Note: Descriptions are shown in the official language in which they were submitted.
1C~7S169~ ;
This application is a divisional oE our copending Canadian Patent
Application Serial No. 215,977 filed December 13, 197~.
The invention relates to pharmaceuticals suitable for use in the
treatment of diseases involving deficiencies in the blood vascular system.
The pharmaceutical compositions contain certain oxoalkyl-dialkyl-xanthine
derivatives having in particular vascular dilatory activi~y and good fibrin-
olytic action.
l-~Oxoalkyl)-3,7-dimethyl-xanthines and 7-~oxoalkyl)-1,3-dimethyl-
xanthines have been prepared. These oxo compounds are readily soluble both
in water and in lipoids and have a pronounced vascular dilatory action with
a low toxicity.
Medicaments which contain, as active ingredient, xanthine derivatives
substituted by identical or different alkyl groups with 1 to 6 carbon atoms,
preferabl~ 1 to 4 carbon atoms, in the 1-, 3- and 7-positions, at least one of
which alkyl groups carries a hydrophilic group, preferably 0~l or COOH, are
also alread~ known. The number of hydrophilic groups per alkul group is gen-
erall~ between 1 and the number of carbon atoms in the given alkyl group and
the alkyl group which carries the hydrophilic group preferably contains 1 to
4 carbon atoms. ~Compounds having a hydroxyl substituent on a carbon atom
ad~acent to a ring nitrogen atom are unstable). The last-mentioned prior art
does not disclose, however, that the hydrophilic group may be an oxoalkyl
group, but there have only been disclosed compounds in which the hydrophilising
groups contain oxygen and have 2 or 3 carbon atoms and one h~dr~ph~l~s~ng group
is in the ~-position to the nearest ring nitrogen atom and all those alkyl
groups ~ich are not hydroxylated are methyl groups. Furthermore, the only
compound5 with only one hydrophylic group which have been specifically dis-
clos;ed are derivatives of theo~romine and of theophylline.
Pharmaceutical compositions are also known which contain as active
- 1 - ~ .,
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ingredient, xanthines having an oxoalkyl group with 6 to 20 carbon atoms in
the 1- or 7-position and an alkyl group with 1 or 2 carbon atoms in the other
of these two positions and in the 3-position. ~lowever no specific oxoalkyl
compounds nor the preferred positions of the carbonyl group have been dis-
closed in the literature describing these compositions.
According to the present invention we now provide compounds of
general formula
O R3
1~, (1)
wherein Rl is a straight-chain 5-oxohexyl-group, R2 is alkyl having at most
2 carbon atoms and R3 is a straight-chain or branched alkyl group containing
rom 2 to 4 carbon atoms, and physiologically acceptable acid addition salts
thereof.
Th`i~s ~nvent~on also relates to a process for the preparation of the
c~mpounds of general formula
1 ~ ~ 9/> (1)
O N
'~2
.
~herein Rl is a straight-chain 5-oxohexyl-group, R2 is alkyl having at most
~ carbon atoms and R3 is a straight-chain or branched alkyl group containing
from 2 to 4 carbon atoms, and physiologically acceptable acid addition salts
: : , :. - ' .^ " ~ :
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thereo~, which comprises
a) reacting an alkali metal salt of a 3-methyl- or 3-ethyl-7-alkyl-
xanthine with a substance selected from the group consisting of a 1) a com-
pound of formula
O
CH3-C-A-Hal ~III)
wherein A is an alkylene group containing ~ carbon atoms and Hal is a halogen
atom; b 1) an acetal, c 1) ketal and d 1) thioketal therefrom and subsequently
hydrolysing the product, or
b) reacting an alkali metal salt of l-~5-oxohexyl)-3-methyl- or 3-
ethyl-xanthlne with an alkylating compound selected from the group consisting
of alkyl halides and a dialkyl sulphate wherein the alkyl group or groups
contain 2 to ~ carbon atoms in the presence of a solvent, or
c~ reacting a compound of formula
Hal-X-N ~ N-R3
1 N ~ ~ ~IV)
O t
wherein X is an alkylene group containing 3 carbon atoms and Hal is a halogen
atom wlt~ an alkali metal salt of an acetoacetate and subsequently subjecting
th-e reaction product to ketone splitting to obtain a product of general for-
mula ~ as de~ined aBove, and wherein the product obtained is isolated per
se or reacted w~th an acid to form a physiologically compatible acid addition
s~alt t~ereof.
~ n general the new compounds according to the invention have a
~ascular dilat~r~ activlty, a good fibrinolytic action and a low toxicity.
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1~7569~L
Certain of the new compounds are soluble in lipoids. They additionally havethe effect of improving the circulatory properties of blood and are therefore
effective in the treatment of arterial blood flow disturbances. The pharma-
cological activity spectrum of the new compounds is otherwise substantially
similar to that of the previously known oxoalkyl-dimethyl-xanthines (oxoalkyl -
theophyllines and oxoalkyl-theobromines~.
The following are specific examples of the new compounds according
to the invention:
1-(5-Oxohexyl)-3-methyl-7-ethylxanthine, and
1-(5-oxohexyl)-3-methyl-7-n-butylxanthine.
As indicated above the compounds of this invention are prepared by
one of several reactions.
These reactions are carried out in known manner, generally at tem-
peratures of 50 to 150C, preferably 60 to 120C, optionally at elevated or
reduced pressure but usually at atmospheric pressure. The various starting
materials may be used in stoichiometric quantities or for economic reasons in
nonstoichiometric quantities. In methods a) and b), the alkali metal salts
are preferably prepared in situ. However, reactions (a} and (b) are prefer-
ably carried out in an organic solvent either alone or in admixture with water.
Ketone splitting in method a) is carried out in the usual manner.
The organic solvents used are preferably those which are miscible
with water, particularly monohydric alcohols, e.g. methanol, ethanol, propa-
nol, isopropanol, the various butanols, also comprising ethylene glycol mono-
methyl ether and monoethyl ether, polyhydric alcohols such as ethylene glycol,
aprotic solvents such as acetone, pyridine, formamide and dimethylformamide.
Reactions (`a) and (b) are preferably effected in a solvent mixture comprising
water and an organic solvent selected from the group consisting of an alcohol
having up to 4 carbon atoms, an aprotic solvent comprising acetone, formamide
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and dimethylformamide.
According to a still further feature of the invention there are
provided pharmaceutical compositions comprising as active ingredient a com-
pound of formula I as hereinbefore defined or a physiologically compatible
acid addition salt thereof in association with a pharmaceutical carrier or
excipient.
The pharmaceutical compositions according to the invention may be
presented in a form suitable for oral, rectal or parenteral administration.
They may be administered in solid form or in solution. Many of the xanthine
derivatives according to the invention are sufficiently soluble in sterile
water to be made up into injection solutions for parenteral administration.
Sui~able forms for administration include for example solutions,
emulsions, tablets, coated tablets, suppositories, capsules, granulates and
sustained release forms. These may be prepared in known manner using the
usual auxiliary agents such as excipients, disintegrants, binders, coating
substances, swelling agents, lubricants flavourings, sweeteners, substances
to produce a sustained release effect and solubilising agents. Suitable
auxiliary agents include for example lactose, mannitol, talcum, lactalbumin,
starch, gelatine, cellulose and its derivatives such as methyl cellulose,
hydroxyethyl cellulose and suitable swelling and non-swelling copolymers.
Disintegration of the composition and hence also release of the active in-
gredient can be influenced by the addition of larger or smaller quantities of
extending agents.
Advantageously the new compositions according to the invention are
presented in the form of dosage units, each dosage unit being adapted to sup-
Plr a fixed quantity of active ingredient, preferably 10 to 400 mg of active
ingredient.
The compotmds of the invention may be administered in an amount of
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11375691
e.g. 0.1 mg of 125 mg, preferably 1 mg to 50 mg per kg/body weight. The sub-
stances may be administered in a single dose or a plurality of doses per day,
if desired per infusionem.
If desired the new compositions may additionally contain a further
active ingredient, for example a vitamin.
The following Examples serve to illustrate the preparation of ~he
new compounds according to the invention:
Examples
Example 1
437.2 g of 3-me~hyl-7-propyl-xanthine suspended in a mixture of
240 g of methanol and 321 g of water are brought into solution by adding
160 g of 50% sodium hydroxide solution at elevated temperature. The mixture
is heated to boiling and 358 g of 1-bromo-hexanone-~5) are then added. The
mixture is heated under reflux for ~.5 hours. After cooling, the unreacted
3-methyl-7-propyl-xanthine is separated and the alcohol is distilled off.
The aqueous solution is adjusted to pH 11 with sodium hydroxide solution and
extracted with methylene chloride. 1-(5-Oxohexyl)-3-methyl 7-propyl-xanthine
with a melting point of 69 to 70C is obtained in approximately 90% yield
(based on reacted 3-methyl-7-propyl-xanthine) by recrystallising the residue
2Q of the methylene chloride solution from 5.2 litres of diisopropyl ether.
The solubility of the product in water at 25C is about 3.2%. The solubility
in ethanol and dimethyl sulphoxide lS over 10%.
Example 2
1.26g of a colourless oil is o~tained from 131 g of 3-methyl-7-n-
hex~l-xanthine, 100 g of water, 60 g of methanol, 20 g of sodium hydroxide and
89.5 g of 1-bromohexanone-(5) analogously to Example 1. The oil is recrys-
tallised ~y dissolving it in 60 ml of methanol and reprecipitating it from
this methanolic solution with 1500 ml of diisopropyl ether. 1-[5-Oxohexyl~-
~,:
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3-methyl-7-n-hexyl-xanthine with a melting point of 50 - 52C is obtained in
90% yield (based on reacted 3-meth~1-7-n-hexyl-xanthine). The product is only
sparingly soluble in water. The solubilit~ in ethanol, dimethyl sulphoxide
and dimethylformamide is over 10%.
Example 3
86 g of a crude product is obtained from 92.1 g of 3-methyl-7-
isobutyl-xanthine, 80 g of water, 48 g of methanol, 16 g of sodium hydroxide
and 71.5 g of 1-bromohexanone-~5) analogously to Example 1. After vacuum dis-
~tillation C196 - 200C/0.2 mm) and recrystallisation from diisopropyl ether,
1-(5-oxohexyl)-3-methyl-7-isobutyl-xanthine with a melting point of 75 - 76 C
is obtained ln 90% yield. The solubility in ethanol, dimethyl sulphoxide and
dimethylformamide is over 10%.
Example 4
A suspension of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine in a
mixture of 120 g of ~ater and 72 g of methanol is brought into solution by
the addition of 18 g of sodium hydroxide at about 60C. 55.5 g of n-propyl
bromide are then added. After boiling under reflux for 24 hours, the reaction
mixture is treated with 1 ml of concentrated sulphuric acid and cooled. Un-
reacted 3-methyl-7-C5-oxohexyl)-xanthine is filtered off and the alcohol is
distllled off in vacuo. The remaining solution is made alkaline with 4 ml of
50% sodlum hydroxide solution and extracted with 350 ml of methylene chloride.
l-n-Proprl-3-methy1-7-(5-oxohexyl)-xanthine with a melting point of 76 - 78C
is obtained in 85% yield from the residue of the methylene chloride solution
by recrystallisation from isopropanol. The solutility of the product in
ethanol~ di~ethyl sulphoxlde and dimethylformamide is over 10%.
Example 5
A crude product is obtained from 20.4 g of 3-methyl-7-ethyl-
xanthine, 24 g of water, 24 g of methanol) 8 g of 50% sodium hydroxide solu-
.
:,
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~7S69~L
tion and 17.9 g of 1-bromohexanone-(5) analogously to Example 1. After re-
crystallisation from a small quantit~ of methanolJ 1-~5-oxohexyl)-3-methyl-7-
ethyl-xanthine with a melting point of 102-103C is obtained in almost quan-
titative yield. The solubility in water at 25C is about 2%. The solubility
in ethanol and dimethyl sulphoxide is between 1 and 10% and in propylene glycol
between 0.1 and 1%.
Example 6
110 g of a ~ellow oil is obtained from 117 g of 3-methyl-7-n-butyl-
xanthine, 140 g of water, 85 g of methanol, 20 g of sodium hydroxide and 95 g
of 1-bromohexanone-(5) analogously to Example 1. The oil is first distilled
in vacuo ~219C/0.5 mm) and then crystallised from 700 ml of diisopropyl ether.
1-~5-Oxohex~1)-3-methyl-7-n-butyl-xanthine ~melting point: 79 to 80C) is
obtained in 60% yield.
A mixture of 79.2 g of 3-methyl-7-~5-oxohexyl)-xanthine, 75 g of
water, 75 g of methanol, 18 g of sodium hydroxide and 74.4 g of n-hexyl
bromide is boiled under reflux for 4 days and then worked up in a manner
analogous to Example 4. 82.9 g of a crude product are obtained from which
l-n-hexyl-3-meth~1-7-(5-oxohexyl)-xanthine is obtained in 90% yield after
vacuum distillation ~230 - 232C/0.3 mm). AFter recrystallisation from 500
ml of diisoprop~l ether, the melting point is 35 - 38C.
~ .
A mixture of 106 g of 3-methyl-7-~5-oxohexyl)-xanthine, 100 g of
water, 100 g of methanol, 24 g of sodium hydroxide and 82 g of isobutyl bro-
mide is boiled under reflux for 85 hours and then acidified with 5 ml of con-
centrated sulphuric acid. I~ is then boiled under reflux for a further 1.5 -
hous and then the unreacted 3 methyl-7-(5-oxohexyl)-xanthine ~58.8 g) is re-
moved by filtration. The crude product is worked up in a manner analogous to
.
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Example 4 to ~ield 57.7 g of a colourless residue from which 1-isobutyl-3-
meth~l-7-(5-oxohex~l)-xanthine with a melting point of 96 - 97C is obtained
in 95% yield ~based on reacted 3-methyl-7-~5-oxohexyl)-xanthine} by recrys-
tallisation from 120Q ml of diisopropyl ether.
Example 9
.,
80.3 g of 3-methyl-7-n-decyl-xanthine, 140 g of water, 90 g of
methanol, 10 g of sodium hydroxide and 44.6 g of 1-bromohexanone-(5) are
boiled under reflux for 4 hours. After acidification with 2 ml of concentrat-
ed sulphuric acid, the reaction mixture is filtered hot to remove the unreacted
3-methyl-7-n-decyl-xanthine and the filtrate is worked up as in Example 1.
66.1 g of a crude crystalline product are obtained and are recrystallised from
500 ml of diisopropyl ether. The 1-~5-oxohexyl)-3-methyl-7-n-decyl-xanthine
which is obtained in 85% yield melts at 64 - 66C.
Example 10
4.16 g ~0.02 mol) of 3-n-butyl xanthine are added to a solution of
5.5 g of water, 4.4 g of methanol and 0.8 g (0.02 mol) of sodium hydroxide.
The mixture is heated to 70C and stirred for one hour, 3.7 g ~0.0206 mol) of
l-bromo-hexanone-C5~ are added at 70C. The solution is then stirred for 5
hours at 70C. After cooling down to *oom temperature the crystals are isolat-
ed by suctlon~ then washed with 20 ml of water and 20 ml of methanol and dried
in the vacuum of the water jet pump at 70 to 100C.
The yleld is ~.4 g of a crude product ~72% of thé theory, referred
to the buty~l xanthine used) melting at 122C.
4.3 g of the crude product are dissolved in 15 ml of water and
0.86 g of sodium hydroxide at 60C; 0.5 g of active carbon is added thereto,
and the mixture is stirred for 15 minutes and then filtered. The filtrate is
adjusted with sulphuric acid of 33% strength to pH 9.5 at 60C, and the mix-
ture is then cooled in an ice bath. ~The precipitated crystals were isolated
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by suction ; washed with water until they were free from alkali and dried at
100C in the vacuum of a water jet pump.
The yield is 2.6 g ~42,5% of the theory, referred to the 3-butyl-
xanthine used). The product proves to be uniform on thinlayer chromatography
and has a melting point of 134 C.
Example 11
B 166 g (1 mol) of ~-methyl-xanthine are introduced, while stirring,
into a mixture of 275 g of water, 220 g of methanol and 40 g ~1 mol) of sodium
hydroxide. The mixture is heated to 70C and stirred for about one hour.
Then 183 g ~1,02 mol) of 1-bromo-hexanone-~5) are dropped at this temperature
into the mixture in the course of one hour. After about half an hour a thick
pulp is formed which however can still be stirred and is stirred for further
5 hours at 70C. The pH-value does slightly fall and is at the end of the re-
action in the range from 5 to 7. It is cooled to room temperature and the
crystals are isolated by suction. These are dried at 70 to 100C in the
vacuum of a water jet pump, after having been washed with 500 ml of water and
5Q0 ml of methanol. 210 g of a crude product containing 73% of 3-methyl-7-
(5-oxohexyl)-xanthine ~=88% of the theory, referred to the reacted 3-methyl-
xanthine) are obtained.
205 g of the crude product are dissolved at 60C in 1000 ml of water
and 40 g of sodium hydroxide. 13 g of active carbon are added thereto; the
mixture is then stirred for 15 minutes and filtered. The filtrate having a
temperature of 60C is adjusted to pH 9.5 by adding 97 g of sulphuric acid
~33% strength) during one hour. The mixture is stirred for a further hour at
60C. The crystals precipitated are isolated by suction, washed with water
until they are free from alkali and dried in the vacuum of the water jet pump
at 100C.
The yield is 125 of 3-methyl-7-~5-oxohexyl)-xanthine ~=48% of the
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1C~7569~L .
theory, referred to the 3-methyl-xanthine used). Melting point 217 C.
A further 5% of this compound may be obtained from the motherlye
by acidifying with additional sulphuric acid down to a pH-value of about 4
and subsequent purification.
After intraduodenal administration to narco~ized cats the compound
caused a significant and permanent increase in the cerebral blood circulation
which is by several times superior to that of ethylenediamine-theophylline.
The compound is also much more compatible if administered intraperitoneally
to mice. The LD50-value at mice is in the range from 100 to 1500 mg/kg, while
that of ethylenediamine-theophylline is 217 mg/kg only.
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Supplementary Disclosure
Example 12
104.1 g of 3-n-butylxanthine are added under stirring to a solution
of 20.4 g of sodium hydroxide in 200 ml of water and 200 ml of methanol. Then
at 70C 83.1 of the the ethylene ketal of 1-chloropentanone-~4) are dropwise
added to the clear solution. After stirring for 41 hours at 70C the reaction
mass is cooled to 20C and 34.5 g of the ethylene ketal of 3-n-butyl-7-(4'-
oxopentyl)-xanthine are obtained. It has a melting point of 128 to 129C.
This ~etal is heated to 70C for one hour in 1250 ml of 80% aqueous methanol
in the presence of sulfuric acid and at a pH value of 1 to 2. After neutralisa-
tion and recrystallization of the precipitate from alkaline solution wherein
the pH value was changed from 13.5 to 10 there are obtained 26.8 g of 3-n-
butyl-7-~4'-oxopentyl)-xanthine having a melting point of 140.5 to 141 C
(yield 43.7%, referred to reacted xanthine).
Example 13
24.8 g of 3-n-butyl-7-(4'-oxopentyl)-xanthine are added to a solution
of 3.5 g of sodium hydroxide in 80 ml of methanol and water ~1 : 1). After
stirring for 30 minutes at 40C 12.2 g of methyliodide are dropwise added.
After stirring for 50 hours to clear solution is concentrated under reduced
pressure until dryness and the residue is diluted with ether and deliberated
from the starting material by addition of 1 n sodium hydroxide. After concen-
tration the neutralized ether solution and subsequent distillation at a tem-
perature of the mixture of 130C under a pressure of 0.02 mm Hg 17.8 of 1-
meth~l-3~n-~utyl-7-(4'-oxopentyl)-xanthine having a melting point of 65 to
66 C are obtained ~yield: 84.2%, referred to the reacted starting xanthine).
Example 14
80.1 g of 3-n-butylxanthine are added to a solution of 15.5 g of
sodium hydroxide in 220 ml of a methanol/water mixture ~1 : 1). After drop-
- 12 -
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1~7~9~L
wise adding 53.7 g of 1-chlorohexanone-~5) to the clear solution which has a
temperature of 70 C the mixture is stirred at this temperature ~or 10 hours.
After cooling to 20C and one recrystallization of the precipitate from alka-
line solution wherein the pH value changes from 13.5 to 10 there are obtained
34.4 g of pure 3-n-butyl-7-(5'-oxohexyl)-xanthine having a melting point of
141C ~yield: 51.3%, referred to reacted 3-n-butylxanthine).
Example 15
60 g of 3-n-butyl-7-(5'-oxohexyl)-xanthine are added to a solution
of 8 g of sodium hydroxide in 160 ml of a methanol/water mixture ~1 : 1). 28 g
of methyl iodide are dropwise added to the clear solution having a temperature
of 40C and the mixture is stirred at 48C for 24 hours. After concentration
under reduced pressure the residue is diluted with 300 ml of diethylether and
the unreacted 3-n-butyl-7-~5'-oxohexyl)-xanthine is removed by shaking with 1
n sodium hydroxide. After neutralisation, drying, concentration under reduced
pressure and distillation at 140C temperature of the mixture and 0.02 mmtlg
48.5 g of 1-methyl-3-n-butyl-7-~5'oxohexyl)-xanthine are obtained from the
ether phase as a viscous oil ~n20 = 1.5320; yield 77.2%, referred to reacted
starting xanthine). Analysis: C16H24N4O3 = 320.396
C H N
calculated: 59.98% 7.55% 17.49%
found: 60.05% 7.74% 17.36%
Examples 16 to 19
In the same way as under exa~ple 15 the following compounds were
prepared.
16. 3-n-butyl-7-~6'-oxoheptyl)-xanthine, melting point 110 to 111C~
~rom 3-n-butylxanthine and 1-chloroheptanone-~6) at 70C temperature of the
mixture and under stirring for 43 hours ~yield 80.8%, referred to reacted 3-
butylxanthine). ;
- 13 -
~L~)7~9~
17. 3-n-Butyl-7-~7'-oxooctyl)-xanthine, melting point 98.5 to 99 C,
from 3-n-butylxanthine and 1-bromooctanone-(7) at a mixture temperature of
70C under stirring for 39 hours ~yield: 52.2%, referred to reacted 3-butyl-
xanthine).
18. The reaction is performed according to example 21 from 3-n-butyl-7-
~6'-oxoheptyl)-xanthine and methyl iodide, but at a temperature of the mixture
of 50 C under stirring for 46 hours. Prior to the distillation at a bath tem-
perature of 140C and 0.02 mmHg the product is purified by column chromatogra-
phy at silicagel 60 (Merck) with methylene chloride/acetone ~80 : 2) as eluent~
- 1-Methyl-3-n-butyl-7-~6'-oxoheptyl)-xanthine was obtained as a viscous oil
(n20 = 1.5280; yield: 80~1%, referred to reacted 3-n-butyl-7-(6'-oxoheptyl)-
xanthine. Analysis: C17H26N403 = 334-~23
C ~I N
calculated: 61.06% 7.84% 16.75%
found:60.85% 7.87% 16.59%
19. 1-Methyl-3-n-butyl-7-(7'-oxooctyl)-xanthine from 3-n-butyl-7-(7'-
oxooctyl)-xanthine and methyl iodide at a temperature of the mixture of 50 C
under stirring for 46 hours. The product is ob~ained in colorless crystals,
melting point 52C (yield: 94.4% referred to reacted 3-n-butyl-7-~7'-oxooctyl)-
xantine.
Example 20
A solution of 2.3 g of sodium in 150 ml of absolute ethanol is ad-
mixed wlth 26.4 g of 1,3-dibutylxanthine and 16.6 g of 1-chloro-4-pentanone-
ethyl0neketal and subsequently refluxed under stirring for 26 hours. After
heating for one hour with 30 ml of water and 10 ml of 33% sulfuric acid at a
temperature of 80C of the mixture and subsequent cooling the reaction mass is
neutralized with a saturated solution of sodiumbicarbonate and concentrated
under reduced pressure. The residue is adjusted with diluted sodium hydroxyde
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to a pH value of 13 and repeatedlyextracted with chloroform. The chloroform
extracts are combined and after washing with water and drying over sodium
sulphate they are concentrated. After column chromatography at silica gel
with methylene chloride/acetone in a ratio by volume 8:1 as the solvent and
bulb tube distillation at a bath temperature between 145 and 150C and 0.02
mm/Hg 7.3 g of 1,3-dibutyl-7-~4-oxopentyl)-xanthine having a melting point of
75 to 75.5C is obtained in a yield of 64.8% ~referred to reacted 1,3-dibutyl-
xanthine~.
Example 21
2.1 g of 3~methyl-7-propylxanthine, 0.7 g of 1-chloro-heptanone-~6~
and 1.4 g of potassium carbonate are refluxed in 15 ml of dimethylformamide at
120C under stirring for 7 1/2 hours. After concentration under reduced pres-
sure the residue is poured into 100 ml of water. Subsequently the mass is
three times extracted with 100 ml of chloroform each, the combined chloroform
extracts are subsequently treated with 1 n sodium hydroxide and water and then
dried over sodium sulphate. The concentration residue is then submitted to
chromatography in a column containing silica gel 60 and chloroform/ethanol
(9:1~ as a solvent. After recrystallisation from petrol ether/diisopropyl
ether ~3:1) 2.45 g of 1(6-oxoheptyl)-3-methyl-7-propylxanthine having a melt-
ing point of 69 to 70C are obtained in a yield of 76.6%.
Example 22
20 8 g of 3-methyl-7-propylxanthine, 16.9 g of l-chloropentanone-
C4~-ethyleneketal and 14.2 g of potassium carbonate are stirred in 150 ml of
dimath~lformamide at 120C for 7 hours and a half. After concentration
under reduced pressure the residue is admixed with 250 ml of water and twice
extracted with 300 ml of chloroform each. The combined chloroform phases are
washed ~ith 100 ml of 1 n-sodiumhydroxide and water. After concentration the
residue is dissolved with 1 1 of methanol/water ~8:2~, then 15 ml of 33%
- 15 -
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sulphuric acld are added and the mass is heated under stirring for one hour at
70C. After cooling it is neutralised with a saturated solution of sodium
bicarbonate and concentrated to about 100 ml. By three times extraction with
300 ml of chloroform each, washing of the chloroform phase with water, drying
over sodium sulphate and concentration 34 g of raw product are obtained. This
product is then submitted to chromatography at silica gel 60 with chloroform/
ethanol ~9:1) as a solvent. After recrystallisation from diisopropylether/
acetic ester (18:1) 19.1 g of 1-~4-oxopentyl)-3-methyl-7-propylxanthine having
a melting point of 67.5 to 68 C are obtained in a yield of 67.4%.
Example 23
22.2 g of 3-ethyl-7-propylxanthine, 14.1 g of 1-chlorohexanone-~5~
and 14.2 of potassium carbonate in 150 ml of dimethylformamide are stirred at
120C for 8 hours. After concentration under reduced pressure the residue is
suspended in 100 ml of water, three times extracted with 200 ml of chloroform
each, the combined chloroform extracts are successively treated with 1 n-sodium
hydroxide and water and then they are dried over sodium sulphate. The concen-
tration residue is submitted to chromatography in a column with silica gel 60
and Nith chloroform/ethanol ~9:1~ as a solvent. After recrystallisation of
the pure fractions from diisopropylether 12.2 g of 1-~5-oxohexyl~-3-ethyl-7-
propylxanthine having a melting point of 81 to 82C are obtained in a yield
of 38%.
Example 24
17.1 g of 1-(~-hydroxypentyl)-3-methyl-7-propylxanthine in 25 ml of
methylene chloride are dropwise added under stirring at 25C within 10 minutes
to 19.4 of pyridinium chlorochromate ~E.J. Corey and J.W. Suggs, Tetrahedron
Letters, Volume 31 ~1975~ page 2647 to 2650). Within 20 minutes the tempera-
ture increases to 34C. After three hours stirring and staying over night it
is decanted from the greasy precipitate and four times washed with 200 ml
~:
- 16 -
.. . .
- . : . :: , .
'- . . , ' . , ~
,
6~1
diethylether each. After washing with water and drying over sodium sulphate
the combined organic phases are concentrated under reduced pressure. After
column chromatography of the residue at silica gel 60 with chloroform/ethanol
(9:1) as a solvent and recrystallisation from diisopropylether/acetic ester
(18:1) 14.5 g of 1-(4-oxopentyl)-3-methyl-7-propyl-xanthine having a melting
point of 67 to 68C are obtained in a yield of 82.5%.
Example 25
It is worked as in example 24, however, lg.3 g of 1-(6-hydroxy-
heptyl)-3-methyl-7-propyl-xanthine are used as starting xanthine substance.
14.1 g of 1-(6-oxoheptyl)-3-methyl-7-propyl-xanthine having a meltinK point
of 69C are obtained after recrystallisation from petrol ether/diisopropyl
ether (3:1) in a yield of 73.4%.
Example 26
It is worked as in example 24, however, 18.5 g of 1-~5-hydroxy-
hexyl)-3-methyl-7-propylxanthine are used as starting xanthine substance.
14 g of 1-~5-oxohexyl)-3-methyl-7-propylxanthine are obtained in a yield of
76.3%.
It is worked as in example 24, however, 17.7 g of 1-(5-hydroxy-
hexyl~-3-methyl-7-ethylxanthine are used as starting xanthine substance.
13.3 g of 1-(5-oxohexyl)-3-methyl-7-e~hylxanthine are obtained in a yield of
78%.
Example 28
It is worked as in example 24, however, 19.3 g of 1-(5-hydroxy-
hexyl)-3-methyl-7-butylxanthine are used as starting xanthine substance.
13.7 g of 1-~5-oxohexyl)-3-methyl-7-butylxanthine are obtained in a yield of
71.2 %,
- 17 -
I
.
.
':
- ~ \
~197~
Example 29
It is worked as in example 24, however, 19.4 g 1-~5-hydroxyhexyl)-
3-ethyl-7-propylxanthine are used as starting xanthine substance. 13.4 g of
1-(5-oxohexyl)-3-ethyl-7-propylxanthine are obtained in a yield o 69%.
Example 30
.
It is worked as in example 24~ however, 18 g of 1-propyl-3-methyl-7-
(5-hydroxyhexyl)-xanthine are used as starting xanthine substance. 11.6 g Of
l-propyl-3-methyl-7-(5-oxohexyl)-xanthine are obtained in a yield of 65%.
Example 31
6.6 (23 mol) 3-methyl-7-(3-bromopropyl)-xanthine are added at ambient
temperature to a solution prepared from 6.0 g acetic acid ethyl ester, 1.06 g
scdium and 100 ml absolute ethanol. The mixture is refluxed for 2 hours.
After cooling the precipitated crystals are filtered off and the filtrate is
evaporated to dryness. The residue is first treated at ambient temperature
for 2 hours with 100 ml of 5 percent aqueous sodium hydroxide solution, then
acldified with 14 ml of 50 percent sulphuric acid and then boiled for 1 hour.
After standing for 2 days the 3-methyl-7-(5-oxohexyl)-xanthine is fil~ered off.
~he yîeld is 3.5 g = 50% of ~heory.
For purification the crude product is dissolved in a little aqueous
sodium hydroxide solution and 3-methyl-7-(5-oxohexyl)--xanthine is then obtain~d
by precipitating with aqueous hydrochloric acid in a yield of 40 percent.
Melting point 215C.
Example 32
437.2 g of 3-methyl-7-propylxanthine, suspended in a mixture of
240 g of methanol and 321 g of water are dissolved in 160 g of 50% sodium
h~droxide, heated to boiling temperature and at this temperature admixed wi~h
358 g of 1-bromohexanone-~5) and refluxed for 4 and a half hour. After cool-
ing the unreacted 3-me~hyl-7-propylxanthine is separated and the alcohol is
- ~ ~ ; ~ . . - '
.
.
1~75691
distilled off. The aqueous solution is adjusted with sodium hydroxide to a
pH-value of 11 and extracted with methylene chloride. From the residue of
the methylene chloride solution and after recrystallisation from 5.2 1 of di-
isopropylether 1-~5-oxohexyl)-3-methyl-7-propylxanthine having a melting point
of 69 to 70C is obtained in a yield of about 90% ~referred to unreacted 3-
methyl-7-propylxanthine). ~The solubility in water/25C is about 3.1%, that in
ethanol and dimethylsulphoxide above 10%).
Example 33
26.4 g of 1-~5-oxohexyl)-3-methylxanthine, 13.~ g of ~ropylbromide
and 13.8 g of potassium carbonate in 100 ml dimethylformamide are heated under
stirring to 120C for 3 hours. After distillation off of the solvent under
red~ced pressure and after addition of 100 ml of water the residue is extracted
with methylene chloride. The organic solvent is distilled off under reduced
pressure and the residue is recrystallised from diisopropylether. 22 g of
1-~5-oxohexyl)-3-methyl-7-propylxanthine having a melting point of 69 to 70C
are obtained in a yield of 72%.
Example 3~
A solution of 2.5 g of sodium in 150 ml of absolute ethanol is ad-
mixed with 14.3 g of acetoacetic acid ethylester and 32.9 g of 1-~3-bromo-
propyl)-3-methyl-7-propylxanthine and refluxed for 5 hours. The alcohol is
practically distilled off and the residue is refluxed with 150 ml of 5% of
sodium hydrox~de for 3 hours. For decarboxylation the mass is acidified with
half-concentrated sulphuric acid and heated for further 2 hours. The reaction
mass is made alkaline with sodium hydroxide and extracted with methylene chlo-
ride. After evaporation of the solvent the obtained residue is submitted to
chromatograph~ over silica gel with benzene/acetone ~7:3) as a solvent. After
recrystallis~tion of the residue of the main fraction from diisopropylether
1-~5-oxohexyl)-3-methyl-7-propylxanthine having a melting point of 69 to 70 C
-- 19 -
- . - : , . . . . .
- . : ,
~1~756~:~
is obtained in a yield of 41%.
Example 35
It is worked according to example 33, but in using 12.5 g of 1-(4-
oxopentyl)-3--methylxan~hine, 6.8 g of propylbromide and 7 g of potassium car-
bonate in 100 ml dimethylformamide as starting ma~erials. 11 g of 1-~4-oxo-
pentyl)-3-methyl-7-propylxanthine having a melting point of 67 to 68C are
obtained in a yield of 75% (recrystallisation from diisopropylether/acetic
ester).
Example 36
10 - It is worked as in example 34, but in using 1.9 g of sodium, dis-
solved in 120 ml of absolute ethanol, 10.4 g of acetoacetic acid ethylester
and 25.2 g of 1-~2-bromoethyl)-3-methyl-7-propylxanthine. 20 g of a raw
product is obtained which is submitted to chromatography at silica gel with
chloroform/ethanol (9:1) as a solvent. After recrystallisation 9.2 g 1-~4-
oxopentyl)-3-methyl-7-propylxanthine are obtained in a yield of 48%.
Example 37
.:
It is worked as in example 33, but in using 27.8 g of 1-(6-oxo-
heptyl)-3-methylxanthine, 9 g of propylchloride and 13.8 g of potassium car-
bonate in 100 ml of dimethylformamide as starting substances. 26.6 g o~ 1-(6-
oxoheptyl)-3-methyl-7-propylxanthine having a melting point of 69 to 70 C are `
obtained in a yield of 83%.
Example 38
It is worked according to example 34, but in using 3.4 g of 1-(4-
bromobutyl)-3-methyl-7-propylxanthine, 0.3 g of sodium and l.7 g of acetoacetic
acid ethylester. 1.7 g of 1-(6-oxoheptyl)-3-methyl-7-propylxanthine are ob-
tained.
Example 33
~t is worked according to example 32, but in using 117 g o~ 3-
methyl-7-n-but~lxanthine, 140 g of water, 85 g of methanol, 20 g of sodium
- 20 -
- - ,: . . . , . - . . . . .
~ . , ~ . , : :~
1~7~ii69~
hydroxide and 95 g of 1-bromohexanone-(5) as starting substances. 110 g of a
yellow oil is obtained which is firstly submitted to a distilla~ion under
reduced pressure (219C/0.5 mm) and then it is crystallised with 700 ml di-
isopropylether. In a yield of 60% 1-(5-oxohexyl)-3-methyl-7-n-butylxanthine
having a melting point of 79 to 80C is obtained.
Example 40
rt is worked as in example 33, but in using 26.4 g 1-~5-oxohexyl)-
3-methvlxanthine, 10.2 g of n-butylchloride, 13.8 g of potassium carbonate
and 100 ml of dimethylformamide as starting substances. 28 g of 1-(5-oxo-
hexyl) 3-methyl-7-butylxanthine having a melting point of 79 to 80C are ob-
tained in a yield of 87%.
Example 41
It is worked as in example 34, but in using 0.3 g of sodium, dis-
solved in 25 ml of absolute ethanol, 1.4 g of acetoacetic acid ethylester and
3.4 g of 1-(3-bromopropyl~-3-methyl-7-butylxanthine. 3 g of an oily raw pro-
duct are obtained which is two times submitted to chromatography at silica
gel with chloroform/ethanol ~9:1) as a solvent and after recrystallisation from
diisopropylether 1-~5-oxohexyl~-3-methyl-7-butylxanthine having amelting point
of 79C is obtained in a yield of 48%. -
Example 42
It is worked according to example 32, but in using 20.4 g of 3-
methyl-7-ethylxanthine, 24 g of water, 24 g of methanol, 8 g of 50% sodium
hydroxide and 17.9 of 1-bromohexanone-~5). A raw product is obtained from
which after recrystallisation from a little methanol 1-~5-oxohexyl)-3-methyl-
7-eth~lxanthine having a melting point of 102 to 103C is obtained in a nearly
quantitative yield.
Example 43
It is worked as in example 33, but in using 13.2 g of 1-~5-oxohexyl)-
.
- 21 -
- . . .. . . . . . : . ~ . , .
. . . . . A .
.,, ................. . , ' , ,~ '
1~7569~
:
3-methylxanthine, 7 g of potassium carbonate and 6.6 g of ethyl bromide in
100 ml of dimethylformamide as startlng substances. 10 g of 1-(5-oxohexyl)-
3-methyl-7-ethylxanthine are obtained which is recrystallised two times from
a little m0thanol. The final product has a melting point of 103 C.
Example 44
It is worked as in example 34, but in using 15 g of 1-(3-bromo-
propyl)-3-methyl-7-ethylxanthine, 7.5 g of acetoacetic acid ethyl ester and
1.3 g of sodium as starting substances. 8 g of 1-~5-oxohexyl)-3-methyl-7-
ethylxanthine having a melting point of 103C are obtained.
Example 45
21.8 g of 1-~5-oxohexyl)-3-ethylxanthine, 8.5 g of propylbromide,
13.8 g of potassium carbonate in 15~ ml of dimethylformamide are reacted as in
example 33. After recrystallisation from diisopropylether 24 g of 1-~5-oxo-
hexyl)-3-ethyl-7-propylxanthine having a melting point between 81 and 82C are
obtalned in a yield of 75%.
Example 46
3.4 of 1-~3-bromopropyl)-3-ethyl-7-propylxanthine9 1.3 g of aceto-
aceti~ acid ethyl ester and 0.3 g ofsodium are reacted as in example 34. 1-(5-
oxohexyl)-3-ethyl-7-propylxanthine is obtained in a yield of abou~ 20%.
Example 47
A suspension of 79.2 g of 3-methyl-7-~5-oxohexyl)-xanthine in a mix-
ture of 120 g of water and 72 g of methanol is dissolved with 18 g of sodium
hydroxide at about 60C and admixed with 55.5 g of n-propylbromide. After
refluxing for 24 hours 1 ml of concentrated sulphuric acid is added to the re-
action mixture and the mixture is cooled reacted 3-methyl-7-~5-oxohexyl)-
xanthine is filtered off and the alcohol îs distilled off under reduced pres-
sure. The residue is made alkaline with 4 ml of 50~ sodium hydroxide and then
extracted ~i~h 350 ml of methylene chloride. After recrystallisation from
- 22 -
:. ' .
, ~ . . . . . . : ... . .
:: . . . : , . .
, ,, - ~: , , ,,: .
. . .
5t;~
isopropanol l-n-propyl-3-methyl-7-(5-oxohexyl)-xanthine having a melting point
of 76 to 78C is obtained in a yield of 85% from the residue of the methylene
chloride solution. The solubility in ethanol, dimethylsulfoxide and dimethyl-
formamide is above 10%.
Example 48
20.8 g of 1-n-propyl-3-methylxanthane and 13.8 g ofpotassium carbonate
are heated in 150 ml of dimethylformamide to 120C and 1~ g of l-chlorohexanone-
(5) are dropwise added during 10 minutes. The reaction mixture is stirred for
one hour, ~hen the solvent is distilled off under reduced pressure and the
cooled residue is admixed with 100 ml of water and extracted with 100 ml of
methylene chloride. After washing the organic phase with l-n-sodium hydroxide
the solvent is distilled off. After recrystallisation of the residue from di-
isopropylether l-n-propyl-3-methyl-7-(5-oxohexyl)-xanthine having a melting
point of 53C is obtained in a yield of 25~1 g (= 83%).
Example 49
249 g of 3-methylxanthine and 126 g of sodium bicarbonate are sus-
pended in 750 g of dimethylformamide and 210 g o l-chlorohexanone-5 are por-
t~onwise added under stirring, wherein the reaction mixture is heated to 75C.
After finished addition the reaction mixture is heated to 130 to 1~0C for
2a further 6 hours. Subsequently it is cooled to ambient temperature, the crys-
tals are separated by suction and washed with isopropanol~ The dried residue
is suspended in 1 1 of 90C warm water, the suspension is adjusted to a p~l-
value of 9.6 with sodium hydroxide and strongly stirred. The suspension is
cooled and after one day of staying the crystals are separated by suction.
~$ter washing ~ith water and drying 325 g of 3 methyl-7-(5-oxohexyl~-xanthine -
~aving a melting point of 219C are obtained in a yield of 62%.
, . . - . .
.
.
1~7569~ ~
As illustrated in certaln of the above Examples, the compounds of
the invention conforming ~o general formula I are prepared by a further pro-
cess which comprises oxidation of a compound of formula
~ !3
y-NI ~ 7 ~ ~V)
wherein R2 and R3 have the meaning as defined above and Y is a 5-hydroxyhexyl
group; and wherein the product obtained is isolated per se or reacted with an
acid to form a physiologically compatible acid addition salt thereof.
Thus in its broadest form the invention relates to a process for the
preparation of the compounds of general formula
o
Rl -Nl~6~
~ N N
R2
~herein Rl ls a straight-chain 5-oxohexyl group, R2 is alkyl having at most 1-
2 carbon atom~ and R3 is a straight-chain or branched alkyl group containing
from 2 to 4 carbon atoms, and physiologically acceptable acid addition salts
thereof, hhich comprises
a) reacting an alkali metal salt of a 3-methyl- or -3-ethyl-7-alkyl-
xanthine with a substance selected from the group ~onsisting of a 1) a com-
pound of formula
- 2~ -
.
~7~69~
CH3-C-A-Hal ~III)
wherein A is an alkylene group containing ~ carbon atoms and Hal is a halogen
atom; b 1) an acetalJ c 1) ketal and d 1) thioketal therefrom and subsequently
hydrolysing the product~ or
b) reacting an alkali metal salt of l-~5-oxohexyl)-3-methyl- or
-3-ethyl-xanthine with an alkylating compound selected from the group con-
sisting of alkyl halides and a dialkyl sulphate wherein the alkyl group or
groups contain 2 to 4 carbon atoms in the presence of a solvent, or
c) reacting a compound of formula
R3
Hal-X-N N
o ~1 N ~ ~ N > (IV)
R2
~herein X is an alkylene group containing 3 carbon atoms and Hal is a halogen
atom with an alkali metal salt of an acetoacetate and subsequently su~jecting
the reactlon product to ketone splitting to obtain a product of general for-
mula ~1) as defined above, or
d) oxidation of a compound of formula
R3
O /J ~, N (V~
- 25 -
~.
- . .: . - .. .- . - . . . . .. . .. .
, ~ , . : , ,, , , , : . .
" ~ , . , ~ . .. . .
. ~, : . . . :
- ,`. .. ... : .
, , . . , - :
- . . : . .. :
~75~9~L
~herein R2 and R3 have the meaning as defined above and Y is a 5-hydroxyhexyl
g~oup; and wherein the product obtalned is isolated per se or reacted with an
acid to form a physiologically compatible acid addition salt thereof.
Pharmacological ex~ rimen~s
.
Furthermore with a number of oxoalkyl-xanthines various pharmacolo-
gical tests have been performed. The results are evident from the following
table 1.
Pharmacological experiments
Table 1
(cf. example
No. of ~he Present case~ Pharmacological effects
.
4 1-n-Propyl-3-methyl-7-(5-oxohexyl)-xanthine
(melting point 76-78 C): LD50 = 100-250 mg/kg i-p-
(mouse), strong broncholytic effect at the guinea
pig to acetylcholine, histamine and serotonine,
increase of the cerebral and muscle perfusion at
the cat, fibrinolytic effect.
8 1-Isobutyl-3-methyl-7-~5-oxohexyl)-xanthine
(melting point 96-97 C): LD50 = 250-500 mg/kg i.p.
(mouse), strong broncholytic effect to histamine,
phosphodiesterase inhibition at bronchii of cattle
about the same as after addition of theophylline:
ED50 = 6.1 x 10 ~ M (theophylline ED50 = 7.5 ~ 10 ~M),
increase of the cerebral blood perfusion at the cat.
7 1-Hexyl-3-methyl-7-(5-oxohexyl)-xanthine (melting
point 35-38 C): LD50 = 250-500 mg/kg i.p. (mouse),
strong broncholytic effect at the guinea pig to
acetylcholine, histamine and serotonine, phospho-
''
~ - 26 -
,
~ . . . . .
: ~ , . : .. ~- . , :
-
~L~7S~
continuation
(cf. example
No. of the present case ) Pharmacological effect
diesterase restriction at bronchii of cattle
stronger than that by theophylline : ~D5~ =
1.95 x 10 4 M ~theophylline ED50 = 7 5 x 10 M).
1 1-(5-oxohexyl)-3-methyl-7-propyl-xanthine (melting
point 69-70C): LD50 = 107 mg/kg i.v. ~ouse),
860 mg/kg per os (mouse), strong broncholytic
effect at the guinea pig to acetylcholine,
histamine and serotonine; at the isolated tracheal
chain in the concen~ration of 3 x 10 5 strong
inhibition ~9~%) of the isoprenaline ef~ect which
may not be inhibited by propanolol (i.e. it is not
caused by a ~2-mimetic effect). Long-lasting
increase of the cerebral blood perfusion at the
cat after a dosis between 1 and 5 mg/kg i.v
Fibrinolytic effect in vitro in hanging-clot-test
from 25 mmol. A~ the isolated guinea pig heart
from 30 ~ positive inotropic effect.
6 1-(5-oxohexyl)-3-methyl-7-n-butyl-xanthine
~melting point 79-80C): LD50 = 250-500 mg/kg i.p.
(mouse), strong broncholytic effect at the guinea
pig to acetylcholine, histamine and serotonine,
increase of the cerebral blood perfusion.
3 1-~5-oxohexyl)-3-methyl-7-isobutyl-xanthine
~melting point 75-76C): LD50 = 500-700 mg/kg i.p.
Cmouse~, fibrinolytic effect in vitro from 20 mmol,
- 27 -
,:
.
. . - : . -
. .
. . . ", , ~ ,
. .
69~
continuation
~cf. example
No. of the present case) Pharmacological effect
increase of the duration of the hexobarbital
narcosis.
9 1-~5-oxohexyl~-3-methyl-7-decyl-xanthine
~melting point 64-66C): LD50 = 500 mg/kg i.p.
~mouse), broncholytic effect at the guinea pig to
acetylcholine, histamine and serotonine, increase
of cerebral blood perfusion at the cat.
1-(5-oxohexyl)-3-methyl-7-ethyl-xanthine
tmelting point 102-103 C~: LD50 = 120-200 mg/kg i.v.
(mousej, 250-500 mg/kg i.p. ~mouse), strong broncho-
lytic effect at the guinea pig to acetylcholine,
histamine and serotonine. Strong and long-lasting
improvement of the cerebral blood perfusion at the
cat after doses of 1 to 5 mg/kg i.v., increase of
the muscular blood perfusion, fibrinolytic effect
in vitro in hanging-clot-test from 25 mmol.
Comparison of the activities
Comparison 1 (Cl~
~ 1-(5-Oxohexyl)-3-methyl-7-propyl-xanthine; the cerebral blood perfusion
was measured at narcotized cats by means of fluvography under administration
of doses of 0.3, 1, 2 and 5 mg/kg i.v.. The present compound effects a long-
lasting increase of the cerebral blood perfusion being dependent on the dosis.
The effect~ ~as superior to that of the 1-~5-oxohexyl)-3,7-dimethyl-xanthine
lQ ~ which was administered in a dose of 3 mg/kg i.v..
- 28 -
569t~
Comparison 2 (C2)
1-~5-Oxohexyl)-3-methyl-7-ethyl-xanthine: the cerebral blood
perfusion at narcotized cats was measured by fluvography after administration
of doses of 0.3~ 1, 2 and 5 mg/kg i.v.. The present compounds effected a
distinct increase of the cerebral blood perfusion being dependent on the dose.
It proved to be more effective than 1-~5-oxohexyl)-3,7-dimethyl-xanthine which
was used for comparison and which had been administered in a dosis of 3 mg/kg
i.v..
Comparison tests for cerebral blood perfusion
Several experiments were performed with various oxoalkyl-xanthine
derivatives wherein the increase of the cerebral blood perfusion at the cat
was measured. The results were compared with those of the known substance
1-(5-oxohexyl)-3,7-dimethyl-xanthine and with aminophylline.
~he tested compounds are evident from the following table 2.
Table 2
No.
(cf. example? ___ Substance Melting point C
4 1-propyl-3-methyl-7-(5-oxohexyl)-xanthine76 - 78
8 l-isobutyl-3-methyl-7-(5-oxohexyl)-xanthine 96 - 97
7 1-hexyl-3-methyl-7-(5-oxohexyl)-xanthine35 - 38
1 1-(5-oxohexyl)-3-methyl-7-propylxanthine69 - 70
6 1-(5-oxohexyl)-3-methyl-7-n-butylxanthine79 - 80
4 1-(5-oxohexyl)-3-methyl-7-decyl-xanthine64 - 66
l-(5-oxohexyl)-3-methyl-7-ethyl-xanthine102 - 103
Cl l-~5-oxohexyl)-3,7-dimethyl-xanthine102 - 105
Ccomparison~
C2 aminophylline 270 - 274
(comparison)
- 29 -
- -- .; . . .: . . - . : . . - ,
:. ~ . . . . . . .
., . : . ~ :: .
1~7569~
Test method
The test principle of K.-Golenhofen, H.-Hensel and G.-Hildebrandt,
"Durchblutungsmessungen mit Warmeleitelementen in Forschung und Klinik"
(="blood perfusion measurements with heat conducting elements in research and
clinics", Thieme edition Stuttgart 1963) was used. The test animals were cats
in chloralose-urethane narcosis (70 + 200 mg/kg i.p.). The calvaria was opened
in the area of the frontal gyrus marginalis or suprasylvicus respectively.
The measurements occured with a modified surface measurement head according to
~ensel (cf. Pflugers Arch. 268 (1959), page 604) which was laid thereon after
opening of the dura of the cerebral cortex. The duration of effectivity was
registered as half-life-time, the intensity of activity was registered accord-
ing to Golenhofen et al as heat transport number ~. The registration was
performed by thermosonds over a two-channel fluvograph for the ~irm Hartmann
~ Braun, Frankfurt on Main. Other circulation parameters registered simul-
taneously were conducted to a Helligemore-channel-graph.
Experimental results
The results obtained at the mentioned experiments are represented
~n the following table 2 as a~ and as half-life-time in minutesO ~ is the
change of blood perfusion.
- 30 -
..
;
~7S~9~
Table 3
_ ~ .
Sample change of the cerebral
No. dosis mg/kg blood perfusion animals
(cf. i.v. half~life-~ime n
example) ~ in minutes
. . .
1 + 1.85 1.0 2
+ 3.45 14.3 2
7 1 + 0.97 0.4 3
2 + 1.45 7.0 2
. __ _
1 + 4.33 4.0 3
1 2 + 6.33 5.8 3
._ 5 +13.00 14.7 3
1 ~ 2.50 1.3 2 :~
6 2 + 2.55 1.3 2 `~
+ 2.40 3.0 2
_ .__ _
1 + 1.40 0.2 1
3 + 2.80 0.5 1
. . ___ .. _ _
1 + 2.46 1.5 5
2 + 5.17 5.0 3
+ 8.07 8.2 3 :
.. .___ __
Cl 1 + 0.44 0.9 13 .
(comparison) .
+ 0.86 2.4 40 -
+ 1.15 8.6 33 ..
_ _ ..
. _ _
C2 1 + 0.19 1.8 7
~comparison)
2 + 0.15 1.8 2
: 5 + 0.18 3.3 8
_ _ 10 + 0.53 1.7 7 _
- 31 -
- . - . , . . , , , , - - ~ ~, .- , . ... . . . . .
7~6~
Discussion of the results
As it is evident from table 3 above sample No. 8 shows a stronger
and more extended cerebral blood perfusion. Thus, a dose of 5 mg has an
effect being four times stronger and a half-life-time being five times longer
than those of the comparison sample No. Cl. In a dose of 2 mg/kg of sample
No. 7 the effect is about double so strong and the half-life-time about three
times so long as the corresponding effects of the com~parison substance No. C2
but with a higher dose of 5 mg/kg of the comparison substance. In all doses
of sample No. 1 an essential ~i.e. more than ten times) stronger and longer
cerebral blood perfusion is obtained compared with the corresponding dosages
of the comparison substance No. Cl. Sample No. 6 effects an increase of
cerebral blood perfusion compared with a comparison substance No. Cl. Thus,
at a dose of 1 mg/kg the cerebral blood perfusion is abou~ six times higher
and at a dose of 5 mg/kg it is about three times higher than that of the
substance No. Cl. An improvement over substance No. Cl is also shown at
sample No. 5 wherein the cerebral blood perfusion at a dose of 1 mg/kg is
about five times higher and at a dose of 5 mg/kg it is about nine times
higher than that of the comparison substance. At a dose of 1 mg/kg the half-
life-time is 1.5 times longer and at a dose of 5 mg/kg it is more than three
times longer than that of the comparison substance No. Cl.
There is also a distinct improvement of the effectivity of cerebral
blood perfusion over the comparison substance aminophylline.
The technical advance of the invention over the substances of the
prior art is distinctly proved.
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