Note: Descriptions are shown in the official language in which they were submitted.
~633~7
- This Application is a Divisional of Canadian P~tent
Application Serial Nu~ber 412,172, Filed September 24, 19820
The invention relates to new medicaments which
are sultable, in particular, for the treatment of
obstructive diseases of the respiratory tract, the
uharmacologically active vicinal dihydroxyalkylxanth-
ines contained in them, processes for the preparationo~ these xanthine derivatives and intermediate products
for this purpose.
m e xarthine compounds, which act as phospho-
diesterase inhibitors, have a pre-eminent position among
10 the bronchospasmolytic agents hitherto known (c~. B.
Hellwlg; M~d~rne Ar~neimittel (Mode~n D~ugs)~S~att~art
1980, page 1,274)S since they have no ~2-sympatho~imetic
activity and are thus particularly suitable for the
long-term therapy ~hich is always necessary for chronlc
15 obstructive disorders of the respiratory tract. 0~
this group o~ substances, the naturally occurring xan-
thine derivativetheophylline (1,~-dimethylxanthine),
has been the undisputed agent of choice in asthma ther-
apy for several decades now. Its activity, which is
20 clinically well established, is, however, contras'ed by
the disadvantages of its very narrow therapeutic range,
its serious gastrointestinal, cardiovascular and renal
side-eLfects, as well as those.in the central nervous
sys~em, and the fact that it can onl~ be used enterally
25 due to its lack.o~ water solubility, and these
~6;~38'7
disadvantages are the basis for the desire OL clinicians
for, and the pharmaceutical research directed at find-
ingS products having a greater ther~peutic safety.
It has in fact been possible, by t}e prepara-
tion of water-soluble salts or addition compounds, such
as, for example, theophylline ethylenediamine (amino-
ph~rlline), to obtain formulations of theopkylline which
can also be administered parenterally, but bhese ~re
not associated with a significant increase in the thera-
10 peutic range or a decrease in the abovementionedundesired side-effects; especially since the ethylene-
diamine itself, which functions as a solubilizer in
am~inophylline, exerts a deleterious effect on the cardio-
vaccular system.
Thus~ there haYe been many attempts to obtain,
by va.riations in the structure of the theophylline mole-
cule, better tolerated compounds having5 if possible, a
greater bronchospasmolytic activity.
e only synthetic theophylline derivative which
20 has found a certain therapeutic use is diphyllinc [ 7-
(2,3-dihydro~ypropyl)-1,3-dimethylxa.nthine]. The
2r3-dihydroxypropyl group in the 7-position does confer
a good water solubility on this product, so that the
un~lesired use of solubilizers ~or parenteral administra-
25 tion is no longer nec.essary and the int.erferingtheophylline-like side-effects are much less pronounced,
but these advantages are, at the same time, paid for by
a drastic decrease in the bronchospasmolytic activity
co~pared to that of theophylline.
.~
.
... ,. i . ~; ... . . .
63387
4 --
In systematic continuatlon of these investiga- -
tions, the .~o methyl groups in the 1- and 3-positions
hàve been exchanged ~or longer alkyl groups, while
retaining the 2,3-dihydroxypropyl radical in the
5 7-position of the xanthine skeleton. This led to
7-~2,3-dihydrox~-propyl)-1,3-dipropylxanthine, which is .
described in Canadian Patent 1, 082,184 and
which is a compound readily soluble in water, which is
said alnlost to reach the bronchospasmolytic activity of
10 theophylline and, at the same time, to have a lower
acute toxicity and fewer disadvantageous side-effects.
Nevertheless, this product has not hitherto found
acceptance in ast~ma therapy. Further~ore, according
to the abovementicned Offenlegurgsschrift, it induces
}5 stimulation of -the centra3. nervous system~ although
this is markedly weaker than that of theophylline, which
can lead to restlessness and sleep disturbances.
Accordingly, water-soluble xanthine compounds, which
are superior to theophylline in respect of strength of
action and therapeutic range and which induce no sig-
nificant side-effectsS in particular no.stimulation o~
the cen-tral nervous system, would still represent a
genu.ine enrichmellt o~ the the~apy of obstructive dis-
orders of the respira-tory tract.
~5 . It has now been found, surprisingly., that
increasing the length of the dihydroxypropyl radical,
which has not hitherto been investigated~ irrespective
of i-ts posi~tion on the xanthiné skeleton, leads to com-
pounds which fulfil these stric.-t therapeutic demands.
~;33~7
_ 5 _
It is true that ~rc xanthine derivatives of this type,
namely l-(5,6-dihydroxyhexyl)-3 7 7-dimethylxanthine and
1-~4j5-dihydroxyhexyl)-3 7--dimethylxanthine in the
threo and erythro forms, have already been described in
~ne literature (Arzneimittelforschung (Drug Res.) 22,
1,151 (1972)), but these compounds were merely
isolated and identified as metabolites of the vasof,hera-
peutic agent pentoxifylline. Accordingly, there
are no da-ta on their pharmacological properties in this
0 pu~lication.
us, the present invention relates to medica-
~ents which contain vicinal dihydroxyalkylxanthines of
the general formula I
K
R~
~/~3 ~ /> (I) .
12
R
wherein one of the radicals Rl, R2 or R3 denotes a
straight-chain alkyl group having 4 to 8 C atoms and
~Q vicinal hydroxyl groups in the ~,~-1 or ~ 2
posltlons and the two other radlcals represent straighL-
- chain or branched al~yl groups having up to 12 C atoms
in the position of Rl and R3 and up to 4 C atoms in the
posit:lon of R2, the total of C atoms in these two alkyl
~bstituents belng a maximum of 14.
In this context~ those medicaments are pre-
ferred whlch contain compo~mds of the formula I ln which
~3;3 ~7
-- 6 --
- Rlor R2 represents zn (w,~ dihydroxyall~1 radical having5
or 6C atoms and the two alkyl substituents R2 and R3 or
~1 and R3 together comprise 3 to 6 C atoms.
R fur~her preferred embodiment of the invention
relates to medicaments which contain those compounds of
. the formula I in which R3 denotesan (~,w~ dihydroxy-
alkyl group having 4 to 7 C atoms or a 4,5-dihydroxy~
hexyl group, and the total of C atoms in the two
alkyl radicals R1 and ~2 is 3 to 7. Among these
medlcaments, those in turn are particularly preferred
which contain those compounds o~ the formula I in which
R3 represents a 5,6~dikydroxyhexy1 radical, such asf for
example, in 3-ethyl-7-(5,6-dihydroxyhexyl)-1-propyl--
xant.hine.
A fur~her particular embodiment of the invention
comprises the compounds of the,formula I not being
a~ministered per se, but in the form of a prodrug, from
which the dihydroxyalkylxanthines, having bronchospasmo-
lytic activity; with their substituen-ts Rl, R2 and R3
2~ defined in the foregoing, can only be liberated by bio-
transformation in the organism. For this purpose, for
example, the epoxides
having the structural element of the for~ula IV and, in
particular, the acetals ` havin~-
the structural element of the formula IX, when these &recompletely alkylated, which are dealt with below as
intermediate products in the preparation process, are
- suitable.
The invention also relates to new vicinal
,, .~ . .
~L2633~7
- - 7 -
- dihydroxyalkylxanthines of the formula I, in which one
of the radicals Rl, R2 or R3 denotes a straight-chain
alkyl group having 4 to 8 C atoms and two vicinal
hydroxyl groups in ~,w-l or w~ -2 positions and
5 the ~wo other radicals represent straight-chain
or branched alkyl groups havillg up to 12 C atoms in the
position of Rl and R3 and up to 4 C atoms in the posi~-
tion of R2, the tota- of C atoms in these ~o a7ky
substituents being, however, a maximwm of 14 and R and
R3 not both being methyl, when Rl represents a 4,5- or
5,6-dihydroxyhe~yl radical.
In this context, particularly suitable compounds
are those in which Rl or R2 represents an (w,~-l)-di-
hydroxyalkyl radical having 5 or 6 C atoms and the two
alkyl substituents R2 and R3 or R1 and R3 together con-
taln 3 to 6 C atoms, and also those ~herein R3 denotes
~n(~,~-l)-dihydroxyal~yl group having 4 to 7 C atoms or
a 4,5-dihydroxyhe~yl group, and the two alkyl radicals
Rl and R2 together contain 3 to 7 C atoms. Amongst the
20 compol~ds mentioned latterly, the 7-(5,6-dihydroxyhexyl)-
1,3-dialkylxanthines having a total of 3 to 7 C atoms in
the two alkyl radicals R1 and R2, s~ch as, for example,
3-ethyl-7-(5,6-dihydroxyhexyl)-1-propylxan-thine 9 in
turn represent particularly preferred compo~ds accord-
25 ing to formula I.
The invention further relates to processes forthe preparation of the vicinal dihydroxyalkylxanthines
according to formula I.
An example of a process comprises starting with
~6~3~7
-- 8 --
xanthines of the formula II
. ~ ~3'
R
0~1 '
R
in which one of theradicals Rl, R2 or R3 is an (~-1?- or
(w-2)-alkenyl group of the formula III
-(CH2)n-CX=CH-R4 (III),
having 4 to 8 C atoms, R4 denoting hy~rogen or methyl,
and -the other two substituents represent hydrogen or
alkyl as defined in formula Is and
a) reacting them on the olefinic double bond with suit-
10 able oxidizing agents to give n~w epoxyalkylxanthines -
having the structural element of the formula IV
-(CH2)n-CH-CH-R4 (IV),
'\G(
and hydrolytically opening their oxir2ne ring with forma-
tion of dihydroxyalkylxanthines having the structural
15 unit o~ the formula V
--( CH2 )1l-CH-CH-R4 (V )
OH OH
or
b~ dihydro~ylating on the olefinic double bond with
customa~y oxidizing agen-ts to give direc-tly the dihyd-
20 roxyalkylxantnines having the structural elementcharac-terized by formula V,
.
~ 6 ~3 ~7
_ g .
and then alkylating those diols obtained according to
a) or b), which still car~ hydrogen in the positions
of Rl, R2 and/or R3~ optionally in the presence of basic
agents or in the form of their salts, with alkylating
5 agents of the formula VI
R5-X (~I),
In which X denotes halogen, preferably c~lorine or bro -
mi~e, o.r a sulfonaie or phosphate grouping and R5
derotes the alkyl radicals defined. for formula I to
10 give the compounds of the formula I.
~ he alkenyl-, monoalkyl- and dialkyl-alkenyl-
xanthines of ~he formula II used as starting ma+erials
in this process are known, inter alia, from Canadian
- Patents 1,123,435 and 1,12~,083.
~xamples of suitable oxidizing agents for the
epoxidation of the olefini.c side-chain according to
formula III are chromium(VI) oxideS preferably.in acetic
anhydride and carbon disulfide or carbon tetrachloride;
or compounds containing peroxide groups, such as potas-
siu~ peroxomonosulfate in the presence of ketones,
preferably acetone, in a homogeneous phase or in a ~wo-
phase system with phase-transfer catalysis, perox~
boranes,.which are advantageously produced in situ from
boric acid or its derivatives and hydroperoxides; -tri-
25 phenylsilyl hydroperoxide; hydrogen peroxide in thepresence of coreact.~nts, such as, for example~ aliphatic
or aromatic carbonitriles (for example acetonitr le or
benzonitrile), optionally substituted cyanamide or
.
. ~2633~7
-- ~o -- .
isocyanates (for e~ample phenyl isocyanate); hydrogen
peroxide or al~yl or ara~yl hydroperoxides, such as,
for example, tert.-butyl hydroperoxide, l-phenylethyl
hydroperoxide and cumene hydroperoxide, in the presence
5 of either basic agents or, pre~erably, particular cata-
lysts, such as, for example, tungstic acid, vanadium(V)
oxide, molybdenum hexacarbonyl and vanadium or molyb-
denu~ acety~acetonates; and, in particular, percarbo~ylic
acids, such as, for example, performic, peracetic, tri
10 fluoroperacetic, monopermaleic, monopersuccinic, per-
benzoic, 4-nitroperbenzoic and, preferably, 3-chloro
perber.zoic and monoperphthalic acid.
Epoxid2tion with the aid of percarboxylic acids
(Prileschajew reactlon) is advantageously carried out in
.
a solvent or distributing agent which is inert towards
the reactants and which has been found to exe~t a con-
siderable effect on the rate of reaction. Since
solvents which can form hydrogen bonds with the per-
carboxylic acids generally decrease the rate of reac-
tiOll, aromatic hydrocarbons, such as benzene or toluene,arld halogenai:ed hydroca~bons, such as dich]olomethane,
chloroform or carbon tetrachloride, are frequently pre-
ferred to ethers, such as diethyl ether, dioxane,
tetrahydrofuran or ethylene glycol dimethyl ether, alco
25 ~-hols, esters and carbo~lic acids. The reaction is
customarily carried out at temperatures between -10
and +40C, preferably at room temperature~ the reaction
time varying from a few minutes up to several hours.
The percarboxylic acids are usually employed for
~L~633~7
the reaction in an-isolated form, but they can also be
produced in situ in the reaction mixture from, for
examples the corresponding carboxylic acid and hydrogen
peroxide.
On using peracids of strong carboxylic acids, -
such asp for example, trifluoroperacetic acid, it is
advisable to decrease the acid concentration by working
in a heterogeneous system or bytne addition ol~buf~er sub-
stances~ such as sodium carbonaté, sodiunt bicarb~nate or
disodium hydrogen phosphate, in order to suppress undes-
- ired secondary reactions of the carbo~ylic acid, which
is produced in the reaction, with the initially formed
epoxide.
The epoxyalkylxanthines according to form~la II
hav ng the ~truc~t~ral ~nit of the fûi~u'a I~ cân, hG~
ever, also be obtained by base-catalyzed dehydrohalo-
- . genation of corresponding ~alogenohydrins, which in
curn can be obtained, for example, by adding hypohalous
aci~s, such as, for example, hypochlorous acids9 to
the olefinic double bond of the alKellylxanthine~ accord-
ing-to formulae II and IlI. The reaction:of these
olefins with N-halogenostlccinimides, such as N-bromo- -
succinimide, or chloramine ~ in water or mixtures of
solvents containing water also leads to the nalogeno-
hydrins. The basic dehydrohalogenating agents usuallyused are alkali metal or alkaline eartll me-tal hydrox-
ides or carbonates, prcferably sodium potassitlm or
calcillm nydroxide or soditLm or potassium carbonate, but
organic bases or other oxiranes~ such as ethylene oxide
33 ~7
- 12 -
or 1,2-epox~propane, can also be employed successfullyO
m e eFoxyalkylx~nthlnes can ~ither De isolated
in the pure form or further processed ~s crude productsO
The hydrolytic clea~age of the epoxyalkylxan-
. _ .. . ....
thines to give the ~iGinal diols having the structuralelement of the formula ~ is carried out in an aqueous
medium, to which, if necessary to increase ~he solu-
bility, an organic so]vent which is miscible with ~iater
i's added, for example tetrahydrofuran7 dioxane or eth~1
ene glycol dimethy' ether, advantageously in the
presence of acid catalysts~ preferably weakly nucleo- -
philic acids, such as sulfuric, perchloric or p-toluene-
sulfonic acid, or strongly acid cation exchanger resins
(~or e~ample Nafion-H)~ at tempe-atur~s be-~een 20 and
15 100C, bui preferably at room temper~ture, by stirring for
several hours. However, in principle, the oxi.ralle ring
opening is also possihle under neutral or alkaline
conditions.
Customary oxidizing agents for the direct vici-
20 nal dihydrox~rlation o~ the alkenylxanthines according
to formulae II and III to give the dihyd-oxyalkylxan-
thines char~cterlzed by the structural unit of formula
V9 are represented byl for example, hydrogen peroxide
in the presenc.e of form.ic acid or glacial acetic acid,
~5 chromyl chloride, potassium permanganate~ triphenyl~
methylphosphonium permanganate, iodine in the presence
of silver carboxylates or thallium(l) carboxyla-ces, such
as, for e;~ample, thallium(I) acetate, seleniùm dioxide,
molybderum(VI) oxide and, i.n par~icularg osmium
* denotes trade mark.
33~7
-- 13 --
~etroxide. .
When using osmi.wm ~tetroxide as the oxidizing
agent~..the reagen~ can eil~her be employed in the stoi-
chiometric amo~nt or in catalytic amounts with the
addition of a secondary oxidizing agent, which regener~
ates the osmium ~etroxide from ~he initially produced
cyclic esters, with oxidati~e hydrolysis to give the
diols.
,' Xn the non-catalytic dihydroxylation of the ole-
finic double bond with stoichiometric amounts of osmium
-~etroxide, the process is advantageously carried out n
sol~e1lts not having a reducing action, preferably ethers,
. such as diethy] ether, tetrahydrofuran and dioxane, or
hydrocalbons, such as benzene, cyclopentane or cyclo-
hexane, optionally with the addition of a tertiaryamine, such as, in particular, p-~rldine or qu.inoline,
- isoquinoline, 3- or 4-picoline, at temperatures be~een
0C and the bolling point of the particular solvent,
preferably at room temperature, it being possible .,or
the reaction times to be from a few minutes to several
hours. Then the osmium(~rI) ester complexes, which are
produced as intermediates in this process, are advan-
tageously reductively hydrolyzed, the use of sodium or
potass~um sulfite or bisul~ite, hydrogen sul,ide, lith-
ium aluminum hydride or catecllol or alkaline mannitol~olution in a4ueous or aqueous-alcoholic medium having
been found particularly useful. However, oxida-ti.ve
hydrolysis of the complexes is 21so possible; but it
is ad~Tisable, in this case, to carry out the
.
~2633~7
4 --
dihydroxylation at t~.e outset with cataly~ic amounts
of osmium tetroxide in the presence of secondary oxidiz-
ing agents, such as, for example, hydrogen peroxide,
metal chlorates (for example sodium or potassium and,
i~ particul~r, silver or barium chlorate)~ sodium per-
chlorate, oxygen, sodium perlodate or hypochlorit~ and,
in particular, tert.-butyl hydropero~ide or trialkyl-
; amine N-oxides (for example ~-methylmorpholi.ne .~I~o~ide,
trlmethylamine N-oxide or triethylamine N-oxide).
The alkylation of the dihydroxyalkylxanthines
~ith the compounds of the formula VI is usually carried
out in a distribu-ting agent or solvent which is inert
towards the reactants. Dipolar aprolic solvents, Io..
example formamide5 dimethylformamide, dimethylacetamide~
~5 ~-m~thylpyrrolidone, tetramethylureaf hexamethylphosp}loric
triamide, dimethyl sulfoxide, acetone or butanone are
particularly suitable; ho~;ever, alcohols, such as metha-
nol, ethylene glycol and its ethers, ethanol, propanol~
is~propanol and the various butanols; hydrocarbons,
such as benzene, toluene or xylenes; halogenated hydro
oarbons,suchas dichloromethane or chloroform; pyridine
and mixlures of the solvents mentioned or their mix-
tures with water can also find use.
1'he reactions are advantageollsly carried out in
the presence of a basic condensing agent. Examples o~
suitable agents for this purpose are al~ali metal or
alkaline earth metal hydroxides, carbonates, hydrides,
alcoholates or organic bases, such as trialkylamines
- (for example triethylamine or tributylamine), quaternary
:~ ~63~Y~7
-- 15 --
- ammonit~m or phosphcrium hydroxides and crosslinked
resir.s having fixed ammoniunt or phosphonium groups,
which are optionally substi~uted.
However, the xanthine derivatives can also be
employed directly in the al~ylation reaction in the
form of their salts pre~ared separately, such as the
alkali metal, alkaline earth metal or optionally sub-
stituted ammonium or phosphoniu~ sal~s. Furthermore,
the dihydroxyalkylxallthines and their monoalkylated
10 derivatives can be readily all~ylated both in the pre-
sence of the abovementioned inorganic condensing agents
and also in the fo~m of their alkali metal or alkaline
earth metal salts, with the assistance of so-called
phase-.rans~er catalystss for ex~mple ter-tiary amines,
]5 ~udte,na-i~ a~o~ m ur ph~sphoIlium salts or crown ethers,
preferably in a t~o-phase sys-tem under the conditions
of phase-transfer catalysis.
In the introduction of the alkyl radicals by
~le prooedures describe~ in the foregoing, the reaction
20 is generally carried out at a lemperature between 0C and
the boi]ing point of the reaction meditLm used in each
case~ preferably bet~een 20 and 130C, if appropriate
tmder elevated or reduced pressure, but usually under
atmospheric pressure, it being possible for the reac-
tion time to be from less -than orle hour to several hours~
In -this process for those dihydroxyalkylxanthines,
into which ~o all~yl radicals are still to be introduce~,
eicher ldentical or different substituents can be
at-tached consecuti~ely or t~ro similar alkyl g~roups can
.2633~37
-- 16 --
be at~cached with the xanthine skeleton without isola-
tion of in~e~ediate products in a one-pot reaction.
A further process for the preparation of com-
pounds of the formula I, which is like~ise preferred,
comprises reacting xanthines of the formula VII
. .
~ R
0 ~ (VII)~
R
in~.rllich amaximum oftwo ofthe substituents Rl to R3 rep-
resent the alkyl àefined for formula I and a formula of
t~ro of these radicals denote hydrogen, optionally in
the presence ol basic agents or in tne form of their
salts
a) with alkylating agen-ts.of the formula VIII
X - (CH23n - CH - CH - R4
\ / (YIII),
~ \ 7
in which the alkyl chain has a total of 4 t.o 8 C atoms
and R4 denotes hydrogen or methyl, R6 ~nd R7, independ-
encly of one another, denote hydrogen, lower alkyl
preferably having up to ~ C atoms, phenylalkyl having
up to 2 C atoms in the alkyl moiety or optlonally su~-
sti~uted phenyl and X denotes halogen, preferably
33~37
-- 17 --
chlorine or bromine, or a sulfonate or phosphate group~
ing,to give new dialkylated or trialXylated xanthines
having the structural element of the formula IX
~~C~2)n ~ IH ~ IH ~
O \ f (IX)
~6/ ~ ~7
5 and opening their 1,3-d~oxolane ring hydrolytically,
split~ing off R6-Co-R7 and forming dihydro~yalkyl-
xanthines having the structural unit of the formula V
-~CH2)n - ~ CIi -
o~ OH
or
b) ~lith alkylating agents of the Lormula X
Y~ - (C~I2) n ~ fI~ - IH R (Y.)
OH OH
in which the alkyl chain has a total of 4 to 8 C a-toms
and- ~4 and X have the meanings indicated for formula
VIII, directly to gi~e the dihydroxyal'l~ylxanth mes,
having tne structural element characterized by
fo~mula V,
and then reactirlg the monoall;yldihydroxyalkylxanthines
obtained according to a) or b), ~hich still carry a
hydrogen atom in the position of Rl, R2 or R3, op~tion-
ally in the presence cf basic agents or in tlle form of
~ ~633~7
their salts with alkyiating agents of the formula VI
P.5 X (VI)
in rh-ch X and R5 have the meanings defined for formula
Yl in claim 12, to give the compounds of the formula
5
or initially alkylating the dialkylated xanthines pre-
pared according to a), having the structura- element
.of.~he ~ormula IXs with ~le compounds of the formula
~5~ (VI) and then hydrolytically cleaving the di~
oxolane rin~ with forma~ion ofthe dihydroxyalkylxantll-
ines according to formula I.
m e monoalkylxanthines or dialkyl~anthines of
the formula ~rII and the alkylating agents OI the for-
m~lae VIII and X used as starting materials in this
process are lar~ely k~o~.m or can easily be prepared by
methods kno~n from the literature.
~ hus, the compounds of the formula VIII, ~or
example, can be obtained from the triols of the formula
XI
~Q -- ( cu ) -- C!I -- C~ -- R
2 n ~ I (XI )
0~1 01~
by reaction of the two vicinal hydroYyl groups with alde-
- hydes or ketones or with their acetals, ~Yith proton
catalvsis, and subseqlent replacement of the isolated
terminal hydro~l function with halogen using inorganic
acid halides, or its est.erification ~r-th sulfonyl or
phospho.nyl halides or al~lydrides, advantageously in the
~ ~6 ~3 ~7
-- 19 -
- presence of basic agents, from which in turn the com-
pounds of the formula X can be prepared by acid hydroly-
sis of the l,~-dioxolane ring. The alkenyl halides of
the formula XII
Hal-(CH2)n-CH=CH-R4 (XII)
can also serve as starting materials for the prepara-
tion of compounds of the formulae VIII and X, ei ~her by
subjecting them, as described for the alkenylxanthines9
to epoxidation on the olefinic double bond and then
10 hydrolyzing the oxirane ring with acid or by oxidizing
in a one-step reaction directly to the dihydroxyalkyl
hal.ides of the formula X and converting these, if appro-
priateS ~ith aldehydes or ketones.or their acetals into
1,3-dioxolanes o~ the formula ~III.
m e reactions of the xanthine derivatives with
the alkylating agents of the formulae VI, VIII and X
are advantageously carried out under the reaction con-
ditlons already described in detail for the alk~lation
of the dihydroxyalkylxanthines and monoalkyldihydroxy-
alkylxanthines with the compounds of the formula VI.
~Iowever, if the compounds of the formula X are used to
introduce the dihydroxyalkyl radical, those hav,ng a
total of either 6 to 8 C atoms, when R4 has the meaning
o~ hydrogen, or 7 or 8 C atoms, when R4 denotes a
25 methyl group, in the alkyl chain are preferred, since
the diols of the formula X having shorter chains have a
par-~icular tendenc-y to ~orm tetrahydrofuran derivatives
under the alkaline conditions of the alkylation reac
tion, which can lead to a noti.ceable reduction in the
2633t~3
-- 20 --
yields of desired alkylation product~.
m e hydrolytic cleavage of the 1~3-dioxolane
ring in the xanthines of the formula V~I having the
structural element of the formula IX to give the d~hyd-
5 roxyalkylxanthines characterized by the structural ~nitof the formula V is normally carried out in an aaueous
medium, optionally with the addition of a solubilizer,
such as tetrahydrofuran, dioxane or ethylene glycol
din~ethyl ether, advantageously in the presence of acids,
10 for example formic, oxalic, ~a~taric, citric, sulfuric,
perchloric, phosphoric or p-toluenesulfonic acid, or an
a id ion exchanger (for example Nafion H)s at tempera-
tures between 20C and the boiling point of the reaction
mixture, preferably 50 and 100C5 it being possib~e
15 ~G-' the -eaction time to be f~om several ~inu-tes to a
few hours. ~oist silica gel, having a water content
up to 10%, is also a reagent which can be used for the
deacetalization, the reaction preferably belng carried
out in optionaily halogenated hydrocarbons, such as
20 benzene, toluene, dichloromethane or chlorofolm, at
room temperature.
A further method for preparing the xanthines of
the formula VII with the structural element of the for-
mula IX containing the dioxolane ring comprises adding
25 carbonyl compounds of the formula R~-Co-R7 onto the
oxirane ring of the epoxyalkylxanthines according to
~ormula II, having the struc~ural unit of the ~or-
mula IV. m is reaction is advantageously carried out in
the presence of acid catalysts, ~referably Le~is acids,
Z~33~ .
-- 21 --
such as boron trifluoride, zinc(II) chloride~tin(IV)
chloride or copper(II) sulfate, at temperatures between
0 and 60C. However, quaternary ~onium salts, for
example tetraethylammonium halides, are also able to
catalyze the addition reaction to give the cyclic .
acetals.
The vicinal dihydroxyalkylxanthines of the for~
mula I have either one or two asymmetric C atoms~
depending on the position of the two hydro~rl groups in
10 the side chain according ~o formula V, and can thus be
present in stereoisomeric forms. lThe invention thus
relates both ~ the pure scereoisomeric compounds and
also to their mixtures~
The medicamerts acoording to the invention can
be a.tnin stered orally, ~ec'.al3;, parentela'ly VL as an
a.erosol.
Examples of suitabie solid or llauld galenic
formulations are granules, powders, tablet~ 5 coated tab-
lets, (micro)capsules, suppositories~ syrups5 emulsions,
suspensions, aerosols, drops or injectable solutions as
well as ~ormulations ~ith protracted release ol the act-
ive compo~d5 in the preparation of which, auxiliaries,
such as vehicles, disintegrants, binders, coating
agents, swelling agents, lubricants or emollients,
flavoring materials 5 sweetening agents or solubilizers
are used. ~xamples of frequently used auxiliaries which
may be mentioned are lactose, mannitol and other sugars,
talc, lactal~umin, gelatin, starch, cellulose and its
derivatives~ animal and vegetable oils, polyethylene
6;~3~7
-- 22 -- ;
glycols and solvents, such as, for example, sterile
water.
'~he for.mulations are preferably produced and
administered as dosage units, each unit containing a
sp~cified dose of active substance according to ~ormula
I. m is dose can be up to 1,000 mg,.but preferably 5G
to 300 mg~ for fixed dosage units, such as tablets, cap--
sules and suppositories, and can be up to 200 mg, but
p~eferably 20 to 100 mg, for injection solutions in
10 vials.
For the treatment of an adult pat-ent suffering
from bronchial obstruction, daily doses of 100 to 500 mg
o~ active compound, preferably 200 to 300 mg, on oral
administratior. and of 20 to 150 mg~ preferably 40 to ~0
5 mg, on intravenous a~inistratio- arc in~ioatcd, depend~
i~g on the effectiveness of the compounds according to
formula I in humans. In certain circumstances, however,
higher or lower daily doses can also be approprlate.
The administration of the daily dose can be carried out
- 20 either by a single administration in the form o~ a
single dosage unit or of several smaller dosage units 5
or by several a~ministralions of sub-divided doses at
specified intervals.
Finallys in the preparation of the abovementioned
25 galenic formulationsS the xanthine der vatives of the
formula I can also be formulatedtogether with other suit-
able active compounds~ for example antiallergic and
ailtitussive agents, expectorants, sédatives, peripheral
vasotherapeutic agents, antihistamines and also other
~6 3~'87
. - 23 -
bronchospasmolrticagents, such as ~2-sympathomimetic
agents or parasympatholytics.
Exam~les
~he structure of,all tne compounds described in
5 the follo~Ying text was confirmed by elementary analy~
sis and IR and lH I~R spectra.
Exam~le 1
Ethyl--7-(5,6-dihvdroxs~hexvl~ ro~ lYanthine~
a) ~=~ydroxy-5,6-isopro~vlidened~o~yhexane
H0 (C~2)4-lH ~2
O\ O
.,/\
~3C: C~3
- ~ ml of 98~'strength sulfuric &cid were added '
drop~.~ise in the course of 5 minutes to a mixture of
830 g of 1,236-hexanetriol (97~0 pure) and 828 ml of
2,2-dimethoxypropane (98% pure) at room temperature.
Af-ter stirring for a further hour at 25C, 30 g o~
potassium carbonate ~ere added~ the mixture was stirred
another hour and then vacuum-distilled over a 10 c~
packed colu~n.
Yield: 897 g (86% of theory)
Boiling point (0.5 mbar) 83 - 87C
Re:Eractiv~ index nD =1.4452
.
~33~7
-- 2~ --
- b) l~Chloro-5,6-iso~ro~lidenedloxyhexane
Cl - (CH2)4 - IH I~2
\~
~ C/ \CH
.
77 ml ofthionyl chloride were added dropwise
with stirring in the course of ~ hours to a solution of
5 176.4 g of 1-hydroY~y-5,6 isopropylidenedioxyhexane and
155 ml of triethylamine in 1,300 ml of toluene at
5 - 7C internal temperature. After stirring at
2~ - 25C for a further half an hour, the mixture was
heated at 70C until evolutiorl of S02 was complete
(about 4 hours~. m e mixture was then cooled do~m and
t~e precipi~ate whicll s~para~ed out ~ras flilered off
~Jith suct on. After washing ~rIth 100 ml of toluene,
the toluene phases were combined, washed to neutrality,
dried and evaporated under reduced pressure. 15 g of
potassiws carbonate ~rere added to the residue and this
~ras distilled in vacuo over a packed colwnn.
Yield: 149.6 g (77.6S' of theory)
Boiling ~point (0.15 mbar) 4~ - 50C
Re~ractive index I~8 = 1.44&2
c) 3-EthY] ~ 6-lso~ropylidenedioxyhexyl)Yanthirle
~ . .
o ( f H 2 ) ~ f 12
H3C / CR3
Cl~2-C~I3
:
.
3 ~7
- 25 -
A mixture of 360.4 g of 3-ethylxanth~nej 40902
g o~ l-chloro-5,6-isopropylidenedio~xyhexane and 284.7
g of potassium carbonate in 3 1 of dimethylformamide
was heated at 100C ~ith stirring for 2 hours. After
evaporation of tne suspension under reduced pressure,
the residue was taken up with 1.1 1 of 2N sodium hyd-
roxide solu~ion and thoroughly extracted with methylene
chloride. The collected me~hylene chloride phases
were washed again with 2N sodium hydroxide solulioIl,
therl washed with water to neutrality, dried and evapor-
ated under reduced pressure. 94.5 g o~ crude 3-ethyl
1,~-bis(5,6-isopropylidenedioh~hexyl)xanthine were
obtained as a by-product. The combined aqueous phases,
which were alkaline with sodium hydroxide, were treated
dro~ e with 33% s-trenOth sulfllric acid at room
temperature, with stirring, ~ntil pH 10 was reached.
The precipitate ~laS filtered off with suction, washed
to neutrali~y and dried at 100C in vacuo.
Yield: 508 g ~75.5~ o~ t~leory); 9
Melting poir.t: 123 - 124C
C16H24N404 (~Y - 336-4)
Ana]vs~s: calculated: C 57.13% H 7.19% N 16.66%
found: C 56.92% H 7.21% N 16.68%
dj 3-Ethyl-7-(5;6-dihvdrox~hexvl)-l-Prop-~lxanthine
( I 112 ] ,~ . CEI2
H3C-C~2-CH ~ ~ ~ OE~ OH
Cli2 -Cli 3
.
33~7
-- 26 --
~ 336.4 g of 3-ethyl-7-(5,6-isopropylidenedioxy-
hexyl)xanthine, 151 g of l-bromopropane and 138 g of
potassit~t carbonate in 1.5 1 of dimethylformamide were
stirred for 48 hours at an internal temperature of 70C.
After removal of the solvent under reduced pressure,
the residue ws taken up with methylene ch-oride, ~ashed
with dilute soditlm hydroxide solution and the neutIal
i7ed and dried methylene chloride phase was evaporatedO
~he residue was heated in 1 1 of sulfuric acid, at a pH
10Of 0.5~ for 2 hours at 100C. After cooling down, the
mixture was neutrali ed, evaporat~d t~tder reduced pres-
sure and the residue was taken up wi~h me-thylene
cllloride. The methylene chloride phase was washed with
dilute sodit~t hydr?xide solution and with water, dried
15 and evaporated t~lder reduce~~piessure.
The crude product ~as recrystallized from metlly-
lene chloride/diethyl ether.
Yield: 259 g (76.5~/o of theory~
Melting point: 96 - 98C
Cl~H26N404 (I~l = 338-4)
~alysis: calculated: C 56.79% H 7.74~o N 16.56%
~ found: C 56.86% H 7.56% N 16.60,,~
Exa~le 2:
..
, 3-D~l~=b~lhine
( CH 2) 4 - f ~ ClH 2
~13C-cH~ . OH H
CH -CH 3
~6331~7
-- 27 --
~ A) A mix'cure of 62.5 g of 1,3-diethylxanthine,
62.7 g of 1-chloro-5,6-isopropylidenedioxyhexane, 42~7
g of potassium carbonate and 450 ml of dimethylformamide
was stirred at 120C for 10 hours. A~ter evaporation
under reduced pressure, the residue was taken up with
300 ml of lN sodium hydroxide solution and extracted
with methylene chloride. The methylene chloride phase
was washed with dilute sodium hydroxide solution, washed
to neutrality, dried and evaporated under reduced pres-
sure. The crude product was distilled under 0.027 mbarand at a bath temperature of 1~0 - 150C in a thin-
la~er evaporator, and 107.2 g were obtained.
3-Diethyl-7-(5,6-iso~rG~lidenedioxyhexyl~xar.lhinG
O ~ 4 - fH ~ ~H2
~3C-C~
C~2-CH3
~le latter was taken up in 1.~ 1 of methanol
and 353 ml of water and, after the addition of 1.5 ml
of perchlorlc acid (7~% strength), was stirred at 70~
for 1 hour. After cooling dol.~n to room temperature,
the mixture was neutralized with sodium bicarbonate
solution and evaporated co dryness under reduced pressul~e.
T~e residue was ext~iac'~edwlth 1.5 1 of methylene chloride
and the extrac-t was evaporated. 92.5 g (95% of theory)
of crude product were obtained, which, after recrystal-
lization twice fro~ mechylene chloride/diethyl ether
~;~63387
- 28 -
(~olume ratio 2 : 3), gave 1,3-diethyl-7-(5,6-dihydroxy-
he~yl)xanthine, which was pure by thin-layer
chromatography.
Yield: 81.7 g (83.9% of theory)
Melting point: 94 - 95C
~ 15H24N44 (~1 = 324.4)
Analysis: calculated: C 55.54/~ H 7.46% N 17~27%
found: C 55.52% H 7.52yo N 17.02%
B) The above product was also obtained by hydroly-
sis o~ 1,3-diethvl-7-(5,6-e~oxyllexyl~xarlthine (melting
point: 58 - 59C)
!15C~/ ~2)4-C\~-~C-~2
. C,2~5
.
in analogy to Example 3.
C) The same compound was also obtained by hydroxyla-
tion of ~ ethyl-7-(5-hexenyl)xanthine
5C~12) ,~~C~l=C~2
C2~s
with os~ium tetroxide: 0.73 g of ,3-diethyl-7-(5-hex-
enyl)xanthine in 11 ml of diethyl ether was added drop-
wise with stirring in 5 minutes to 0~65 g of osmiumtetroxide in 11 ml of diethyl ether at room temperature.
.. . .
,.
.......... ... .
i33~37
29 -
After standing overnight, the precipitate (lr2
g) was filter~d off with suction. This was stirred
under reflux in a mixture of 55 ml OI water, 15 ml of
ethanol ar.d 11.2 g of sodium sulfite heptahydrate for 3
5 hours. After coolin~; down, the precipitate formed was
separated off and the filtra',e was extracted with methy-
lene chloride. After drying ancl evaporating the col-
lected methylene chloride phases under reduced pressure,
0.6 g of crude product ~as ob~tained, which gave
- 10 ~.3-diethyl-7-(5,6-d hydro~he~rl)xanthine as the mono- -
hydrate after recrystallization from diethyl ether.
Yield: 0.47 g (57.7% of theo~y)
Melting point: 77 - 78C (monoh~,-drate)
C15H24N44-H2~ r = 342.4)
15Aralysis: calculated: C 52.62% H 7.65~o N 16.35/~
found: C 52.480/o H 7.69% N 16.2Q%
xamp] e 3:
l ~im. ethvl -7 - (~L6-d ihydro~h exSTl ~ xanth in e
a) 1 ~-Dimethyl-7- ( 5, 6-e~o~hexyl ) xanthine
( I H 2 ) 4 ~ C\ / ~ 2
20~3C~
A solution of 31 g OI 1, 3--dimethyl-7-(5-hexenyl)
xanthine and ~4.9 g of m-chloxoperbenzoic acid (70%
pure) in 700 ~11 of chloroform was stirred at room
te.nperature for 48 hours. The mix-ture was: shaken with
25 lO~o s trength sodium di thionite solution until the test
~63~37
~o
- with starch-iodide-paper was negative, and washed with
sodium bicarbonate solutioIl and then with water to
neutrality, dried and evaporated under reduced pressure.
Purification of the crude product was ~y means
of column chromatography on silica gel (mobile phase:
methylene chloride/acetone, volume ratio 7/3) and by
recrystallization from petroleum ether.
Yield: 20.8 g (63.20~o of theory), melting point
! 59 - 6~C
13 18 4 3
y~calculated: C 56 10~ H 6.52% N 20.13%
found: C 55.87% H 6.51% N 19.91%
b) 1,3-Dimethyl~-7~ 6-dih-~droxyhexYl~.Yanthine
)4_lH_IH~
~3C-~ ~ ~ OH OH
C 3
0024 ml of perchloric acid (70,' strength) was
added dropwise with stirring in 5 minutes to a solution
o~ 3.6 g of 1,3-dimetllyl-7-(5,6-epox~hexyl)xanthine in
280 ml OL a mixture of ethylene glycol dimethyl ether
and ~Jater (volume ratio 3 : 2) at roo~ temperature.
A~ter s~irring at room tempera~ture for 16 hours, the
mixture W3.S neutralized with sodium bicarbonate solu-
tion and evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel
(mobile phase: chlorofor,~/ethanol~ volume ratio 8/2)
and recrystallization from ethyl acetate
,
~G3387
-- -- 31 --
Yield: 3 g (7& . ~qb o f theory)
Melting point: 98 - 100C
Cl3H20N404 (~J = 2~6.3)
Analy~: calculaied: C 52.69% H 6.80~o N 18.91%
found: C 52.39% H 6.7~6 N 18.83%
Bo~th the reaction of l,3-dimethyl-7-(5-hex-
enyl)xanthine ~rith osmium tetroxide in analogy to
Example 2 C) and also the alkylation of 1,3-dimethyl-
xanthine with l-chloro-5,6-isopropylidenedioxyhexane
and subsequ~n'L, acid hyd~lysis of the dioxolane ring
according to ~xample 1 o'r 2 A) led to the s~me compound.
Example 4
Dibutvl-7-(~,4--dihydrox~-butvl)xantlline
a) l~ Dibutyl--7-(3,4-e~oxvbvt,yl ~ e
f CH~-C~I2--~, H2
il3C-(C~)3 ~ ~ o
) -C~
39,4 g of m-chloroperbenzoic aci.d (70~0 pure)
were added to a solution of 42.7 g of 1,3-dibutyl-7-
(3--butenyl)xarlthine in 900 ml of chloroform within l~
~,ir,utes, with stirring. hfter.stirring at room -tempera-
ture for 27 hoursj the ~.ix-ture was washed with 10,b
~trength sodi~.~ dithionite solution, saturated sodium
bicar~onate .solution and waterj dried and evaporated
under reduced pressure. The res:idue was cnroma+ographed
on a'silic~a gel column with a mixture of methylene
~;33~37
-- 32 --
c~iloride/aceto~e (7 : ~, v: v) and recrystallized
from petroleum ether.
Yield: 19 g (42.4~ of theor~7)
Melting point: 52 - 53C
C17H26N43 (~Y = 334.4)
Ana~yxis: calculated: C 61.06~o H 7~84~ N 16.755'
__
found: C 61.01% H 7.89% ~ 16.74
b) 1,3-Dibut~1-7 (3,4-dlh~droxvbutvl)xanthine
~C~2)2- CH ~H2
H3C-(CH2)3 ~ ~ OH OH
lC~ )3-C~3
0.~ ~1 of perchlo:^ic acid (70% strength) was
added clrop~rise ~Yith stirring in 5 minutes to a solution
of 7 g of 1,3--dibutyl-~-(3,4-epox~butyl)xanthine in 300
ml of a mi~ture of ethylene glycol dimethyl ether/water
(volume ratio 3 : 2) at room temperature. After stir-
ring at room temperature for 45 hours5 ~he mixture was
neutralized with sodium bicarbonate and the solution
was evaporated. The re,sidue was t~ken up with methylene
chloride and purified by column chromatography on silica
gel wi-th a mixture of chlorofcrm and ethanol (volume
r~-tio 8 : 2) as the mobile phase and by recrystalliza-
tion from methylene chloride/petrolellm ether.
Y ld: 4.8 g (65,b of theory)
~leltin~ point: 92 - 93C
Cl~H28N404 (~n~ = 352.4),
~63~3~37
nalysis: calculated: C 57.946 H 8.00% N 15.90,b
fo~d: C 58.06% H 8.060~o N 15.77%
Alternatively, this diol can be obtained by a
one-step oxidation of 1,3-dibutyl-7-(3-butenyl)xanthine
with osmium tetroxide in analogy to Example 2 C) or by
alkylation of 1,3-dibutylxanthine with the l-halogeno-
~,4 isopropylidenedioxybutanes known from the litera~ure
(for example Tetrahedron ~4 (1978), pages 2,873 -
2,878) and subsequent acid hydrolysis of the dioxolane
ring in analogy to Example 1.
EY.am~le 5
~3-Diethyl-7-(6,7-dihydrox~heptyl)xanthine
a) l-Bromo-6~7-ePoxyhe~tane
2 ~ \ / 2
. ` ' O
37.~ g of 1-bromo-5-heptene were added dropwise
within 40 minutes, with stirring and flushing with
nitrogen, to 50.~ g of m-chloroperbenzoic acid (~5~
pure) in 300 ml of methylene chloride at room
temperature.
After standing overnight, the precipitate was
~iltered off with suction and the filtrate was washed
with 10% strength Na2S204 solution, with saturated sodium
bicarbonate solution and with wat2r and (after-drying)
evaporated under reduced pressure. 42.2 g of crude
l-bromo-697-epoxyheptane were obtained.
33
- 34 -
~ b) l-Bromo-6,7-dihvdroxy~ptane
OH OH
Br-(Ci~2)5-CH-CH2
42 g of 1-bromo-6,7-epoxyheptane were introduced
into ~ mixture of 400 ml of tetrahydrofuran and 235 ml
of wacer, which had been adjusted to pH 2 with per-
chloric acid, at rocm temperature. After stirring at
room temperat~re for ~ hours, the mixt~re ~Yas neutral-
ized, evaporated under reduced pressure and the residue
was extracted with methylene chloride. A~ter removal
of the solvent~ 41 5 ~ of crude 1-bromo-6,7-dihydrox~-
heptane were o~tained.
_~ .
c) l-Bromo-6,7-isopropvlidenedio~vhe~tane
\ /
.
~ O
Br-(CII2)5-CH CH2
0.1 ml of concentrated sulfuric acid was added,
15 wi-th stirring under nitro~en,-to 41 g of 1-bromo-6,7-di-
hydroxyheptane and 22.2 g of 2,2-dimethoxypropane in
100 ml of acetone at room tempera-ture. After 4 hours,
0 6 g of sodium bicarbonate was added. After s-'cirring
for a ~urther one hovr, the solid was filtered off, the
filtrate was evaporated under reduced pressure and the
residue was subjected to fractional vacuum distillation.
.
, ,, ,:~ ,~, .. . .
~633~'7
-- 35 --
Yie-d: 38 g (77.9YO cf theory~ -
Boiling poin~ (0.4 ~bar) 73 - 76C
Refractive index n20 = 1.4556
d) 1,3-Diethyl-7-(6,7-dihydrox~he~tYl~xanthine
.
- (CH2)s~ H2
~5C2 ~ OH OII
I C~H5
1~.9 g of l,~-diethylxanthine, 18 g of l-bromo-
6,7-isopropylidenedioxyheptane and 9.5 g OL potassium
carbonate in 100 ml OL d~methylformamide ~lere ileated at
100C with stirring for 7 hours. After evaporation
under reduced pressure, dilute sodium hydroxide solu-
tion was added to the residue and this was extracted
-several times with methylene chlorlde. The collected
methylene chloride phases were washed with water, dried
and evaporated. The residue was distilled in a bulb-
1~ tube apparatus under OoOl mbar and at a bath tempera-
ture of 100 - 1]5C. 17 g of 1,3-diethyl-7-(6~7-iso-
~____ edioxvhe~-tvl ~aothine were obtained, which
. . .
were ta~enup in 70 ml of sul~uric acid at a pH o. 0.5
and heated under reflux for 2 hours After cooling, the
m:ixture was neutralized~ evaporated ~mder reduced pres-
sure and the residue was recrystallized ~rom methylene
chloride/diethyl ether.
" ~ , ,, .,. . , ~., ~.
33~37
_ 36 --
~ Yield: 13.8 g (61~i% of theory)
Meltin~ point 105C
C16H26N404 (~IW = 338 . 4)
Analysis: calculated: C 55.79% H 7.74% N 16.56~o
5found: C 56.83% H 7.70% N 16.67%
m e l-bromo-6,7-dihydroxyheptane prepared in
step b) can also be employed directly for ~he alkyla-
tion of the 1,3-diethylxanthine in step d) without
previous reaction with 2, 2-dime ~oxypropane to giv~ tne
dioxolane derivative.
xample 6
.
~,7-Diethyl-1-(4,5-dihydrox~hexyl) anthine
a) l-Chloro-4-hexene
Cl-(CH2)3-CH=CH-CH~ ~
476 g ~4 moles) of thionyl chloride were added
from a dropping funnel to a solution of 330 g (3.3
moles) of 4-hexen-1-ol (Organic Syntheses, Vol. 55,
page 62 et seq.) in 400 ml of pyridine, with stirring
and cooling in ice, in such a manner that the reaction
temperature did not exceed 55C. The mixture was then
heated at 80C for 1 hour. Thereaiter, the mixture was
allowed to cool down slowly~ water was added and the
mixtvre was extracted several times with diethyl ether~
m e combined ether extracts were ex.tracted by shaking
with saturated sodivm bicarbona-te solu-tion, washed with
water to neutrality, dried over sodiv~ sulfate and
evaporated vnder norma pressure. l-Chloro-4-hexene,
~rhich was pure by gas chromatography, was obtained by
~L2633~7
- . . -- 37 --
- fractional distillation of the residue under reduced
pressure.
Yield: 196.2 g (50.1% of theory)
Boiling point (]40 mbar) 80C
Refractive index n21 = 1.4400
b) ~s7-Diethyl~ 4,5-dihvdrox~rhexyl~xanthine
R IH2 CH3
CH3-~H-IH-(cH2)3 ~ ~
CH2 3
20.8 g (0~1 mole) of 3,7-diethylxanthine, 15.2
g (0.11 mole) of potassium carbonate and 13.0 g (0.11
mole) of 1-chloro-4-hexene in 600 ml o~ dimethylforma-
mide were stirred at 110C ~or 18 hours. After cooling
down, the mixture was filtered, th filtrate was evapor-
ated ~nder reduced pressure and the residue was taken
~p in chloroform. lhe ~nreacted 3,7-diethylxanthine
was removed b-y- extracting with lN sodium hydroxide
solution by shaking, the organic phase was washed to
neutrality with water, dried over sodium sulfat;e and the
solven-t was distilled off in a rotary evaporator. After
dryin~ the solid residue from evaporationS 27.5 g (94.7%
of theory) of crude ~,7-di thyl-1-(4~hexenyl)xanthine
were ob~ained,
~ ~633~7
- 38 -
;
~H3-Cu=c~-(cl~2)3 ~
.. .
which,after dissolving in 350 ml of chloroform and add-
ing 23.1 g (0.114 mole) of 3-chloroperbenzoic acid (85%
pure)~ras stirred under a nitrogen atmosphere at room
temperature ~or 48 hours. The mixt~re was then initi-
ally e~tracted by shaking with 10,' strength sodium
dithionite solution until the iodine-starch reaction
disappeared, and then with 10% strength sodium bicarbon-
ate solution, and the solution was washed with water
until neutral and free of salt9 dried 2nd evaporated
under reduced pressure. 29.0 g (100% of theory) of
c~lde 3,7-diethyl-1-(4,5-epoxvhex~l)xanthine were
.
obtained
CH -C~l-\H-(CH~)3 ~ 15
~2~5
which, af-ter beir~g taken up in a solvent mixture com-
posed of ~50 ml of tetrahydrofuran and 100 ml of water
and addition of 0.46 ml of perchloric acid (70% strength),
was stirred at room temperature for 90 hours. The mix-
ture was then neutralized ~ith saturated so~ium bicarbon- .
ate solution, the solven-t was dlstilled orf under reduced
.
.:
.
~LZ6~ 7
-- 39 -- -
pressure and the residue was chromatographed on silica
gel with chloroform as the mobile phase. This produced
26.4 g (86% of theory) of a ~rystalline product, which
was recrystallized from ethyl acetate/petroleum ether~
and wilich was almost pure by thin-layer ch~omatographyO
Yield: 21.5 g (70% of theory)
Melting point 91 - 93C
C15H24N404 (i~ = 324.4)
~nalvsis: calculated: C 55.54~ H.7.46g~ N 17 27
found: C 55.54% H 7 . 59% N 16 . 97~o
m e same compound was obtained by a one-step
oxidation of 3,7-diethyl-1-(4--hexenyl)xanthine with
osmium tetroxide in analogy to ~xample 2 C).
Exam~le 7
3-But~l-1=~4,5-dihydroxyPen~yl)-7-methylxanthine
~ CH3
0~ ON ~ ~
(CH2~3 3
33.3 g (0.15 mole) of 3-butyl-7-methylxanthine,
24.3 g (0.16 mole) o~ 1-bromo-4-pentene and 22.1 g
(0.16 mole) oi potassium carbonate in 500 ml of dimethyl-
formamide were heated with stirring at 100C ~or 15
hours. A~ter cooling down, the reaction mixture was
evaporated under reduced pressure, the residue was taken
up in methylene ehloride, filtered and the filtrate was
extracted by sha.king with lN sodium hydrcxide solution,
-` ~L~33~37
-- 40 --
the organic phase was washed with water to neutrali~y,
dried over sodium sulfate and solvent was removed in a
rotary evaporator. m is produced 42.2 g (97% of the-
ory) of crude, crystalline 3-butvl-7-methyl-1-(~-pe~lt-
en~l~xanthine
0 CH3
CH2=~-~C~)3- ~ ~
(C~2'3-C~3
which was dissolved in 550 ml of chloroform, 35.6 g
(0.175 mole)of 3-chloroperbenzoic acid (85% pure) were
added and the mixture, a~ter covering with an atmos~
phere o~ nitrogen? was stirred at room temperature for
67 hours. Extraction by shaXing wi~h 10% stren~th
sodium dithionite solution until disappearance of the
iodine-starch reaction, washing, i~itially with 10%
strength sodium bicarbonate solution and then with water,
drying over sodium sulfate and evaporation under reduced
pressure provided 37.7 g (84.7y of theory) of crude
3 bu-tyl~ ,5~e~ OJYYPent ~ -7-m~ __ hine,
.
which was subjected to hydrolytic opening of the oxirane
ring without intermediate puri~ication. For this purpose~
2633~37
-- 41 --
the 37.7 g of epoxide was dissolved in a mixture of
200 ml of tetrahydroIuran and 135 ml of water, and
0.61 ml of perchloric acid (70% strength) was added
dropwise with stirring within about lO minutes at room
temperature. After stirring at room temperature for
14 hours~ the mixture was neutralized with saturated
sodium bicarbonate solution and evaporated under
reduced pressure. The remaining oily crude product
(100% of theory) could be purified by column chromatog-
raphy on silica gel with chloroform/meth~nol (volumeratio lO/1) as the eluting agent and subsequent recrys~
tallizat~on from ethyl acetate with the addition o~
petroleum ether at the boiling poir.t until cloudy.
Yi~ld: 29D2 g (73.2yQ of theory)
l~ lvieiting point 76 - 78C
C15H24NL~04 (~*.'i = 324-4)
Anal~Tsis: calculated: C 55.54% H 7.46% N 17.27%
found: C 55.38% H 7.450,6 N 17.625'.
The same compound was obtained by direc-t
dihydroxylation of the C=C double boIld of 3-butyl-
7-methy]-l (4-pentenyl)xanthine with OSI~iUm tetroxi~e
in analogy to Example 2 C).
Exam~le 8
1,7-Diethyl-3-(~,5~dihydroY~yh
a) 1.7-Diethylxar.th1ne
~ i2~5
~sC2~
8~7
- 42 -
18 g of 3-benzyl-1,7-diethylxanthine (mel~ing
point 119C? in 1,500 ml OL glacial acetic acid were
hydrogenated in the presence of 2.5 g of 10% palladium
on active charcoal at 80C and under ~.4 bar while
shaking for 47 hours. After cooling down, the mixture
was covered with an atmosphere of nitrogen while the
catalyst was filtered off and the filtrate was evapor-
- ated under reduced pressure. ~le residue was dissolved
in a mixture of 250 ml of methylene chloride and lG0 ml
~f lN sodium hydroxide solution. .4fter washing the
methylene chloride phase again with lN sodiu~ ~lydroxide
solution, the combined aqueou~ phases were adjusted to
pH 6 by addlng 33% streng~h sulfuric acid dropwise ~rith
stirring. After washing to neutrality and drying the
precipitate produced, 8.1 g ~54.~% of theory) of ls7~di~
ethylxanthine, of melting point 204 - 205C, were
obtained.
4.6 g of 3-benzyl-1,7-diethylxanthine were
recovered from the methylene chloride phase.
b) 1,7-Diethyl--3-(5^6-dihy~o~yhexYI)xanthine
~ IC2~5
0~ 0~
.
A mixtul-e of 7 g of 1,7-diethylxanthine, 7.2
of l-chloro-5,G-isopropylidenedioxy~lexane, 5 g of
~L~633
-- 43 --
potassium carbonate and 50 ml o~ dimethylformamide was
stirred at 120C for 8 hours. After evaporation under
reduced pressure, the residue was taken up with 50 ml of
lN sodium hydroxide solution and e~tracted with methylene
chloride. The methylene chloride phase was washed again
with dilute sodi~ hydroxide solution, washed to neutral-
ity, dried and evaporated under reduced pressure. The
residue was distilled under 0.01 to 0.02 mbar and-at a
bath temperature of 120 - 150C in a thin-layer evapora-
tor and 11.5 g of 1,7-diethyl-3-(5,6-isopropylidene-
dioxyhexvl)xanthine were obtained This was taXen up
with 325 ml o~ methanol and 80 ml of ~ater and, after
the addition of 0.4 ml o~ perchloric acid (70,~ strength),
stirred at 70C for 1 hour. After cooling down to room
temperature, the mixture was neutralize~ with sodium
bicarbonate solution and evaporated to dryness under
reduGed pressure. The residue was taken up with 200 ml
of methylene chloride and the e~tract ~ras evaporated.
m e residue was purified by column chromatog
raphy on silica gel with methylene chloride/ethanol
(volume ratio 8!2) as the mobile phase and by sub-
sequent recrystalli2ation from nethylene chloride/
diethyl ether.
Yield: 7.9 ~ (72.5,6 of theory)
Melting point: 115 - 116C
j~ C15H24N44 (M~J = 324-4~
Ana~ calculated: C 55. 54,6 H 7 . 46/o N 17 .27%
found: C 55-37% H 7 . 51% N 17 . 08%
:,~
,
. ~ .
i33
-- 44
This diol was also obtained by reaction of
1,7-diethyl-3-~5-hexenyl)xanthine with osmium tetroxide
in analogy to Example 2 C) or by epoxidation of the
foregoing xanthine compound, followed by acid hydroly~
sis of the epoxide ring in analogy to Examples 3, 4 and
7.
Example 9
7~( ?,3-DihvdroxvbutYl)-1,3-di~ropylxanthine
a ) Chloro-2, ,3--e~oxybutane
' ~O
Cl-CH2-CH-CH-CH3 '
93.4 g of crotyl chloride (97% pure) were added
dropwise with stirring ~rithin one hour to a solution of
244 g of 3-chloroperbenzoic acid (850~6 pure) in 1.5 1 o~
chloroform while cooling in ice. After stirring for a
further 70 hours at room temperature, the precipitate
wa~ filtered off with suction, and the filtrate was
washed with 10% strength sodium dithionite solution
(until the starch-iodine test was negative), with satur-
ated sodi-lm bicarbonate solution and with ~rater. After
drying over sodium sulfate, the soîution was fraction-
ally distilled over a paGke~ column.
Yield: 58 g (54.30,6 of theory)
Boiling point (133 mbar) 70 - 73G
Refractive index n20 = 1.4327
C4H7C10 (I~ = 106.55)
Analysis: calculat:ed: C 45.09% H 6.62% Cl 33.27%
found: C 45.28% H 6. 78Q~o Cl 33 . 30%
~2~ 8~.
-- 45 --
b) l-Chloro-2,3-dih~rdroxybutane
. . .
Cl-C~2-CH-~ CH~
0~ OH
57 g of 1-chloro-2S3-epo~,rbutane were stirred
in a mixture of 500 ml of water, 800 ml of tetrahydro-
~uran and 1.2 ml of perchloric acid (70% strength) atroom temperature for 7 days. After neutralization with
sodium bicarbonate solution, the mixture was evaporated
to d~yness under reduced pressure and the residue was
taken up with 2 1 o die~lyl ether. The ethereal solu-
tion was dried and evapcra~ed under reduced pressure.
Yield: 54 g (81~o of theory)
c) l-Chlcro-213-isoproP-ylidenedioxybutane
f
. O\ O
~ .
~Er3 3
1 ml oX perchloric acid (70% strength) was added
dropwise witll stirring within 6 minutes to a solution of
53 g of 1--chloro-2$3-dihydroxybu-tane in 50 ml of acetone
and 71 g of 2f2-dimethoxypropane under an atmosphere of
nitrogen at room temperature After stirring at room
temperature for a further hour, 5 g of finely powdered
sodium bicarbonate was added, the mixture was stirred for
half an hour, filtered and the filtrate was dislilled
over a packed colu~n. - .
~63~87
-- 46 --
Yield: 36.8 g (52.5~ of theory)
Boiling point (6.5 mbar) 49 - 53C
d) 7-(2,3-Dihvdroxybutvl)-l.3-di~lo-G~lxanthine
¦H2~1H_f~_CH3
3 ~ ~ OH 01
A mixture of 47.2 g of l,3-dipropylxanthi1le,
~3.6 g of l-chloro-2,3-isopropylidenedioxybutane, 28.2
g of potassium carbonate and 300 ml of dimethylformamide
was stirred at 120C for 8 hours. The mixtvre was
evaporated under reduced pressure and the residue was
take~ up with 250 ml of lN sodium hydroxi.de solution
and 500 ml of methylene chloride. After washing the
aqueou~ pha~e again Wi~l methylene chloride, the com-
bined methylene chloride phases were washed with lN
~: sodi~ hydroxide solution and water, dried and evapor-
ated under red~lced pressure. The residue was distilled
in a bulb-tube apparatus under 0.03 - 0.07 mbar and at
a bath temperature of 90C. 26.8 g of 7-(2S3-isopropyl-
idenedioxybutyl)~l,3-dipropylxanthirle (91.5~ o~ +heory
relative to reacted l,3~dipropylxanthine) wer.e obtained,
~ C~2 - fH ~ ~ C~3
H7C3 ~ ~ 3 C~3
c3~7
~6 33
- 47 -
ich was s~irred in a mixture of 700 ml of tetrahydro~
furan, 100 ml of water and 0.8 ml of perchloric acid
(70% strength) at 70C ~or 1 hour. After neutral'za-
tion with sodium bicarbonate solution7 the mixture was
e~aporated under reduced pressure, the residue was taken
up with 800 ml of methylene chlori~e, and the solution
was dried and eva~orated under reduced pressure. The
residue was purified by recrystallization from methylene
chloride~diethyl ether.
ield: 20~9 g (87.6% of theory)
Melting point: 99 - 101C
C15H24N404 ( ~1 = 324 . 39 )
~alysis: calculated: C 55.54% H 7.46% N 17.27~o
found~ C 55049% H 7.49~ N 17.18%
~5 ~ne compounds afo-em~ntioned and those prepared
in an analogous ~anner are complled in Table 1.
.
i33~37
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-- 49 --
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57 -
Table 2: Int2~ediate products ha-~ing a structural
element ol the formula IY (arrangement of the
- radical~ Rl, R2 ard R3 as ~or formula I)
Co~- ~ R~ R3 Melting
pol~d point~
C
~ . . .. .
1~ ~ 2~3 ~ / 2 C2H5 3 76-7~
O
2a n C~Hg CH3 ( Example
Y.~I C H C H
2 3 ~0/ 3 2 5 ~ 5 (E~ample
~C~2) 4 ~ / 2 3 ~3
5d F;~-s O U
G2 CH3 C1~3 ~ (CH2~ 4~ 59 ~ ~?
72 C~ET5 CZ~S ~ 2 3 ~ /-2 ~8 - 5
~b
8~ C21~5 C2H5 ,~ (Cq ) ~ C 58 ~ 59
Sd C4Hg C~ 9 ~CH2~ 2 C~ 2 ~2 ~ 5 3
$~3~
able 3: Inter~.ediate prGducts havlng a s~ruc~ural element
of the formula IX (R6 = Cn39 ~4, R7 and n: see table,
arran~emen-t o~ Rl~ R2 and R3 as for ~crmula I)
Com Rl R2 R3 Bulb-~ube~istillalion Meltin
PO1~rAd ~C mbar ~oint ~C
_ _ . . _ ~
1b ~ a~ n=4, ~4=~ 3 .7-188
R7 = ~3
Zb ~ c2~;ts n=4, R-=R 146
=H
3b E ~2H5n;4, R =H 123-124
R = GI3
. ~ . . . ~
4}~ CE~3 C2~ 0 o, 0?
. . . _ ~
5b ~5 c2~5 " 130-150 0,027 *
.,
n;5, ~4 ~ , 1 0C- 1 15 0, 0 1
R = Cff3
7b " C3~7 n;4, R4=ETr 150-160 0,02
R = CH3
~b C~,.TI7 2 5 135--1~10 0,Ql
~ ..
g~ n ~I n=5, R4=H, 130 0,02
R7 = C~13
lOb " C3,-17 n--4, Rds= H 140-150 0,05
R = CH3
11b -- " n=1, R4= CH3 90 0, G3-0, 07
R7 = C~3
12b C~ 3 C2H, n-4, P~ = H 17.0-130 0,03
R = CH3
13b ~5E~ T 1l 13;)-140 0,03
14b " C2H5 " 130-140 0,02
--r!--~---r-- ___ ____
~ b C~EI5 R7~'~`EI3 ~ O, 02*
?6!:) n-~ RG- C ''i C3~7 140-1rl? 0,2
~ _
17b . ~3~7 ~3 ~ ~,2
~Th..i~-lay~r e-~apor~to~
33.~3
- 59
Example 52
Medicamerlt formulation: For the production of
1,000 coated tablets, 100 g of 3--ethyi-7- ~ -dihydroxy~
hexvl,~- -pr ~Ylxanthine (eompound acco~ding to Example
1), 20 g OI lactose, 30 g of corn starch, 8.5 g of talc~
005 g of ccllloidal silicic acld and 1 g of magnesium
stearate we~e mixed and compressed to form tablet cores
weighing 160 mg, ~Ihich were then trea1ed with a coating
mixt~re eomposed of 40 g of sucrose~ 23.5 g of t21e and
very small a~ounts of wax 9 titanium dioxide and gum
arabie added so that f~he final weight o~ each o:~ the
~oated tablets was 225 mg.
Example 5~
TIe_icament formulaflon: For the production of
1,000 coated tablets. ll:L.8 g of 3-eth~1-7-(5,~-iso-
prop~-licenediox~,rle~yl~ pro~vlxanthlne (from Example 1J,
20 g of lactose, 30 g of corn starchg 8.5 g of talc~
0.5 g of eolloidal silicic acid and 1 g of magnes um
stearate were mixed and compressed to form tablet cores
weighing 171.8 mg, which were then-treated with a coat-
ing mixture composed oî 40 g of ~ucros~, 2305 g of talc
a~d very small amounts o:f waxS titanium dioxide and
arabic ackled so tllat the final weight of each of the
coated tablets was 240 m~.
Z5 ~Yample ~
Medicament form~ ation: For the productiorl of
1,000 coated tablets, 100 g cf 1,3-di~y~ ,6-c-~oxy-
hexyl)xanthine (from Example 2 B)), 20 g of lacto~e 30
g o~ corn ~tarch~ 8.5 g of talc5 0.5 g of colloidal
33sQ~ -
_ 50 --
silicic acid and 1 g of ma~nesium stearate were mixed
and compressed to form tablet cores weighing 160 mg,
~hich were then treated with a coatin~ mi;{ture composed
o~ l~o g of sucrose, 23.5 g of talc and very small
~mounts of wax9 tita~ium dioxide and gum arabic added so
that the final weight of each ol the coated tablets was
225 mg.
~3~L~aoææL~ testin~ and results
____ __
1.' Bronchos~asmo]ytic activity
~le co~pounds according to the invention were
tested ~or bronchospasmolytic activity essentially using
the experimental design described by H. Konzett and
. Rossler (Arch~ e~p. Path. u. Pharmak. 195 (1940) 75),
comparing Wit'l the stanc'ard therapeutic agent, theo-
'5 ~lly-lliln~-e-thyle~îe~iamill~9 an~ ith ~he t~o ~,~-d~lyd ox~r-
.
propyl compour.ds already known diphylline[ 7-( 2,3-di-
hyAroxypropyl)-1~3-~imethylxanthine] ~nd 7-(2~3-di-
hydro~Jprop~,rl)-1,3-diprop~lxanthine. In this method,
the inhibition of experimontal bronchspasms - induced
by intravenous admin~stration of amines havl~g spasmo-
~enic activi-t~9 such as acetylcholine, histamine and
- serotonine - in guiIlea-pigs of bo-th sexes urder ure-
thaneallaestrlesia (1.25 g/kg i.p~) i.s i~:vestigated~
m e test substances were ad~irlistered in aque-
ou5 solution elther intravenously (i.v.) or intra~duodeIIally (i.d.). Ihe ED~o values~ which represent 1,hat
dose in mg/kg at w.lich tne experimen~ally produced spasm
-is decreased by one ha'lf compared -to tnat in untreated
animals9 Je~e de-termined ~raphlcally ~'ro~ the dose-activit,v
633
-- 61 -
cu~ves .
. 2. Acute toxicity
.
Determination of the LD5~ values was by the
st~ndard method of the mortality occurring within 7
days amongI~ I mice after a single intravenous (i~Vo )
illtraperitoneal ~i.p.) or oral ~p.o.) administra-tion.
m e results of these investigations 3 which
demonstrate the superiority of the compounds according
to the invention corresponding to ~or~ula I compared to
the standard prod~ct theo~hylline-ethylenedi2mine and
the two oth~r comparj-son substances (particularly taking
into accol~nt the more favorable ratio of LD50 to ED50),
are compiled in the following Table 4-.
.
.
;33Y~
-- 62 --
C~
~; ~rl~
.. . . . _. _ __ .
o,i . ~ X
~ ~ o u- O O O O O O ~ r_ ~ r~ o ~ ,
:~ X ~ ~ c~J o o u~ o o o o .5 ~ .D O
~ ~ ~, ~ ~ r~ ~ ~D ~ ~ r~ , ~ ~ r~ ~
~ ~ o E~ ~ . f~ ~\ ~ J~ O
'X ~ > O- ::~' o Q > ~ .
Ei h . . . . . . . . . . . . . . ~
E~ O ~_ Q ,_ ._ ., ~_ .~ ~_ .. ,_ .~ ., .~ ~
1~o 1 n- l ~ I
~H O I _ ¦ r O ¦ O ¦ O O ~ U~ O O .n ¦ O
~1 o h l o I u~ C~J I c~ I ~ o I I ~D ~ I ~ ~ C ¦ ~
+ ~,~I I ! ! ~ _
,1 ~ o E; ~ ~ 1 ~ N I o ~ o ~ Ln ~n ~ o o ~ L~ ~ O ¦ O O ~ O ~ ~
it~5 1 ~ i ~
~ I O X I a~ I I I I
I~ 11 I ~ ~O I I~ Ic I~ I n Io, I~
4 1 ~ T
o I h ~ > I ~ ¦ > ~ ¦ > ¦ > ~
1 ~ L ~- `
~33~,~
-- 63 --
" .. ~ __ - I _ _ _
. . _~
. a~
t~
. ' ~ O C c `D ~ a~ .~ O ~ C~J O C~J
a) ~ ~ _ ~, r~ ~n ~ ~ ~ , ~ ~
~ ~ ~ ~ i~ \~ ~ \l ~!
~ a~
. ~ , __ . _
O T O n O O O O ~n O ' ~ # O
-:1 . O O O L-') o o c,~ Ln 0 c:2
3~ D ~_ C~ C~J C~l ~ ~ _ ~> c~ c~
,~ T~ /~ A c
:~ ~ l > o ~ > , ~.
_ ~... _. ___ ......
o ~ . ~_
~ ~ o~ o o ~ o o o
. l ..
C) ~ 1, ~ o I ~ ~ , o o o
~ o I ,. ~ ~ ~ X o
q~ h h i l . ~ . O
a~, Ul l . i . r~
~ ~ o ~l~o ~
r,q bO ,S~ 1 S~
U~ 1 1 1 1 11 1 1 1 1 I CH t~
O ~ D ~ tq
~ O ~ I I I I I '-~ I I I I (~ I I I I +)
h Q ~,~ ~ o I o I o I ~ ~,
o ~ F ~F ~ m~ ~ O '1-!
Ht~ I> I~ I> I ~ r~
Ll ~ $
s~" I h ~ I ~
tl) I I Ll~ I t J I ! t~- l ~. 1 1~ I r-l I ~ S~ D C)
r~ t!) ~ ~ r-l r~ O
O ~ ~ S~l tD I ~ I ~_ ~ O ~ r~ ¦ ~~
t~ I o h ~' 1 1 1 1 1 1 1 1 15~ -1 S~ I I ~ h
E~ l I r~ ~ r_~ I I I I I I I I I E~ ~ a.) I ~ I ~~ .~ S 4 ;~1 Q~ I ~Y *'
~6;~3
-- 64 _
The unequivocal superiority of the compounds
ac~ording to the invention, e~pecially compared to the
xanthine derivative which is most frequently emplo~Jed
for the therapy of obstruc,ive respirctory -tract dis
eases, theophylline-ethylenediamine (aminophylline),
was also impressively confir~ed in further specific
experiment~:
Since it is regarded as proven that, apart from
the biogenic amines, acet~-lcholine3 histamine and sero-
tonineS listed in Table 49 bladykinin also plays an
impor~ant part as a mediator substance in the provoca~
tion of asthma attacks, the inhibito~y effect on the
b~onchospas~ induced in ~linea-~igs with-bre~d~kinin was
investigated~ In ~liS test, lor exa~ple5 the compound
15 from EXa~ .e 15 0~ intravenous ~ ) acl~inistration,
~as found to ha~ean ED50 of 1 - 3 mg/kg and~ after intra-
duocleIlal (i.d.) ad~inistration5 an ED50 of 4.0 - 6.3 mg/kg
and thus ~ras abollt 3 times and about 6 times respectively
more effective than theophylline-ethylenedia~ine, for
~.rhic~ the corresponcling total ~50 values ~ere .~ound to
~e ~ - lO mg/kg i.v. and 25 - 40 mg/kg i.d.
The compounds of the foImlla I also e ert a
strcnF ir~ib-~ory e~fect ol1 tile broncho.spasm incluced with
ovalb-l~ir~ cg/k~ i~v~ 3 in ~the presensltized ~uirlea-pig~
~hich is hardly c~fected by th~ cus-toma~y~ xantline
derivatives. rm1~ for e:~ample~ -tne E~50 val~ for the
cGm~o-~ncl of Exa~ple 1 is be~een 6 and 12 ~Ig/kg i.v.~
w~ilst theophyl e-e-thylenediamine shows no effect in
tnis desic;n of e ~eriment ~ th doses up to 12 mg/kg.
31~'7
~5
~ ke superior bronchospasmolytic activity of the
x2nthines according to formula I was finally demonstrat~d
- in ~he pulmona-y ~unc tion test on the anaesthetized dog
usi~g the ir~ibition of the bronchospastic reactlons
induced with aerosols of acetylcholine, hista-.~ine and
asG2ris extract.
mus, for e~a~ple, the co~pound ln Example 1
already sho-led a siGnificant inhibitory effect at 12
mgfkg i . v., ~lhilst theophylline , in dos es up to 20 mg/kg
10 i.v~, proved to have no e~fect~ .
As has already been mentioned in -the introduction9
th~ bronchospasmolytic effect o~ theophylline
which is clinically well established9 is con-
trcsted by the considerable dlsadvantage of a very nar-
5 ~ nerapcu-~ic ran~e combined with ~erious si~e-e~tects,
particularly ir the cardiovascular system (hypotensive
activi~y ~ decre~se in cerebr-11 blood flow) and in the
central nervous system (lor example restlessness, in.~omnia
an~ ~rertigo!. ~ne stimulatior of the central nervous
~0 sys em is regarded by pa-tien-ts and clinlcians as being
particularly disturbiIlg, since it fre~uently leads to
~-lsomnia and thus has a persisterlt; adv-erse effe^-t on the
ge~leral stclte ci' heal-th o~ the asthmatic patient. A
e~pression o~ this sti~ulation of tne cent~al nelvous
25 sys~em is the inc.ease iin spcrltaneous mc,tility of male
w~i~e mice by 186% over a perlod of 7 hours after oral
ad~i~istration of ;~0 m~r~lg o~ theo~hylline-ethylene-
di~.ine. According to Canadian Patent 1,082,184,
the otller ti;o comparisorl proc.uct.s dvphyllin
~ ,,6;33~
- - 66
and 7-(2,3-dihydro~ypropyl)-1,3-dipropylxanthine also
bring about a stimulation of the central nervous system
in mic~, although these effects are markedly less pro
nounced than for theophylline. In contrastg the
5 compounds of the formula I according to the invention
have no component stimulating the central nervous sys~
~em, but, on the contrary7 e~ert a slight depressant
~ffect on the central nervous sys-tem which is assessed
to be particularly advantageous from the the~apeutic
10 point of view. ~hus, the spontaneous motility of mice~
~or e~ample~ is decreased by 53Q,~ for a period of 11
hours after oral administration of 50 mg/k~ of the com
pou~d from E~ample 1~
m e inves-tigations o~ the circulatory system
carriecl ou-t on rats and do~s 9 comparing ~,rith theophylline-
ethylellediamine, have sho~rn -that the compo~nds of the
formula I have a hypotensive activity, ifany at all, which
is ~arl;edly lo~-er and that tbey ca~JSe no decrease in
cerebral blQod flow.
