
The xanthine compounds, which act as phospho-dies~terase inhibitors, have a pre-eminent position among 10 the bronchospasmolytic agents hither-to known (cf. B.
He~ ri~; Mode~e A-7neimittel (Modern "rugs~S~utt5art 1980, page 1,27~), since they have no ~2~sympathomimetic activity and are thus particularly suitable for the long-term therapy ~rhich is always necessary for chronic 15 obstructive disorders of the respiratory -tract. Of this group o~ substances, the naturally occurring xan-thine deriva~ivetheophylline (1,3-dimethylxanthine), has been the undisputed agent o~ choice in asthna ther-apy for several decades now. Its activity, ~Yhich is 20 clinically well es~tablished, is, however, con,;rasted by -the disadvantages o:~ its very narro~Y therapeutic range, its serious gastrointes-tinal, cardiovascular and renal side-effects, as well as those in the central nervous sys~eril, al~d tile fac-t that i-t can only be used en-terally 25 due -to its lac~ of water solubility, and these . - 3 -disadvantages are the basis for the desire of clinicians for, and the pharmaceutical research directed at find-ing, products having a greater therapeutic safety.
I~ has in fact been poss~ble~ by the prepara-tion of water-soluble salts or addition compounds, such as, for example, theophylline-ethylenediamine (amino-ph~lline), to obtain formulations of theophylline which ca~ also be administered parenterally, but these are no~ associated with a significant increase in the thera-10 peutic range or a decrease in t~e abovementioned undesired side-effects; especially since the ethylene-diamine iteelf, which f~nctions as a solubilizer in ~m~nophylline, exerts a deleterious e~fect on the cardio-vascular syste~. . ' ~hus, there have been many at~empts to obtair, by variations in the structure of the theophylline mole-cule, better tolerated compounds having, if possible, a greater bronchospasmolytic activity.
The only synthetic'theophylline derivative which 20 has ~ound a certain 'therapeutic use is diphylline [ 7-(2~3-dihydroxypropyl)-1,3-dime~hylxa.nthine]. m e 2~3-dihydroxypropyl group in.the 7-position does confer a good water solubility on this product, so that the undesired use of solubilizers ~or parenteral admLnistra-25 ti~n is no longer necessary and ~he interferingt~eophylline-like side-~ffects are much less pronounced, but these advantages are, at the same time, paid ~or by '.
a drastic decrease in the bronchospasmolytic activity compared to that of theophylline.
. .. .
128~29~, I~ systematic continuation of these investiga-tions, the two methyl groups in the l- and 3-positions have been exchanged for longer alkyl groups, Yhile re~aining the 2,3-dihydroxypropyl radical in the 5 7-position of the xanthine skeleton. This led to 7-(2,3-dihydrox~ropyl)-l,3-dipropylxanthine, which is described in Canadian Patent 1~82~184 and wnich ~s a comnound readily soluble in watèr, which is said almost to reach the bro~chospasmolytic activity of lO ~heophylline and, at ~he same time, to have a lower acute toxici-ty and fewer disadvantageous side-ef~ects~
Neverl~heless, this product ~as no~ hither-to found acceptance in asthma therapy. Further~ore, according to ~1~ abovementicned Offenle~ur.gsschrift, it induces 15 s~imulation of the central nervous sys-tem, althoug11 this is mar~edly wea~er than that o~ theophylline, which can lead to restlessness and sleep disturbances.
Accord~ngly, water-soluble xanthine compounds, which are superior to theophylline in respect o~ s-trength of 2~ action and therapeutic range and which induce no sig-nificant side-effects5 in par-ticular no stimulation of ~e central nervous system, ~ould still represent a genuine enric~ment ol the therap~r of obstructive dis-orders of the respiratory tract.
It has now been found, surprisingly, that increasing the length of the dihydroxypropyl radical, which has not hitherto been investigate~15 irrespective o~ its position on the xanthine skeleton, leads ~o com~
pounds which fulf`il these stri.t therapeutic demands.
62~2 _ 5 ~
It is true -that two xanthine derivatives o~ this type, namely 1-(5,6-dihydroxyhe~Jl)-~,7-dimethylxan-thine and 1-(4,5-dihydrox~rhexyl)-3,7-dimethylxanthine in the threo and e~ytkro fo~ns, have already been described in -the literature ~Arzneimittelforschung ~Drug Res.) 22, 1,144 - 1,151 (1972)), but these com~ounds were merely isolated and identified as metabolites of the vasothera-peutic agent pentoxifyll;ne. Accordingly, there are no data on their pharmacological properties in this publication.
Thus~ the present invention relates to medica~
ments which contain vicinal dihydroxyalkylxanthines of ~he general fo~nula I
O R-R~
7/> (I) x2 1~ wherein one of th~ radicals Rl, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and ~Yo vicinal hydroxyl groups in the ~ 1 or ~ -2 positions and the two other radicals represent s-traight-c~ain or branched alkyl grGups having up to 12 C a-toms 2~ in the posi-tion o~ Rl and R3 and up to ~ C ato~s in the posi-tion of R2, the to-tal of C atoms in these t~o alkyl s~lbs-tituents being a maximum of 14.
In -tllis conte~:t, those medicclmen-ts are pre-ferred which contain compounds o~ the :Eormula X in ~hich - ~2~i29X
, or R~ represents an (~,w~ dihydrox~all~l radicalha~ing 5 or 6 C atoms and the two alkyl substituents R2 and R3 or d R3 together comprise 3 to 6 C atoms.
R fur~her preferred embodiment of the invention rela~es to medicaments which contain those compounds of ~e formula I in which R3 denotesan (~ dihydroxy all~yl group having 4 to ~ C atoms or a 4,5-dihydro~y~ -hexyl groupS and the total o~ ~ atoms in the t~o alkyl radicals Rl and R2 is 3 to 7. Among these med~camentss those in turn are particularly preferred which contain those compounds o~ the formula I in which R~ represents a 5,6-dikydroxyhexyl radical, such as, for example, in ~-eihyl-7-(5,6-dihydroxyhexyl)-l-propyl-xa~thine.
A fur~her particular embodiment of the invention comprises the compounds o~ the formula I not being adm~nistered per se, but in the form of a prodrug, from which the dihydroxyalkylxanthines, having bronchospasmo-ly-tic activity, with their substituents Rl, R2 and R3 defined in the fore~oing, can only be liberated by bio-traA~sformation in the organism. For this pu~pose, for e~ample, the epoxides having the structural element of the for~ula IV and, in particular, the acetals ` havin~
2~ the structural element of the formula IX, when these are completely alkylated, which are dealt with below as inter~ediate products in the preparation process, are suitable.
The invention also relates to new vicinal , ~ ........... . ........ .. ..
, . ~. .
~2~3~29 dihydrox~al~ylxanthines of the formula I, in which one of the r~dicals Rl, R2 or R3 deno-tes a straigh-t-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in ~,w-l or~-l,w-2 positio~s and 5 the two oth~r radicals represent straigh-t-chain or branched alkyl groups having up to 12 G atoms in the position of Rl and R3 and up to 4 C atoms in the posi-tion o~ R2, the total of C atoms in these t~Yo alkyl substituents being, however, a maximum of 14 and R2 and 10 R3 not both being methyl, when Rl represents a 4,5- or dihydrox~-hexyl radical.
In ~his context, particul~rly suitable compounds are those in which Rl or R2 represents an (~ di-hydroxyalkyl radical having 5 or 6 C atoms and the two aI~yl substi~uen~s R' and R3 or Rl and R3 together con-tain 3 to 6 C atoms~ and also those wherein. R3 deno~es an(~ dihydroxyalkyl group having 4 to 7 C atoms or a 4,5-dihydroxyhex~rl group, and the two alkyl radicals Rl and R2 together contain 3 to 7 C atoms. Amongst the 20 compounds mentioned latterly, the 7-(5,6-dihydroxyhex~
1,3-dialkylxanthines having a total of 3 to 7 C a-toms in the two alkyl radicals Rl and R29 such as, for example, 3-e-thyl-7-(5,6-dihydrox~rhexyl)-1-propylxan-thille, in turn represent par-ticulclrly pre~erred compo~ds accord-25 i~g to ~ormula I. -, m e i.nvention ~ur-th~r rela-tes -to processes fo1 th~ preparation o.~ the ~ic.i~al dihydroxyalkylx~nthines accordin~ to fornu~a I.
An e};amp:le o~ a ~xocess comprises starting .ril;h 12~6Z9 " . -- 8 ---- xan~hines of the formula II
. ~ ~3' Rl 12~ .
in ~hich one o~ theradicals Rl, R2 or R3 is an (~-1)- or (~-2)-alkenyl group of the formula III
-(CH~)r-C~=CH-R4 (III), .
- having 4 to 8 C atoms, R4 denoting hycLrogen or methyl, and the other ~o substi~uents represent hydrogen or alkyl as de~ined in formula I~ and a) reacting them o~ t~e ol~finic double bond wi~h suit~
10 able oxid~zing agents to give new epoxyalkylxanihines ha~ing the st~uctural element of the formula IV
' -(CH2)n-CH~H-R4 tIV) s a.-d hydrolytically opening their oxir~.ne ring with forma-tion o~ dihydro,xyalkylxanthines having the structural 15 unit of the formula V
- ( CH2 )1l-CH-CH-R4 (V ) OH OH
or b) dihydrox-rlating on the olefinic double bond with customary oxicLizing agents to give direc-tly the dihyd-20 roxyalkylxanthines having the structural element characterized b~r ~ormula V, `~
.
: . :
~2~6292 _ g -~ and then alk~latin~r those diols obtained according to a) or b), which still car~y hyd~ogen in the positions o~ Rl, R2 and/or R3, optionally in the presence of basic age~nts or in the form of their salts,with alkylating 5 a~nts of ~he formula VI
R5-X (YI3, in which X denotes halogenJ preferably chlorine or bro-~ine, or a sulfonaie or phosphate grouping and R5 der.otes Mle a~kyl radicals defined.for formula I to ~0 give the compounds of the formula I.
~ h~ alkenyl-, monoaI~yl- and dialkyl-alkenyl-xanthines of ,~he lormula II used as starting ma+erials in this process are known, in,~er alia, from Canadian ~ Patents 1,123,435 and 1,12~,083.
Examples of suitable oxidizinOc agents for the epoxidation of t~e olefinic side-chain according to ~ormula III are chromium(VI) oxides preferably in acetic ~nhydride and carbon disulfide or carbon tetrachloride;
or compounds containing pero~ide g~oups, such as potas-20 sium peroxomonosulfate in the presence of ke'ones, preferably acetone, in a homogeneous phase or in a two-~hase system with phase-transfer catalysis; perox~7-boranes, which are advantageously produced in situ from boric acid or its derivatives and hydroperoxides; -tri-25 phenylsilyl hydroperoxi~e; hydrogen peroxide in thepresence of coreact.~nts, such as, for example, aliphatic or aromatic carbonitriles (for example acetonitrile or benzonitrile), optionally substi.tuted cyanamide or .
- - lZ~6`~9~ .
- isoc~-anates (for eY~mple phenyl isocyanate); ~ydrogen peroxide or alXyl or ara~yl hydroperoxides, such as, for example, tert.-butyl hydroperoxide, l-phenylethyl hydroperoxide and cumene hydroperoxide, in the presence 5 o~ either basic agents or, preferably, particular cata-lysts, such as, ~or e.ample, t.~gstic acid, vanadium(V) oxide, molybdenum hexacarbonyl and vanadium or molyb-den~m acetylaceionates; and, in particular, percarboxylic acids, such as, ~or example, perfo~mic, peracetic, tri 10 fluoroperacetic~ monopermaleic, monopersuccinic9 per-benzoic~ 4-nitroperben~oic ard, preferably, 3-chioro-perber.zoic a~d monoperphthalic acid.
` E~oxidation with the aid of ~ercarboxylic acids (Prileschajew reaction) is advantageously carried out in 1~ a sol~reri o~ disiributing agren~ which is inert towards the reactants and which has been found to exert a con-siderable effe^t on the rate of reaction. Since solvents which can form hydrogen bonds with the per-carboxylic acids generally decrease the rate of reac-tion, aromatic hydrocarbons, such as benzene or toluene~ -æna halogen~ked hydroca~bons, such as dich]oromethane, chloroform or carbon tetracl~loride, are fr~equently pre-~erred to ethers, such as diethyl ether, dioxæne~
tetrahydro~uran or ethylene glycol dimethyl ether, alco-25 -h~ls, esters and carbo~lic acids. ~he reaction is customarily carried out at temperatures between -10 and ~40C, preferabl~r at room temperature, the reaction time varying :from a ~ew minutes up to several hours.
The percarboxylic acids are usually employed for .
~2~6~92 the reaction ill an isolated ~orm, but they can also be produced in situ in the reaction mixtu~e from, for example, the corresponding carboxylic acid and hydrogen peroxide.
On using peracids of strong carbox~lic acids, suc~ as, ~or example, trifluoroperacetic acidS it is advisable to decrease the acid concentration by working in a heterogeneous system or bythe addition ofbu~fer sub-~tances~ such as sodium carbonate, sod.ium bicarbonate or disod.ium hydrogen phosphate, in order to suppress undes-ired secondary reactions of ~he carboxylic acid, which is produced.in the reaction, with the initiall~r formed epoxide.
The epoxyalkylxanthines according to formula II
vi rl~ tho S+l uc t~ral -~nit ol the ~o~mula T~ ca~, how-ever, also be ohtained by base-catalyzed dehydrohalo-- . gena-tion of corresponding ~alogenohydrins, ~ ich in ~ n can be obtained, for example, by adding hy~ohalous aci~s, such as, for examp'.e, hypochlorous acids7 to the ole~inic double bond of the al~enylxanth.ines accord-illg-to ~ormulae II and III. The reaction:of these olefins ~rith N-halogenosuccininides, such as N-bromo-succinimide, or cllloramine T in water or mix-tures of solvents conk~ining water also leads -to -the halogeno-hydrins. m e basic dehydrohalogenating agents usuallyused are al~ali ~.etal or alkaline ear-th me-tal hydrox-ides or carbona+ves, pre~-erably sodium, potassium or calcium hy~3ro~.ide or sodium or potassium carbonate, bu-t organic bases or o-ther oxiranes, such .tS eth~rlene oxide ~2~629~
-- or 1,2-epox~propane? can also be employed successfully.
m e epoxyalkylx~thines can either be isolated in t~.e pure ~orm or f~rther processed as crude products.
The hydrolytic cleavage of the epoxyalkylxan-. _ . . . ~ . . .
thines to give the ~icinal diols having the s~ructural element of the formula ~T iS carried out in an aqueo~ls medium, ~o which, if necessary to increase ~he solu-- bility, an organic solvent whiGh is miscible with water is added, for example tetrahydrofuran7 dioxan~ or ethyl-e~e glycol dime~kyl ether, cdvanta~eously in the - pr~sence of acid caia ys~s~ pre~e~ably weakly nucleo philic acids, such as sulfuric, perchloric or p-toluene-sul~onic acid, or strQngly acid cation exchanger resins (~or exa~ple Nalion-H)y at tempe~atur~s bet~een 20 and l~ 100C? bui preferGbly at room +e~perature? by stirring for several hours. Ho~ever, in principleJ the oxiralle ring opening is also possihle under neutral or alkaline co~ditions.
Customary oxidi ing agents for the direct vici- -20 nal dihydrox~ation of the ali~enylxanthines according ~o formulae II and ITI to give the dihyd~ox~alkylxan-thines char~c-ter7zed by the struciural unit of formula ~Tg are represented bys for example, hydrogen peroxide in the presence of formic acid or glacial acetic acidJ
chromyl chloride, potas~ium perma~ganate~ triphenyl~
metlvlphosphoniu~ permanganate, iodine in the presence of sllver carboxylates or thalliu~(I) carboxylates, such as, ~or ~:~ample, thallium(I) acetate, seleniùm dioxide, molybderum(VI) oxide and, in particular~ osmiwm * denotes trade mark.
- 13 - i - tetroxide ` ~
When using osrr.ium tetro~ide as the oxidizing agent,.the reagent can ei~er be employed in the stoi-- ¦
chiometric amount or in catalytic amounts with the addition of a secondary oxidizi.ng agent, which regener-ates the osmium te-troxide ~rom the inltially produced cyclic esters, with oxidative hydrolysis to give the diols.
In the non-catalytic dihydroxylation of the ole-~0 ~inic double bond with stoichiome-tric amo~mts of osmium tetroxide, the process is advantageously cal~ried out in solvents not having a reducin~ action, preferably ethers, such as die-thyl ether, tetrahydro~u~an and dioxane, or hydrocar~ons$ such as benzene, cyclopen-tane or cyclo-15 hexane, optionally ~rith the addition of a tertiaryamineS such as, in particular, pyridine or auinoline, - isoquinoline, ~- or 4-picoline, at temperatures be~een 0C and t~e bolling point of the particula~ solvent, - prelerably at roor~ lemperclture7 i-t being possible for the reaction times to be from a ~ew minutes to several hours. Then the osrnium(VI) ester complexes, which are produced as intermediates in this process~ are advan-tageously reductively hydrolyzed~ -the use of sodiurn or potassium sulfi-te or b:isulfite, hydrogen sulfide, llth-~5 iu~ aluminurn hydride or catechol or all~aline~ malmi-tol solu~ion .in aqueous or aqueous-alcoholic mediu~ havin~
heen found par-t.icula.ly useful . Ho~Yever, oxi.dative hydrolysis ol the~ cornple~es is ~lso possibl~; but i-t is ~dvis~l~le, in thi.s case~ to car~y O~IC the ~286~:9 _ 14 --- ~ihydroYylation at the outset with catalytic amounts of osm~um tetroxide in the presence of secondary oxidiz-in~ agents, such as, ~or example, hydrogen peroxide, metal chlorates (for example sodium or potassium and, in particular, silver or barium chlorate)~ sodium per- -chlorate, o.Y~rgeIl, sodium perio~ate or hypochlorite and, in particular, tert.-butyl hydroperoxide or trialkyl-amine N-oxides (for example N-methylmorpholine ~-oxide, trimethylamine N-oxide or triethylamine N-oxide).
m e alkylation of the ~ihydroxyalkylxanthines wi~h the compounds of the for~ula VI is usually carried ouc in a distributing agent or solvent ~ihich is inert towards the reactants. Dipolar aprotic solvents, for e~:ample formamide, dimethyl~ormamideS dime-thylacetamide, i~ ~-methylpyrrolidone, tetramethylurea, hexamethylphosphoric triamide, dimethyl sulfoxide, acetone or butanone are par-ticularly suitabl~; however, alcohols, such as metha--nol, ethylen~ col and iis ethers, ethanol, propanol~
isopropanol and the various bu-tanols; hydrocarborlsg su~ll as benzene, toluene or xylenes; halogenatecl hydro- -:
carbons,such as dichlorome-thane or chloroform; pyricline and mix-tures o~ the .solvents mentioned or ~heir mix-~ur~s with ~;ter can also find use.
me reaC-tJ ons are aclvan-tageollsly carrièd out in ~ presei-lce of a bas:ic conclensing agen-t. Examples o~
~uitable a~en-ts for t;his purpos~ are alkali mecal or alkaline ear-th me-tal hydro~ides, carbona-tes, hydricles 9 al~nholates or organic base.s, su^h as tria].kylarnines t~or e~am~le ~rie-thylam.ine or -tributylam:ine), ~ua-ternary ~L2~
ammonium or phosphonium hydroxicles and crosslini~ed resins having fi~ed am~!onium o~; phosphonium groups, ~hich are optionally substituted.
However, ~he ~a.nthine deri~atives c.an also be employed directly in the alkylat.ion reacti.on in the form of their salts prepared separately, such as ~the alkali metal, alkaline earth me~tal or optionally sub-stituted ammoni~m or phosphonium saltsr Further~ore, the dihydro~yalkylxanthines and their monoalkylated 10 derivatives can be readily a Xylated both in the pre-sence of the abovementioned inorganic condensing age.n-ts ar.d also in the form of ~heir alkali metal or alkaline earth me-tal salts, with -the assistance of so-called phase-transler catalysts~ for example tertiary am~nes, ~ua-~ a"~uniu~ u~ u}~ p}~ iU~ leI'~ ?
prèferably in a -~o-p}iase system under the conditions of phase-transfer catalysis.
In the in-troduction of -the allcyl radicals by the procedures described in the foregoing, -the reaction 20 is generally carried out a-t a temperature between 0C and the boiling poin-t of the react.ion medil~ used in each ~ase, preferably bet~/een 20 and. 13~C, if appropria-te under elevated or reduced pressure, but usually under atmospheric pressure, i-t being poss.i.bl~ for -the reac-tion time -to ~e ~rom less -than one hour to several hours In -this process ~or -those clihydro~alkylxan-thines~
in-to ~Yhich two all~yl radicals are slill -to be introduced:
~ither identi.cal or di.f~eren-t substi-tuents can be attached consecu-tively or t~o similar all~yl groups can 1 2 ~ ~2 92 be atcached with the xanthine skeleton without isola-tion of in~ermediate products in a one-pot reaction.
A ~urther process for the preparation of com-pounds of the formula I, which is likewise pre~erred, co~prises reacting xanthines of the formula VII
- R1 ~ ~3"
O ~ (YII), l2~-in w~ich a maximum oftwo of ~he s-ubstituents Rl to R3 rep-rese~t the alkyl defin~d for formula I and a formula of ~lO of these radicals denote hydrogen, optionally in ~h~ presence o~ basic agents or in tne form o~ ~heir sa~ts ~) with 21 kylating agents.of the formula VIII
X - (CH2)n - CH - CN - R
\ (VIII), C~
in which the alkyl chain has a total of 4 to 8 C atoms and R4 denotes hydrogen or methyl, R6 and R7, independ--ently of one another, denote hydrogen, lower alkyl preferably h~v.ing up to 4 C atoms, phenylalkyl having up to 2 C atoms in the alkyl moiety or optionally sub~
sti~ute~ phenyl and X denotes halo~en, pre~erably G
;292 c~lorine or bromine, or a sulfonate or phosphate group~
ing~to give new dialkylated or triaL~-lated xanthines having the ~tructural element of the forml~la IX
-tC~;2)n - IH ~ R
,f~ X) . ~6/ ~7 .
5 and ope~ing theil 1,3-dioxolane ring hydrolytically, spli~ing off R6-Co-R7 and forming dihydroxyalkyl-xanthines having the struc~ural uni~ of the fo~mula V
~ 2)n ~ - R~
0~ o~ ~
or lQ b) with alkyla-ting agents of the formula X
X - (C~ cH - CH - R4 OH OH
in which the alkyl chain has a total of 4 -to 8 C a-t~ms and ~4 and X have the meanings indicated for ~or~ula VIII, directly to gi~e the di7nydroxyall,~ylxant~lines, having the st~uctural element charact~ri~ed by fo~mula V, al`ld then reacting the monoal~;yldihydroxyalkylxar.thines obtained acco:rding to a) or b), ~hich still carry a hydr~gen atom in the position of Rl, ~2 or R3, option-all~ in the p:resence of basic agents or in the ~orm of .
B~iZ9 -- 18 --their salts with alkylating agents of the formula VI
. R5-X ~VI) Ln ~hich X and R5 have -the meanings defin~d for for~ula VI in claim 12, ~o give the compounds of the formula or initially alkylating the dialkylated xanthines pre-pareci ac ording to a), having t,h~ s-tructural element o~ the ~or~ula IX; with the compo~tlas of the formula R5-X (VI) and then ~lydrolyiically cleaving -the di-~
oxolane rin~ with formati.on ofthe dihydrox~alk~rlxanth-i~es according to formula I.
r~he monoalkylxanthines or dial~ylxanthines of the ~ormula VII and the al~ylating agents OI' the for-~ulae VIII and X used as startin~ materials in -this ~rocess are Largely ~no~.~ or can`easily be prepared by methocls kno.rn fro~ the li..erature.
l'hus~ the com~ounds of -the formula VI~I, for e~ample~ can be obt.ained from the -triols of -the formula XI
~!0 - ~CH.) - Cl~ - CH - R
~ n l l (~I) 013 0~1 by react.ion o:E the -~ro vicinal hydro~yl groups ~Yi-th alde-hydes or k~tones or ~rith -their acet~-lls, ~ith proton catalysis, ancl subs~quent replacemento~-the isolated terminaJ. hydroxyl :~unction wi.th halogen Usillg inorganic acid ha:lr,.cles, or .i-ts esteri~ica-tion wi-th sul.fonyl or p~osijhon~ ha:Licles or ar~ycirides~ advanta~eou;-,ly in -the ~X~3~29~
presence of basic agentsS from which in turn the com-po~ds o~ the formula X can be prepared by acid hydroly~
sis of the 1,3-dioxol~ne ring. m e 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 o.~ the formulae VIII and X~ either by subjecting them, a~ described for the alkenylxanthi.nes, to epoxidation on the ole~inic double bond and then 10 hydrolyzing the oxirane ring with acid or by oxidizing in a one-step reaction direc-tly to the dihydlox~alkyl halides of the formula X and converting -these~ if a~pro-priate, with aldehydes or ketones.or their acetals into 1,3-dioxolai~es of the formula VIII. .
~ne reactions of the xanthine derivatlves ~Yith the alkylating agents o~ the formulae VI, VIII and X
are advantag~eously carried out under the reaction con-di-tions already described in detail for the alkylation of the dihydro -yalk~lxanthines and monoalkyldiny-droxy--20 alkylxanthines ~Yith the compo~ds of the formula VI.
HoweverJ il the compounds of -the formula X are ~sed to introduce -the clihydroxyalkyl radical, those havino a -total of either 6 to ~ C atoms, when R~ has -the meaning of hydro~en, or 7 or 8 C atoms, ~Yhen R4 denotes a 25 methyl ~roup, in the alkyl chain are preferred, since the diols of -the ~ormula X having shorter chains have a p?~rt.icular -tendency -to .~orm te-tra.hydrof~lran dcrivatives under tho alha'.ine condi-tions o.~ the alkylation reac-tion, which can lead to a noticeahle reduction i.n -the 1~629 yields of desired alkylation product.' The hydroly~ic cleavage of the l,~-dioxolane ring in the xanthi.nes of the formula Y~I having the structural element of the formula IX to give the dihyd-5 roxyalk~lxanthines characterized by the structural unit.
of the formula V is normally carried out in an aqueous medium, optionally with the addition of a solubilizer~
such as tetrah~drofuran$ dioxane or ethylene glycol dimethyl ether, advantageously in t.he presence of acids, 10 for example ~ormic, oxalic, tartaric~ citric~ sulfuric, perchloric, phosphoric or p-toluenesulfonic acid, or an `
acid ion exchanger (for example Nafion-H)~ at tempera-tures be~/een 20C and the boiling point of the reaction mixture, pre~erably 50~ and 100C~ it being possible 1, ~vr ~hc reac~ioii ~i~e tû '~e fro~ several minuies to 2 ~ew hours. Moist silica gels having a water conten-t up to 10~, is also a reagent which can be used for the deace~talization, the reaction ~referably belng carried out in optionally halogenat~d hydrocarbonss sush as 20 benzeneS toluene, dichloromethane or chloroform, at room t.cmperature.
A further methG~ for prepari.ng the xan-~hines of the ~ormula ~rII ~ith the structural element of thé T`or-mula IX containing the ~io~olane ring comprises adding 25 carbonyl co~pounds o~ the formula R -Co-R7 onto the oxirane ring o~ the epox~ralkyl~anthi.n.es according t;o ~ormula II, having t.he structural unit of the ~or-~ula I~i. Thi~; reaction is advantageously carried ou-t .i.n ~he ~resence o.~ clC.i~ catalysts, prelerabl~ L~w:is acicls~
~ 2 9 - such as boron trifluoride, 2inc(II) chloride)tin(lV) chloride or copper(II) sulfate, at temperatures bet~een 0 and 60C. However, quaternary ammonium salts, for example tetraetnylammonium halides, are also able to catalyze the addition reaction to give the cyclic acetals.
~ le vicinal dihydroxya~;yl;anthines of the ~or-mula I have either one or two asymmetric C atoms, depending on the position of the two hydroxyl groups in 10 the side chain according to formula V, and can thus be present in stereoisomeric forms. ~he invention thus relates both t~ the pure stereoisomeric compounds and also to thei~ mixtures. : -m e medicaments according to the invention canbc a~ is'e~ed o-al y, rGc'ally, parGnte ally or as an aerosol.
Examples of suitable solid or ll~uld galenic for~ulations are gra~ules, po~ders, table-ts, coa~ed tab-lets, (micro)ca~sules, suppositories, Syl~lps~ emulsions~
suspensions, aerosols, drops or injectable solutions as well as fo-rmulations wi-th protrac~ed release of the act-ive compound, in the prepara-tion of ~hich, auxiliaries, such as vehicles, disi~ltegran-ts,`binders, coating agents~ swelliIlg agen~ts, lubricants or emollien-ts, flavQrinO materialss s~leetening agents or solubilizers are used. Examples of frequen-tly used au~iliariev ~hich n~ay be ~entioned are ~actose, manni-tol and o-tller sugars, talc~ laclalbumin, gelatin, starch, cel]ulose and its ~eriv~tives, animal and vegetab~e oils, polyethylene `- ~Z~6Z92 -- 22 -- ;
glycols and solventsS such as, ~or example9 sterile ~ater.
Thc? fG~mulations a~e preferably produced and adminis-tered as dosage units, each ~it containing a specified dose of active substance according to formula I. This dose can be up to 1,000 mg,.but pre~erably 50 to 300 mg, for fixed dosage units, such as tablets, cap-sules and suppositories, an~ can be up to 200 mg, but preferably 20 to 100 mg, for injection solutions in lC) YialsO
For the treatment of an adult patient suffering ` from bronchial obstruction~ daily doses o~ 100 -to 500 mg - o, active compound~ pre~erably 200 to 300 mg, on oral administration a~d o~ 20 to 150 mg, preferably 40 to 80 mO; on in-tra~.~er~o-ls a~ministra-tiol~ arc nd.icatcd, depe.ld--ing on the ef~ective~ess of the compounds acccrding to formula I .in hu~ans. In certain circurnstances, however, h~gher cr lo~er daily doses can also be appropriate~
m e administration of the daily dose can be carried out ~0 either by a single administra-tion in the form of a sin~- e dosage unit or of several smaller dosage units, or b~r several adminis-trations o~ sub--div~ded doses at sp~cified i~tervals.
Finally, in -the prepa:ration o.~ the abovemen-tionecl 25 ~alenic ~ormulations, the xanthine derivat.ives of -the formula ~ can also be ~ormulatedtoge-ther wi-th o-ther suit-able active compoullds, for example antiallergic and an-l:it~l3si~e ag entsS e~pectorants 9 sedatives, peliphc-r~l va~otherapeut:ic agentsJ antihistamines and also other Z9~ , brollchosp2smolyticaOents,su^h as ~2-sympa~homime~ic agents or parasympatholytics.
Exam~les ~he struc~lre o~ all tne compounds described in 5 ~le following text was confirmed by elementary analy-sis and IR and lH I~ spectra.
Exam~~e 1 3-Ethyl--7-(5~6-dih~droxvhexvl~ ro~vlxanthin~
a) ~ o~ro~vliden&d~o~yhexane Ho-(c~2)4-~H ~2 O\ O
3 ml o~ 98~', strength sulfuric acid ~ere added drop;rise in the course of 5 minutes to a ~ixture of 830 g o~ 1,2,6-hexanetriol (97~ p-lre) and 828 ml of 2,2-dimethoxypropane (98~ pure) at room temperature.
A~ter stirring for a ~ur'her hour at 25C, 30 g of potassium carbonate ~ere added, the ~ixture was stirred anotber hour and then vacuum-distilled over a 10 cm packed column.
Yield: 897 g (8~5~ of theory) BoilinO~ ~oin~ (0.5 mbar) 83 - 87C
Re~ractive ir.dex nD =1.4452 .~ .,; .
2~6292 - b) l-Chloro-5~6-isopropylidenedio~yhexane Cl - tCH2)4 IH 1~2 O\ ,~
77 nl ofthionyl chlorlde were added drop~Jise wi~h stirringr in the course o~ 3 hours to a solution of 5 176.4 g of 1-hydroxy-5,6-isopropylidenedioxyhexane and 155 ml o~ triethylamine in 1,300 ml of toluene at 5 - 7C internal tempe.ature. After stirring at 20 - 25C ~or a further hal~ an hour, the mixture was heated at 70~ until evolu1ion o~ S02 was complete (about 4 hours). rne mixture w-as then coo]ed do~.rn and ~LL.hr pl'eCipi~.dt,e -~Y-i-li.C.il ~;epa~ e;i Uuc ~YaS îiltered OI~
wit-h suc~ion. After t~raxhing with 100 ml of ~oluene, the toluene phases were combined5 washed to neutrali-ty, dried and evapora-ted under reduced pressure. 15 g o~
p~tassium carbona~e-~ere added ~o the residue and this was distilled in vacuo over a packed column.
Yield: 149.6 ~ (77.693 of theory) Boiling point (0.15 mbar) ~ - 50C
Refractive index nl8 = 1.4482 c) 3-~thyl-'7- ~ 6-isop~ y~denediox~hex~rl~xant;hine ( (`'H 2 ) ~ f EI 2 ~*,X ~ ~ C/ CE~3 C~2 il3 A mixture of 360.4 g of 3-ethylxanthinej 409.2 g of l-chloro-5,6-isopropylid~nedioxyhexane ~nd 284.7 g of potassium carbonate in 3 1 of dimethylformamide was heated at 100C with stirring for 2 hours. After evaporation of the suspension under reduced pressure, ~he residue was taken up with 1.1 1 of 2N sodium hyd-- roxide solution an~ thoroughly extracted with methylene chloride. m e collected meihylene chloride phases were washed again with 2N sodium hydroxide solution, then washed with water to neutrality, dried and evapor-ated under reduced pressure. 94.5 g of crude 3-ethyl-1,7-bis(5,6-isopropylidenedioxyhexyl)xanthine were obtained as a by-product. The combined aqueous phases, which were alkaline with sodium hydroxide, were treated ~5 ~r!)pT,'~SC' ~ h 33b c~rQn~oth s~ ric ~d ~t ro~
temperature, with stirring, until pH 10 was reached.
The precipitate was filtered off with suction, washed to neutrality and dried at 100C in vacuo.
Yield: 508 g (75.5% of theory);
Melting point: 123 - 124C
C16H24N404 (~ = 336.4) Anal~sis: calculated: C 57.13% H 7.19% N 16.66%
~ound: C 56.92% H 7.21% N 16.68%
;~ d) 3-~thyl-7-(5,6-dJhydrox~he ~ lxanthine O
25 ~l3F'-C~2-C~ 0~1 0~1 G
~2~29?.
3~5.4 g of 3-ethyl-7-(5,6-isopropylidenedioxy-he~l)xanthin~, 151 g of l-bromopropane and 138 g of potassiu~ carbonate in 1.5 1 o* dimethylformamide were stirred for 48 hours at an internal temperature of 70C.
5 A~ter remo~ral of the solvent under reduced pressure, the residue was -t~en up with mel~hylene chloride, washed with dilute sodium hydro~ide solut~on and the neutral-ized and dried methylene chloride phase was evaporated.
~he residue was heated in 1 1 of sulfuric acid, at a pH
of 0.5, for 2 hours at 100C. After cooling do~l, the ~ixture was r.eu-tralized~ evaporated under reduced pres-sure and the residue ~ras taken up wi-th methylene chloride. m e methylene chloride phase was washed with ~ilute sodilum hydro~ide solution and with wa-ter~ dried .L5 and e~aporated ~nder reduc~d pressure.
m e crude ploduct ~las recrystallized from methy-lene chloride/diethyl ether.
Y~eld: 259 g (75.5% of theory) Mel-ting point: 95 - 98C
C16H26~404 (~ = 33~ 4) hnalysi.s: calculated: C 56.79% H 7.74% N 16.56~o founrl: C 56.85% H 7.56S~ N 16.60~b Example 2:
____ ~ Diet.h~l 7-55,6-dihydro_y~ h: e ~ (Cl~-l2)~ - f~ 2 Tl3C~ . 0}l E~
C~2 ~l3 h) A mixi~e of 62.5 g Q~ 1,3-diethylxanthille, 62~7 g of 1-chloro-5,6-isopropylidenedioxyhexane, 42.7 g of potassium carbonate and 450 ml of dimethylformamide was stirr~d at 120G for 10 hours. After evaporation under reduced pressure, the residue was taken up with 300 ml of lN sodium hydroxide solution and extracted with mèthylene chloride. The ~ethylene chloride phase was washed ~Yi-~h dilute sodium .~ydroxide solution, washed ltO neutrality, dried and evapora-ted under reduced pres-sure. The c~ude product was distilled ~nder 0.027 mbar~nd at a bath temperature of 13Q - 150C in a t~in-layer evapora-tor, and 107.2 g were obtained.
Die ~i~vl-7~ 6-iso~rop~. l idenedio~cvh ~ IH2 ) 4 -- ICH fH2 H3C C~I2~ \C/O
~7 N H3C~/ CH3 .. C~l2 CH3 T~e latter was taken up in 1.~ 1 of me-thanol and 350 ml of ~a-ter and, after the addition of 1.'-, ml of perchloric acid (70j' s-t~ength), was s-tirred at 70C
for 1 hnur. After (:ool.i.ng do~rl-to room temperQture~
.he mixtu~ as neu-trali.zed with sodiuM bicarbonal;e solution and evaporated ~oc~ryn2ss under reduced pressure.
T.he r~si.due ~las extr~ct~d ~ithl.5 ~ o~ methylene chlnride and t;he e~tr~c-' was evapora-ted 92.5 ~ (95~o of -theory) o~ crude. prodllct; were ob-t:ained, ~lhich, after recrys~al~
~ ation t~lce from methylene chloride/diet;h~l ether `q2~62~
- ~volume ratio 2 : 3), gave 1,3-diethyl-7-(5,6-dihydro~y-hex~rl)xanthi~e, which w~s pure by thiIl-layer chromatography.
Yield: 81.7 g (83.95~ of theory) ~Ielting point: 94 - 95C
C15H24~44 (MW = 324-4) Analysis: calculated: C 55.5~yO H 7.46% N 17.276 found: C 55.52~ H 7.52% N 17.02%
B) ~he above product l.ras also obtained by hydroly-sis of 1,3-diethvl-7- ~~6-ep?x~hex~rl)xanthine (melting poin-t: 58 - 59C) o (C~2)4 - ~ CH2 C
C~1~5 i~ analogy to Exa~ple 3.
C) m e same compound was also obtained by ~Iydro~Yyla~
-~ion of 1,~-diethyl-7--(5-hexen~l)xaQth ne (C1~2) 4~ CH2 C~I5 with osmium tetroxide: 0.73 g of 1,3-diethyl-7-(5-he}~-~nyl)xanthine ln 11 ml o~ diethyl ether was add~d drop-2(~ wise with stirring in 5 m;nlltes -to n,6s g oI` osmium -t~troxicle in 11 ml of dietllyl e-ther at room terllpera*ure.
~28~i29~ 1 -- 29 -- i After standing overnight, the precipitate (1.2 g) was filtered off with suction. m is was stirre~
under reflux in a mixture of 55 ml of water, 1~ ml of ethanol and 11.2 g of sodium sulfite heptahydrate for 3 - 5 hours. After cooling do~rn, the precipitate formed was separated off and the ~iltrate was extracted with methy lene chloride. After drying and ev~porat~ng the col-lected methylene chloride phases under reduced pressure, 0.6 g of crude product was obtained, which gave 1,3-diethyl-7-(5,6-dih~droxyhexvl~xanthine as the mono-hydr~te after recrystallization from diethyl ether.
Yie~d: 0.47 g (57~7% o~ theory) Melting point: 77 - 78C (~onohydrate) ClsH~ 4o4-H2o (~r:.~ = 342.~) ~nalysis: calculated: C 52.620,~ H 7.65~' N 16.3~%
found: C 52./r850 H 7.69% N 16. 20~Q
Example 3:
~Dim~l_7_~ ~!~hine a) 1.3 Dim~th 1-7-(5~ ~ rl)xanthine 1~ ~7~2) ~'! C\ ~ 2 A solution o~ 31 g o~ 153-dirnethyl-7-(5-hexen~rl) xanthine and 34.9 g of m-cl~loroperberlzolc acid (70%
pure) in 700 ml of clllorof:orm ~as s-tlrred a-t rOoI~
tempera-t~-re ~or lS houls. 11~e mix-~re ~/as shaken wi-th 1OSQ strength sodium d:i-t~ionite solu-tion un-til the tes-t ~ 2c~6Z9~
-- ~o -- .
with starch-iodide paper was negative, and washed with sodium bicarbonate solution and then ~Yith water to neutrality; dried and evaporated under reduced pressure.
Purification o~ -the crude product was by means of column chromato~raphy on si:lica gel (mobile phase:
methylene chloride/acetone9 ~-o:Lume ratio 7/3) and by recrystallization from petroleum ether.
Yield: 20.8 g (63.2~ of t.heory), melting point ! 59 - 60C
C13H18N403 (i~W = 278.3 Anal~sis: calculated: C 56.10S6 H 6~52% N 20.13%
found: C 55 87% H 6.51% N 19.~1 b) 1,3-~imethyl-7-(5~6-d ~ i_ I, (C~I., ) "--CH--C~I,, ~
. 3 0.24 ml o~ perchlorlc acid (70% strengtl~ as added drop~ise with s-tirring in 5 n~inutes -to a solution of 3 6 g oi 1,3-dime-thyl-7~-(5,6-epoxyhexyl)xan-th:ine in 28~ ml o~ a mixtul7e of ethylene g~ycol dime-thyl ether and water (volu~e ratio 3 : 2) at roorn ternperature~
~ter sti.r.ling at roorn -tempera~ture ~or 16 hours, ~he mixture was neu-trall~e~cl ~.rith sodiv.m bicarbona-te solu-tiOll and evaporatc-cl ~n~ler red-lced press-lre. l~e residue was purifiecl by column chrcmato~,raphy on silica gel (mobile ph~se: chl OI o~orrn~ethanol5 vo~.urne ra-t:io 8/2) ~5 a~d r~crystallizatio.rl ~roM e-thyl ~cetate.
2~i292 - Yield: 3 g (78.3~ of theory) Melting point: 9~ - 100C
13 20N404 (~W 296.3) Analy~is: calculated: C 52.6~ H 6.80% N 18.~1~
foun~: C ~2.39% H 6.72% N 18.83%
Bo-th the reaction of 1,3-dimethyl-7-(5-hex-enyl)xanthine with osmium tetrox-de in analogy to Example 2 C) and also the alkylation of 1,3-dim~thyl-xanthine with l-chloro-5,6-isopropylidenedioxyhexane ~d subsequent acid h~drolysis of the dioxolane ring accordin~ to Example 1 or 2 A) led to the same compound.
EXamPle 4 .
1,3-Dibut,v~1-7-(~?4-dih~,~droxYbu!~l)xanthine a~ -Dibutyl-7-~4-epoxy~ hine - I ` c~I2-CEt2 ~H-CH2 ~3C-~C-32)3-N ~ ~ o (CE~3-CH3 .4 g of m-chloroperbenzoic acid (70~ pure) ~ere added t~ a solution o~ 42.7 g o~ 1,3-dibu-tyl-7--(3-butenyl)~an-thine in 9~0 ml o~ cl-lloro~orm ~ritn~n 15 minutes, with s-cirrin~. A:~ter stirring at room ternpera-.
2~ ture ~or 27 hours, the rnixture was was~led w:it~ lO~bstrength sodium dit:hionit~ solll-tion, sa-turat;ed sodium bicarbonate sol~!tion and ~terj dried and t~vaporated der rcduced ~ress~lre. The resid~le ~as chroma-tograplled o~ a silica ~el column wi-'-h a mix-hlre o~` mechylene g~, - ~2 -chloride/acetone (7 : ~, v~ v) and recrystallized ~rom petroleum ether.
Yield: 19 g (42.4~o of theory) Melting point: 52 - 53C
17 26 4 3 ( 334.4~
Analysi~: c~lculated: C 61.06% H 7~84% N 16.75%
found: C 61.01% H 7.89% ~ 16~74%
b) 1,3-Dibutyl-7 ~ r~utyl ~anthille ~ ~CH2)2- CH CH2 3~ (CH2)3 ~ ~ ~ OH OH
ln 0.4 ~1 of perc}-loric ~cid ~70% streng~h) was a~de~ dropwise with stirring in 5 minutes -to a solution o~ 7 g of 1~3~dibutyl-7-(3,4~epoxybutyl)xan~thine in 300 ml of a mixture of e-thylene glycol dimethyl ether/la1er (~olume ra~tio 3 : 2) at room temperature. hfter stir-ring at room temperature for 45 hours, the mix-ture ~as neu-tralized with s~dium bioarbonate and the solu-tion was evapo~ated. '~ne residue was taken up with me-thylene chloride and purified by cGlumn chromatography on sil:ica gel with a mixture ol chloro:~orm ancle-thanol (volume ratio 8 : 2) as -the mobile phase and by recrys-talliza-tion from m~thylene chloride~petrQleu~n e~ler~
,Y ld: 4~8 g (65~ of theory) ~el t:ill~ point: 9~ - 9~C' ~iH2~3N~iO~ T ~2 ., ~i ~
~286~92 - ~3 4nalysis: calculated: C 57.94% H 8.00% N 15.90%
- found~ C 58.06% H 8.06% N 15.77~
Alternatively, this diol can be obtained by a one-step oxidation of 1,3~dibu-tyl-7-(~-butenyl)xanthine 5 with osmium tetroxide in analcgy to Example 2 C) or by alkylation of 1,3~dibutylxanthine with the l~halogeno-3,4-isopropylidenedioxybutanes kno~n from the literature (for example Tetrahedron 34 (1~378), pages 2,873 -2,878) and subsequent acid hydrolysis o~ the dioxolane ring in analog~ to ~xample 1.
Æxam?le 5 1~3-Diethyl-7-(b,7-dih~droYyhe~tyl)xanthine a) l-Bromo-6,7 e~ox~heptane Br-(CH2)~-C\--~H2 . ` O
37 3 g of 1-bromo-6-hep-tene were added dropwis~`
wi~hin 40 ~inutes, with stirrin~ and flushing wi-th nitrog~r., to 50.~ ~ of m-chlorQperbenzoic acid (~5%
pu~e) in 300 ~1 of methylene chlor:ide at room t~mperature.
A~ter standing overnight, the plecipi-tate was ~`iltered o~f with suction and -the :filtrate was washed ~ith lO~o st.rength Na2S20~ solution, wi-th saturated sodium bica.bonate solu-ion ancl ~lith wa-ter alld (a:f-ter drying) e~aporated under recluced pressure. 42.2 g of cl~de 1-bromo-6,7-e~o~yyhep-tane ~tere obtainecl.
b) l-Bromo-6,?-dihYdrox~he~-tane OH OH
~r-(CH2)5-cf~-c~
42 ~ of 1-bromo-6~7-epox~rheptane were introduced into a mixture of 400 ml of tetrah~rdrofuran and 235 ml of water, lr~hich had been adjus~ted to pH 2 with per-chloric acid, a-t room temperature. After stirring at ~oom ~er~perature for 8 hours, the mix-ture was neutral-ized, evaporated under reduced pressure and the residue was ex-tracted with methylene chloride. After removal ol -t~e solve~t, 41.~ t~ ~7-dihydro~-h~ptane were obtaine~.
c) l-~rom~-6,7-iso~ro~Yl id enedloxyheptane H3C C~3 - \C/
Br-(Cil2)5-Cll ~ C~I2 .
0.1 ml of concentrated sulfuric acid was added, ~riih s-tirrin~ under ni-trogen~ -to ~] g of 1-bro~o-6,7-di-h~rdroxyheptane and 22.2 g of 2,2-dimetho~rpropane in 100 ml o~ acetone a-t room tempera-ture. After 4 hours~
o.6 g of sodium bicarbonate was added. A:~ter ~tirring for a ~urther one houIs the solid ~as ~il-tered o.f:~, the fil-trat~ was e~raporated under reduced pr~ssure and tllc ~esi~lu~ wa.C; sllbjected to fractional vacuum di~-til:La-tion - . . .
12~6292 Yield: 38 g (77.9y of theory) Boiling point (0.4 mbar) 73 - 76C
Refractive lndex n20 = 1.4656 d) 1,3-Diethyl-7-(6.7-dihydro~yhe~tyl)xanthine R ~IH2)5~l}~ 2 ~5C2-N~ ~ ~ OH 0~l ~ I
., C2H5 13.9 g of 1~3-die+~hylxanthine, 18 g of l-bromo-- 6,7-isopropylidenedioxyheptane and 9.5 g oi` potassium carbonate in 100 ml o.~ dimethylIormamide were heated at 100C with stirring i`or 7 hours. Ai.`ter evaporation - 10 un~er reduced pressllre~ dilute sodi~tm llydroxide solu-tion was added to the residue and thi.s was extracted several times with methylene chloride. The collec-t~
methylene chloride phases ~rere washed with water~ dried and evaporated-. The residue was dis~tilled in a `oulb~
~ub~ app~.ra-tus under 0.01 mbar and at a bath tempera-ture of 100 - 115C. 17 g of _ -7-(6~Z~=so~
propylidene~iox~hep-tvl~xant~ ne were obtained, ~h:ich were'takenup in 70 3nl of sul~uric acid a-t a pH o:~ 0.5 and hea-ted ~der rei.'lux for 2 }lours. A~ter coolin~ the ~ix-t~lre was neutralized, evapo.a~ted under r'~duced pres--sure ancl the residue was recx~tallized fro~ methylene ch'loride/diethyl etht?r.
-` 12~292 ~ 36 --Yield: 13.8 g (61.1% of theory) Melting point 105C
Cl6H26N44 (~r = 3~8.4) Analysis: calculated: C 56.79~ H 7.74% N 16.56%
5fou-nd: C 56.8~% H 7.70~ N 16.67%
The l-bromo-6,7-dihydroxyheptane prepared in step b) can also be e~ployed directly ~or the alkyla-tion of the 1,3-diethylxan-thine in step d) without previous rea~.~ion with 2,2-dimethoxypropane to give the ~ioxolane deriva-tive.
Example 6 ~,7-Diethyl~1-(4,5-dihyclroxyhe~yllxanthine a) l-Chloro-4-hexene - Gl-(CX2)3-CH=~H-~H3 .
47~ g (4 moles) of thiony]. chloride were added ~rom a ~rcpping f~l-nel -to a ~olution of 330 g (3.3 moles) of 4-~exen-1-ol (Organic Syni,heses, Vnl. 55, page 62 et se~-.) in 400 ml o~ pyridine, with stirring and cooling in ice, in such a ma~ner tha-t the reaction t.empera-ture did not exceed 55C. ~ne mixtul-e was then hea~te~l a-t; 80C :~or 1 hour~ Therea:~ter 9 -the mixture was allowed to cool do~n slo-rly~ water ~a.s addecl and the mixiure was extrac-ted se~reral time3 wi-th ~i.eth~rl ether~
~ne coIr,bined ether extracks werc ex~,rac-ted by shal~ing with saturated sodiurn bicarbona-te solut.ion, washcd with wa~;e~ to ne-~tralii.y; dried over socl.ium sul~a-te and e~l~poral;cd Imder norrnal pressure. l-Chloro-4--hexei-le~
whic~l was ~?ure by gas chro;nato~ra~hy, was obtained by ~2~6292 ~ractional distillation of the residue under reduced pressure.
Yield: 196.2 g (50.1% of theory) Boiling point (140 mbar) 80G
Refractive index nDl = 1.4400 b) ~s7-Dietllyl-l- ~ c~-dihvdro~exyl)xanthine CH3-fH-fH-(C~2~3 OH OH
CH2~ 3 20.8 g (0.1 mole) of ~,7-diethylxanthine, 15.2 g (0.11 mole) of potassium carbonate and 13.0 g (0.11 mole) of 1-chloro-4-hexe~e in 600 ml o~ dimethylforma-. mide ~rere stirr~d at 110C i~or 18 hours. After cooling do~m, the mixture was filtered, the filtrate was evapor-ate~ under reduced pressure an~ the residue was taken ~p in.chlorofor~. ~.he ~nreacted 3,7-die-thylxanthine ~as removed by ex~rac-ting wi~h lN sodium hydroxide solution by shaking, the organic ph.a~e was washed to nel--trality with water, dried over sodium sulfa"e and the solven-t was distillod off in a rotaly evaporator. After dryinO the solid residue from evaporation~ 27.5 g (94.7%
o~ theory) o~ crude ~,7-diethy'-i-(4-hex_l ~ nthine were ob-tained, . ' ' .
.li,, ~
- 12~2 -3~ --. 0 C~H5 H3 C~=CH-(C~
~ .
which~after dissolving in 350 ml of chLoroform and add-ing 23.1 g (0.114 mole) of 3-chloroperbenzoic acid (85%
pure), was s-tirred under a ni+rogen atmosphere at room temperat,ure for 48 hours. ~ne mixture was then initi-ally ex-tracted by shakinG wi-th lO~o st,~ength sodium dithionite solution until the iodine-starch reaction - disappeared~ ar.d then with 10~ sirength sodium b'carbon-~t~ solution9 ~nd th~ solution .as washed wi-th ~Yater ~ntil neutra]. and free of salt, dricd and evapora~ted under reduced pressure. ~9.0 g (100% ol theory~ of crud~ ~ ~,JL~_anthine were obtained C}13-C~-\c~l-(c~2 ~15 whicll, af-ter beillg takell up i.n a solvent mlxt,ure com-posed o~ 150 ml ol te-trahydro~uran and 100 ml of wa-i;er antl adtiltion o 0.4G ~:L of perch:Loric ac:;d ('/0~ s-treng-th)~
was s-~ red at room -temperclt~ o fol~ 90 hou.rs. l~e mix t~lre ~a.~ th~n nel.ll;ral.i~.ed w.ii;h sa~urc~teti sod.iurn bicarbon~
a~ solu-tion, t.he so:l.vent wac; di.,ti~.led o~f undel~ reduced -` 12~629~
pressur~ and the residue was chromato~raphed on silica gel with chloroform as the mobile phase. This produced 26.4 g (85% of theory) of a crystalline product, which was recrystallized from ethyl acetate/petroleum ether, and wnich was almost pure by thin~layer chromatography.
Yield: 21.5 g (70% of theory) Melting point 91 - 9~C
C15H2~44 (~ = 324-4) alysis: calculated: C 55.54~ H 7.46% N 17.27%
~ound: C 55.54~6 H 7.5~j' N 16.97%
m e san~e compound ~as obtained by a one-step oxid~tion of 3,7-diethy~ exenyl)xan~thine ~ith osmiu~ te-troxide in analogy to Example 2 C).
E~a~P~ ?
3-But~ 4,5~ rox~elltyl)-7-meth~lx_n hine C~l2~ C~2)3 ~
(CH2)3~C~3 33.3 g (~.15 ~ole) ol 3-butyl-7-met.hylxcn-thine, 24.3 g (0.16 mole) of 1-b~omo-4--pentene and 22.1 g ` (0.16 molc) of po-tassium carbo~la-t~ in 500 ml of dimethyl-~ormamid~ wc~re he~~ted wi-th stirring a~t 100C for 15 hours. After cooling do~m~ the reac-tion mixture was evapoxa-ted ullder reducfd pressure, the residue was talie up in me-thy7.e~f! chlori~le~ f:i.lkered and the fil-tra-te was e~-trclci,ed ~y shaki.ng with lN sodium hydroxide so~.ut:ion~
c~6Z92 _ 40 --the organic p~lase was washed with water to neu-trali~y~
dried o~er sodium sulfate and solvent was removed in rotary evaporator. m is produced 42.2 g (97y o~ the-ory) of crude, crystalline ~butyl-7-methyl-1- ~ t-~l)xanthine .
C112-CH- (CH2) j~
~l2)3 CH3 ~Yhich w~s dissolved in 550 ml of chloroform, ~5.6 g ~0.175 mole)of 3-chloroperbenzoic acid (85~ pure) were ra~ded ~nd the mixture, after covering with an atmos-phere o~ nitrogen, was stirred at room temperature for 67 ~louls. ~x~~rac-~ioll by sh~Xing with 10,' strength sodium di-thionite solution unt~l disappearance of the iodine-s.arch reaction, ~ashing, ini-tially with 106 streng-th sodiu~ blcarbona-te solu-tio;q and then wlth ~rater9 drying over SOdiWII sullate and evaporation under reduceci pressure pro~ided 37.7 g ~r . 7% of theory) of crude ~ en~ a " ~rp~
~ fl~3 C\2r~CH-(~H2) O
2~3~C~13 ~.nich Iras subjectecl -to hydroly-ti.c Ope~ling of ~the oxirarlr-~
~ing ~r~ out interl~edi.a-te pu-:i Fication,. For -t.his purpose9 the 37.7 g of epoxide was dissolved in a mix~lre o~
200 ml of tetrahydrofuran and 1~5 ~1 of water, and 0.61 ml of perchloric acid (70% strength) was added dropwise with stirring within about 10 minutes at room temperature. After stirring at room tempera~ure for 14 hoursA the mix~ure was neutrali~ed 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 or silica gel with chloroform/meth~nol (volume ratio 10/1) as the eluting agent and subsequen~ recrys-iallization from ethyl acetate with the addition o~
petroleum ether at the boiling poir.t until cloudy.
Yield: 29.2 g (73O2~o of theory) iel~n~ point 7O - 7~C
C15H24N404 (~,~, = 324.4) Analysis: calculated: C 55.54% H 7.46% N 17.27,h - fo~nd: C 55.38S~ H 7.45,~ N 17.52 The same compound ~as obtained by direc-t dihydroxylation OI the C=C double b^nd o~ 3 butyl-7-methyl-1-(4-pentenyl)xanthine with osmium tetroxide in anals~y to Example 2 c!.
Exam~le 8 ,7-Diethyl-3-(5,5-dihydro,~x~he~vl);-an~hi e a) 1~7-Dieth~rlxar.tline 1 2~I5 12~292 18 g of ~-benzyl-1,7-diethylxanthine (mel-ti.ng point 119C? in 1,500 ml of glacial acetic acid were hydrogenated in the presence of 2.5 g of 10% palladium on active charcoal at 80C and under 3.4 bar while shaking for 47 hours. After cooling do~n, the mixtur~
was covered with an atmosphere of nitrogen ~hile the catalyst was filtered off and the filtrate ~as evapor-- ated under reduced pressure. The residue was dissolved in a mixture of 250 ml of methylene chloride and 100 ml 1~ of lN sodium hydroxide solution. After washing the methylene chloride phase again with lN sodium hydro~ide - solution, the combined a~ueous phases were adjusted to pH 6 by add ng 335S s-trength sulfuric aci.d dropwise with siirrin~. After washing to neut.rali-ty and drying the preoipital~ produc~d~ ~.l.g (~4.5~0 of theory) of lr7~di--e-thylxanthi;1e~ of melting point 204 - 205C 3 WQre o~tailled ~
4~6 g of 3-benzyl-1s7-diethylxaIlthine ~ere recovered flo~ ihe methylene chloride phase.
b) _~7-Die-thy-.-3 ~5~6-di'~drox~he~:y.~xanthin3 ,~ s 1~
,~ .
(c~ j r~ f~l~
- OH 0~3 ~ mi~-ture of rl g of 1,7-diethylxantilille, 7.2 g .o~` l-chloro-59~-isoprol~y:Lidenedio~yhe~ane, 5 g of ~.X3~Z9;~
-- , potassi~ln carbona-te and 50 ml o~ dimethylfo~mamide was stir~ed at 120C for 8 hours. After evaporation under reduced pressure, -the residue was taXen up with 50 ml of lN sodi~ hydroxide solution and extracted with methylene 5 chloride. The methylene chloride phase was washed again with dilute sodium hydroxide solution, washed to neutral-ity? dried and evaporated mder reduced pressure. The residue was distilled under 0.01 to 0.02 mbar and at a bath temperature of 120 - 150C in a thln-layer evapora-tor and 11.5 g of 1~7-diethyl-3-(5,6-isopropylidene-diox~hexyl)xanthine ~ere obtained. This was -taken up`
with 32~ ml of me-thanol and 80 ml of water and, after ihe addition of 0.4 ~1 of perchloric acid (70~' strength), s-tirred at 70C lor 1 hour. After cooling do~m -to room 1~ te~perature~ the mixture ~as neuirali~ed ~rith sodi~m bicarbonate solution c~nd evapora-ted to dryness ~nder reduced pressure. The residue was tal~en up ~ri-th 200 ml of metnyleIle chloride and the ex-tract was evaporated.
~ne Iesidue las puri:Eied by colu~n chrom~toD--r~phy on silica gel ~/ith ~e-thylene chloride/eth~nol (volume ratio 8/2) as -the mobile phase and by sub-sen~ent recrystalli-~ation from m~-thylelle chlorideJ
diethyl ether.
Yiel~: 7.9 g (7~.5O oi theor~r) I~;eltin~ ~oll-~-t: ]15 ~ C
C15H2~N~04 (1~ = 32~
An~lYs.i5: calcul~tccl: C r,5~5'l~,0 H 7.ll6% N 17~27~' :~nund: C ~5.37S' ~ 7.51% 1~ ~7~C'3%
29~
. . I
_~4~ _ mis diol was also obtained by reaction of l,7-diethyl-3-(5-hexenyl)xanthine ~rith osmium tetroxide in analogy to Exa~ple 2 C) or by epoxidati.on of the foregoing xanthine compound, followed by acid hydroly-sis of -the epoxi~e ring in analogy to Examples 3, 4 and 7.
Exam~le 9 __ 7- ~,3~Dih~droxvbutyl)-l,3-diP~.op~lxanthine a) l-Chloro-2,3-e~ox~Tbutane ` ~0 Cl-CH2-C~I-CH-CH3 93.4 g of crotyl chloride (~7S' pure) were added dropwi3e ~!ith stirring within one hour to a sol~tion of 244 g of 3-chloroperbenzoic acid (~5% pure) in 1.5 1 of ~hlnroform ~ ile cooling in ice. Af-ter s-tirring for a ~5 fur~ther 70 hours a-t room te.mpela-ture, the precipitate was fil-tered o~Cf with suct~on, and the filtrate was washed wi.th lO^.~ streng-th sodium di-thionite solution ~until -the s-tarch-iodin~ test ~:as negative), wi-th sa.-tur-~ed sodiu~ bicarbonat.e solu-tion and ~ith wa-ter. Af~ter drying over sodium sulfa-te, the solu-tion ~as fraction~
ally dis~tilled over a ~acked colur~1.
Yield: 5~ ~ (54.3-,~ Or ~theory) Boilin~ ~Oil1t (~ mbar) 70 - 73C;
Ref~ct.ive inde~ nD = l.l~327 C~ .`lO (11'~ .55) si : cal(ul-a-t d~ C 45.~095~ II 6.62% Cl ~j.27%
~C~Uil~ ~ L~5, 2~ f 6 . 78,b C~ . 30 ` 12~6292 -- ~5 -- ;
b) -Chloro-2,3-dihvdrox~bu~ane Cl_cll2_l ~ f~ CH3 OH 0.'1 57 g of 1-chloro-2,3-epoxybutane were stirred in a mixture of 500 ml o~ water, 800 ml of tetrahydro-furan and 1.2 ml of perchloric acid (70~0 strength) atroom tempera~ture for 7 day~. A~ter neutraiization with sodium bicarbona^te solution, the mixture was evaporated ~o dryness under reduced pressure and the residue was t~ken up with 2 1 of diethyl ether. ~he ethereal solu-tion was dried and evaporated ~lder reduced pressure.
Yield: 54 g ~81,S of theory) c.) l-ChlQro-2,~-isopr ~ylidenedioxvbutane Cl CH~-f~l - CH-C~I3 O\ O
/~
c~r3 c~
1 ml of perchloric acid (70~0 strength) was added dro~ise ~ith stirri.n~ ~iitnin 6 minu-tes to Cl solution of 5~ g o~ 1-chloro-~3-dihydrox.ybu-~ane in 50 ml ol acetone and 71 g o.f 29~-dime-tlloxypropane under a.n atmosphere of ni-trogen ~t roo~ tempera~ture~ ~fter stlrring a-t room temperature ~or a ~urther hour, 5 g o~ ~inely powdered sodi~ bicarbonate was added, t.he mixtur~ was sl;irred .ror halI an hour, iil-tered an~ -the :~iltrate was dis-t:illed ovcr a pac~eci cnlumn.
Yield: 36.S g (52.5~ of theoryr) Boiling point ~6.5 mbar) 49 - 53C
d) 7-52,3-Dihydro ~ ylxanthine fH2-cH-cH-cH
H7C3 ~ ~ OH OH
C3A~ 7 A mixture ol 47.2 g o~ ~,3-dipropylxanthine, 33.6 g o~ 1-chloro-2,3-isopropylidenedioxybutane, 28.2 g of potassium carbonate and 300 ml o~ dimethylfor~a~nide ~s stirred at 120C for 8 A~Aours. The mixture ~as evapora'ed under reduced pressure and the residue was 10 ~kel1 UA~ with 250 ml of lN sodium hydroxide solution and 5~0 ml of me-thylene chloride. A~ter washing -the aaAueou~ phase ag~in Wi-tAA methyleA~Ae chloride, the co~--~ined methylerle chlori~e pha~ses were washed ~Yith lN
sodi~m hydrox~de solution and water~ dried and e~apor-~.te~ under reduceci. pr~ssure I~le residue was distilled in a bulD-tube apparatus un~er 0.03 - 0.07 m~ar a~;l at a ~atil te:n.p~rature 01 90OCI O 260~3 g Oi 7-(25 3-isopropyl~
i~enedioxybut~-] )~ 3- dipropylxanthine (91.5So O:f theory rela-t:i~re to reacted 1,3-dipropylx-lI).thine) ~rc ol~tai.ned . g ~i2 ~ C~l C~l - C~I~
~7C~J `~-~ ~` o . ~ ~`}1 2/ \C"
C~
whic~ was stirred in a mixture of 700 ml o~ tetrahydro-furan, 100 ml of water and 0.8 ml of perchloric acid (70YJ strength) at 70C for 1 hour. hfter neutraliza-tion with sodium bicarbonate solution, the mixture was evaporated under reduced pressure, the residue was taken up with 800 ml of methylene ch:loride, and the solution was dried and evaporated under reduced pressure. The residue was purified by recrys-tallization from methylene chloride/diethyl ether. 0 Yieid: 20.9 g (87.6~' of -theory~
Melting point: 99 - 101C
C1~24N404 (I~ = 324.39) ~nal~rsis: calculaled: C 55O54~ H 7.46% N 17.27-' found: C 55.495' H 7.49~ N 11.18S~
L`~10 compounas a~ore~en~icned and -those prepared in an analogous manner are compiled in Table 1.
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- . Table 2:- Int~r2e~iate products having a structural element of the formula IV (arrangement of the radicals Rl, R2 ard ~; as fF formula I) Co~- Rl R2 R3 Melting pound ~ point~
\ / 3 76-77 O
2a - n - ~Exa~le 1 2 3 ~ ~ 3 C2H5 C2~I5 (Example g~ ~CH2)4-C\~ ~ 2 CH3 CY.3 99 - 100 .
r 2 5 ~Q
b) _~7-Die-thy-.-3 ~5~6-di'~drox~he~:y.~xanthin3 ,~ s 1~
,~ .
(c~ j r~ f~l~
- OH 0~3 ~ mi~-ture of rl g of 1,7-diethylxantilille, 7.2 g .o~` l-chloro-59~-isoprol~y:Lidenedio~yhe~ane, 5 g of ~.X3~Z9;~
-- , potassi~ln carbona-te and 50 ml o~ dimethylfo~mamide was stir~ed at 120C for 8 hours. After evaporation under reduced pressure, -the residue was taXen up with 50 ml of lN sodi~ hydroxide solution and extracted with methylene 5 chloride. The methylene chloride phase was washed again with dilute sodium hydroxide solution, washed to neutral-ity? dried and evaporated mder reduced pressure. The residue was distilled under 0.01 to 0.02 mbar and at a bath temperature of 120 - 150C in a thln-layer evapora-tor and 11.5 g of 1~7-diethyl-3-(5,6-isopropylidene-diox~hexyl)xanthine ~ere obtained. This was -taken up`
with 32~ ml of me-thanol and 80 ml of water and, after ihe addition of 0.4 ~1 of perchloric acid (70~' strength), s-tirred at 70C lor 1 hour. After cooling do~m -to room 1~ te~perature~ the mixture ~as neuirali~ed ~rith sodi~m bicarbonate solution c~nd evapora-ted to dryness ~nder reduced pressure. The residue was tal~en up ~ri-th 200 ml of metnyleIle chloride and the ex-tract was evaporated.
~ne Iesidue las puri:Eied by colu~n chrom~toD--r~phy on silica gel ~/ith ~e-thylene chloride/eth~nol (volume ratio 8/2) as -the mobile phase and by sub-sen~ent recrystalli-~ation from m~-thylelle chlorideJ
diethyl ether.
Yiel~: 7.9 g (7~.5O oi theor~r) I~;eltin~ ~oll-~-t: ]15 ~ C
C15H2~N~04 (1~ = 32~
An~lYs.i5: calcul~tccl: C r,5~5'l~,0 H 7.ll6% N 17~27~' :~nund: C ~5.37S' ~ 7.51% 1~ ~7~C'3%
29~
. . I
_~4~ _ mis diol was also obtained by reaction of l,7-diethyl-3-(5-hexenyl)xanthine ~rith osmium tetroxide in analogy to Exa~ple 2 C) or by epoxidati.on of the foregoing xanthine compound, followed by acid hydroly-sis of -the epoxi~e ring in analogy to Examples 3, 4 and 7.
Exam~le 9 __ 7- ~,3~Dih~droxvbutyl)-l,3-diP~.op~lxanthine a) l-Chloro-2,3-e~ox~Tbutane ` ~0 Cl-CH2-C~I-CH-CH3 93.4 g of crotyl chloride (~7S' pure) were added dropwi3e ~!ith stirring within one hour to a sol~tion of 244 g of 3-chloroperbenzoic acid (~5% pure) in 1.5 1 of ~hlnroform ~ ile cooling in ice. Af-ter s-tirring for a ~5 fur~ther 70 hours a-t room te.mpela-ture, the precipitate was fil-tered o~Cf with suct~on, and the filtrate was washed wi.th lO^.~ streng-th sodium di-thionite solution ~until -the s-tarch-iodin~ test ~:as negative), wi-th sa.-tur-~ed sodiu~ bicarbonat.e solu-tion and ~ith wa-ter. Af~ter drying over sodium sulfa-te, the solu-tion ~as fraction~
ally dis~tilled over a ~acked colur~1.
Yield: 5~ ~ (54.3-,~ Or ~theory) Boilin~ ~Oil1t (~ mbar) 70 - 73C;
Ref~ct.ive inde~ nD = l.l~327 C~ .`lO (11'~ .55) si : cal(ul-a-t d~ C 45.~095~ II 6.62% Cl ~j.27%
~C~Uil~ ~ L~5, 2~ f 6 . 78,b C~ . 30 ` 12~6292 -- ~5 -- ;
b) -Chloro-2,3-dihvdrox~bu~ane Cl_cll2_l ~ f~ CH3 OH 0.'1 57 g of 1-chloro-2,3-epoxybutane were stirred in a mixture of 500 ml o~ water, 800 ml of tetrahydro-furan and 1.2 ml of perchloric acid (70~0 strength) atroom tempera~ture for 7 day~. A~ter neutraiization with sodium bicarbona^te solution, the mixture was evaporated ~o dryness under reduced pressure and the residue was t~ken up with 2 1 of diethyl ether. ~he ethereal solu-tion was dried and evaporated ~lder reduced pressure.
Yield: 54 g ~81,S of theory) c.) l-ChlQro-2,~-isopr ~ylidenedioxvbutane Cl CH~-f~l - CH-C~I3 O\ O
/~
c~r3 c~
1 ml of perchloric acid (70~0 strength) was added dro~ise ~ith stirri.n~ ~iitnin 6 minu-tes to Cl solution of 5~ g o~ 1-chloro-~3-dihydrox.ybu-~ane in 50 ml ol acetone and 71 g o.f 29~-dime-tlloxypropane under a.n atmosphere of ni-trogen ~t roo~ tempera~ture~ ~fter stlrring a-t room temperature ~or a ~urther hour, 5 g o~ ~inely powdered sodi~ bicarbonate was added, t.he mixtur~ was sl;irred .ror halI an hour, iil-tered an~ -the :~iltrate was dis-t:illed ovcr a pac~eci cnlumn.
Yield: 36.S g (52.5~ of theoryr) Boiling point ~6.5 mbar) 49 - 53C
d) 7-52,3-Dihydro ~ ylxanthine fH2-cH-cH-cH
H7C3 ~ ~ OH OH
C3A~ 7 A mixture ol 47.2 g o~ ~,3-dipropylxanthine, 33.6 g o~ 1-chloro-2,3-isopropylidenedioxybutane, 28.2 g of potassium carbonate and 300 ml o~ dimethylfor~a~nide ~s stirred at 120C for 8 A~Aours. The mixture ~as evapora'ed under reduced pressure and the residue was 10 ~kel1 UA~ with 250 ml of lN sodium hydroxide solution and 5~0 ml of me-thylene chloride. A~ter washing -the aaAueou~ phase ag~in Wi-tAA methyleA~Ae chloride, the co~--~ined methylerle chlori~e pha~ses were washed ~Yith lN
sodi~m hydrox~de solution and water~ dried and e~apor-~.te~ under reduceci. pr~ssure I~le residue was distilled in a bulD-tube apparatus un~er 0.03 - 0.07 m~ar a~;l at a ~atil te:n.p~rature 01 90OCI O 260~3 g Oi 7-(25 3-isopropyl~
i~enedioxybut~-] )~ 3- dipropylxanthine (91.5So O:f theory rela-t:i~re to reacted 1,3-dipropylx-lI).thine) ~rc ol~tai.ned . g ~i2 ~ C~l C~l - C~I~
~7C~J `~-~ ~` o . ~ ~`}1 2/ \C"
C~
whic~ was stirred in a mixture of 700 ml o~ tetrahydro-furan, 100 ml of water and 0.8 ml of perchloric acid (70YJ strength) at 70C for 1 hour. hfter neutraliza-tion with sodium bicarbonate solution, the mixture was evaporated under reduced pressure, the residue was taken up with 800 ml of methylene ch:loride, and the solution was dried and evaporated under reduced pressure. The residue was purified by recrys-tallization from methylene chloride/diethyl ether. 0 Yieid: 20.9 g (87.6~' of -theory~
Melting point: 99 - 101C
C1~24N404 (I~ = 324.39) ~nal~rsis: calculaled: C 55O54~ H 7.46% N 17.27-' found: C 55.495' H 7.49~ N 11.18S~
L`~10 compounas a~ore~en~icned and -those prepared in an analogous manner are compiled in Table 1.
2~
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~ j h h Uh c~ h a> ~ ~1 a) ~o Q) u~ a) ~ ~ u~ O u~
h ~ ~ I G) ~ a) a) ~ ~ ~ a) a W h ~a ~ _ w ~ w ~), ~n &~ o . . _ N o _ X I X ' X
~ X~ O I~`J ON
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r-~ ¦ 1 ~ _ ~ r~ ~ - ~n .
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V V V C~
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11 o~ ~ . ~ ~t , ~ r~ ~0 S ~ 11 ~ tD ~t O-t ~ r_ ~ ~ !
r ~ ~
h~ U l l t t--o o--c_t 1~1,.'- . ~,X .' ,~, --~ ~ ~ t 1l ~t ~ . ~ 0 I ~ ~ 1-t~ ,' ~ ~ C.
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~ I I' X X X X
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ti C~i C~ l X C~J . C X
C~ C~ C~ t~ V
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ti ru ~
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`- --`" 12~36~29;~
- . Table 2:- Int~r2e~iate products having a structural element of the formula IV (arrangement of the radicals Rl, R2 ard ~; as fF formula I) Co~- Rl R2 R3 Melting pound ~ point~
\ / 3 76-77 O
2a - n - ~Exa~le 1 2 3 ~ ~ 3 C2H5 C2~I5 (Example g~ ~CH2)4-C\~ ~ 2 CH3 CY.3 99 - 100 .
r 2 5 ~Q
6~ CH3 ~-(CH2~4-~H\ / 2 5Q - 6?
O
O
7~ C~-5 C~-~C~ J _~u~ ~ _ 5q \~ .
C2H5 C2H5(CR2)4{~\-Cj 2 58 - 59 o C4Hg C~H9 (CH2~2 \ / 2 52 - 53 O ~:
~ ~ 2 ~ 6 ~able 3: Inter~edia~e products having a structural elemen~.
of the for~ula IX (R6 = C~3, R4, R7 and n: see ~able;
arr2n~ement o1 Rl,. R and R~ as for formula I) Com- Rl ~2. R3 Bulb-tu~è ~istillation Meltin~
po~ d - C mbar point C
1b ~ ~ n;4, R4=d 187-188 R Cd 2b ~ c2~s n=4, R-,R7 146 ~b E C2HS n;4,R =E~ 123-124 R = CE~3 .. . .
~b ~ C2H5 " 150 0,02 .
5b c~5 C2~5 " 130-lS0 0,027 *
. .
6b ~ " n=5,R4=~, tO~-115 .1 R7 = CH
7b ~ C~E~7 n-4, R4=E~ 150-160 0,02 R = C~3 _ _ _ ~b C~? C7H5 135-i40 n, Q1 -Sb n 1~ n=5 ~4--H 130 -0,02 R = CH3 10b `~ C3,~7 n=4, R4= H 140-150 0,OS
R7 = CH3 ~-~~~- n;1, R4= CH3 ao 0,03-0,07 C~3 . _ 12~ C ~ 3 C ~ 5 n;4, P~4- H 1~0-130 0,03 R = CH3 13b C5~1~ C}J~ " 130-140 0,03 14b " C 1 " 130-140 0,02 tS~ C~iS n-~ ~ 12~-150 0,01 - 0,02*
16b n ~srR ~, C~ 5 C3~7 140-1~0 0,2 . ~
17b " C3~17 CH3 140 0,2 ,,~ _ . . ... _ .. _.
~h.in-la~r~r evapor~tor - S~ -12~6~9 _ 59 Exampl e ~ 2 Medicament ~ormulation: For the production of 1,000 coated tablets, 100 g o~ ~-eth~1-7- ~ ~ x~y=
hex~Tl)-l-pro~ylxanthine (compound according to Example i), 20 g of lactose, 30 g of corn siarch, 8~5 g o~ talc9 0.5 g of colloidal silicic acid and 1 g of magnesium stearate were mixed and Gompressed to form tablet cores weighing 160 mgS which were then treated wi~h a coating . mix~ure composed of 40 g oi sucrose, 23.5 g of talc and very small amounts of ~rax, titaniu~ dioxide and g~m ~ ~rabic added so -thaT the final weigh of each o~ the coated tablets was 2~5 mg.
Example Medica~ent fo~mulation: For the production o.
1~00~ coated tableTs, 111.8 ~ of ~-e~hyl-~-iso-E~ eiledlo~he~ iro~y~ra~th~ne (from E~ample 1)~
20 g O~r' lactose, 3~ g of corn starch9 ~05 g of talc9 Q.5 g of col]oidal silicic ac-d ar~d 1 ~ of magnesi~m sieara-te ~rere mixed alld compressed to form ta~blet cores 2~ ~;ei~h.ing i71.8 m~, wh ch were the~.l--treated with a coa+
in~ ~ixtur e composed oi 40 ~ o~ sucrose~ 23~ g of -talc and ~er~r s~ail amourlts o.~ ~-a~, ~itanlum dic~id..e and ~um arab.ic added sv that the fina~ ~cigh-t of eacn o~ the coat~ -table-ts was 2I-LO mg~
~5 ~ a~Lr~ r~ ~L
Mcdioa~ner2 ~ r~ la-; ~on; l~`or tn~ ~.)ro luct-ioli o.;
l, ~C~l? c o~ t c~ t~ )t) ,~ c :E ~. 7 ~ t ~!y:~.~7--(~ f~ )ox~r -2~ or~ arrlp~ 2 ~) ), 20; o:~ ].ac-tc~se~ 3'~) C :~ C (~ I A 1 S ., ~ :~ C 11 J ~7 ~ ; O ~ L C, V ~ j ~, o E c o l _. ( .i. cl a l 29~
silicic acid and 1 g of magnesium stearate were mixed and compressed to form tablet cores weighing 160 mg, hich were then treated with a coating mi;~ture composed of 40 g of sucrose~ 23.5 g o~ talc and very small 2mounts of wax, titanium dioxide and gum arabic added so that the ~inal weight o~ each o,~ the coated tablets was 225 mg.
Pharmacological testin~ and results -1.' Bronchos-~asr,lol~rtic activitv .
'le cempounds accordingr to the invention were tos~ed ~or bronchospasmolytic activity essentially using ~he ex~eriment~l desiO~n described by H. Konzett and . R~ssler (Arc~. e~p. Pat~ u. Pharmak. ~ (1940) 75), comparing Wi"l tile stan~ard therapeutic agent, ~he~-'5 ~hyliine-e-ti-ly~ iami~ rl~ ~Yi~h tne tw~ 2,~ inyuro~-propyl compour~s already known diphylline[ 7-( 2,3-di-hy~-oxypropyl)-173-dimethyLYanthine] and 7-~2,3-dl-h~rd~r~Jpropyl)-1,3-dipropylxanthine. In this methodS
th~ i~ihibition of e.x~erimontal bronchspasms - induced ~y i~tra~renous adminlstr~~tion ol amines ha~ing spasmc-~nic acti-~ ty9 such as acetylcho1ii;e, histamine an~
- s~ro~onine - in Fuinea-pigs of both sexes under ure-ih~e ~laes~hesia (1.25 g/kg i.p.) .i.s inves-tiga-ted.
'~he test substances were ad~inis-tered in aaue-ous solution either in-travenously (i.v.) or in-tra~
duodcna~ly (i.d.). The ~D50 values, ~lich represent that dose in mg/kg at w'.lich the experimentally produced spasm ~ decre~se~; by one half compared to that in untrea~ed anim~ls,~lere de~el~.ined graphlc~ y ~rom the ~ose-ac~tivitv ~62 _ 61 --curves.
2. Acute toxicity __ .
Determination of the LD50 values was by the standard method of the mortality occurring within 7 5 days a7nong ~L~I m~ce after a single intravenous (i.v.), intraperitoneal (i.p.) or oral p.o.) administration.
m e results of these investigations, which demonstrate the superiority of the compounds according to the invention corresponding to formula I compared to the standard product theophylline-ethylenediamine and the two other comparison substa7ces ~particularly taking into account the more ~avorable ratio of LD50 to ~D50)~
are compiled in '~he following Table ~.
~ 62 ~ _~
, - O~
I
~ .. _ _ .__ _ _ I_ _ ~
R
~D I ~ o ~> O O O O O c~ o ~ .n I~ O
:~ I ~ ~ c~.l O O u~ o o o o ~ n ~ o ~) I~ c~ r~ t~ r~ C~l '~D C~ ~ <~ . . ~ ~0 ~o$~ I > o > > ~ ; > > > > >' i~l `~O I I c~ .,_ .~ .,_ .~ .,. i ., .,_ .. .,_ .~ .. ., + I u a r / ¦ ~ E ;~ ~
.,3 ~ O u~ c~ ~. ~ ~ ~ ~ ~n c~J 3 ~) I ~) C~) r o ~ rrl T r r 1 1 ~
r--3 1 ~) ~ C=~ ~ O ~n ¦ u~ ¦ G ¦ ~ O ~ C~ ¦ L'> 1-~
p .~. 3C~ C~ ~3 ~ D C'~ C~ ) c~ ~ ~.
rl ~lf 'Q¦ E~ r!, ~ c~
__ .. ~ .. ~ _ . _ _. _ , ~ . _ . _ . _ . , . ..... ~, _ , ... ~., _. . ~ ~, ~ _ . .. _ ._ _ _. _ . , . _ . _ . _ . ~ __ . _ -- 6~ --. .. k ~ ~
~ U~ ~f _ ~ r- ~ L~ ~ C`J . <~ ~
h a) ~ ~ . ~ ~ \/ ~
~: ~ h 0~' - ___ _ _ ~ . __ ~ ' ~_ - u~ O O O O u~ O ~ ~r- ~ .' ~ ~ o o o ~ A o c~ ~ ~ ~ ~o ~x~I > 1> - '> ~ ~
. - ~ 1~ ~ - .~ - ~ ~1 __ .
o ~ I . ~ . `
~do lc 1 . o ~ ~ o o x~
W~, ~ _--I ~ l ~ ~, E t" C-~ u~ ~ o C I o I o I ~D o ~ ¦ - ~d C o ~ C o ~o ¦ o ¦ ~ ¦ ~ O
¦ ¦ ;x~ J N ~ I ¦ C ¦ C~) P9~ A j A ~o . ~ 11 1 1 1 1 I' 11 1 1 1 .. ~q~
> I > I > I ~; I > I ~ > I ~ . I .c ~' o ~- i i r~
¦ ~ ~¦ ¦ Ul ~ ¦ O ¦ ~ ¦ ¦ ¦ r~ r~ ¦ ~r~ ?0 5~ 1 e ? ~
r~ t~ I r,~, I r.'? I r~ u ¦ ¦~ 1~) 1 ~1 ¦ t~ ~ r I ~J S~ I ~ C>
i i o ~ ~ I ~ I ~ ?o ~ ~
~ I ~L L I ! 1~ ~ aI I ~ ? ~
m e unequivocal superiorit~ of the compounds according to the inventio~, especially compared to the xanthire derivative which is most frequently employed ~or the therap~,r of obstructiYe respirGtory tract diso eases, theophylline-ethylenedia~ine (aminophylline), was also impressively confirmed in further specific experiments: -Since it is reO~a-ded as proven that, apart ~rom ~he Diogenic amines, acetylcholi~e, histamine and sero-tonineS listed in Table 4, bradykinin also plays animpo~ ~Qnt part as a mediator subs~,ance in the provoca-tiçn of ast~a a~tacks, the inhibitory ef~ect on the b~onchcspas~ induced in guirea-pi~s with-brad~kinin was inyestigated~ In this ~est, ~or e.xa~ple, the compound lrom E~am~le ls on i~travenous ti~v~) administration5 was ~ound to h~.vean ED50 o~ 1 - 3 mg/kg and aIIer intra-duodeIlal (i.d.) ad~inistration an ED5~ o~ 4~0 - 6.3 mg/kg &nd ~ S was a~out 3 times and aoout 6 times res~ectively more el~ective than theophylline-e~hylenediamine, for 20 ~r~ ~ ch the corresp3nding tota~l ED50 ~alues were .~oun~ to ~e ;, - 10 m~,/Xg i.v. and 25 - 40 m~/kg i~do The com ounds o~ the fo~ la I also e*ert a st~c~g ir~ibito~~y effect on the bronchospa~m induced with ~val~u~ln (1 m;,~k,, i,~r~ ) ln -tlle presensitized guinea-pigp 2~ ch is hardly a~fec-ted by th~ cus-l;o~a~ .xantiline derivatives . rml3 p f~r e:;a}:~ple~ tlle ~50 value ~or the COZlpO "ncl c.î Example 1 is be~een ~ and 12 mg/kg i.v. p ~:hils L tlleophy~ e-e tllylenediaminc- shows no effect in this desic~n o:E e~x~e.rimellt ~i-i;h closes up to 12 mg/l~.
l~B~
.
- ~he superior bronchospasmolytic activity of the - ~ xan~hines according to formula I was finally demonstrated - in the pulmona~y ~unction test on the anaesthetized dog - us~ ~ ~he inhibition of ~he bronchospastic reactlons ~ in~uced with aerosols of acetylcholine, histamine and - asczris ex~ract.
~ hus, for exa~ple, the compound in Example 1 alre~dy showed a significant ~nhibitory effect at 12 ~gjkg i.v., whilst theophylline, in doses up to 20 mg/kg 10 i.v., proved to have no e~fect.
-- As has already been mentioned in the introduction~
~e bronchospasmolytic effect o~ theophylline whi~h is clinlcally well establishedg is con-~r-csted by the ccnsidera`~le disadvantage of a very nar-1~ rc~ ~erapQutic ranOe comDined wiin serious side-o~tects.
p~r~icularly in the cardiovascular system (hypotensive a^~ivii~r~ decrease in cerebr~l blood flow) and i~ ~he ce~ral rervous system (l~or example restlessness, insomnia an~ ver'igo) ~ne stimulatior of the central nervous 20 sy~em is regarded by patients and clinicians as being pa~icularly distu.rbing, since it fre~uen~ly lea~s to ~so~nia and thus ilaS a persistent adverse effe^i on the g~neral state G~ healt3l o~ the asthmatic patient. A~
e~pression o~ this stimulation o.f tne central nerv¢us 25 ~sti-m is the increase in spontaneous motility o.~ male ~-ki~e mice by 186% ov~r a pe~..iod o.~ 7 ho-~rs after oral ~ ist.ation of ;~0 m~/lsg o~ theop~rlline--et3lylene- : .
di~.ine. According to Canadian Patent 1,082,184, the other t~o compariso.n procuc.ts d~rphyllin ~ 3 and 7-(2,3-dihydro~ypropyl)-l,3-dipropylxanthine also brIng ~bout a s-timulation of the cen-tral nervous system - in mice, although these effects are marXedly less pro-nounced ~han for theophylli~e. In contrast~ the compounds of the formula I acco~ding to the invention ha~e no component stimulatin~ ~le central n.ervous sys-tem7 but, on the contrary~ e~er~t a slight depressant e~fecL on the central nervous s~stem ~;~hich is assessed to be particularly advantageous from -the therapeutic 1~ point of view. Thus, the spontaneous motilit~ of miceS
~or example, is decreased by 53~ for a period of ll hours after oral admini.stration of 50 mg/kg of the com-pound lrom Exa~ple l.
m e inYestigations of the circulatory syste-~
~5 carried ou-t on rats and dogs~ comparin~ th ~theophylline-et~len~cliamine1 have sho~r.. that the c~mp,un;1s of the ~o~mula I ha~Te a h~potensive ~ctivi-l:ys ifany a-t all, ~ihich is m~r~;edly lo~er and tllat they cause no decrt?ase in cerebral bl~od :~lo-~.
C2H5 C2H5(CR2)4{~\-Cj 2 58 - 59 o C4Hg C~H9 (CH2~2 \ / 2 52 - 53 O ~:
~ ~ 2 ~ 6 ~able 3: Inter~edia~e products having a structural elemen~.
of the for~ula IX (R6 = C~3, R4, R7 and n: see ~able;
arr2n~ement o1 Rl,. R and R~ as for formula I) Com- Rl ~2. R3 Bulb-tu~è ~istillation Meltin~
po~ d - C mbar point C
1b ~ ~ n;4, R4=d 187-188 R Cd 2b ~ c2~s n=4, R-,R7 146 ~b E C2HS n;4,R =E~ 123-124 R = CE~3 .. . .
~b ~ C2H5 " 150 0,02 .
5b c~5 C2~5 " 130-lS0 0,027 *
. .
6b ~ " n=5,R4=~, tO~-115 .1 R7 = CH
7b ~ C~E~7 n-4, R4=E~ 150-160 0,02 R = C~3 _ _ _ ~b C~? C7H5 135-i40 n, Q1 -Sb n 1~ n=5 ~4--H 130 -0,02 R = CH3 10b `~ C3,~7 n=4, R4= H 140-150 0,OS
R7 = CH3 ~-~~~- n;1, R4= CH3 ao 0,03-0,07 C~3 . _ 12~ C ~ 3 C ~ 5 n;4, P~4- H 1~0-130 0,03 R = CH3 13b C5~1~ C}J~ " 130-140 0,03 14b " C 1 " 130-140 0,02 tS~ C~iS n-~ ~ 12~-150 0,01 - 0,02*
16b n ~srR ~, C~ 5 C3~7 140-1~0 0,2 . ~
17b " C3~17 CH3 140 0,2 ,,~ _ . . ... _ .. _.
~h.in-la~r~r evapor~tor - S~ -12~6~9 _ 59 Exampl e ~ 2 Medicament ~ormulation: For the production of 1,000 coated tablets, 100 g o~ ~-eth~1-7- ~ ~ x~y=
hex~Tl)-l-pro~ylxanthine (compound according to Example i), 20 g of lactose, 30 g of corn siarch, 8~5 g o~ talc9 0.5 g of colloidal silicic acid and 1 g of magnesium stearate were mixed and Gompressed to form tablet cores weighing 160 mgS which were then treated wi~h a coating . mix~ure composed of 40 g oi sucrose, 23.5 g of talc and very small amounts of ~rax, titaniu~ dioxide and g~m ~ ~rabic added so -thaT the final weigh of each o~ the coated tablets was 2~5 mg.
Example Medica~ent fo~mulation: For the production o.
1~00~ coated tableTs, 111.8 ~ of ~-e~hyl-~-iso-E~ eiledlo~he~ iro~y~ra~th~ne (from E~ample 1)~
20 g O~r' lactose, 3~ g of corn starch9 ~05 g of talc9 Q.5 g of col]oidal silicic ac-d ar~d 1 ~ of magnesi~m sieara-te ~rere mixed alld compressed to form ta~blet cores 2~ ~;ei~h.ing i71.8 m~, wh ch were the~.l--treated with a coa+
in~ ~ixtur e composed oi 40 ~ o~ sucrose~ 23~ g of -talc and ~er~r s~ail amourlts o.~ ~-a~, ~itanlum dic~id..e and ~um arab.ic added sv that the fina~ ~cigh-t of eacn o~ the coat~ -table-ts was 2I-LO mg~
~5 ~ a~Lr~ r~ ~L
Mcdioa~ner2 ~ r~ la-; ~on; l~`or tn~ ~.)ro luct-ioli o.;
l, ~C~l? c o~ t c~ t~ )t) ,~ c :E ~. 7 ~ t ~!y:~.~7--(~ f~ )ox~r -2~ or~ arrlp~ 2 ~) ), 20; o:~ ].ac-tc~se~ 3'~) C :~ C (~ I A 1 S ., ~ :~ C 11 J ~7 ~ ; O ~ L C, V ~ j ~, o E c o l _. ( .i. cl a l 29~
silicic acid and 1 g of magnesium stearate were mixed and compressed to form tablet cores weighing 160 mg, hich were then treated with a coating mi;~ture composed of 40 g of sucrose~ 23.5 g o~ talc and very small 2mounts of wax, titanium dioxide and gum arabic added so that the ~inal weight o~ each o,~ the coated tablets was 225 mg.
Pharmacological testin~ and results -1.' Bronchos-~asr,lol~rtic activitv .
'le cempounds accordingr to the invention were tos~ed ~or bronchospasmolytic activity essentially using ~he ex~eriment~l desiO~n described by H. Konzett and . R~ssler (Arc~. e~p. Pat~ u. Pharmak. ~ (1940) 75), comparing Wi"l tile stan~ard therapeutic agent, ~he~-'5 ~hyliine-e-ti-ly~ iami~ rl~ ~Yi~h tne tw~ 2,~ inyuro~-propyl compour~s already known diphylline[ 7-( 2,3-di-hy~-oxypropyl)-173-dimethyLYanthine] and 7-~2,3-dl-h~rd~r~Jpropyl)-1,3-dipropylxanthine. In this methodS
th~ i~ihibition of e.x~erimontal bronchspasms - induced ~y i~tra~renous adminlstr~~tion ol amines ha~ing spasmc-~nic acti-~ ty9 such as acetylcho1ii;e, histamine an~
- s~ro~onine - in Fuinea-pigs of both sexes under ure-ih~e ~laes~hesia (1.25 g/kg i.p.) .i.s inves-tiga-ted.
'~he test substances were ad~inis-tered in aaue-ous solution either in-travenously (i.v.) or in-tra~
duodcna~ly (i.d.). The ~D50 values, ~lich represent that dose in mg/kg at w'.lich the experimentally produced spasm ~ decre~se~; by one half compared to that in untrea~ed anim~ls,~lere de~el~.ined graphlc~ y ~rom the ~ose-ac~tivitv ~62 _ 61 --curves.
2. Acute toxicity __ .
Determination of the LD50 values was by the standard method of the mortality occurring within 7 5 days a7nong ~L~I m~ce after a single intravenous (i.v.), intraperitoneal (i.p.) or oral p.o.) administration.
m e results of these investigations, which demonstrate the superiority of the compounds according to the invention corresponding to formula I compared to the standard product theophylline-ethylenediamine and the two other comparison substa7ces ~particularly taking into account the more ~avorable ratio of LD50 to ~D50)~
are compiled in '~he following Table ~.
~ 62 ~ _~
, - O~
I
~ .. _ _ .__ _ _ I_ _ ~
R
~D I ~ o ~> O O O O O c~ o ~ .n I~ O
:~ I ~ ~ c~.l O O u~ o o o o ~ n ~ o ~) I~ c~ r~ t~ r~ C~l '~D C~ ~ <~ . . ~ ~0 ~o$~ I > o > > ~ ; > > > > >' i~l `~O I I c~ .,_ .~ .,_ .~ .,. i ., .,_ .. .,_ .~ .. ., + I u a r / ¦ ~ E ;~ ~
.,3 ~ O u~ c~ ~. ~ ~ ~ ~ ~n c~J 3 ~) I ~) C~) r o ~ rrl T r r 1 1 ~
r--3 1 ~) ~ C=~ ~ O ~n ¦ u~ ¦ G ¦ ~ O ~ C~ ¦ L'> 1-~
p .~. 3C~ C~ ~3 ~ D C'~ C~ ) c~ ~ ~.
rl ~lf 'Q¦ E~ r!, ~ c~
__ .. ~ .. ~ _ . _ _. _ , ~ . _ . _ . _ . , . ..... ~, _ , ... ~., _. . ~ ~, ~ _ . .. _ ._ _ _. _ . , . _ . _ . _ . ~ __ . _ -- 6~ --. .. k ~ ~
~ U~ ~f _ ~ r- ~ L~ ~ C`J . <~ ~
h a) ~ ~ . ~ ~ \/ ~
~: ~ h 0~' - ___ _ _ ~ . __ ~ ' ~_ - u~ O O O O u~ O ~ ~r- ~ .' ~ ~ o o o ~ A o c~ ~ ~ ~ ~o ~x~I > 1> - '> ~ ~
. - ~ 1~ ~ - .~ - ~ ~1 __ .
o ~ I . ~ . `
~do lc 1 . o ~ ~ o o x~
W~, ~ _--I ~ l ~ ~, E t" C-~ u~ ~ o C I o I o I ~D o ~ ¦ - ~d C o ~ C o ~o ¦ o ¦ ~ ¦ ~ O
¦ ¦ ;x~ J N ~ I ¦ C ¦ C~) P9~ A j A ~o . ~ 11 1 1 1 1 I' 11 1 1 1 .. ~q~
> I > I > I ~; I > I ~ > I ~ . I .c ~' o ~- i i r~
¦ ~ ~¦ ¦ Ul ~ ¦ O ¦ ~ ¦ ¦ ¦ r~ r~ ¦ ~r~ ?0 5~ 1 e ? ~
r~ t~ I r,~, I r.'? I r~ u ¦ ¦~ 1~) 1 ~1 ¦ t~ ~ r I ~J S~ I ~ C>
i i o ~ ~ I ~ I ~ ?o ~ ~
~ I ~L L I ! 1~ ~ aI I ~ ? ~
m e unequivocal superiorit~ of the compounds according to the inventio~, especially compared to the xanthire derivative which is most frequently employed ~or the therap~,r of obstructiYe respirGtory tract diso eases, theophylline-ethylenedia~ine (aminophylline), was also impressively confirmed in further specific experiments: -Since it is reO~a-ded as proven that, apart ~rom ~he Diogenic amines, acetylcholi~e, histamine and sero-tonineS listed in Table 4, bradykinin also plays animpo~ ~Qnt part as a mediator subs~,ance in the provoca-tiçn of ast~a a~tacks, the inhibitory ef~ect on the b~onchcspas~ induced in guirea-pi~s with-brad~kinin was inyestigated~ In this ~est, ~or e.xa~ple, the compound lrom E~am~le ls on i~travenous ti~v~) administration5 was ~ound to h~.vean ED50 o~ 1 - 3 mg/kg and aIIer intra-duodeIlal (i.d.) ad~inistration an ED5~ o~ 4~0 - 6.3 mg/kg &nd ~ S was a~out 3 times and aoout 6 times res~ectively more el~ective than theophylline-e~hylenediamine, for 20 ~r~ ~ ch the corresp3nding tota~l ED50 ~alues were .~oun~ to ~e ;, - 10 m~,/Xg i.v. and 25 - 40 m~/kg i~do The com ounds o~ the fo~ la I also e*ert a st~c~g ir~ibito~~y effect on the bronchospa~m induced with ~val~u~ln (1 m;,~k,, i,~r~ ) ln -tlle presensitized guinea-pigp 2~ ch is hardly a~fec-ted by th~ cus-l;o~a~ .xantiline derivatives . rml3 p f~r e:;a}:~ple~ tlle ~50 value ~or the COZlpO "ncl c.î Example 1 is be~een ~ and 12 mg/kg i.v. p ~:hils L tlleophy~ e-e tllylenediaminc- shows no effect in this desic~n o:E e~x~e.rimellt ~i-i;h closes up to 12 mg/l~.
l~B~
.
- ~he superior bronchospasmolytic activity of the - ~ xan~hines according to formula I was finally demonstrated - in the pulmona~y ~unction test on the anaesthetized dog - us~ ~ ~he inhibition of ~he bronchospastic reactlons ~ in~uced with aerosols of acetylcholine, histamine and - asczris ex~ract.
~ hus, for exa~ple, the compound in Example 1 alre~dy showed a significant ~nhibitory effect at 12 ~gjkg i.v., whilst theophylline, in doses up to 20 mg/kg 10 i.v., proved to have no e~fect.
-- As has already been mentioned in the introduction~
~e bronchospasmolytic effect o~ theophylline whi~h is clinlcally well establishedg is con-~r-csted by the ccnsidera`~le disadvantage of a very nar-1~ rc~ ~erapQutic ranOe comDined wiin serious side-o~tects.
p~r~icularly in the cardiovascular system (hypotensive a^~ivii~r~ decrease in cerebr~l blood flow) and i~ ~he ce~ral rervous system (l~or example restlessness, insomnia an~ ver'igo) ~ne stimulatior of the central nervous 20 sy~em is regarded by patients and clinicians as being pa~icularly distu.rbing, since it fre~uen~ly lea~s to ~so~nia and thus ilaS a persistent adverse effe^i on the g~neral state G~ healt3l o~ the asthmatic patient. A~
e~pression o~ this stimulation o.f tne central nerv¢us 25 ~sti-m is the increase in spontaneous motility o.~ male ~-ki~e mice by 186% ov~r a pe~..iod o.~ 7 ho-~rs after oral ~ ist.ation of ;~0 m~/lsg o~ theop~rlline--et3lylene- : .
di~.ine. According to Canadian Patent 1,082,184, the other t~o compariso.n procuc.ts d~rphyllin ~ 3 and 7-(2,3-dihydro~ypropyl)-l,3-dipropylxanthine also brIng ~bout a s-timulation of the cen-tral nervous system - in mice, although these effects are marXedly less pro-nounced ~han for theophylli~e. In contrast~ the compounds of the formula I acco~ding to the invention ha~e no component stimulatin~ ~le central n.ervous sys-tem7 but, on the contrary~ e~er~t a slight depressant e~fecL on the central nervous s~stem ~;~hich is assessed to be particularly advantageous from -the therapeutic 1~ point of view. Thus, the spontaneous motilit~ of miceS
~or example, is decreased by 53~ for a period of ll hours after oral admini.stration of 50 mg/kg of the com-pound lrom Exa~ple l.
m e inYestigations of the circulatory syste-~
~5 carried ou-t on rats and dogs~ comparin~ th ~theophylline-et~len~cliamine1 have sho~r.. that the c~mp,un;1s of the ~o~mula I ha~Te a h~potensive ~ctivi-l:ys ifany a-t all, ~ihich is m~r~;edly lo~er and tllat they cause no decrt?ase in cerebral bl~od :~lo-~.
Claims (29)
1. A process for the preparation of a xanthine derivative of the formula I
(I) in which one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C atoms in these two alkyl substituents being, however, a maximum of 14 and R2 and R3 not both being methyl. when R1 represents a 4,5- or 5,6-dihydroxyhexyl radical, which comprises treating a com-pound of the formula II
(II), in which one of the radicals 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, with an oxidizing agent and hydrolyzing the oxirane, which may be obtained as an intermediate in this reaction, and then alkyating the resulting diol, which still carries hydrogen in at least one of the positions of R1', R2' and R3', alone or in the presence of a basic agent or in the form of its salt, with an alkylating agent of the formula in which X denotes halogen or a sulfonate or phosphate grouping and R5 denotes the alkyl radicals defined in formula I, to give the compound of the formula I, or reacting a compound of the formula II, in which a maxi-mum of two of the substituents R1' to R3' represent the alkyl defined in formula I and a maximum of two of these radicals denote hydrogen, alone or in the presence of a basic agent or in the form of its salt, with an alkylat-ing agent of the formula X - (CH2)n - ? - ? -R4 in which the alkyl chain has a total of 4 to 8 C atoms and R4 denotes hydrogen or methyl, X denotes halogen or a sulfonate or phosphate grouping and Y denotes hydrogen or both Y together, as members of a dioxolane ring, denote a group of the formula in which R6 and R7, independently of one another, denote hydrogen, lower alkyl, phenylalkyl having up to 2 C
atoms in the alkyl moiety , phenyl, the dioxolane ring being unchanged or hydrolyzed with R6-CO-R7 being split off, and then reacting the mono-alkyldihydroxyalkylxanthine obtained, which still carries a hydrogen atom in the position of R1', R2' or R3', alone or in the presence of a basic agent or in the form of its salt, with an alkylating agent of the formula R5-X, in which X and R5 have the meanings defined above, to give the compound of the formula 1, or initially alkylat-ing a dialkylated xanthine, having a dioxolane group, with a compound of the formula R5-X and then hydrolytically cleaving the dioxolane ring with formation of the dihydroxyalkylxanthine according to formula I.
(I) in which one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C atoms in these two alkyl substituents being, however, a maximum of 14 and R2 and R3 not both being methyl. when R1 represents a 4,5- or 5,6-dihydroxyhexyl radical, which comprises treating a com-pound of the formula II
(II), in which one of the radicals 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, with an oxidizing agent and hydrolyzing the oxirane, which may be obtained as an intermediate in this reaction, and then alkyating the resulting diol, which still carries hydrogen in at least one of the positions of R1', R2' and R3', alone or in the presence of a basic agent or in the form of its salt, with an alkylating agent of the formula in which X denotes halogen or a sulfonate or phosphate grouping and R5 denotes the alkyl radicals defined in formula I, to give the compound of the formula I, or reacting a compound of the formula II, in which a maxi-mum of two of the substituents R1' to R3' represent the alkyl defined in formula I and a maximum of two of these radicals denote hydrogen, alone or in the presence of a basic agent or in the form of its salt, with an alkylat-ing agent of the formula X - (CH2)n - ? - ? -R4 in which the alkyl chain has a total of 4 to 8 C atoms and R4 denotes hydrogen or methyl, X denotes halogen or a sulfonate or phosphate grouping and Y denotes hydrogen or both Y together, as members of a dioxolane ring, denote a group of the formula in which R6 and R7, independently of one another, denote hydrogen, lower alkyl, phenylalkyl having up to 2 C
atoms in the alkyl moiety , phenyl, the dioxolane ring being unchanged or hydrolyzed with R6-CO-R7 being split off, and then reacting the mono-alkyldihydroxyalkylxanthine obtained, which still carries a hydrogen atom in the position of R1', R2' or R3', alone or in the presence of a basic agent or in the form of its salt, with an alkylating agent of the formula R5-X, in which X and R5 have the meanings defined above, to give the compound of the formula 1, or initially alkylat-ing a dialkylated xanthine, having a dioxolane group, with a compound of the formula R5-X and then hydrolytically cleaving the dioxolane ring with formation of the dihydroxyalkylxanthine according to formula I.
2. The process as claimed in claim 1, wherein a compound of the formula II, in which one of the radicals R1, R2 and R3 is an alkenyl group of the formula III, is oxidized with a compound containing peroxide groups to give the oxirane, and this is hydrolyzed in an aqueous med-ium at 20 to 100°C or is oxidized with hydrogen per-oxide, chromyl chloride, a permanganate, iodine, selenium dioxide, molybdenum (VI) oxide or osmium tetroxide.
3. The process as claimed in claim 2, wherein the oxidation is carried out with percarboxylic acids at a temperature of -10 to +40°C.
4. The process as claimed in claim 2, wherein the oxidation is carried out with Stoichiometric amounts of osmium tetroxide, and the osmium(VI) ester complex formed as an intermediate is reductively hydrolyzed.
5. The process as claimed in claim 1, wherein a compound of the formula II, in which a maximum of two of the radicals R1', R2' and R3' represent the alkyl defined in formula I and a maximum of two represent hydrogen, is reacted with an alkylating agent of the formula and the dioxolane ring is cleaved in an aqueous medium at temperatures from 20°C to the boiling point of the reaction medium.
6. The process as claimed in claim 5, wherein for a compound of the formula II, in which, after the reaction with the alkylating agent mentioned, two of the radicals R1', R2' and R3' denote hydrogen, the remaining hydrogen atom in one of the positions of R1', R2' and R3' in the dioxolane compound is reacted with an alkylating agent of the formula R5-X, R5 and X having the meanings indicated in claim 1, and the dioxolane ring is then cleaved.
7. The process as claimed in claim 1, wherein R1' or R2' represents an (.omega.,.omega.-1)-dihydroxyalkyl radical having 5 or 6 C atoms and the two alkyl substituents R2' and R3' or R1' and R2' together contain 3 to 6 C atoms.
8. The process as claimed in claim 1, wherein R3' denotes an (.omega.,.omega.-1)-dihydroxyalkyl group having 4 to 7 C
atoms or a 4,5-dihydroxyhexyl group and the two alkyl radicals R1' and R2' together contain 3 to 7 C atoms.
atoms or a 4,5-dihydroxyhexyl group and the two alkyl radicals R1' and R2' together contain 3 to 7 C atoms.
9. The process as claimed in claim 1, wherein R3' is a 5,6-dihydroxyhexyl group and the alkyl radicals R1' and R2' together contain 3 to 7 C atoms.
10. The process as claimed in claim 8, wherein R3' is a 5,6-dihydroxyhexyl group and the alkyl radicals R1' and R2' together contain 3 to 7 C atoms.
11. The process as claimed in claim 1, wherein R1' is propyl, R2' is ethyl and R3' is the 5,6-dihydroxyhexyl group.
12. A compound of the formula I
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1, .omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C atoms in these two alkyl substituents being a maximum of 14 and R2 and R3 not both being methyl, when R1 represents a 4,5- or 5,6-dihydroxyhexyl radical.
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1, .omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C atoms in these two alkyl substituents being a maximum of 14 and R2 and R3 not both being methyl, when R1 represents a 4,5- or 5,6-dihydroxyhexyl radical.
13. A compound of the formula I as claimed in claim 12 in which R1 and R2 represents an (.omega.,.omega.-1)-dihydroxyalkyl radical having 5 to 6 C atoms 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 claimed in claim 12 such that R3 denotes an (.omega.,.omega.-1)-dihydroxyalkyl group having 4 to 7 C atoms or a 4,5-dihydroxyhexyl group and the total of C atoms in the two alkyl radicals R1 and R2 is 3 to 7.
15. 1,3-Dialkyl-7-(5,6-dihydroxyhexyl)-xianthine, the alkyl radicals R1 and R2 of which together contain 3 to 7 C atoms.
16. 3-Ethyl-7-(5,6-dihydroxyhexyl)-1-propylxanthine.
17. A medicament comprising a compound of the formula I
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C
atoms in these two alkyl substituents being a maximum of 14, and a pharmaceutically acceptable auxiliary.
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C
atoms in these two alkyl substituents being a maximum of 14, and a pharmaceutically acceptable auxiliary.
18. A medicament as claimed in claim 17, containing a compound of the formula I, in which R1 or R2 represents an (.omega.,.omega.-1)-dihydroxyalkyl radical having 5 or 6 C atoms and the two alkyl substituents R2 and R3 or R1 and R3 together comprise 3 to 6 C atoms, and a pharmaceutically acceptable auxiliary.
19. A medicament as claimed in claim 17, which contains a compound of the formula I in which R3 denotes an (.omega.,.omega.-1)-dihydroxyalkyl group having 4 to 7 C atoms or a 4,5-dihydroxyhexyl group and the total of C atoms in the two alkyl radicals R1 and R2 is 3 to 7, and a pharmaceutically acceptable auxiliary.
20. A medicament as claimed in claim 17 or 19 which contains 1,3-dialky1-7-(5,6-dihqdroxy-hexyl)xanthine, the alkyl radicals R1 and R2 of which together contain 3 to 7 C
atoms, and a pharmaceutically acceptable auxiliary.
atoms, and a pharmaceutically acceptable auxiliary.
21. A medicament comprising 3-ethyl-7-(5,6-dihydroxyhexyl)-1-propylxanthine, and a pharmaceutically acceptable auxiliary.
22. A medicament as claimed in claim 17 which contains a compound of the formula I as defined in claim 17, in which R2 and R3 are not both methyl, when R1 represents a 4,5- or 5,6-dihydroxyhexyl radical, and a pharmaceutically acceptable auxiliary.
23. A medicament as claimed in claim 17, 21 or 22, in a dosage unit form, each unit containing from 20 to 1000 mg of the compound of the formula I, and a pharmaceutically acceptable auxiliary.
24. A medicament as claimed in claim 17, 21 or 22, in a solid dosage unit form, each dosage unit containing from 50 to 300 mg of the compound of formula I, and a pharmaceutically acceptable auxiliary.
25. A medicament as claimed in claim 17, 21 or 22, in a dosage unit form of an injection solution, each dosage unit containing from 20 to 200 mg of the compound of formula I, and a pharmaceutically acceptable auxiliary.
26. Use of a compound of the formula I
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C
atoms in these two alkyl substituents being a maximum of 14, for the treatment of obstructive respiratory tract diseases.
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C
atoms in these two alkyl substituents being a maximum of 14, for the treatment of obstructive respiratory tract diseases.
27. Use of a compound of the formula I
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C
atoms in these two alkyl substituents being a maximum of 14 and R2 and R3 not both being methyl, when R1 represents a 4,5-or 5,6- dihydroxyhexyl radical for the treatment of obstructive respiratory tract diseases.
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C
atoms in these two alkyl substituents being a maximum of 14 and R2 and R3 not both being methyl, when R1 represents a 4,5-or 5,6- dihydroxyhexyl radical for the treatment of obstructive respiratory tract diseases.
28. A compound of the formula I
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C
atoms in these two alkyl substituents being a maximum of 14, for use in the treatment of obstructive respiratory tract diseases.
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C
atoms in these two alkyl substituents being a maximum of 14, for use in the treatment of obstructive respiratory tract diseases.
29. A compound of the formula I
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C
atoms in these two alkyl substituents being a maximum of 14 and R2 and R3 not both being methyl, when R1 represents a 4,5-or 5,6- dihydroxyhexyl radical for use in the treatment of obstructive respiratory tract diseases.
(I) wherein one of the radicals R1, R2 or R3 denotes a straight-chain alkyl group having 4 to 8 C atoms and two vicinal hydroxyl groups in the .omega.,.omega.-1 or .omega.-1,.omega.-2 positions and the two other radicals represent straight-chain or branched alkyl groups having up to 12 C atoms in the position of R1 and R3 and up to 4 C atoms in the position of R2, the total of C
atoms in these two alkyl substituents being a maximum of 14 and R2 and R3 not both being methyl, when R1 represents a 4,5-or 5,6- dihydroxyhexyl radical for use 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 (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3138397.1 | 1981-09-26 | ||
| DE19813138397 DE3138397A1 (en) | 1981-09-26 | 1981-09-26 | "MEDICINAL PRODUCTS CONTAINING VICINALS OF DIHYDROXYALKYLXANTHINE AND PRODUCTION METHOD FOR THESE XANTHINE COMPOUNDS" |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000529856A Division 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1286292C true CA1286292C (en) | 1991-07-16 |
Family
ID=6142714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000412172A Expired - Fee Related 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 |
Country Status (18)
| Country | Link |
|---|---|
| US (2) | US4616020A (en) |
| EP (1) | EP0075850B1 (en) |
| JP (1) | JP2550301B2 (en) |
| KR (1) | KR880002300B1 (en) |
| AT (1) | ATE17005T1 (en) |
| AU (1) | AU554227B2 (en) |
| CA (1) | CA1286292C (en) |
| DE (2) | DE3138397A1 (en) |
| DK (1) | DK148844C (en) |
| ES (3) | ES8606346A1 (en) |
| FI (1) | FI73681C (en) |
| GR (1) | GR76734B (en) |
| HU (1) | HU186125B (en) |
| IE (1) | IE53911B1 (en) |
| IL (1) | IL66864A0 (en) |
| NO (1) | NO158678C (en) |
| PT (1) | PT75604B (en) |
| ZA (1) | ZA827012B (en) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4636507A (en) * | 1984-04-30 | 1987-01-13 | Hoechst-Roussel Pharmaceuticals Inc. | Host defense mechanism enhancement |
| DE3525801A1 (en) * | 1985-07-19 | 1987-01-22 | Hoechst Ag | TERTIA HYDROXYALKYLXANTHINE, METHOD FOR THE PRODUCTION THEREOF, THE MEDICINAL PRODUCT CONTAINING IT AND THEIR USE |
| EP0260428A3 (en) * | 1986-08-07 | 1989-07-26 | MEDICEChem.-Pharm. Fabrik Pütter GmbH & Co. KG | Cationic surfactants and pharmaceutical compositions containing them |
| FR2611716A1 (en) * | 1987-03-06 | 1988-09-09 | Uriach Cia Sa J | Diisobutylxanthine derivatives substituted in position 7 which are useful as bronchodilators, process for their preparation and pharmaceutical composition containing them |
| JP2661666B2 (en) * | 1988-02-19 | 1997-10-08 | ヘキスト薬品工業株式会社 | Anti-peptic ulcer agent |
| DE4109169A1 (en) * | 1991-03-20 | 1992-09-24 | Koehler Chemie Dr Franz | WATER-SOLUBLE NON-IONIC X-RAY CONTRASTING AGENTS AND AGENTS AND METHOD FOR THE PRODUCTION THEREOF |
| US5342841A (en) * | 1992-03-12 | 1994-08-30 | Kyowa Hakko Kogyo Co., Ltd. | Xanthine derivatives |
| US5473070A (en) * | 1992-11-16 | 1995-12-05 | Cell Therapeutics, Inc. | Substituted long chain alcohol xanthine compounds |
| US6469017B1 (en) * | 1998-01-16 | 2002-10-22 | Cell Therapeutics, Inc. | Method of inhibiting interleukin-12 signaling |
| GB9312853D0 (en) * | 1993-06-22 | 1993-08-04 | Euro Celtique Sa | Chemical compounds |
| US5446046A (en) * | 1993-10-28 | 1995-08-29 | University Of Florida Research Foundation | A1 adenosine receptor agonists and antagonists as diuretics |
| US5736528A (en) * | 1993-10-28 | 1998-04-07 | University Of Florida Research Foundation, Inc. | N6 -(epoxynorborn-2-yl) adenosines as A1 adenosine receptor agonists |
| US5591776A (en) * | 1994-06-24 | 1997-01-07 | Euro-Celtique, S.A. | Pheynl or benzyl-substituted rolipram-based compounds for and method of inhibiting phosphodiesterase IV |
| US5922751A (en) * | 1994-06-24 | 1999-07-13 | Euro-Celtique, S.A. | Aryl pyrazole compound for inhibiting phosphodiesterase IV and methods of using same |
| EP0799040B1 (en) * | 1994-12-13 | 2003-08-20 | Euroceltique S.A. | Trisubstituted thioxanthines |
| JPH10508032A (en) * | 1994-12-13 | 1998-08-04 | ユーロ−セルティーク，エス．エイ． | Arylthioxanthines |
| US6166041A (en) * | 1995-10-11 | 2000-12-26 | Euro-Celtique, S.A. | 2-heteroaryl and 2-heterocyclic benzoxazoles as PDE IV inhibitors for the treatment of asthma |
| US6075016A (en) * | 1996-04-10 | 2000-06-13 | Euro-Celtique S.A. | 6,5-fused aromatic ring systems having enhanced phosphodiesterase IV inhibitory activity |
| US5864037A (en) * | 1996-06-06 | 1999-01-26 | Euro-Celtique, S.A. | Methods for the synthesis of chemical compounds having PDE-IV inhibitory activity |
| US5789416B1 (en) * | 1996-08-27 | 1999-10-05 | Cv Therapeutics Inc | N6 mono heterocyclic substituted adenosine derivatives |
| US6576619B2 (en) | 1999-05-24 | 2003-06-10 | Cv Therapeutics, Inc. | Orally active A1 adenosine receptor agonists |
| EP1315508B1 (en) * | 2000-09-08 | 2004-03-24 | Cv Therapeutics, Inc. | Purine ribosides as antiarrhythmics |
| JP4483683B2 (en) | 2005-04-28 | 2010-06-16 | 日立工機株式会社 | Double screw driver |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2575344A (en) * | 1946-03-01 | 1951-11-20 | State Of Iowa | Dihydroxypropyl theophylline |
| US2517410A (en) * | 1947-08-15 | 1950-08-01 | Searle & Co | Hydroxy alkyl xanthines and the production thereof |
| DE2335170C2 (en) * | 1973-07-11 | 1989-07-20 | Hoechst Ag, 6230 Frankfurt | 1,3-Dialkyl-7- (hydroxyalkyl) -xanthines, processes for their preparation and pharmaceuticals containing them |
| DE1911279A1 (en) * | 1969-03-05 | 1970-11-12 | Eckert Dr Theodor | Process to increase the ability of drugs to be absorbed |
| US4031218A (en) * | 1976-04-28 | 1977-06-21 | Mallinckrodt, Inc. | 7-(2,3-Dihydroxypropyl-1,3-di-n-propylxanthine and a pharmaceutical composition containing same useful as a bronchial muscle relaxant |
| US4397779A (en) * | 1978-08-09 | 1983-08-09 | Baxter Travenol Laboratories, Inc. | Preparation of xanthine tracers |
| IL59664A0 (en) * | 1979-04-05 | 1980-06-30 | Wuelfing J Kg | Xanthine derivatives,process for their preparation and their use in pharmaceutical compositions |
| IT1195267B (en) * | 1980-04-15 | 1988-10-12 | Abc Ist Biolog Chem Spa | THEOFILLINMETHYLSOXANANIC DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS |
-
1981
- 1981-09-26 DE DE19813138397 patent/DE3138397A1/en not_active Withdrawn
-
1982
- 1982-09-17 US US06/420,932 patent/US4616020A/en not_active Expired - Lifetime
- 1982-09-22 DE DE8282108751T patent/DE3268041D1/en not_active Expired
- 1982-09-22 AT AT82108751T patent/ATE17005T1/en not_active IP Right Cessation
- 1982-09-22 EP EP82108751A patent/EP0075850B1/en not_active Expired
- 1982-09-23 FI FI823274A patent/FI73681C/en not_active IP Right Cessation
- 1982-09-23 PT PT75604A patent/PT75604B/en unknown
- 1982-09-24 NO NO823239A patent/NO158678C/en unknown
- 1982-09-24 JP JP57165147A patent/JP2550301B2/en not_active Expired - Lifetime
- 1982-09-24 AU AU88663/82A patent/AU554227B2/en not_active Ceased
- 1982-09-24 HU HU823086A patent/HU186125B/en not_active IP Right Cessation
- 1982-09-24 ZA ZA827012A patent/ZA827012B/en unknown
- 1982-09-24 KR KR8204320A patent/KR880002300B1/en active
- 1982-09-24 GR GR69358A patent/GR76734B/el unknown
- 1982-09-24 IE IE2322/82A patent/IE53911B1/en not_active IP Right Cessation
- 1982-09-24 IL IL66864A patent/IL66864A0/en not_active IP Right Cessation
- 1982-09-24 ES ES515936A patent/ES8606346A1/en not_active Expired
- 1982-09-24 DK DK426982A patent/DK148844C/en not_active IP Right Cessation
- 1982-09-24 CA CA000412172A patent/CA1286292C/en not_active Expired - Fee Related
-
1983
- 1983-12-16 ES ES528123A patent/ES8407048A1/en not_active Expired
- 1983-12-16 ES ES528122A patent/ES528122A0/en active Granted
-
1986
- 1986-04-04 US US06/848,139 patent/US4713455A/en not_active Expired - Lifetime
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