DE1124041B - Process for the production of new xanthine derivatives - Google Patents

Description

GERMAN

PATENT OFFICE

B53554IVd / 12p

REGISTRATION DATE: JUNE 10, 1959

NOTICE
THE REGISTRATION
ANDOUTPUTE
EDITORIAL: 22nd F E B RU AR 1962

The invention relates to processes for the preparation of new, therapeutically valuable xanthine derivatives, the in particular have a broncholytic effect.

These xanthine derivatives are compounds of the general formula

JK R ₁ R ₂ Jx

X-CH ₂ -CH-NAN-CH-CH ₂ -X

(I)

in which X are identical or different xanthinyl (1 or 3 or 7) radicals, two of the nitrogen atoms in the 1-, 3- or 7-position of the xanthine structure being substituted by methyl or ethyl radicals, and in the A a direct bond or an alkylene radical with 1 to 12 carbon atoms or a cyclohexamethylene radical, optionally substituted by low molecular weight alkyl groups, R is a hydrogen atom or an alkyl radical with 1 to 5 carbon atoms, R ₁ and R ₂ , which can be identical or different, hydrogen atoms or low molecular weight alkyl radicals or R ₁ and R ₂ together with the group N-A-N also denote a piperazine radical, and their acid addition salts.

The compounds of the formula (I) can be prepared by the following processes known per se:

Method of manufacture
new xanthine derivatives

a) A xanthine of the general formula X-CH ₂ -CH ₂ -HaI

(Π)

where Hai denotes a halogen atom, is with a diamine of the general formula

R ₁ -NH-A-NH-R ₂

(III)

implemented at elevated temperatures.

In general, 1 mol / 5-halogenoethylxanthine is employed in the reaction, Va mol of diamine. The reaction can be carried out with or without a solvent, the hydrogen halide split off being captured by appropriate additives, such as calcium carbonate, sodium bicarbonate, triethylamine or pyridine. It is also possible to bind the hydrogen halide by means of an appropriate excess of diamine. A preferred embodiment of this process without a solvent, with 1 mol / J-Halogenäthylxanthin is reacted with 1 mol of diamine at temperatures of 80 to 200 ⁰ C.

The reaction products are isolated, depending on the properties of the substances, by digestion with water and separation of the applicant in water:
CH Boehringer Sohn, Ingelheim / Rhein

Dr. Wilhelm Konz and Dr. K. line,

Ingelheim / Rhine,
have been named as inventors

poorly soluble product or extraction with a water-immiscible solvent, e.g. B. Chloroform. In other cases, the reaction products can be removed by boiling with alcohol or chloroform isolate etc.

The following are examples of starting components for this process: 7 - (/? - chloroethyl) -theophylline, l-Q9-chloroethyl) -theobromine; Hydrazine, ethylene, trimethylene, tetramethylene, dodecamethylene diamine, N, N'-diethylethylene diamine, Ν, Ν'-diethylhexamethylenediamine and piperazine.

Such compounds of the general formula (I) can also be prepared by this process, which contain two different xanthine residues. The reaction is carried out in two stages, with one condenses first with more than 1 mole of diamine the one / S-haloethylxanthine and then with another, different from the first / 9-haloethylxanthine continues to implement. For example, hexamethylenediamino-N- (7- / S-ethyltheophylline) -N '- (l-y3-ethyltheobromine) and trimethylenediamino-N- (7 - ^ - ethyltheophylline) -N '- (7 - ^ - ethyl-1,3-diethylxanthine) produce.

b) 2 moles of a xanthine of the general formula X-CH ₂ -CO-R (IV)

are hydrogenated with 1 mol of a diamine of the general formula (III) condensed. Here you can Bis-Schiff bases are also produced first, which are then catalytic Hydrogenation with or without pressure, for room

209 510/422

temperature or elevated temperature in the presence or absence of a solvent will.

From theophylline-7-acetaldehyde and trimethylene diamines for example trimethylenediamino-N, N'-bis- (7-, 8-ethyltheophylline) is formed and from 7-acetonyltheophylline and hexamethylenediamine, the hexamethylenediamino-N, N'-bis- (7-ß-propyltheophylline).

Compounds can also be obtained in process b) if the reaction is carried out in stages of formula (I) which have two different xanthine residues in the molecule.

c) condensation of a xanthine of the general formula

RR ₁

i I (V)

X-CH ₂ -CH-NH denote hydrogen atoms or low molecular weight alkyl radicals, condensed by hydrogenation, it being possible for this reaction to be preceded by the bilateral formation of the Bis-Schiff bases. 5

The reaction conditions are the same as given under b).

This process leads to compounds of the formula (I) in which R ₁ and R ₂ are hydrogen atoms. Subsequent alkylation also gives the compounds in which R ₁ and R _{2 are} alkyl radicals.

This procedure can also be carried out in two stages so that compounds with various xanthine residues can be obtained.

with a compound of the general formula Hal —A —Hal (VI)

in the presence or absence of solvents, at elevated temperatures and with use an acid binding agent. The aminoalkylxanthines used as starting materials can from haloalkylxanthines and ammonia, from cyanoalkylxanthines by reduction or prepared from oxoalkylxanthines by hydrogenating condensation with ammonia or amines will.

d) condensation of 2 moles of a xanthine of the general formula

X B (VII)

wherein B is a hydrogen atom or an alkali metal atom with 1 mole of a compound of general formula

RR ₁ R ₂ R

Hal-CH ₂ -CH-NAN-CH-CH ₂ -HaI

(VIII)

The alkali salts of the xanthines are expediently used in accordance with the method of the German Auslegeschrift 1 014 998 in dimethylformamide as a solvent with the compounds of the general formula (VIII) around. If the stability of the latter permits, the reaction can also be carried out in aqueous, alcoholic Solution or in suspension with the addition of an acid-binding agent. Here too the condensation can be carried out in two stages, leading to compounds with different Xanthine residues can get.

e) 2 moles of a xanthine of the general formula (V), in which R _{1 is} a hydrogen atom, are mixed with 1 mole of a biscarbonyl compound of the general formula

R ₃ Rj

I I (ix)

OC-A '-CO

in which A 'is an alkylene radical optionally substituted by low molecular weight alkyl groups and having 1 to 10 carbon atoms and R ₃ and R ₄

f) condensation of 2 moles of a xanthine of the general formula

X-CH = CH-R (X)

with 1 mole of a diamine of the general formula (III) at elevated temperatures in an or Absence of a solvent, optionally with the addition of a catalyst such as alkali hydroxide, Alkali metal, alkali amide or copper (II) acetate.

The xanthines used as starting materials, which contain a vinyl group, are derived from the corresponding ß-Halogenäthylxanthinen by splitting off of hydrogen halide, for example by means of an alkali metal alcoholate.

Is obtained from 7 - (/? - chloroethyl) -theophylline the 7-Vinyltheophyllin (F. 176 ⁰ C) and from 7 - (/? - chloroethyl) -l, 3-diäthylxanthin the 7-vinyl-l, 3 diethylxanthine (F. 119/120 ⁰ C).

This process can also be carried out in stages, so that you can make connections with different Xanthine residues can get.

g) A compound of the general formula R ₁ R ₂

(Xl)

X-CH ₂ -CO-NAN-CO-CH ₂ -X

respectively.

RR ₁

R ₂ R

X ~ CH ₂ -CH-N-CO-A'-CO-N-CH

'-CH ₂ -X (XII)

in which R _{1 has} all the meanings given for the general formula (I), it is reduced with lithium aluminum hydride.

The starting compounds of the general formulas (XI) and (XII) given above, which are new, are produced by methods known per se. The new compounds of the general formula (I) can be converted into their salts in a customary manner, using both the mono- and the bis-salts can produce.

The bronchospasmolytic (broncholytic) efficacy of some of the new compounds was determined when

Guinea pig asthma was determined by the Konzett-Rössler method. In the following The values for this are compiled in the table; the comparison substance 7 - (/? - hydroxypropyl) -theophylline the value 1 was assigned here. All substances were injected intravenously.

substance

LD ₆₀ sc (determined on white mice)

substance Bronchosp
we
spasm
by
Acetylcholine asmolytic
kung
spasm
by
histamine 7 - (/? - hydroxypropyl) -theo-
phyllin 1 1 Trimethylenediamino -
N, N'-bis- (7- / S-ethyltheo-
phyllin (example 3) 25th 100 Tetramethylene diamino
N, N'-bis- (7- / 3-ethyltheo-
phyllin) (example 4) 105 40 to 105 Pentamethylene diamino
N, N'-bis- (7 - /? - ethyltheo-
phyllin) (example 5) 6.5 90 Hexamethylene diamino
N, N'-bis- (7- / 3-ethyltheo-
phyllin) (example 6) 375 30th Heptamethylene diamino
N, N'-bis- (7 - /? - ethyltheo-
phyllin) (example 7) 175 15th Octamethylene diamino
N, N'-bis- (7-ß-ethyltheo-
phyllin) (example 8) 450 0 Nonamethylene diamino
N, N'-bis- (7- / 3-ethyltheo-
phyllin) (example 9) 185 5 Dekamethvlendiamino-
N, N'-bis- (7- / S-ethyltheo-
phyllin) (example 10) .... 100 0 Dodecamethylene diamino
N, N'-bis- (7 - /? - ethyltheo-
phyllin) (example 11) .... 12.5 5 Hydrazino-N, N'-bis-
(7- / 3-ethyltheophylline)
(Example 1) 7.5 5 Hexamethylene diamino
N, N'-bis- (7- / 3-ethyl-
1,3-diethylxanthine)
(Example 12) 50 50

7-QS-hydroxypropyl) -theophylline

Trimethylenediamino-N, N'-bis- (7-ß-ethyltheophylline)
(Example 3)

Tetramethylenediamino-N, N'-bis- (7- £ -äthyltheophylline) (Example A)

Pentamethylenediamino-N, N'-bis- (7- / S-ethyltheophylline) (Example 5)

Hexamethylenediamino-N, N'-bis- (7- / 3-ethyltheophylline) (Example 6)

Heptamethylenediamino-N, N'-bis- (7- / 3-ethyltheophylline) (Example 7)

Octamethylenediamino-N, N'-bis- (7- / S-ethyltheophylline) (Example 8)

Nonamethylenediamino-N, N'-bis- (7 - ^ - ethyltheophylline) (Example 9)

theophylline) (example 1)

435 mg / kg 870 mg / kg 575 mg / kg 1650 mg / kg 625 mg / kg 625 mg / kg 825 mg / kg

480 mg / kg

between 2000 and 3000 mg / kg

A comparison of these bronchospasmolytic effects clearly shows that all of the compounds examined significant in terms of their effect against spasms of the comparison substance 7- (/ 3-hydroxypropyl) -theophylline caused by acetylcholine are superior; in addition, almost all compounds also show a better effect on histamine bronchospasm.

The table below shows the toxicity values of all substances tested for broncholysis in comparison to 7 - (/ S-hydroxypropyl) -theophylline indicated:

The following examples are intended to explain the invention:

Example 1 hydrazino-N, N'-bis- (7 - ^ - äthyltheophyllin) A mixture of 24.2 parts of 7 - (^ - chloroethyl) -theophylline with 5 parts of hydrazine hydrate is gradually increased to 100 ⁰ C heated; The case has become homogeneous reaction mixture is heated slowly increase until the temperature is about 12O ⁰ C was reached. The onset of reaction causes the temperature to rise to about 145.degree. The cooled to about 100 ⁰ C melt is cooked with 50 parts of water under reflux; after cooling, the snow-white reaction product is separated off. Yield 18.3 parts (83% of theory).

Recrystallized from dimethylformamide, melting point 236 to 238 ° C. The monohydrobromide has a melting point of 235 ^° C .; easily soluble in water.

Example 2

Ethylenediamino-N, N'-bis- (7- / S-ethyltheophylline) 24.25 parts of 7 - (^ - chloroethyl) -theophylline are heated to 100 ° C. with 9 parts of ethylenediamine, the reaction occurring which increases the temperature 160 ° C can rise. After cooling to 100 ^° C., the mixture is rubbed with water and the reaction product is separated off. Melting point 215 to 216 ° C; the dihydrochloride melts at 284 ° C.

g Example 3

Trimethylenediamino-N, N'-bis- (7 - ^ - ethyltheophylline)

242 parts of 7- (ß-chloroethyl) -theophylline are in a reaction vessel with stirrer, thermometer and

7 8

Condenser with 78.5 parts of trimethylenediamine heated to 80 until the dihydrochloride of the reaction product was heated to 120 ° C .; the homogeneous reaction mixture has a melting point of 276 to 280 ° C. stirring is continued without heating, the temperature rising to about 200 ° C. and the batch solidifying to give an example 7 crystal slurry. It is allowed to cool to 120 ° C. 5. _XTXT ,,. _fn ο- ^. ixt t n- \ and then add about 400 parts of boiling water, heptamethylene diammo-Ν, Ν -bis- (7-MhyltheophyUm)

whereby everything goes into solution. The cooled solution is analogous to Example 4. Dihydrochloride: melting point

Stirred with 100 parts of sodium sulfate and the oily 130 to 135 ⁰ C.

Deposition taken up in chloroform. To

Separating the chloroform solution is the chloroform ίο examples

evaporated, 205 parts of reaction product (84% octamethylenediamino-N, N'-bis- (7- _/ S-äthyltheophylHn) of theory) being obtained in crystalline form.

Recrystallized from alcohol and dioxane, melting. Analogous to examples. Melting point 143 to 146 ° C. point 185 to 188 ° C. The dihydrochloride has the dihydrochloride: melting point 240 to 244 ° C. Melting point of 260 to 270 ° C, from 200 ⁰ C sintering. 15th

Example 9

Example 4 _; Nonamethylenediamino-N, N'-bis- (7-j5-ethyltheophyUin)

Tetramethylenediamino-N, N'-bis- (7 - ^ - ethyltheophylline) _{An £ llog Example} 4. Melting point of the dihydro-

From 24.2 parts of 7- (/ S-chloroethyl) -theophylline and 20 chlorides: 196 to 198 ° C. 9.5 parts of tetramethylenediamine are obtained from a
Reaction temperature from 85 to 195 ° C a reaction example 10

mixture ^ that boiled under reflux with chloroform decamethylenediamino-N, N'-bis- (7- _/ S-ethyltheophylline)

will. The tetramethylenediamine hydro-

chloride undissolved and is separated off by suction. 25 Analogous to Example 4. Melting point from alcohol After evaporation, the filtrate gives 24 parts of recrystallized substance: 124 to 126.degree. Dihydrodes Reaction product (96% of theory). Man chloride: melting point 230 to 234 ° C.

converts it into the dihydrochloride as usual, which

has a melting point of 276 to 280 ^° C. Example 11

3 ° Dodecamethylene diamino - N ₅ N '- bis - (7 - β - ethyltheo-Ti · phylline)

"Analogous to example 4. Dihydrochloride: melting point

Pentamethylenediamino-N, N'-bis- (7- _i S-äthyltheophyUin) of the recrystallized substance (from methanol analogous to Example 4 with pentamethylenediamine. ₃₅ ^ethanol ) ^{: 225 to 228} ° ^C -The dihydrochloride has a melting point of _. . . , "

270 to 272 ° C. Example 12

Hexamethylenediamino example 6 N, N'-bis- (7- _J S-ethyl-1,3-diethylxanthine)

Hexamethylenediamino-N, N'-bis- (7- ₎ S-ethyltheophylline) ⁴ ° 5.42 parts 7 - (^ Chloräthyp-l ₃ 3-diethybcanthin werden

with 2.4 parts of hexamethylenediamine carefully

^{a) 100 °} C. are melted homogeneously in a corresponding reaction vessel. Without further heating

242.5 parts of 7 - (^ - chloroethyl) -theophylline with 120 parts, the reaction occurs, and the temperature rises to

Hexamethylenediamine at 80 to 90 ° C to a homo- about 21O ⁰ C to. The crystalline reaction mixture

stirred up the melt. After a few minutes the mixture is ^{allowed to cool to 90 °} C. and boiled with chloroform

the temperature is increased to reflux with thorough stirring until the hexamethylenediamine hydro-

about 100 ⁰ C, whereupon the reaction occurs. The chloride settles out as a white precipitate, it becomes

The temperature rises to about 210 ^° C. without heating and is suctioned off and the chloroform evaporates. That

the approach crystallizes. After cooling to a paste-like reaction product, it becomes crystalline

12O ⁰ C is stirred with 400 parts of hot water, about 50 out dihydrochloride; Melting point 212 to

whereby the substance goes into solution. After cooling down to 215 ° C.
is shaken out with chloroform, whereby the

Reaction product goes into the chloroform. According to example 13

Evaporation of the solvent gives 234 parts of hexamethylenediamino-N, N'-bis- (l ^ -äthyltheobromin)

a crystalline substance (89% of theory). From 55

Recrystallized alcohol, the product has the melting point 12.2 parts of l - (^ - chloroethyl) -theobromine are with

point from 170 to 171 ⁰ C. The dihydrochloride melts 6 parts of hexamethylenediamine mixed and thoroughly

at 276 to 280 ⁰ C and is easily soluble in water. Heating to 90 to 100 ⁰ C homogenized. at

The also easily water-soluble dinicotinate has a slow temperature increase to 130 ° C

a melting point of 210 ° C. 60 reaction starts, and the temperature rises to 210 ^° C.

b) 242.5 parts of 7 - (/? - chloroethyl) theophylline are The ^{melt cooled to about 80 0} C is with about

heated in about 1.51 of methanol with 60 parts of hexamethylene 50 parts of water, the resulting solution with

made diamine alkaline in a stirred autoclave at a slow temperature - concentrated sodium hydroxide solution and

increase to about 150 to 160 ⁰ C heated. Once isolated the viscous oil with chloroform.

Solution is neutral (after about 4 to 5 hours), yield is 65: ^ 12.4 TeUe (94% of theory). the end

Most of the methanol is distilled off in vacuo, ethanol recrystallized with ether, melting point 155

and the residue triturated with alcohol or acetone to 158 ⁰ C. The dihydrochloride has the melting point

and sucked off. About 80% point 302 to 305 ^° C. is obtained and is easily soluble in water.

9 10

Example 14 stirred; the pasty deposit is made in chloroform

_XT , _T , "...,, ..,,,. · recorded; obtained after trituration of the chloroform

i'ul ^ Ä Tir °; ²⁰⁸ parts of reaction product (85% of theory);

N, N-bis- (7 - /? - ethyltheophylline) _{aug alcohol md Oiox} ^ _umkr l _sta n? _siert , _{has d} - _e

24.5 parts of 7 - (^ - chloroethyl) -theophylline will have a melting point of 185 to 187 ° C with 5 substance.
11.6 parts of Ν, Ν'-diethylethylenediamine at 140 to

160 ° C implemented. By boiling with chloroform Example 19 (procedure d)

the product is isolated and converted into the crystallized ... _{tn o} - ^ _U uu «· ν

Dihydrochloride transferred. Melting point 172 to ethylenediammo-Ν, Ν -bis- (7 - /? - ethyltheophyllm)

173 ⁰ C. ίο 210 parts of theophylline sodium are divided into 500 parts

Dimethylformamide with 95 parts of Ν, Ν'-Bis-QS-chlorine example 15 ethyl) -äthylenendiamm at 80 ° C with stirring.

Ν, Ν'-Diäthylhexamethylendiamino- f _T ^ f ^{TZT, nadl about 4 to 6 stun de} _t, ⁿ * ^{d bee} et »st

N, N'-bis- (7-iS-ethyltheophylline) After cooling, one sucks off the precipitated sodium

15 chloride and distilled the dimethylformamide im

24.5 parts of 7- (/ S-chloroethyl) -theophyllm are largely removed under vacuum; the residue is dissolved in 17.2 parts of Ν, Ν'-diethylhexamethylenediamine at 100% hydrochloric acid, decolorized with activated charcoal and react up to 190 ° C. and the product is isolated by evaporating in vacuo; the remaining hydro-decoction with chloroform. The initially syrupy chloride is recrystallized from alcohol and the reaction product (87% of theory) has a melting point of 282 to 284 ^° C.
Treat with hot alcohol in crystalline form
bring. Melting point 134-136 ° C. The dihydro example 20 (procedure e)

chloride has a melting point of 254 to 255 ^° C.

Pentamethylenediammo-N, N-bis- (7 - /? - ethyltheophyllm)

Example 16 25 223 parts of 7- (j8-aminoethyl) -theophylline are used in

Piperazino-N, N'-bis- (7- ^ äthyltheophyllin) ^ \ ⁸ ^ ^{0 parts of} chloroform with 50 parts of glutaric

aldehyde heated to boiling and the water of reaction

24.5 parts of 7 - (/ 3-chloroethyl) theophylline are distilled off with part of the solvent. Then 8.6 parts of piperazine at 90 to 170 ⁰ C implemented. The mixture is evaporated in vacuo and to about 6O ⁰ C cooled reaction mass water is boiled with 30 Base in 1000 parts of alcohol and 150 parts of 80 parts of bis-alcohol Schiff; Dissolved after cooling, 1 part of platinum black is added and it is suctioned off under pressure and digested with cold water. That hydrogenates at a temperature up to about 100 ° C. After crystalline reaction product has a melting point the calculated amount of hydrogen is has 247-248 ° C. The dihydrochloride which the solution is filtered off from the catalyst in a vacuum melting point 310-312 ⁰ C. 35 evaporated and the reaction product as is usual in

the hydrochloride transferred. The melting point of Example 17 Dihydrochloride is 27O ⁰ C.

Trimethylenediamino-N, N'-bis- (7-ß-propyltheophylline) "..," ,,.,. . ^

* ^v ' ^{F 1} ^ * ^{y J} Example 21 (working method f)

59 parts of 7-acetonyltheophylline are used in 300 parts of 40 _TT ,,,. . ,. ,,. ",. , " _N , ,,, ..."

Chloroform and 10 parts of trimethylenediamine to hexamethylenediammo-N, N -bis- (7 - /? - ethyltheophylline)

Heated to the boil and the water of reaction slowly mixed with 103 parts of 7-vinyl theophylline with 30 parts

distilled off part of the solvent. Then hexamethylenediamine and about 1 part is powdered

evaporated in vacuo and the bis-mixed Schiff base sodium amide and slowly heated to 180 ° C of melting point 174 to 176 ⁰ C in 250 parts of alcohol 45 and held about 1 hour at this temperature,

and 15 parts of water and dissolved in the presence of After cooling, it is hot in 500 parts of chloroform

0.6 parts of platinum black dissolved at about 100 ^° C. and 150 atm., Filtered, and chromatographed over aluminum oxide

hydrogenated with hydrogen. After taking up the loading and after evaporation of the solvent the reac-

If the amount of hydrogen required is required, the catalyst ablation product is recrystallized from alcohol; the melt filtered and the almost colorless solution in a vacuum 50 point is at 171 ⁰ C.
evaporates. The reaction product almost falls
quantitative yield and is used as usual in Example 22 (procedure g)

the hydrochloride transferred. Yield: 63.8 parts "," _T ^ ",. ._ " ,,,," ■ ^

(87% of theory). Melting point of the dihydrochloride, decamethylenediamino-Ν, Ν -bis- (7 - /? - ethyltheophyllm)

which was recrystallized from methanol-alcohol, 55 parts of sebacic acid 6,12-bis (7-ß-äthyltheophyllin-275 ⁰ C. amide) of melting point 198-200 ⁰ C.

Example 18 (procedure c) in portions to a stirred suspension of

". .,,,. . -MXT / u · in ο - ^ uu t. 11 · λ 2 parts Lithiumalumimumhydrid m 500 parts of tetra-Trmiethylendiammo-N, N -bis- (7 - / -? Athyltheophyllm) _h y _{drofuran added. After 15 hours of heating under}

223 parts of 7- _(j S-aminoethyl) -theophylline 60 are switched reflux with stirring is cooled and mixed with 2 parts together with 101 parts of 1,3-dibromopropane and water are added dropwise, with 2 parts of 20 ° / _o sodium 185 parts of tributylamine stirred in 1000 parts of xylene under sodium hydroxide solution and 5 parts of water; the two stirring and reflux are heated until the phases are complete, the organic phase with reaction (about 10 to 15 hours). After cooling, anhydrous magnesium sulfate is dried and filtered off with suction and the xylene mother liquor is evaporated in vacuo. The remaining reaction product is evaporated; the precipitate and the residue are converted into the dihydrochloride as usual, the xylene solution is dissolved in hot water which, after recrystallization from alcohol, has the melt-cold solution with about 100 parts of sodium sulfate at 230-234 ° C.

Claims (2)

PATENT CLAIMS:
1. Process for the preparation of new xanthine derivatives of the general formula R ₁ JKg R X_CH _a -CH-N-A-N-CH-CH ₂ -X CO in which X are identical or different xanthinyl (1 or 3 or 7) radicals, two of the nitrogen atoms in the 1-, 3- or 7-position of the xanthine structure being substituted by methyl or ethyl radicals, and in A one Direct bond or an alkylene radical optionally substituted by low molecular weight alkyl groups with 1 to 12 carbon atoms or a cyclohexamethylene radical, R a hydrogen atom or an alkyl radical with 1 to 5 carbon atoms, R ₁ and R ₂ , which can be identical or different, hydrogen atoms or low molecular weight alkyl radicals or R ₁ and R ₂ together with the NAN group also mean a piperazine radical, and their acid addition salts, characterized in that either a) a xanthine of the general formula
X-CH ₂ -CH ₂ -HaI ^a 5 (II) wherein Hal denotes a halogen atom, with a diamine of the general formula R ₁ -NH-A-NH-R ₈ (III)
reacts at elevated temperatures or b) 2 moles of a xanthine of the general formula X-CH ₂ -CO-R (rV) with 1 mol of a diamine of the general formula (III) condensed or hydrogenated c) a xanthine of the general formula RR ₁ 35 40 X-CH ₂ -CH-NH with a compound of the general formula Hal —A —Hal (VI) condensed or at elevated temperatures using an acid scavenger 50 d) 2 moles of a xanthine of the general formula XB (VII) wherein B is a hydrogen atom or an alkali metal atom is, with 1 mole of a compound of the general formula RR ₁ R ₂ R (VIII) Hal-CH ₈ -CH-NAN-CH-CH ₂ -HaI or 60 e) 2MoI of a xanthine of the general formula (V), in which R ₁ denotes a hydrogen atom, with 1 mol of a bis-carbonyl compound of the general formula R ₃ R ₄ l 1 OC-A '-CO (IX) in which A 'is an alkylene radical optionally substituted by low molecular weight alkyl groups and having 1 to 10 carbon atoms and R ₃ and R _{4 are} hydrogen atoms or low molecular weight alkyl radicals, hydrogenated condensed and optionally the two secondary nitrogen atoms in the bridge member or alkylated f) 2 moles of a xanthine of the general formula X-CH = CH-R (X) with 1 mole of a diamine of the general formula (III) at elevated temperatures or g) a compound of the general formula X-CH ₂ -CO-NAN-CO CH ₂ -X or RR ₁ I I X-CH ₂ -CH-N-CO-A'-CO-. R ₂ R I j N-CH-CH ₂ -X (XII) wherein R _{1 has} all the meanings given for the general formula (I), reduced with lithium aluminum hydride and optionally the products obtained by one of these procedures into their acid addition salts convicted. 2. The method according to claim 1, characterized in that the reactions a), b), d), e) and f) carried out in two stages and optionally two different xanthine residues for Implementation brings. Considered publications:
"Die Medizinische", 1955, pp. 321 and 322. © 209 510/422 2.62