CA2187081A1 - Use of xanthine derivatives for reducing the pathological hyper-reactivity of eosinophilic granulocytes, novel xanthine compounds and process for producing them - Google Patents

Abstract

Use of xanthine derivatives for reducing the pathological hyperreactivity of eosinophilic granulocytes, novel xanthine compounds and process for their preparation.
Tertiary 1-(hydroxyalkyl)-4-alkylxanthines are suitable for the production of pharmaceuticals for the treatment of disorders which is associated with a pathologically increased reactivity of eosinophilic granulocytes. Novel xanthine derivatives and process for their preparation are described.

Description

W0 95/26727 2~ 8708 1 P~ P95/01060 Description ~rse of YAr~h~ne derivatives for reducing the pathological hyperreactivity of eo~inr~rh; l; C granulocytes, novel xanthine compounds and process for their preparation.
The present invention relates to the use of tertiary ydrc,~y~13cyl)-3-alkyly~nth;nD~ for the production of pharmaceu~ for th~ treatment of disorders which are ~ssociated with a pathologically increa~ed reactivity of D~s;n~philit grar~ulocytes, novel ~Anth~n~ ~ .u.ld8 having the abovementioned substitution pattern and process for their prep~ration.
The hyperreactive eosinophilic granulocyte is the focus of attention of the pathogenesis of certain pulmonary, cardiac and cutaneous disorders which are mainly classi-fied a~ of the atopic type.
The atopic type embraces disorders having an allergic diathesis, which are caused on the basis of a specific-ally modi~ied level of immunity by exogenous, noninfec-tious substances (envi, t~l allergens). Allergic disorders can in principle concern all main organ ~ystems o~ the human body and are manifested in a multiplicity of different ~l;ni~ Al symptoms such as arthalgias, asthma, erythema exsudativum multiforme, enteritis, nephritis, rhinitis or vasculitis (Wien Klin h'~-hDn~rhr (1993) 105/23: 661-668).
In clinical practice, the immunoglobulin E (IgE)-mediated immune reactions (type I allergies) dominate in the form o~ anaphylaxia, allergic bronchial asthma, allergic rhinitis and conjunctivitis, allergic urticaria, allergic 30 gastroenteritis and atopic dermatitis. There seems to be a genetic predi~position here for the reA~line~ to react to substances from the natural environment ~e.g. grass pollen, spores, house dust and mites, animal hair or food) with a hypersensitivity of the immedi~te type _ _ _ _ _ _ _ _ _ _ _ .. .. . . _ _ . .. _ . . . .

21 87~
Wt~ 95/26727 - 2 - PI~T/BPg5/01060 mediated by atopic antibodies (reagins). The incidence rate is currently approximately 10 96 of the population (P8CI1YL~ ;n; R~h~-R Worterbuch [Clinical Diction-ary], Walter de Gruyter-Verlag, 255th Edition, 1986, page 5 148~ with continually rising prevalence, in particular in the industrialized countries.
It is a worrying finding that, despite intensive attemptR
to improve poggibilitieg of A~ ~n~sig and therapy, the glob~l increage in morbidity is also linked with a rise 10 in mortality, for example in bronchial a23thma (Deutsche Apotheker Zei~ung (1993) 133/18: 1635-1636). Asthma -characterized by inflammatory procegses with progressive, irreversible damage to the airwayR - is thus the only chronic disorder in the indu8trialized countrieg, in 15 which, as a result of ;nAd~ Ate therapy, the number of cases of death are rising (Therapiewoche (1993) 43/7:
340 -341) .
According to the present state of knowledge, chronic ;nfl tion is the focal point of the p~thogenetic 20 procesa, in which a multiplicity of ~ tent cells is involved with the release of pro;nf1 tory medi-ators. It is assumed here that in the acute phase of the ;nfl tion, the so-called early-phase or immediate reaction, mainly basophilic granulocytes and mast cells 25 are involved, whereas for the chronic symptomatology with progressive tissue death and 1088 of function in the late-phase reaction eos;n~ph;1;c granulocytes and pos-sibly also neutrophilic granulocytes play the main part (Nunch. med. Wschr. (1993) 135/5: 52).
30 Basophilic granulocyteR and mast cell~, al~o known as histaminocyteEi, not only releaRe hiRtamine, but also numerous other inflammatory mediators, a_ter activation by binding of Ig~ produced in B ly~phocytes to specific high-affinity receptors on the cell surface and aub-35 se~uent crosE~linking of the bound IgE molecules by theantigen concerned. These mediators include proteases, _ ~

2 1 87~8 1

- 3 - PCT/EP9S/01060 lipld mediators, such as the platelet activating factor (PAF), prostaglandinE~ and leukotrienes, as well aa a wide b~fCt~u~ of cytokines (T h.~--COlOgy (1994) 27:
1 -11) .
S In the main, these mediators have a vaso- and broncho-constrictive action, increa6e mucus secretion and inter-vene in hemostasib regulation. I~OL~V~, chemotactic propertieg are ascribed to them, which make them capable of bilizing further cells involved in the ;nfl tion 10 procesg, inter alia also the eosinnphi 1; c granulocytes responsible for the late-phase reaction which, after activation by degranulation, likewise secrete inflam-matory mediators, whereby the ;nfl: tion process is perpetually maintained and its conversion to the chronic 15 phase is initiated.
The eosin<~ph~lir granulocyte is a highly potent effector cell having ~arked leukocyte-~rpecific properties, such aa chemotaxis, adherence, phagocytosis, release of granula proteins and formation and becretion of lipid mediators 2 0 and reactive oxygen species, which make their dominant role in the pathogenetic process of the allergic ;nfl tory reaction intelligible (Dt. Arzteblatt (1992) 89/43, A1: 3574-3585) .
The event is initiated after allergen ~I!Gc~u~ ~ by 25 recruitment of eosinophils from the bone marrow and their targeted invasion into the tissue affected by the anti-gen, which leads to a local eosinoph;l;A with subses~uent cell activation. Various immunocompetent cells, such as T-helper cells of the Th2 type, macrophages, neutrophils, 30 mast cells and ens;nnph;lF: themselves, which produce and secrete a number of factors responsible for differentiation, proliferation, migration and activation are involved in these pathophysiological processes.
These include the; l~A~ting cytokines, such as the 35 eosinophil-selective interleukin-5 (IL-5) formed by the T-helper cells, which controls both the differentiation and proliferation and the functional activation of the 2~87~
WO g5/26727 - 4 - PCT/l~P95/01060 eos~nophilic granulocytes, and the granulocyte/macrophage colony 6timulating factor (GM-CSF) with marked cell-activating action; and also the chemotactic factors simultaneously rPf~pon~;hle for migration and activation, 5 such as PAF and leukotriene B" (LTBi).
TnA~F~n~lPntly of this, the complement cleavage product C5a also has potent chemotactic and cell-stimulating activity for eo8~nrrh;1~.
The activated eO~n~lrh~ l~c granulocyte for its part also 10 reacts with mediator ~ynthesis and release in the form of granular proteins, lipid mediators and cytotoxic oxygen metaholites .
The proinflammatory lipid mediators include, in parti-cular, leukotriene C~ (LTC"), t~ A2 (TXA2) ~nd, 15 in turn, PAF, which increAse vascular permeability, cause va~oc~ Liction and obstruction of the bronchi and ~timulate mucus production (Pharmazie in unserer Zeit (1992) 21/2: 61-70). Among the protein mediators, eosin~Fh;l peroxidase (EP0) impress with enzy~atic action 20 and especially the nonen~ymatic, ba~ic proteins particularly relevant for the destructive ~- ~,ces6es, ~uch as the major basic protein (MBP), the eQs;n~ph;l cationic protein (ECP) and the eosinophil-derived neurotoxin/eosinophil protein X (EDN/EPX). PL- 'nPnt 25 among their varied biological properties are cytotoxic effects on a wide spectrum of cellg, which extends from para~ites via bronchial epithelial cells, nerve cells, cardiac muscle cells up to tumor cells. Together with the secreted reactive oxygen metaQolites, they therefore 30 contribute crucially to tissue destruction with progreEI3ive 1088 of function in areas of allergic ; n f 1 i tion reac tions .
Moreover, they also stimulate histamine release from mast cells and thus induce, in the aense of a vicious circle, 35 new early-phase attacks again.
The highly toxic protein mediators are additionally ascribed great diagnostic importance, as in patients with 21 87~8 1 WO 95/26727 - 5 - PCT/~P95/01060 disorders of the atopic type, increased ECP concen-tration3, in part$cular, can be detected i~ the serum and in other body fluids, such ag the bronchoalveol~r lavage, the sputum and nasal secretions, but also deposits of 5 these proteins in the affected tissues as a sign of the eosinophil activation which has taken place, the ECP
serum level correlating ~ n;f;r~ntly with the degree of severity of the disorder, 80 that this parameter appe~rs suitable both for objectivizing the disease zlctivity and 10 for ~n8~ ;n~ the success of treatment after t~ ic intervention (Therapiewoche ~1991) 41/45: 2946-2947).
The pathogenetic rela~;n~n~h~ps degcribed in the case of disorders of the atopic type make it clear that the allergic ;nfl: tion process which is the focal point 15 with its early- and late-phage reaction is the result of a complex interaction of immune cells and their inflam-matory mediators, and that therapeutic advances are only to be expected of a multifunctional rh~ eutical which both blocks the mediators of the immediate reaction and 20 is able in a lasting manner to inhibit the recruitment and, e3pecially, the activation of the er~8in~lrh; 1 n in the chronic late-phase reaction (Ph~ eutische Zeitung (1992) 137/5: 249-258; Agents and Actions (1991) 32/lf2:
24-33) .
25 Surprisingly, it has now been found that 1,3-dialkyl-xanthines of the f ormula I having a tertiary hydroxyl function in the alkyl radical in position 1 fulfil the afc,re t;~n~d requirements of a therapeutic suitahle for the treatment of disorders of the atopic type.
30 1- (5-~ydroxy-5-methylhexyl) -3 -methylxanthine is described in the publication W0 87/00523. It is proposed there for the treatment of peripheral and cerebral circulatory disorder3 and mitochondrial mypopathies, _ut without any information on it3 utility for the reduction of patholog-35 ical hyperreactivity of eos;n~h~l;c granulocytes andthus for the treat~.ent of atopic disorders being given.

2 1 87~8 1 WO 95t26727 - 6 - PCT/XP95/01060 Admittedly, numerous xanthine - __ '~ are known which, on nccount of their phr~lFh~; eE~ter~e-inhibitory action, have br--nrhosp-l -lytic ~ctivity and are therefore suitable for the prophylaxis and symptomatic treatment of S the acute br~n~hospA~ induced by mediators in the course o$ the asthmatic early reaction, but do not allow a curative therapy of atopic disorders, as they le~ve unaffected the underlying condition, the eosinophil-mediated, chronic ;nfl~ tion process of the late-phase 10 reaction. The most pr~ ;n~nt r~ eee.-tatives of this group of substances is theophylline.
More recently, a few 8-gubstituted 1,3-dialky~ nth;
(EP 389 286; WO 92/11260~, 1,3,7-trialkyl~r~nth;n"~
(EP 421 587) and also 7-sulfonylated 1,3-dialkylxanthines and 1,3,7,8-tetrasubstituted xanthines (WO 92/11260) have also been reported which should reduce the nulDber of eo8i noph; 1 ~ in the blood in an animal model having artificially induced eos;n~ph; ~ It was not possible, however, to show an inhibition of the functional state o$
20 the eosinophils, which is pa~h~lo~ lly raised in atopic disorders and in the finAl analysis det~rm;n~ the course o$ the disease, pr;n~-;p-lly in the tiasue affected by the allergic ;nf~ tion process, 80 that the therapeutic worth of the c _ '~ described is not c~nf; - ' .
25 On the other hand, on the level of the cellular mediators relevant for the disease event, the c __ '~ of the formula I show that they inhibit the early-phase reac-tions and, in the context of the late-phase reaction, inhibit not only the recruitment of the eos;n~ph; 1 ~, but 30 also reduce their pathological hyperreactivity in the target tissue and thus selectively switch off the effec-tor functions of this highly potent ;nfl tion cell at the centre of the chronic disease process.
The publication EP 544 391 proposes the 1,3,7-trialkyl-35 ated xanthines pentoxifylline (3,7-dimethyl-1- (5-oxo-hexyl)xanthine), propentofylline (3-methyl-1- (5-oxohexyl-7-propylxanthine) and torba$ylline (7-ethoxy~Lethyl-_ 2 1 8~08 1 1- (5-hydroxy-5-methylhexyl) -3-methylxanthine) for the topical treatment of p~oriasis and atopic dermatitis, but without any indication that l.) the~e Y~nth;ne deriva-tive~ are also active in nontopical use or 2 . ) can al~o 5 be employed topically or even n~ntopi~l ly against other di30rders of the atopic type.
The invention thus relates to the use of at least one , _ ~ of the f ormula and/or a physiologically tolerable ~alt of the compound 10 of the formula I and/or a stereoi~ 'c form of the c __ ' of the formula I, where R1 is a methyl or ethyl group, R2 iB an alkyl group having 1 to 4 carbon atom~ and X is a LY-1LOge~ atom or a hydroxyl group and 15 n is an integer from l to 5, for the produ~tion of rh~ euticals for the reduction of the pathological hyperreactivity of eos;n~ph;lic granulocytes . The compound of the f ormula I is particu-larly suitable for the prophylaxi~ and treatment o~
20 atopic disorder~ such a3 anaphylaxis, allergic bronchial asthma, allergic rhinitis and conjunctivitis, allergic urticaria, allçrgic gastroenteritis or atopic dermatiti~.
Preferably, those compoundE~ of the formula I are employed here in which R2 is a methyl or ethyl group.
25 Furth -re, the use of the c ~ of the formula I i~
preferred in which Rl and R2 ;n~r--n~ tly of one a~other WO 95/26727 - 8 - PCT/I~P95/01060 are methyl or ethyl, X i8 a L~d~vy.~ atom or hydroxyl group and n is sn integer f rom 3 to 5 .
The use of 1- (5-hydroxy-5-methylhexyl) -3-methylxanthine is very particularly preferred.
5 The inveLttion furth~~ e relates to Ltovel _ ,_ '~ of the f ormula I, aI~td/or a phygiologically tolerabl~ ~alt of the of the formula I, aLtd/or a ~tereoir ~ c form of the c _ _ ~ of the 10 formula I, where Rl i8 methyl- or ethyl, R2 i5 alkyl having 1 to 4 carbon atoms, X is a l~yd- o5~ atom or hydroxyl group and n i8 an integer f rom 1 to 5, 15 where 1- (5-hydroxy-5-methylhexyl) -3-methylxanthine is ~Y~t-~od .
C _ '~ of the formula I are preferred here iLt which R2 is methyl or ethyl, where Rl and R2 are not simultaneous-ly methyl if X is a hydLc,g~-l atom and n i8 the number 4.
20 Furthr fe, the c __ '~ of the formula I are also preferred in which X i8 a LYdLO~I atom, where R1 aI~td R2 are not simultsn~o~ly methyl if n is the number 4.
Particularly preferred c~ Lds o~ the formula I are finally those in which ~5Rl is methyl, R2 is methyl or ethyl, X is a LY-1 Vg~.U atom and Lt is an integer from 1 to 5, where R2 is not methyl if n is the number 4.

218708l WO 95/26727 - 9 - PCT/l~P95/01060 The invention fUr~h~ G' relates to an analogous process for the preparation of the novel ,_ '- o~ the formul~
I whose ~mhQrl; t8 are described in principle in Wo 87/00523. A procedure is then advantageously used in 5 which a 3, 7-disuhstituted xanthine derivative of the formula II
0 /R~
o~ NJ~ N>

in which R2 is an alkyl group having 1 to 4 carbon atoms and RA ia a readily ~l ;m;n~hle leaving group, for example the hydrolytically removable meth-, eth-, prop- or butoxymethyl radical or the reductively removable benzyl or diphenylmethyl group having unsubstituted or substi-tuted phenyl rings, is expediently reacted in the presence of a basic conden-sing agent or in the form of its salts 15 a) with an alkylating agent of the formula III
X~Z (~
in which Rl, X and n have the ah~.vG t; ~n~d mean-ings and Z is halogen, preferably chlorine, bromine or iodine, or a sulfonic acid ester or phosphoric acid ester group, 2 0 to give a l, 3, 7 - trisubstituted xanthine of the formula IV

~ Wo 95/26727 2 1~7 0 8 ~ PCT/~P95/01060 o~J ~ N

R
where Rl, R2, R-, X ~nd n have the me~ninge defined above, or alternatively in the ca~e where X ia L2 d~ ~/Y
b) with a keto - ~ ' of the formula Y
H3C-C0- (C~2) n~Z (V) in which n and Z have the ab-,v~ t;-~n~d meanings, to give a 1, 3, 7-triaubatituted xanthine of the f ormula VI
N N

thia ia then converted using a methyl- or ethyl-metal compound (Rl-M), pre~erably methyl- or ethyll-ithium (Rl-Li) or the correaponding Grignard com-pounds (Rl-Ng~al), with reductive alkylation o~ the carbonyl group into a 1,3,7-triaubatituted xanthine of the formula VII

WO 95/26727 -2111~7~ PCT/I~P95/01060 H,e,,~ N;
N N

in which Rl, R2, R~ and n have the abovementioned meanings, or alternatively in the case where X iB 1.YdLOYe~1 and Rl ia methyl, 5 c) with a carboxylic acid ester of the formula VIII
(Cl-C4) alkyl-O-CO- (CX2) ,~Z (VIII) in which n and Z have the abovementioned - -n;l~
to give a 1,3,7-trisubstituted xanthine of the f ormula IX
C4)1U~ ~'lx ,; (lX), this i8 then converted with two equivalents of a methyl-metal ~ ,~Ld, preferably CX3-Li or CX3-~6gXal, with double reductive alkylation of the ester function into a 1,3,7-trisubstituted xanthine of the formula X

WO 95/26727 - 12 - PCT/~P95/01060 O Ra where R2, R' and n have the abovementioned meanings, and finally the Y~nth;n~ of the formula I according to the invention is obtained by elimination the leaving group R' from the i~t~ te of the formula IV, VII or 5 X.
The 3,7-disubstituted xanthines of the formula II used in this context as starting materials and alkylating agents of the ~ormula III, V and VI~I are for the most part known or can easily be prepared by methods known from the literature (see, for example, WO 87~00523). Thus the tertiary z~lcohols of the formula III can be obtained, for example, by organometallic synthesi~ by reacting the sterically llnh;n~red haloketones of the formula l~al-(C~2) I-CO-CO2X in ~ ~o-called synthesia reaction with 15 reductive alkylation of the carbonyl group using alkyl metal compounds Rl-M, in which M is metal, ~pe~ lly magnesium, zinc or lithium, for example in the form of the alkylmagnesium halides Rl-lIg}lal (Grignard ~
or the alkyllithium c~ ds Rl-Li, under customary 20 conditions. A aimilar reaction of the haloketones of formula ~al- (C~2) -CO-Rl with methylmagnesium halides or methyllithium likewise leads to compounds of the formula III in which X is 11YdLO~ . A convenient accesa to compounds of the formula III in which R1 i8 methyl and X
25 is a ~lydLO~ atom is also o~fered by the reaction of alkyl w-hA1oAlkAn~ates (~Ial-(C}I2)D-COO-alkyl) with two eguivalents of a methyl-metal ~ ~, the ester _ WO 95/26727 - 13 - PCT/I~P95/01060 reacting via the ketone to give the tertiary alcohol with $ntroduction of Swo 31ethyl radicals. In the same manner, w-l~.l~ arboxylic acid esters can be converted into diols using methyl-metal compounds, without or with 5 protection of the hydroxyl group, for example in the form of the tetra~.ydL~y~ -2-yl or methoxymethyl ether or, if Ll~te, also the lactones as cyclic esters, from which active alkylating agents of the formula JII are obtained by selective esterif ication of the primary 10 hydroxyl function with sulfonic acid or rh~sFh~ric acid halides or ~Inhydrides.
The reaction of the disubstituted ~nth;n~ derivatives of the formula II with the alkylating agents of the formula I~I, V or VIII c~nrern~d iR usually carried out in 15 dispersing agent or solvent which ig inert to the reac-tion participants. Possible solvents are ~Rpec;ally dipolar, aprotic solvents, for example for---m; ~, di-methylf~r-^-m;rl.o, dimethylacetamide, N-methylpyrrolidone, tetramethylurea, hexamethylphosphoric triamide, dimethyl 20 sulfoxide, acetone or butanone; however, alcohols, such as methanol, ethylene glycol and its mono- or di (Cl-C~,) -alkyl ethers, eth_nol, propanol, is~ anol and the various butanols; hydro~-~rh~nR, such as benzene, toluene or xylenes; halogenated hydro~honR, such as dichloro-25 ~nethane or chloroform; pyridine and also mixtures of thesolvents mentioned or mixtures thereof with water can also be used.
The alkylation reactions are expediently carried out in the presence of a basic cn~ nRin~ agent. Those suitable 30 for this are, for example, alkali metal or AlkAl;n~- earth ~etal hydroxides, carbonates, hydrides or ~ n~ R and organic bases, such as trialkylamines, e.g. triethyl- or tributylamine, Siuaternary amnonium or rho8rh~n; llm hydroxides and cro~Rl inked resins having fixed, 35 optionally subatituted =nium or rh~Rphon;un groups.
The xanthine derivatives, however, can also be employed directly in the fo-m of their separately prepared salts, ~18708~
WO 95/26727 - 14 - PC~/~SP95/01060 for example the alkali metal, ~lkAl~n~ earth metal or optionally gubstitutod a~monium or rhl~Fh~ni salt~.
Fur~h~ ~, the disubstituted xanthine - _ '- c~n be conveniently alkylated both in the presence of the 5 abovementioned inorganic c~n~i~n~in~ agents and in the form of their nlkali metal or ~lk~l;ne earth metal salts with the additional aid of so-c~lled phase-transfer catalysts, for example tertiary amines, qUaternAry ammonium or rh~gph~n~um galts or alternatively crown 10 ethers, preferably in a two-phaE~e system under the conditions of a phage-tr~ngfer catalygis. Suitable, mostly commercially available phage-transfer catalysts, ~re, inter alia, tetra (C1-C4~ alkyl- and methyltrioctyl ~mmonium and rh~8Fh~n;~n saltg, methyl, myrigtyl, phenyl 15 and benzyl-tri(Cl-C")alkyl and cetyltrimethyl ~l.m salts and (Cl-C12)alkyl and benzyltriphenylrh~srh~n~um salts, where ag a rule those ~ which have the larger and more gy~metrically congtructed cation prove to be more e~fective. In the procedureg described above, the 20 reaction is in general carried out at a reaction temperature of between 0C and the boiling point of the reaction medium used in each cage, preferably between 20 and 130C, if appropriate at elevated or reduced pressure, but ugually at atmogpheric pressure, it being 25 possible for the reaction time to be from less than one hour up to several hours.
In the case of the organometallic reactions of the ~ n~h;ne8 VI and IX funct~n~ ed in the radical in position 1, the procedure is in principle carried out in 3 0 the same manner as described f or the preparation of the tertiary ~lcoh~ of formula III uged as alkylating agents. Thus the reductive alkylation of the ketones VI
or of the esterg IX can be carried out, for example, using alkyl-potaggium, -godium, -lithium, -magnesium, 35 -zinc, -cadmium, -aluminum and -tin c ,~,u..ds. The recently rec ~l~d alkyl-titanium and -zirconium c~ ds (D. Seebach et al., Angew. Chem. 95 (1983), pp. 12-26) can also be employed. A8, however, the alkyl-27 87~
WO 95/26727 - 15 - PCT/~P95/01060 metal ~ ~ of godium and potasgium are prone to 8ide re~ "n-l on account of their high reactivity and those o~ zinc and aadmium are cparatively sluggish to react, the alkyl-lithium ~nd -magnesium (Grignard) ~ are usually preferred.
The strongly nucl~rh; 1 i c o- ,_ tallic c~ re very sensitive to hydrolygi8 and oxidation. Their safe l~nr71; n5 therei~ore requires working in anhydrous medium, if appropriate under a protective gag ai _,h~re. Custom-ary solventg or digper~3ing agents ar~ prln~;p-l ly those which are algo guitabl~ for the preparation of the alkyl-metal c ~ . Those come r ~pe~ 1 l y ethers having one or re ether oxygen atoms, for example diethyl, dipropyl, dibutyl or diisoamyl ether, 1,2-dimethoxy-ethane, tetrahydrofuran, dioxane, tetraLy~ y e~ furan and anisoIe, and aliphatic or aromatic hydro~rh~n~, such as petroleum ether, cyclohexane, benzene. Toluene, xylenes, diethylh~n~n~g and tetrahydr~narhth~lene in guestion; however, tertiary amines, such as triethylamine, or dipolar, aprotic solvents, for example hexamethylphosphoric triamide, and also mixtures of the solvents ~ ned can also be used with success. In the case oi~ reaction of the carbonyl c _ ~ VI or IX with the Grignard ~ ~ds of the formula RlMglIal, a procvl~ e can algo advantageously be used in which the org~nometallic r __ ' is initially int~,d~c~d in an ether and the ketone or the egter is added dropwise as a so7nt;~n in dichloromethane or 1,2-dichloroethane. Often r~ '-1 is addition oi magnesium bromide, which on account of its participation in the complex-like cyclic transition state is ab;e to increase the nucl~oph;l;~ity o~ the organometallic c~ ,_ '.
The purification of ketone or ester and organometallic c~ _ .~.d is generally carried out at temperatures between -20 and 100C preferably between 0 and 60 or at room temperature without external cooling, the alkyl metal c __ r7 cu3tomarily being u8ed in a slight excess. The reaction ig then usually ended by brief he~ting under ~1 ~7~
WO 95/26727 - 16 - PCT/E~P95/01060 reflux, for which, as a rule, time spans of ~ few minutes up to a few hours are sufficient. The ~i~c -~ition of the A~ . formed i8 preferably carried out using aqueous: illm chloride golution or dilute acetic acid.
5 The leaving group R~ is eliminated from the _ ,_ '~ of the f~ IV, VII and X with formation of the xan-thines of the formula I according to the invention under standard conditions, which were ~pe~;~lly developed in the context of the protective group terhn;g~l~ in ~lk~loid 10 and peptide syntheses and can thus be assumed to be widely known.
The benzyl or diphenylmethyl group which is optionally substituted in the phenyl ring is then preferably reduc-tively removed. Beside chemical reduction, in particular 15 of the benzyl c~ '~ with sodium in liguid ammonia, the elimination of the two abovementioned aral~cyl groups by catalytic LylL~y~ olysis with the ~id of a noble metal c~talyst is preferably suitable for this purpose, the rl~r1 :~r t of molecular Lyl~v~eL by ammonium formate as 20 a L~lL~ye . donor often having proven suitable. The reaction medium usually used in this case is a lower alcohol, if appropriate with the addition of formic acid or alternatively ammonia; an aprotic solvent, such a8 dimethylfsrr ~m; de or in particular glacial acetic acid;
25 but also mixtures thereof with water can be used. Suit-able LydLvyG~lation catalysts are especially palladium black and palladium on active carbon or barium sulfate, while other noble metals such as platinum, rhodium and ruthenium, as a result of competing nuclear hydLOyG la-30 tion, often cause side reactions and therefore can onlybe employed to a limited extent. The l~ydLo~el~olysis is expediently carried out at temperatures between 20C and 100C and under ai -_~h~ic pre3sure or preferably slight overpressure up to approximately 10 bar, as a rule 35 reaction times of a few minutes up to several hours being needed .
The 1,3,7-trisubstituted xanthines of the formulae IV, 21 87~81 95/26727 - 17 - PCT/~P95/01060 VII and X, which carry an allcoxymethyl group in the po~ition of R~, are 0,N-acetala ^nd can ~ccordingly be easily ~1 ~ked under the customary conditions of acidic hydrolysis. Preferred radicals ~re, for example, the 5 methoxy-, ethoxy-, propoxy- and butoxymethyl group. The reaction is advantageously carried out with warming in dilute mineral acids, 3uch as hydrochloric or sulfuric acid, if ~1~L~ ate with addition of glacial ~cetic acid, dioxane, tetrahydrofuran or ~ lower alcohol as a 10 soll~hil ~ 7-er. 0cc~ n~l ly, perchloric acid or organic acids, ~uch as trifluoroacetic, formic and acetic acid, in association with catalytic amounts of miner~l ~cids are also suitable. In principle, the cleavage of the ether group can also be carried out with the aid of Lewis 15 acids, such as zinc bromide and titanium tetrachloride, in anhydrous medium, preferably in dichlorometh~ne or chloroform. In the case of cleavage in mineral acid solution, the reaction temperature is to be selected such that no noticeable dehydration of the tertiary hydroxy-20 alkyl group in position 1 occurs; it should therefore asa rule not exceed 60C.
The - __ '~ of the formula I can be deprotonated in position 7 and therefore form salts and solvates with ba~ic agents. Suitable salts for this purpose are prefer-25 ably the pharmaceutically acceptable alkali metal ~ndalkaline earth metal salts and the salts and solvates with organic bases, for example ethyl~n~ ;ne, or the basic amino acidEI lysine, ornithine and arginine. The invention thus also relates to ph~ ologically toler-30 able salts and/or ~olvates of the 1, 3-dialkylxanthines of formula I.
The tertiary 1- (hydroxyalkyl) -3-alkylxanthines of the formula I have an asymmetric carbon atom if X is hydroxyl or X is 1~YdLOYe~1 and R1 is ethyl. These c ,~ .ds can 35 thus exist in stereoisomeric forms. The invention there-fore relates both to the pure stereoisomeric and to mixtures thereof.

WO 95/26727 - 18 - PCI~ P95/01060 The novel ~r~nthine ~ l# of the formula I according to the $nvention are outstAn~l~n~ly suitablo on account of their useful rhArr~--olo~ical properties for use as active '~ in phAr~ euticals, in particular in those 5 which make possible ef f ective prophylactic ~nd curative treatment of the disorders due to pathological ~78~nr,rh;1iA hyperreactivity, such as those of the atopic type, and thus represent a substantial enrichment of rh~r~ eut~c~l resources. They can either be administered 10 per se, for example in the form of mi~ le~, in mixtures with one another or in -~ tll~n with suitable ~'Y~ri~nt8 .
The invention consequently also relates to ph~rma-ceuticals which contain at least one ~ __ ' of the 15 formula I as ~ctive c~ _ _ d, 1- (5-hydroxy-5-methyl-hexyl)-3-methyl~Anth;n-~ being excluded.
A further aspect of the present invention, which relates to ~11 _ _ '# coming under the formula I, is the productio~ of rh~r~ eutical preparations for oral, 20 rectal, topical, parenteral or inhalative administration in disorders with a pathologically raised reactivity of the eos;n~h;l;c granulocytes. Suitable solid or liquid pharmaceutical prepar~tion forms are, for example, granules, powders, tablets, coated tablets (micro)-25 capsules, suppositories, syrup#, emulsions, suspensions,lotions, creams, ointments, gels, aerosols, drops or injectable solutions in ampoule form and also prepara-tions having protracted release of active ~ ,_ ', in whose preparation AllYi l; Aries, such as excipients, 30 disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners or solubi-lizers, are customarily used. A~r;l;Aries which are often used and which may be mentioned are, for example, magnes-ium carbonate, titanium dioxide, lactose, mannitol and 35 other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose A~d its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as, for example, sterile water, alcohol#, glycerol and _ ~ 1 ~7~
WO 95/26727 - 19 - PCT/l~P95/01060 polyhydric ~1 crlh~
The rh~~~~eutical prepar~tions are pref~rably prepared and administered in dose units, each u~it containing as active constituent a certain dose of a ~- _ ' of 5 formula I. In the case of solid dose units, such as tablets, capsules and suppositories, this dose can be up to 1000 mg, but preferably 100 to 600 mg, and in the case of injection solutions in ampoule form up to 300 mg, but pre f erably 2 0 to 2 0 0 mg .
10 Por the treatment of an adult patient - d~p~n~3~n~ on the efficacy of the c _ 'R of formula I in man - daily doses of 100 to 2000 mg of active ~, ', preferably 300 to 900 mg, are irdicated in the case of oral adminis-tration and from 10 to 500 mg, preferably 20 to 200 mg, 15 in the case of inL ~.v~, oua administration.
Under certain circumstances, however, higher or lower daily doses may also be appropriate. The administration of the daily dose can be carried out either by single administration in the form of ar. individual dose unit or 20 el3e of several smaller dose units or by ~ultiple administratio~ of gubdivided doses at speci~ic intervals.
Finally, the xanthine derivatives of the formula I can also - if n~c~sary - be formulated together with other suitable active compoullds, for example antihistamines, 25 anticholi~ergics, ,~2-mimetics, rh~sph~; esterase, pho~-pholipase A2 and lipoxygenase inhibitors, PAP and leuko-triene antago~istg, corticosteroids, chromoglycic acid, nedocromil and also cyclosporin A, during the preparation of the abovementioned pharmaceutical preparation forms.
30 The structure of all c ul-ds described below and compiled in Table 1 was c~nf; -' by elemental analysis and IR as well as l}I-NMR spectra.
Preparation Examples W0 95/26727 - 20 - PCT/~P95/01060 Example 1: 1- (2 -EIydroxy-2-methylpropyl) -3_methyl-~n~h~
a) l-Chloro-2-hydroxy-2-methylpropane A 301ution of 46.3 g (0.5 mol) of l-chloro-2-propanone in 50 ml of anhydrous diethyl ether was added dropwise with stirring at 0 to 5C to 44.9 g (0.6 mol) of methyl magnesium chloride in the form of a 20 % strength 801uti ~m in tetrahydrofuran and 200 ml of dry diethyl ether. The mixture was then stirred first at room temperature for one hour and then with boiling under re~lux for ~ further hour, the tertiary s~l k~ formed was rlr_ __sel by addition of 50 % strength aqueous ~nmonium chloride solution, the ether phase was separated off and the aqueous phase was extr~lcted by shaking with ether. The conbined ethereal extracts were washed successively with aqueous sodium LYdLOS~ 1 sulfite and sodium llyd o~ll carbonate solution and a little water, dried over sodium sulfate, filtered, concentrated under reduced pressure nd the liquid residue was sub; ected to fractional distillation.
Yield: 31.1 g (57.3 96 of theory) Boiling point: 125-127C
C4}~9ClO (MW = 108 . 6) It was also possible to prepare the rl __ ' in an analogous manner from methyl or ethyl chloroacetate using twice the molar amount of methyl magnesium chloride in yields of around 60 9c of theory.
b) 7-Benzyl-1- (2-hydroxy-2-methylpropyl) -3 -methylxanthine The mixture of 25.6 g (0.1 mol) of 7-benzyl-3-methylxan-thine, 15.2 g (0.11 mol) of potassium car~onate and 11.9 g (0.11 mol) of the tertiary alcohol from stage a) in 500 ml of dimethylformamide was heated at 110 to 120C with stirring for 8 hours, then hot-filtered and evaporated under reduced preaaure. The reaidue waa taken ~1 ~7~

up with chloroform, wa~hed first with 1 N sodium hydroxid~ solution, then with water until n~utral and dried, the solvent wa~3 digtill~d of 4 in vacuo and the solid residue was recryst~ ed from ethyl acetate with 5 addition o~ petroleum ether.
Yield: 26.6 g (81.0 % of theory) Nelting point: 115-117C
C17EI20NjO3 (MW = 328.4) Analysis: Calculated: C 62.18 % ~I 6.14 % N 17.06 %
Found: C 62.60 % ~ 6.18 % N 17.00 %
It was also possible to prepare the - ~ _ ' by f irst reacting 7-benzyl-3-methylYAnthino with 1-chloro-2-prop~-none or nethyl or ethyl chloroacetate under the reaction conditionEI previou~ly described to give 7-benzyl-3-methyl-1- (2-oxv~r~,~yl)xanthine or 7-benzyl-1-neth(or eth) oYycarbonylmethyl-3-methylxanthine and then reduc-tively methylating the ~ r~yl or alkoxycarbonylmethyl ,3ide chain with methylr^-gnosi~m chloride in anhydrous diethyl ether An~l ogo~ly to stage a) .
20 c) 1- (2-~ydroxy-2-methylpropyl) -3-methylY~nthin.
13.1 g (0.04 mol) o~ 7-benzylxanthine ~rom stage b) were ~ydL~ ated with shaking in 200 ml of glacial acetic acid over 1.5 g o4 palladium (10 %) on active carbon at 60 C and 3.5 bar in the course of 100 hours. A~ter 25 cooling, the mixture wa~ blanketed with nitrogen, the catalyst was filtered of ~, the filtrate wa~ concentr~ted under reduced pres~ure and the ~olid residue was recrys-tallized from ethyl acetate.
Yield: 7 . 8 g (81. 8 % of theory) Melting point: 215-217C
Clo}Il"N"03 (MW = 2 3 8 . 3 ) Analysis: Calculated: C 50.41 % ~ 5.92 % N 23.52 %
Found: C 50.10 96 ~ 5.90 % N 23.40 %

2~ ~7~18J
WO 95/26727 - 22 - PCT/l~P95/01060 Example 2: 3-Ethyl-1-(2-hydroxy-2-methylpropyl)YAnt a) 7-B~nzyl-3-ethylxanthine 20 g (0.5 mol) of godium hydroxide dissolved in 200 ml of water were added to a su3pension of 90 g (0 . 5 mol) of 3-ethylxanthine in 500 ml of methanol and the mixture was stirre~ at 70C for one hour, then treated dropwise at the same temperature with 69.6 g (0.55 mol) of benzyl chloride, and the reaction mixture was held between 70 and 80C for 3 hours. It was then cooled, 301id was filtered off cold on a suction filter, and the product was washed with water on the suction filter, diasolved hot in 1000 ml of 1 N sodium hydroxide solution, filtered and brought to p~I 9 . 5 slowly with atirring using 4 N
hydrochloric acid. I~he crystallizate waa filtered off from the atill warm solution, washed with water until chloride - f ree and dried in vacuo .
Yield: 131 g (96 . 9 96 of theory) Nelting point: 217-218C
C14~ N~02 (MW = 270.3) b) 3-Ethyl-1- (2-hydroxy-2-methylpropyl)xanthine By reaction of 7-benzyl-3-ethylxanthine from stage a) with l-chloro-2-hydroxy-2-methylpropane from Example 1~) to give 7-benzyl-3-ethyl-1- (2-hydroxy-2-methylpropyl) -xanthine (C18~22N403 (NW = 342.2); yield: 46.1 5'6 of theory) analogously to Example lb) and subsequent LydL~,ge~olytic debenzylation (yield: 97 . 9 % of theory) ~ccording to Example lc), crude fi~al product wa3 obtained which could be purified by recrystallization ~rom ethanol.
Melting point: 217-219C
C11~l6N403 (MW = 252.3) Analysis: Calculated: C 52.37 % ~ 6.39 % N 22.21 %
Found: C 52.19 96 ~I 6.29 % N 21.75 %

WO 95/26727 ~ 7~ PCT/~P95/01060 Example 3: 1- (3-}~ydroxy-3-methylbutyl) -3-methylYAn~h~ne a) l-Chloro-3-hydroxy-3-methylbutane The compound wa~ prepared from methylr~^gn~si~ iodide and l-chloro-3-butanone (obtainable by addition of }~ydL~Jg~
5 chloride to methyl vinyl ketone in diethyl ether) or from methy~ n-~?;ium chloride and ethyl 3-chloropropionate in dichloromethane as a reaction medium analogously to Example la).
Yield: 60-70 % of theory Boiling point (18 mbar): 66-68C
C~ lC10 ~MW - 122.6) b) 7-Benzyl-1- (3-hydroxy-3-methylbutyl) -3--methyl Y~n~hi n~
prepared analogously to Example lb) from 7-benzyl-15 3-methylxanthine and the tertiary alcohol ~rom stage a).
Yield: 70 % of theory) Melting point: 92-94C
C10~}22N~3 (~W = 342.4) Analy~3is: Calculated: C 63.14 % H 6.48 % N 16.36 %
Found: C 63.10 % EI 6.43 % N 16.28 %
c) 1- (3-~Iydroxy-3-methylbutyl) -3-methylxanthine prepared by LydL~y~Olytic debenzylation o~ the product from stage b) a~alogously to Example lc).
Yield: 87.2 % of theory Melting point: 203-205C
Cll~I16N403 (MW = 252.3) Analysis: Calculated: C 52.37 % ~ 6.39 % N 22.21 %
Found: C 52.13 % ~ 6.52 % N 22.08 %
Example 4: 3-Ethyl-1-(3-hydroxy-3-methylbutyl)xanthine a) 7 -Benzyl-3-ethyl-1- (3-hydroxy-3-methyl-bu tyl ) xan thine ?,~7~1 WO 95/26727 - 24 - PCTJ~P95/01060 prepared ~n-logou~ly to Example lb from 7-benzyl-3-ethyl-Yanthin9 (Example 2a) and 1-chloro-3-hydroxy-3-methyl-butane (Example 3a).
Yield: 71. 8 % of theory Melting point: 133-135C
Clg~I2~N~03 (MW = 356.4) b) 3 -Ethyl -1- (3 -hydroxy- 3 -methylbutyl ) xanthine obtained according to Example lc) by hy-l..age~olytic debenzylation of the product from stage a).
10 Yield: 88.2 % of theory Melting point: 241-243C
Cl2~18N43 (MW = 266.3) Analysis: Calculated: C 54.12 9c }~ 6.81 % N 21.04 %
Found: C 53.89 % ~} 6.86 % N 21.03 %
Example 5 1- (4-hydroxy-4-methylpentyl) -3-methylY nt7~;n~
a) 7-Benzyl-3-methyl-1- (4-oxopentyl)xanthine 38.4 g (0.15 mol) of 7-benzyl-3-methylxanthine, 22.4 g (0.162 mol) of potassium carbonate and 26.7 g (0.162 mol) of l-chloro-4-p-~nt /n~n~ ethylene ketal in 600 ml of dimethylf~ were first reacted analogously to Example lb~ to give 7-benzyl-1- (4,4-ethylenedioxypentyl) -3-methylxanthine, which was sub~ected without further purification to a ketal cleavage by heating under reflux for 2 hours in 600 ml of 1 N hydrochloric acid. After neutralization of the mixture using concentrated ~30dium hydroxide solution, the lcetone formed was taken up in chloroform and the chloroform extract was washed with water, dried over sodium ~ulfate and evaporated to dryness under reduced pressure.
Yield: 50.4 g (98.7 % of theory) Melting point: 104-105C
C18~I20N"03 (MW = 340.4) ~1~7~
WO 95/26727 - 25 - PCT/l~P95/01060 b) 7-Benzyl-1- (4-hydroxy-4-~ethylpentyl) -3-methy~ ntl~n~
A mixture o~ 9 g (0.12 mol) of methylr-~esi-~r chloride in the form of the co~mercially available 20 % strength 5 solution in tetrahydrofuran and 300 ml o~ dichloromethane was cooled to -25C and then treated dropwise with a ~olution of 34 g (0.1 mol) of the product from stage a), the temperature rl ~ ' in~ to 20C. The mixture was subse-quently stirred ~t room temperature for a further hour 10 and treated with saturated l---n chloride solution, the organic phase was separated of f, the aqueous ph~s~
was extracted several time~ by shaking with dichloro-methane, the combined dichloromethane extract wa~ washed with water, dried and evapor~ted and the solid residue 15 was recrystAl li7ed from ethyl acetate.
Yield: 28.3 g (79.4 % of theory) Melting point: 132-133C
C19~124N403 (NW = 356.4) c) l- ~4 -Eydroxy-4 -methylpentyl) -3 -met}lyl YAnthJ n~
20 was prepared ~ccording to Exa;~ple lc) by h~..lro!3 llolytic debenzylation o~ the product ~rom stage b).
Yield: 65 . 9 % of theory Nelting point: 188-189C
Cl2El8N4O3 (NW = 266.3) 25 Analysis: Calculated: C 54.12 % E 6.81 % N 21.04 %
Found: C 53.86 % E 6.88 % N 20.93 %
Example 6: 3-Ethyl-1- (4-hydroxy-4-methylpentyl) xanthine a) 7-Benzyl-3-ethyl-1- (4-oxopentyl)xanthine Preparation was carried out analogously to Example 5a) 30 employing 7-benzyl-3-ethylxanthine from Example 2a) as 8 tarting subs tance Yield: 82.4 % of theory Nelting point: 139-141C

2 1 ~
WO 95/26727 - 26 - PCT/I~P95/01060 ClgH2zN~03 (MW ~ 354.4) b) 7-Benzyl-3-ethyl-1- (4-hydroxy-4-methyl-pentyl ) xanthine The product from stage a) was reacted with methyl-5 r~^~n-~aillm chloride analogously to Example 5b).
Yield: 81. 9 % of theory Melting point: 155-157C
C2 oH2 6N4O3 (MW 3 7 0 . 5 ) Analysis: Calculated: C 64.84 % H 7.07 % N 15.12 %
Found: C 64.95 % H 7.18 % N 15.10 %
c) 3-Ethyl-1- (4-hydroxy-4-methylpentyl)~,Anth;n~
The compound waa obtained by l.yd-~g .lolytic debenzylation of the product from stage b) ~n~ ogo~ly to Example lc).
Yield: 71.3 % of theory) Melting point: 214-216C
Cl3H2 oN4 03 (MW = 2 8 0 3 ) analyais: Calculated: C 55.70 % H 7.19 % N 19.99 %
Found: C 55.50 96 H 7.20 % N 20.23 %
Example 7: 1- (5-Hydroxy-5-methylhexyl) -3-methylxanthine 20 The preparation methods for this __ ~ are described in detail in PCT Application WO 87/00523.
Example 8: l- (S, 6-Dihydroxy-5-methylhexyl) -3-methyl-xanthine a) l-Chloro-5,6-i30propyli~ ne-3~oxy-5-methyl-hexane 1000 ml of anhydroua dimethyl sulfoxide were added dropwise in the course of 10 m$nutes at 40C with stirring to a mixture of 264 g (1.2 mol) of trimethyl-sulfoxonium iodide and 28.8 g (1.2 mol) of sodium hydride 30 which was blanketed with nitrogen. After evolution of gaa 7 ~
Wo 95/26727 - 27 - PCT~P95/01060 was complete (about 2 hours), ~ golution of 134 . 6 g (1 mol) of 1-chloro-5-h--Y~n~ in 30 ~nl of dimethyl-sulfoxide was added dropwise in the course of approximately 2 0 minutes . The mixture was subsequently 5 stirred at room temperature for 2 hours and slowly treated with 500 ml of ice-water with ice-cooling and the l-chloro-5, 6-epoxy-5-methylhexane formed was extracted with diethyl ether (yield: 130 . 5 g (87 . 8 96 of theory);
C7II13C10 (MW = 148 . 6) ) . For hydrolytic cleavage of the 10 epoxide ring, the product wa~ stirred at room temper~ture for 5 d~ys in a mixture of 60 ml of water, 600 ml of tetrahydrofuran and 1 ml of 70 96 strength perchloric ACid. It was then neutr~lized with sodium ~rh~n~t~
solut;c~n, the tetrahydrofuran was distilled off to the 15 greatest possible extent and the resulting 1-chloro-5, 6-dihydroxy-5-methylhexane was extracted with chloroform.
(Yield: 124.8 g (85.3 % of theory); C7H15C102 (16W =
166. 6) ) .
The diol wag then converted into the ~ n~ in a 20 conventional manner uging 2,2-dimeth~...y~",ane in acetone with ~cid catalysis.
Yield: 67 . 2 96 of theory Boiling point (0.5 mhar): 84-86C
Clo~}lgC102 (MW = 206.7) b) 1- (5, 6-dihydroxy-5-methylhexyl) -3-methyl-Y:~nth;n~
The diol from stage a) could be reacted quantitatively with 7-ethoxymethyl-3-methylYAnt~;ne ~n ilogo~ ly to Example lb) to give 7-ethoxymethyl-1- (5, 6-isopropylidene-dioxy-5-methylhexyl)-3-methylxanthine (C19~30N,IOs, MW =
394.5), from which, by acidic hydrolysis with simul-taneou~ opening of the dioxolane ring and removal of the ethoxymethyl radical in position 7, the final product was obtained. For this purpoEie, 19 . 7 g (0 . 05 mol) of the xanthine c _~o~n~l were heated at 70C with stirring for 15 hours in a mixture of 300 ml of 1 N hydrochloric acid and 30 ml of glacial acetic acid, and, after cooling, the ?1 8~0~
WO 95/26727 - 28 - PCT/lsP95/01060 mixture was L~nd~rcd ~lkA1in~ with sodium carbonate and washed with chloroform, then neutralized with 1 N hydro-chloric acid and extracted with chloroform. After filtra-tion on a silica gel column in the eluent chloro~orm/-5 methanol (10:1), the ev~poration re~idue was recrystal-lized ~rom ethyl acetate.
Yield: 11.5 g (7i.6 % of theory) Melting poi~t: 181-182C
C13H2~N"O" (MW = 296.3) Analysis: Calculated: C 52.69 % H 6.80 % N 18.91 %
Found: C 52.46 % H 6.90 % N 18.66 %
Example 9: 1- (5-Hydroxy-5-methylheptyl) -3-methyl~r~nth~n^
7-Benzyl-3-methyl-1- (5-oxohexyl)xanthine, prepared from 7-benzyl-3-methylxanthine and 1-chloro-5-h^Y~n-n^ analo-15 gously to Example lb), wa~3 reductively ethylated on theketo group with ethylr-~n^~3;um chloride according to Example 5b) and the 7-benzyl-1- (5-hydroxy-5-methyl-heptyl)-3-methylxanthine obtained in this process wa then l-y-lLogellolytically debenzylated under the conditions 20 of Example lc).
Yield: 70.2 % of theory Melting point: 169-170C
Cl4H22N4O3 (MW = 294.4) Analysis: Calculated: C 57.13 % H 7.53 % N 19.03 %
Found: C 56.90 % H 7.55 % N 18.96 %
Example 10: 3-Ethyl-1- (5-hydroxy-5-methylhexyl) xanthine 7-Benzyl-3-ethyl-1- (5-hydroxy-5-methylhexyl)xanthine, prepared from 7-benzyl-3-ethylxanthine (Example 2a) and 1-chloro-5-hydroxy-5-methylhexane (WO 87/00523) according to Example lb) in a yield of 65 % of theory (C21H28N"03:
MW = 384.5); melting point: 112-114C) wa~3 llydLog=~o-lytically debenzylated using jllm ~ormate as a source of hydrogen. To do this, 3.84 g (0.01 mol) of the benzyl c~ lld and 1.0 g (0.016 mol) of ammonium formate in 30 ml of ethanol were stirred over 2 g of palladium _ ~ ~7~
WO 95/26727 - 29 - PCT/l~P95/01060 (10 %) on active carbon at 35C for sever~l day~, the success$ve addition of further I ;~lm formate up to a total amount of 4.4 g (0.07 mol) having proven suitable.
The mixture was filtered, the filtrate was concentrated, 5 the residue was taken up in sodium carbonate solution and washed with chloroform, the aqueous phase was brought to pEI 4 using hydrochloric acid, the product was extracted by shaking with chloroform and, after drying and evaporAting, it was recryst~ ed from ethyl acetate.
10 Yield: 2.0 g (67.9 % of theory) Melting point: 180-182C
C14~22N4O3 (NW = 294.4) Analysis: Calculated: C 57.12 % II 7.53 % N 19.04 %
Found: C 56.77 % lI 7.66 % N 18.93 %
1 5 Exampl e 1 1: 3 - E thyl - 1 - ( 5 - hydroxy - 5 -me thylhep tyl ) xanthine 7-Benzyl-3-ethylxanthine (Example 2a) and l-chloro-5_h~Y~none were reacted An -l ogo~Rly to Example lb) to give 7-benzyl-3-ethyl-1- (5-oxohexyl)xanthine (C2~}I24N403;
NW = 368.4; yield: 81.7 % of theory; melting point:
123-125C). Reductive ethylation of the keto group with ethylmagnesium chloride according to Example 5b) yielded 7-benzyl-3 -ethyl-l- (5-hydroxy-5-methylheptyl) xanthine (C22~I3CN,,03, NW = 3g8.5; yield: 86.9 % of theory; melting point: 93-94C), which was l~yd.v~t~lolytically debenzyl-ated analogously to Example 10. The final product could be recrystallized from ethanol.
Yield: 66 . 5 % of theory Nelting point: 165-166C
ClsE24N4O3 (NW = 308.4) 30 Analysis: Calculated: C 58.42 % ~ 7.84 % N 18.17 %
Found: C 58.30 % lI 8.05 % N 18.33 %
Example 12: 1-(6-}~ydroxy-6-methylheptyl)-3_methylY~ntl~;n-~
7-Benzyl-1- (6-hydroxy-6-methylheptyl) -3-methylxanthine (C211I2ôN4O3, NW = 384.5; melting point: 83-85C), prepared with a yield of 77.5 % from 7-benzyl-3-methylxanthine and Wo 95/26727 - 3?l~7~ PCT/~P95/01060 1-bro_o-6-hydroxy-6-methylheptzme (WO 87/00523) an~lo-gously to Example lb), wa~ L~lro-~e.~olytically debenzyl-ated according to Ex~mple lc).
Yield: 82.2 % of theory Melting point: 166-167C
Cl"~22N~03 (MW , 2 9 4 . 4 ) Analysis: Calculated: C 57.12 % ~ 7.53 % N 19.04 %
Found: C 56.82 % ~ 7.74 % N 19.01 %
Exa~ple 13: 3-Ethyl-1-(6-hydroxy-6-methylheptyl)Y,-nth;n-~
10 The reaction sequence was carried out with 7-benzyl-3-ethylxanthine ~rom Example 2a) according to Example 12, the Lyd~ olytic debenzylation being carried out with ~llm formate analogously to Example 10.
Yield: 72.4 96 of theory Melting point: 163-165C
C15H2~NiO3 (MW 5 308.4) Analysis: Calculated: C 58.42 % ~ 7.84 % N 18.17 %
Found: C 57.83 % ~ 7.64 % N 18.04 %
Table 1: C ~ of ~ormula I
o ~ N~ N
N

Example n X Rl R2 Melting point C

4 2 H CH3 C2H5 241-243 WO 95/26727 - 31 - PC~r/BP95/01060 Example n X Rl R2 Melting point C

510 4 H CH3 CzH5 180-182 Ph ~-cological testing and results 10 1. Inhibitory action against the pro;nfl: ~tory medi-ators of the early-phase reaction The inhibitory action of the - ~ o_ _ormula I on the proinfl tory early-phase mediators histamine, PAF
and leukotriene D" (LTD4) was investigated on isolated segments of the respiratory tract organs of albino guinea pigs, the inhibitio~ o_ the contractions which can be caused by these mediators being used as measurement parameters .
To carry out the experiment, freshly prepared organs of male animals were uEIed in each case.
The trachea was divided into its rings, of which 5 tracheal rings in each case were linked with ~ilk thread to give a chain, suspended under a tension of 0.5 g in an organ bath containing Tyrode solution at 37C through which was bubbled 95 % 2/5 % C02, and contracted by addition of histamine dihydrochloride (bath concentra-tion: 3 x 10-7 g/ml) in the absence (control experiment) or in the presence o~ the test substances.
The lungs were cut longitn~;n~l ly into 2 to 3 strips, using which the process as described above was carried out. The tension, however, was 1 g and the contraction , _ . ... _ .. , . . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 2~7 ~7~
WO 95/26727 - 32 - PC~/EP95/01060 was induced by PAF or LTDi at ~ bath concentration of 10-9 or lO-8 g/ml.
Each experiment comprised the parallel investigation of 6 organ preparations (n = 6).

5 The assessment of the action of the preparation was carried out with the aid of the ICso values, which repre-sent that concentration in ~g/ml at which the organ contraction produced in the control experiment was reduced by half . The results are ~ ,; l ed in Table 2 .
O Table 2: Inhibitory action on the pro;~fl~ tory early-phase mediators Compound from ~ i. O.. ~ iv~ action (IC50 in ~g/ml) Example Histamine PAT LTD4 trachea lung lung Pento~cifylline 30-60 3 30-60 Torbafylline 60 3-6 10-30 2. Inhibition of the antigen-induced early-phase reac-tion in the presensitized guinea pig Albino guinea pigs of both sexe3 having a body weight of 180 to 220 g were sensitized on two succeasive days by subcutaneous administr~tion of l mg of ovalbumin (O.l %
strength dis~olved in physiological saline solution) in 2 1 ~7D~ 1 Wl) 95/26727 - 33 - PCT/EPg5/01060 each case.
20 days later, the experiment wal3 carried out according to the method of Ronzett ~nd Rossler (Arch. exp. Path.
und Pharmak. (1940) 195: 75). For this purpose, th~
5 animals were anesthetized with p^nt~ rh; t~l, artifici-ally ventilated, treated with alcuronium chloride to exclude spontaneous respiration and dividcd into groups of 6 animals in each case. By means of inL ~.v~..vu8 administration of ovalbumin as an antigen in a dose of 10 1 mg/kg, a long-lasting asthma attack wa~ induced ag a result of an acute bronrh~sp-r~ induced by mediators in the course of the asthmatic early reaction, the intensity of which was ~uantified by means of the contraction height in the thoracogr m.
15 The test preparations were likewise adminlstered intra-venously 15 minutes before antigen provocation. Instead of this, the animals of the control group received pure O . 9 % strength Elaline solution. To assess the action of the preparation, the number of animals of the respective 20 collective in which the asthma reaction was reduced by at leaJ3t 40 % relative to the control animals waa detPrm;n~d. The results are ~hown in Table 3.
3 . Inhibition of eot3;n~ph; 1 activation by mediators of the late-pha~e reaction 25 The inhibitory action of the xanthines of formula I on the activation ability of human eos;n~Fh;l;c granulocyteE~
by means of the late-phase mediators IL-5, GM-CSF, C5a and PAF was inve~tigated with the aid of the lucigenin-chemiluminescence (CL) reaction.

2 ~

Table 3: Inhibition of the antigen-induced early-phase reactlon in the gulnea pig Compound Protected animals after i v _' of from 10 mglkg 25 mg/kg 5Example number % proportion number % proportion lo 9 416 67 5/6 83 Pentoxifylline I / 6 17 2 / 6 33 Torbafylline 0 / 6 0 0 / 6 0 For thiE~ purpose, purified eo~;nophil~ were obtained from venous human blood according to known proce~ses (Arch.
Dermatol. Res. (1987) 279: 470-477 and J. Invest.
Dermatol. (1986) 86: 523-528), pretreated with tho test substances at the concentration 100 ~LM or with pure water ~positive control (A) ) at 37C for 10 minutea and then activated with IL-5 (102 U/ml), GM-CSF (103 U/ml), C5~
(10-7 M) or PAF (10-6 M) or treated with water for the determination of the bagal activity (B). The CL reaction was monitored over the course of 30 minutes meal3uring ~t 37 C . The residual activity of the cellg pretreated with the test substanceg wag calculated according to the following formula in percent of that of the positive control:

CLA -- CLB
Cl,X describes the activity af ter ~timulation of the cells pretreated with the Y~nthin~

'2 1 ~70~ 1 ,. ..
Wo 95/26727 - 35 ~ '` PCT/ISP95/01060 CLA describeg the activity af ter gtimulation of the c~lls pretreated with water and C~B describes the basal activity of unstimulated cells pretreated with water.
5 The test results are shown in Table 4.
Table 4: Inhibition of eosinophil activation by late-phase mediator~
Compolmd Residual activity in % of the positive control A
from after cri~ q~ n with 10Example I~5 GM-CSF CSa PAF

r~u~iryllill~ 57 7û 56 45 Torbafylline 58 125 51 58 4. Tnhibition of the antigen-induced late-phase re~c-15tion In a chronic long-term experiment on guinea pigs provoked with hu~an serum antigen, the inhibitory action of the C __ -1R of the formula I on the pathologic~lly raised che20tactic infiltration of eos;n~Fh;l;c granulocytes 20 into the peritoneal ~pace (in vivo) and their functional state (ex vivo~ was investigated. The animals of the preparation group (n = 6) were treated with the test substance at a daily oral dose of 80 mg/kg for 15 weeks, while the animals of the control group (n = 6) received 25 the vehicle (carboxymethylcellulose). After the third week of treatment, all 12 animals were provoked by weekly intraperitoneal administration of 1 ml of human serum antigen and 48 hours later in each case subjected to a peritoneal lavage with 50 ml of 5 % strength glucoae 30 solution in which the nunber of infiltrated eo8;nnFh;l~
and, after their isolation on rl;~c~ n~;n~ R Percoll density gr~dients (purity > 95 %; V ability ~ 98 %), the ~1 87D81 95/26727 - 36 - PCT/I~P95/01060 reactivity to PAF and C5a wer~ detenm~ned in a comparison between the two animal collectives by flow cytom~try with the aid of actin polymerization and by means of the 50yden chamber technigue.
5 In this connection, for example, the ~ d from Preparation Example 7 caused a signif icant decreaae (p < 0.01~ in the nu~ber of eos;n~h~l~ which migrated into the peritoneal space (34.9 4.8 %; x SD) compared with the control animals (42.2 5.8 %). Noreover, the 10 eo~;nophll~ of the treated animals, compared with thoae of the control animala, showed a si~n~ f~ nt reduction (p < 0.05) of the c.hemotactic migration induced by PAF or C5a; the initial phaae (< lOa) of actin polymerization induced by PAF (10 nN) was alao aignificantly decreaaed.
15 This is a clear c~nf;~~tion of the fact that the com-pounds of the formula I reduce the antigen-induced, pathological hyperreactivity of eosinol?hi 1 i c granulocytes in the ~nfli tory tissue and are therefore particularly ~uitable for the prophylaxi~ and treatment of disorders 2 0 of the atopic type .

Claims (15)

Claims:

1. The use of at least one compound of the formula I

(I) and/or a physiologically tolerable salt of the compound of the formula I and/or a stereoisomeric form of the compound of the formula I, where R1 is a methyl or ethyl group, R2 is an alkyl group having 1 to 4 carbon atoms and X is a hydrogen atom or a hydroxyl group and n is an integer from 1 to 5, for the production of pharmaceuticals for the reduction of the pathological hyperreactivity of eosinophilic granulocytes.

2. The use as claimed in claim 1, wherein at least one compound of the formula I or its salt is employed in which R2 is methyl or ethyl.

3. The use as claimed in claim 1 or 2, wherein at least one compound of the formula I or its salt is employed in which R1 and R2 independently of one another are methyl or ethyl, X is a hydrogen atom or hydroxyl group and n is an integer from 3 to 5.

4. The use as claimed in one or more of claims 1 to 3, wherein 1-(5-hydroxy-5-methylhexyl)-3-methylxanthine-or its salt is employed.

5. The use as claimed in one or more of claims 1 to 4 for the treatment and/or prophylaxis of disorders of the atopic type.

6. The use as claimed in one or more of claims 1 to 5 for the treatment and/or prophylaxis of anaphylaxis, allergic bronchial asthma, allergic rhinitis and conjunctivitis, allergic urticaria, allergic gastroenteritis and atopic dermatitis.

7. The use as claimed in one or more of claims 1 to 6 for oral, rectal, topical, parenteral or inhalative administration.

8. The use as claimed in claim 7, wherein an effective amount of at least one compound from the antihistamines, anticholinergics, .beta.2-mimetics, phosphodiesterase, phospholipase A2 and lipoxygenase inhibitors, PAF and leukotriene antagonists, corticosteroids, chromoglycic acid, nedocromil and cyclosporin A group is additionally employed.

9. A compound of the formula I
and/or a physiologically tolerable salt of the compound of the formula I, and/or a stereoisomeric form of the compound of the formula I, where R1 is methyl- or ethyl, R2 is alkyl having 1 to 4 carbon atoms, X is a hydrogen atom or hydroxyl group and n is an integer from 1 to 5, where the compound of the formula I in which R1 and R2 are simultaneously methyl, X is a hydrogen atom and n is the number 4 is excluded.

10. The compound as claimed in claim 9, wherein in formula I R2 is methyl or ethyl.

11. The compound as claimed in claim 9 or 10, wherein in formula I the radical X is a hydrogen atom.

12. The compound as claimed in claims 10 and 11, wherein in formula I

R1 is methyl, R2 is methyl or ethyl, X is a hydrogen atom and n is an integer from 1 to 5.

13. A process for the preparation of the compounds of the formula I as claimed in claims 9 to 12, wherein a 3,7-disubstituted xanthine derivative of the formula II

(II) in which R2 is an alkyl group having 1 to 4 carbon atoms and Ra is a readily eliminable leaving group in the form of the hydrolytically removable meth-, eth-, prop- or butoxymethyl radical or the reductively removable benzyl or diphenylmethyl group having unsubstituted or substituted phenyl rings, is expediently reacted in the presence of a basic condensing agent or in the form of its salts a) with an alkylating agent of the formula III

(III) in which R1, X and n have the abovementioned mean-ings and Z is chlorine, bromine, iodine or a sul-fonic acid ester or phosphoric acid ester group, to give a 1,3,7-trisubstituted xanthine of the formula IV

(IV

where R1, R2, Ra, X and n have the meanings defined above, or alternatively in the case where X is hydrogen, b) with a keto compound of the formula V

H3C-CO-(CH2)n-Z (V) in which n and Z have the abovementioned meanings, to give a 1,3,7-trisubstituted xanthine of the formula VI

(VI) this is then converted using a methyl- or ethyl-metal compound (R1-M) in the form of methyl- or ethyllithium (R1-Li) or the corresponding Grignard compounds (R1-MgHal) with reductive alkylation of the carbonyl group into a 1,3,7-trisubstituted xanthine of the formula VII

(VII) in which R1, R2, Ra and n have the abovementioned meanings, or alternatively in the case where X is a hydrogen atom and R1 is methyl, c) with a carboxylic acid ester of the formula VIII

(C1-C4)alkyl-O-CO-(CH2)n-Z (VIII) in which n and Z have the abovementioned meanings, (IX) to give a 1,3,7-trisubstituted xanthine of the formula IX, this is then converted with two equiva-lents of a methyl-metal compound in the form of CH3-Li or CH3-MgHal with double reductive alkylation of the ester function into a 1,3,7-trisubstituted xanthine of the formula X

(X) where R2, Ra and n have the abovementioned meanings, and finally the leaving group Ra is eliminated from the intermediate compound of the formula IV, VII or X with formation of the xanthine of the formula I
and this, if desired, is converted into a pharma-ceutically acceptable salt.

14. A pharmaceutical, which comprises a therapeutically effective amount of at least one compound of the formula I as claimed in one or more of claims 9 to 12 or prepared as claimed in claim 13.

15. A process for the production of a pharmaceutical as claimed in claim 14, wherein at least one compound of the formula I as claimed in one or more of claims 9 to 12 is brought into a suitable administration form using pharmaceutically suitable and physiologically tolerable excipients and additives, diluents and/or other active compounds or auxiliaries.