Note: Descriptions are shown in the official language in which they were submitted.
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This application is a divisional of our copending Canadian Patent
Application Serial No. 215,977 filed December 13, 1974.
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 activity and good
fibrinolytic action.
l-(Oxoalkyl)-3,7-dimethyl-xanthines and 7-(oxoalkyl)-1,3-dimethyl-
xanthines have been prepared. These oxo compo~mds 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 deri-
vatives substituted by identical or different alkyl groups with 1 to 6 carbon
atoms, preferably 1 to 4 carbon atoms, in the 1-, 3- and 7-positions, at least
one of which alkyl groups carries a hydrophilic group, preferably OH or COOH,
are also already known. The number of hydrophilic groups per alkyl group is
generally between 1 and the number of carbon atoms in ~he 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 adjacent to 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 hydrophilis-
ing groups contain oxygen and have 2 or 3 carbon atoms and one hydrophilising
group is in the -position to the nearest ring nitrogen atom and all those
alkyl groups which are not hydroxylated are methyl groups. Furthermore,
the only compounds with only one hydrophylic group which have been specifi-
cally disclosed are derivatives of theobromine and of theophylline.
Pharmaceutical compositions are also known which contain as
- 1 - ~ -,
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active ingredient, xanthines having an oxoalkyl group with 6 to 20 carbon
atoms in the l- or 7-position and an alkyl group with l or 2 carbon atoms
in the other of these two positions and in the 3-position. However no
specific oxoalkyl compounds nor the preferred positions of the carbonyl group
have been disc]osed in the literature describing these compositions.
According to the present invention we now provide compounds of
general formula
wherein Rl is an (~ oxoalkyl group containing from 5 to 7 carbon atoms,
R2 is methyl and R3 is propyl, and physiologically acceptable acid addition
salts thereof.
This invention also relates to a process for the preparation of
the compounds of general formula
13
/ ~ / 7 \
0 ~ ~ N ~ N ~I)
R2
wherein Rl is an ~-l)-oxoalkyl group containing from 5 to 7 carbon atoms, R2
is methyl and R3 is propyl, and physiologically acceptable acid addition salts
thereo~, which comprises
a~ reacting an alkali metal salt of a 3-methyl-7-alkyl xanthine with
a substance selected from the group consisting of a l) a compound of formula
-- 2 --
~. :
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C~13-C-A-Hal (III)
wherein A is an alkylene group containing from 3 to 5 carbon atoms and Hal is
a halogen atom; b l) an acetal, c l) ketal and d l) thioketal therefrom and
subsequently hydrolysing the product or
b) reacting an alkali metal sal~ of l-(~-l)-oxoalkyl-3-methyl-
xanthine wherein the oxoalkyl radical has from 5 to 7 carbon atoms wi~h a
propylating compound selected from the group consisting of propyl halides and
a propyl sulphate in the presence of a solvent, or
c~ reacting a compound of formula
O R3
Hal-X-N 1~ N \
0 ~ ~ ~ N (1V)
wherein X is an alkylene group containing from 3 to 5 carbon atoms and Hal is
a halogen atom with an alkali metal salt of an acetoacetate and subsequently
subjecting the reaction product to ketone splitting to obtain a product of
general formula (I) as defined above, and wherein the product obtained is
isolated per se or reacted with an acid to form a physiologically compatible
acid addition salt thereof.
In general the new compounds according to the invention have a
vascular dilatory activity, a good fibrinolytic action and a low toxicity.
Certain of the new compounds are soluble in lipoids. They additionally have
the e~fect of improving the circulatory properties of blood and are therefore
ef$ective 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-di~ethyl-xanthines (oxoalkyl-
.
. . .
... . . .. . .. ... .. ... . . .
~756gz
theophyllines and oxoalkyl-theobromines).
The following are specific examples of the new compounds accord-
ing to the invention:-
1-~5-Oxohexyl)-3-methyl-7-propyl xanthine,
1-(6-Oxoheptyl)-3-methyl-7-propyl xanthine and
1-~4-Oxopentyl)-3-methyl-7-propyl xanthine
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
temperatures of 50 to 150C, preferably 60 ~o 120, optionally at elevated
or reduced pressure but usually at a~mospheric pressure. The various start-
ing 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, methods a) and b) are advan~
tageously carried out in a solvent mixture comprising water and an organic
solvent. A strong base can also be present. 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, propanol,
isopropanol, the various butanols,also comprising ethylene glycol monomethyl
ether and monoethyl ether, polyhydric acohols 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 ~ carbon atoms, an aprotic solvent comprising acetone, formamide and
dimeth~lformamide.
According to a still further ~eature of the invention there are
provided pharmaceutical compositions comprising as active ingredient a compound
-- 4 --
. ................ , ., . :
. : , . . . . . . . .
5~ 2
of formula I as hereinbefore defined or a physiologically compatible acid
addition salt thereof in association with a pharmaceutical carrier or
excipient.
~e 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.
Suitable 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.
Disintegra~ion of the composition and hence also release of the active -
ingredient can be influenced by the addition of larger or smaller quantities
of extending agents.
Advantageously the new composi-~ions according to the invention
are presented in the form of dosage units, each dosage unit being adapted to
supply a fixed quantity of active ingredient, preferably 10 to ~00 mg of
active ingredient.
The compounds of the invention may be administered in an amount of
-. .. ... - . . . - . .-.. - , . :, .. . : . .. .. . . .
~L~37569~
e.g. 0.1 m~ of 125 mg, prefarably 1 mg to 50 mg per kg~body weight. The sub-
stances may be administered in a single dose or a plurality o~ doses per day~
if desired per infusionem.
If desired the new compositions may additionally contain a further
active ingredientJ for example a vitamin.
The following Examples serve to illustrate the preparation of the
ne~Y compounds according to the invention:
Examples
Example 1
437.2 g of 3-methyl-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. Ihe mixture
is heated to boiling and 358 g of 1-bromo-hexanone-~5) are then added. The
mixture is heated under reflux for 4.5 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. l-~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-xanth m e) by recrystallising the residue
of the methylene chloride solution from 5.2 litres of diisopropyl ether.
The sol~l~ility of the product in water at 25C is about 3.2%. The solubility
in ethanol and dimethyl sulphoxide is over 10%.
Example 2
1,26g of a colourless oil is obtained from 131 g of 3-methyl-7-n-
hexyl-xanthine~ 100 g of water, 60 g of methanol, 20 g of sodiu~, hydroxide and
89.~ g of 1-bromohexanone-~5) analogously to Example 1. The oil is recrys-
tallised by dlssolving it in 60 ml of methanol-and reprecipitating lt from
this methanolic solution with 1500 ml of dilsopropyl ether. 1-~5-Oxohexyl)-
- 6 -
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~1~7~692
3-meth~1-7-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 solubility 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 ~196 - 200 C/0.2 mm) and recrystallisation from diisopropyl ether,
1-(5-oxohexyl)-3-methyl-7-isobutyl-xanthine with a melting point of 75 - 76C
is obtai.ned in 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 water 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-~5-oxohexyl)-xanthine is filtered off and the alcohol is
distilled off in vacuo. The remaining solution is made alkaline with 4 ml of
50% sodium hydroxide solution and extracted with 350 ml of methylene chloride.
l-n-Propyl-3-methyl-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
ethanoiJ dimethyl sulphoxide and dimethylformamide is over 10%.
.
~xample 5
A crude product is obtained from 20.4 g of 3-methyl-7-ethyl-
xanthine, 24 g of water, 24 g of methanol, S g of 50% sodium hydroxide solu-
-- 7 --
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tlon and 17.9 g of 1-bromo}lexanone-~5) analogously to Example 1. .~fter re-
crystallisation from a small quantity of methanol~ 5-oxohexyl)-3-methyl-7-
ethyl-xanthine ~ith 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 yellow oil is obtained from 117 g of 3-methyl-7-n-butyl-
xanthine, 140 g of ~ater, 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 v-acuo (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.
Example 7
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-hex~1-3-methyl-7-CS-oxohexyl)-xanthine is obtained in 90% yield after
vacuum distillation (230 - 232 C/0.3 mm~. After recrystallisation from 500
ml of diisopropyI ether, the melting point is 35 - 38C.
Example 8
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. It is then boiled under reflux for a further l.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 yield 57.7 g of a colourless residue from which l-isohutyl-3-
methyl-7-~5-oxohexyl)-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 120a 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-dec~l-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 - 66 C.
Example 10
-
4.16 g C0.02 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-(5) are added at 70C. The solution is then stirred for 5
hours at 70 C. After cooling down to room temperature the crystals are isolat-
ed by suction, 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 100 C.
The yield is 4.4 g of a crude product ~72% of the theory, referred
to the butyl xanthine used) melting at 122 C.
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
:: - g -
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by suction ; washed with water until they were free Erom 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 134C.
_ample 11
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 70 C. The pH-value does slightly all 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 100 C in the
vacuum o a water jet pump, after having been washed with 500 ml of water and
S00 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 60 C is adjusted to p~l 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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theory, reerred to the 3-methyl-~cmthine used). ~lelting point 217C.
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 subsaquent purification.
After intraduodenal administration to narcotized 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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Supplemen~ary 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 7QC 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 ketal 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 ~alue 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 141C
(yield 43.7%, referred to reacted xanthine).
F,xample 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-
methyl-3-n-butyl-7-(4'-oxopentyl)-xanthine having a melting point of 65 to
66 C are obtained (yield: 84.2%, referred to the reacted startin~ 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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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 for 10 hours.
After cooling to 20C and one recrystallization of the precipitate from alka-
line solution wherein ~he 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 o~ 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 diethy:lether 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 mmHg
48.5 g of 1-methyl-3-n-butyl-7-~5'oxohexyl)-xanthine are obtained from the
ether phase as a viscous oil ~n2D0 = 1.5320; yield 77.2%, referred to reacted
starting xanthine)- Analysis: C16H24N403 = 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 example 15 the following compounds were
~ prepared.
; 16. 3-n-butyl-7-~6'-oxoheptyl)-xanthine, melting point 110 to 111 C,
from 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). ~
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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
70 C under stirring for 39 hours (yield: 52.2%, referred to reactecl 3-butyl-
xanthine).
18. The reaction is performed according to example 21 from 3-n-bu~yl-7-
~6'-oxoheptyl)-xanthine and methyl iodide, but at a temperature of the mixture
of 50C 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 lYas obtained as a viscous oil
Cn D = 1-5280; yield: 80.1%, referred to reacted 3-n-butyl-7-(6'-oxoheptyl)-
xanthine. Analysis: C17H26N403 = 334-423
C H 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 obtained 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 o absolute ethanol is ad-
mixed with 26.4 g of 1,3-dibutylxanthine and 16.6 g of 1-chloro-4-pentanone-
ethyleneketal 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 repeatedlyex~racted with chloroform. The chloroform
extracts are combined and after washing with water and drying over sodium
sulpnate 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 l/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-
(4~-ethyleneketal and 14.2 g of potassium carbonate are stirred in 150 ml of
dimethylformamide 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 with 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%
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sulphuric acid 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 68C 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 with chloroform/ethanol ~9:1) as a solvent. After recrystallisation of
the pure fractions from diisopropylether 12.2 g of 1-(5-oxohexylj-3-ethyl-7-
propylxanthine having a melting point of 81 to 82 C are obtained in a yield
of 38%.
Example 24
17.1 g of 1-~4-hydroxypentyl)-3-methyl-7-propylxanthine in 25 ml of
methylene chloride are dropwise added under stirring at 25 C within 10 minutes
to 1~.4 of pyridinium chlorochromate ~E.J. Corey and J.W. Suggs, Tetrahedron
Letters, Volume 31 (1975) page 2647 to 2650). ~Yithin 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 -
: . . ,, . , . , ~ . . :: .
3Ll317~6~
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, 19.3 g of 1-~6-hydroxy-
heptyl)-3-methyl-7-propyl-xanthine are used as starting xanthine substance.
la 14.1 g of 1-(6-oxoheptyl)-3-methyl-7-propyl-xanthine having a melting point
of 69C are obtained after recrystallisation from petrol ether/diisopropyl
ether (3:1) in a yield of 73.4%.
It is worked as in example 24, however, 18.5 g of l-(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%.
Example 27
It is worked as in example 24, however, 17.7 g of 1-(5-hydr
hexyl)-3-methyl-7-ethylxanthine are used as starting xanthine substance.
13,3 g of 1-(5-oxohexyl)-3-methyl-7-ethylxanthine 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 -
.~
,, ~ . , ' . :
: .
': ' ~' ,, '' '. ' ' ,, . ~, ,. . ." ~
. .
~Q756~
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 of 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
sodium and 100 ml absolute ethanol. The mixture is refluxed for 2 hours.
After cooling the precipitated crystals are Eiltered off and the filtrate is
evaporated to dryness. The residue is first treated at ambient temperature
for 2 hours wlth 100 ml of 5 percent aqueous sodium hydroxide solution, then
acidified 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 filtered off.
The yield is 3.5 g = 50% of theory.
~or purification the crude product is dissolved in a little aqueous
sodium hydroxide solution and 3-methyl-7 ~5-oxohexyl)-xanthine is then obtained
by precipitating with aqueous hydrochloric acid in a yield of ~0 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
hydroxide, heated to boiling temperature and at this temperature admixed with
358 g of l-bromohexanone-~S) and refluxed for 4 and a half hour. After cool-
ing the unreacted 3-methyl-7-propylxanthine is separated and the alcohol is
- 18 -
.
'~ . ' ' '. ; , . ' . ' ' . ; ' . ,, . . ' '
' :, ', ' , ~ ' ' ' , ' ' , , , :
:~7S69Z
distilled off. The aqueous solution is adjusted with sodium ~ydroxide 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 l-~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
i ethanol and dimethylsulphoxide above 10%).
Example 33
26.4 g of 1-~5-oxohexyl)-3-methylxanthine, 13.4 g of propylbromide
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
reduced pressure and after addition of 100 ml of water the residue is extracted
with methylene chloride. The organic solvent is distilled off under recluced
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 34
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-
propyi)-3-methyl-7-propylxanthine and refluxed for S hours. The alcohol is
practically distilled off and the res:idue is refluxed with 150 ml of 5% of
sodium hydroxlde 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
chromatography over silica gel with ben~ene/acetone ~7:3) as a solvent. After
recrystallisation 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
~ .
.
.
- . , , - ::
': : , ., , - ' ~ ': . ' . :
- . ': , . . ~, . . - :
. : . ~ .
~75692
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-methylxanthine, 6.8 g of propylbromide and 7 g of potassium car-
bonate in 100 ml dimethylformamide as starting materials. 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
It is worked as in example 34, but in using l.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.~ g of potassium car-
bonate in 100 ml of dimethylformamide as starting substances. 26.6 g of 1-~6-
oxohsptyl)-3-methyl-7-propylxanthine having a melting point of 69 to 70 C are
obtained in a yield of 83%.
Example 38
It i5 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 1.7 g of acetoacetic
acid ethylester. 1.7 g of 1-(6-oxoheptyl)-3-methyl-7-propylxanthine are ob- -
tained.
Example 39
It is worked according to example 32, but in using 117 g of 3-
methyl-7-n-butylxanthine, 140 g of water, 85 g of methanol, 20 g of sodium
-,
:, -"'' "
.
, " I ,
~75~;;9~
hydroxide and 9S g of l-bromohexanone-~5) as starting substances. 110 g of a
yellow oil is obtained which is firstly submitted to a distilla~ion under
reduced pressure (219 C/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
It 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 a melting 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, ~ 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-ethylxanthine 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 -
~317~92
3-methylxanthine, 7 g of potassium carbonate and 6.6 g of ethyl bromide in
~ 100 ml of dimethylformamide as starting substances. 10 g of 1-(5-oxohexyl)-
: 3-methyl-7-ethylxanthine are obtained which is recrystallised two times from
a little methanol. The final product has a melting point of 103C.
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 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
27.8 g of 1-~5-oxohexyl)-3-ethylxanthine, 8.5 g of propylbromide,
13.8 g of potassium carbonate in 150 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
obtained in a yield of 75%.
Example 46
3.4 of 1-(3-bromopropyl)-3-ethyl-7-propylxanthine, 1.3 g of aceto-
acetic acid ethyl ester and Q.3 g ofsodium are reacted as in example 34. 1-~5-
oxohexyl)-3-ethyl-7-propylxanthine is obtained in a yield of about 20%.
Example 47
A suspension of 79.2 g of 3-methyl-7-~5-oxohexyl)-xanthine in a mix-
tur0 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 is distilled off under reduced pres-
sure. The residue is made alkaline with 4 ml of 50%.sodium hydroxide and then
extracted with 350 ml of methylene chloride. After recrystallisation from
- 22 -
. .
.
-, .
. . . - . . :
. . , :: -
.. . .~
: ' . . , . . . : ' ~ .
. .. . . . . , - ~ , . , . :
, . .. . . : .
~75692
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 14 g of l-chlorohexanone-
(5~ are dropwise added during 10 minùtes. The reaction mixture is stirred for
one hour, then 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 e of sodium bicarbonate are sus-
pended in 750 g of dimethylformamide and 210 g of 1-chlorohexanone-5 are por-
tionwise added under stirring, wherein the reaction mixture is heated to 75 C.
After finished addition the reaction mixture is heated to 130 to 140C for
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 i.n 1 1 of 90C warm water, the suspension is adjusted to a pH-
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.
fter ~ashing ~ith water and drying 325 g of 3-methyl-7-~5-oxohexyl)-xanthine
having a melting point of 219C are obtained in a yield of 62%.
,
- 23 -
,
~ . , . :
~756~
As illustrated in certain of the above examples, the compo~mds of
this invention conforming to general formula I are prepared by a further
process which comprises
oxidation of a compound of formula
o IR3
0~ (V)
wherein R2 and R3 have the meaning as defined in claim 1 and Y is an ~
hydroxyalkyl group having from 5 to 7 carbon atoms, and wherein the product
obtained as isolated per se or reacted with an acid to form a physiologically
compatible acid addition salt thereof.
Thus in its broadest form this invention relates a process for the
preparation of the compounds of general ~ormula
R N "J6' ~ N3
O ~ N ~ N
R2 . . .
wherein Rl is an ~-l)-oxoalkyl group containing from 5 to 7 carbon atoms, .
R2 is methyl and R3 is propyl~ and physiologically acceptable acid addition
salts thereof, which comprises -~
a) reacting an alkali metal salt of a 3-methyl-7-alkyl xanthine with
a substance selected from the group consisting of a 1) a compound of formula
O , .
CH3-C-A-Hal ~III)
- 24 -
'
~07~ 2
wherein A is an alkylene group containing from 3 to 5 carbon atoms and Hal is
a halogen atom; b l) an acetal, c l) ketal and d l) thioketal therefrom and
subsequently hydrolysing the product or
b) reacting an alkali metal salt of l-(~-l)-oxoalkyl-3-methyl-
xanthine wherein the oxoalkyl radical has :Erom 5 to 7 carbon atoms with a
propylating compound selected from the group consisting of propyl halides and
a propyl sulphate in the presence of a solvent,
c) reacting a compound of formula
0 13
Hal-X-N ~ ,N
O / ~ N ~ N (IV)
R2
wherein X is an alkylene group containing from 3 to 5 carbon atoms and Hal is
a halogen atom with an alkali metal salt of an acetoacetate and subsequently
subjecting the reaction product to ketone splitting to obtain a product of
general formula (I) as defined above~ or
d) oxidation of a compound of formula
O R
11 13
O /~ ~XN ~
wherein R2 and R3 have the meaning as defined above and Y is an (~
hydroxyalkyl group having from 5 to 7 carbon atoms, and wherein the product
obtained is isolated per se or reacted with an acid to form a physio]ogically
- 25 -
.~ ' '
:
. :, , ., . .. , .. . . . ~ .. . , : ..
1~75i6~Z
compatible acid addition salt thereof.
Pharmacological experiments
Further~ore 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 the present case) _ Pharmacological effects
~ l-n-Propyl-3-methyl-7-(5-oxohexyl)-xanthine
~melting poin-t 76-78C): 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 96-97C): 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-~lexyl-3-methyl-7-(5-oxohexyl)-xanthine(melting
point 35-38C): LD50 = 250-500 mg/kg i.p. ~mouse),
strong broncholytic effect at the guinea pig to
acetylcholine, histamine and serotonine, phospho-
- 26 -
:';' ,
. ..... .. , . . . " . . . .. . . . . . . ..
- , . . -
.
~175~i~Z
.
- continuation
(cf. example
No. of the present case ) Pharmacological effect
s
diesterase restriction at bronchii of cattle
stronger than that by thaophylline : ED50 =
1.95 x 10 4 M (theophylline ED50 = 7 5 x lO M).
9 1 1- (5-oxohexyl)-3-methyl-7-propyl-xanthine ~melting
point 69-70C): LD50 = 107 mg/kg i.v. (mouse),
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 concentration of 3 x 10 5 strong
inhibition (94%) of the isoprenaline effect 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. At the isolated guinea pig heart
from 30 ~ positive inotropic effect.
6 1-(5-oxohexyl)-3-methyl-7-n-butyl-xanthine
~melting point 79-80 C): 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-(S-oxohexyl~-3-methyl-7-isobutyl-xanthine
(melting point 75-76 C): LD50 = 500-700 mg/kg i.p.
~mouse), fibrinolytic effect in vitro from 20 mmol,
- 27 -
, ~ .. , . , ~ . .............. .. .. . . .
, ~ : .: . .
., . , . . .~ . . . . -
la~s6~
continuatlon
(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 64-66 C): LD5~ = 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
(melting point 102-103 C): ~D50 = 120-200 mg/kg i.v.
(mouse~, 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 activ_ties
Comparison 1 (Cl)
1-(5-Oxohexyl)-3-methyl-7-propyl-xanthine; the carebral 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 OTI the dosis.
The effect was superior to that of the 1-(5-oxohexyl)-3,7-dimethyl-xanthine
which was administered in a dose of 3 mg/kg i.v
.
.
- 28 -
. ~ .
~7~;69~
Comparison 2 ~C2)
l-(5-Oxohexyl)-3-methyl-7-e~hyl-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.
The tested compounds are evident from the following table 2.
Table 2
No.
(cf. example) Substance _ _ Mel~ing point C
4 1-propyl-3-methyl-7-(5-oxohexyl)-xanthine76 - 78
8 1-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
1-~5-oxohexyl)-3-methyl-7-ethyl-xanthine102 - 103
Cl 1-(5-oxohexyl)-3,7-dimethyl-xanthine102 - 105
(comparison)
C2 aminophylline 270 - 274
(comparison)
- 29 -
- .
- , ~ ..
: ~ , . : '. :' ' ' . ': : . ~ ' ' '
.
~756;~
Test method
The test principle of K.-Golenhofen, H.-Hensel and G.-Hildebrandt,
"Durchblutungsmessungen mit ~armeleitelementen in Forschung und Klinik"
~="blood perfusion measurements with hea~ 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
Hensel ~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 registra~ion was
performed by thermosonds over a two-channel fluvograph for the firm Hartmann
~ Braun, Frankfurt on Main. Other circulation parameters registered simul-
taneously were conducted to a Helligemore-channel-graph.
Experimental results ~ :
The results ob~ained at the mentioned experiments are represented
~n the following table 2 as ~ and as half-life-time in minutes. ~ is the
change of blood perfusion.
- 30 -
' ' - ~ ' ' '' :; ~ :' ' ''
:
. .
.
~075691Z
Table 3
Sampie change of the cerebral I
No. dosis mg/kg blood perfusion animals
(cf. i.v. half-life-time n
example) . ~ in minutes
1 + 1.85 1.0 2
t 3,45 14.3 2
__ _
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
tl3,00 14.7 3
. .......................... .... .. ........ ........ __
l + 2.50 1.3 2
6 2 + 2.55 1.3 2
+ 2.40 3.0 2
l + 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) . .
t 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 -,
; . ' -
.
, .
:. ~:- ~ - , . .: -
1~75692
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
effec~ 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 comparison 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
10 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 about 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
hlgher 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
20 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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