DE1545749C - Basically substituted alkyl theophylline derivatives and a process for their manufacture - Google Patents
Basically substituted alkyl theophylline derivatives and a process for their manufactureInfo
- Publication number
- DE1545749C DE1545749C DE19651545749 DE1545749A DE1545749C DE 1545749 C DE1545749 C DE 1545749C DE 19651545749 DE19651545749 DE 19651545749 DE 1545749 A DE1545749 A DE 1545749A DE 1545749 C DE1545749 C DE 1545749C
- Authority
- DE
- Germany
- Prior art keywords
- substituted alkyl
- manufacture
- theophylline
- theophylline derivatives
- basically substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- -1 substituted alkyl theophylline derivatives Chemical class 0.000 title claims description 7
- 238000000034 method Methods 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 title description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 230000001813 broncholytic effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 229960000278 theophylline Drugs 0.000 description 5
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229960001789 papaverine Drugs 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- OQFMNXMRKPNXOY-UHFFFAOYSA-N 1,3-dimethyl-7h-purine-2,6-dione;hydrochloride Chemical compound Cl.O=C1N(C)C(=O)N(C)C2=C1NC=N2 OQFMNXMRKPNXOY-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Natural products O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960004767 proxyphylline Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000005062 tracheal ring Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
in der R ein Wasserstoffatom oder eine niedrigmolekulare Alkylgruppe mit 1 bis 6 Kohlenstoffatomen bedeutet, und ihre Salze und optisch aktive Formen.in which R is a hydrogen atom or a low molecular weight alkyl group having 1 to 6 carbon atoms, and their salts and optically active forms.
2. Verfahren zur Herstellung von basisch substituierten Alkyltheophyllinderivaten nach Anspruch 1, dadurch gekennzeichnet, daß man Ketone der allgemeinen Formel II2. Process for the preparation of basic substituted alkyl theophylline derivatives according to claim 1, characterized in that ketones of the general formula II
H,C —N-C = OH, C-N-C = O
O=C C-NO = C C-N
H,C — N — C — NH, C-N-C-N
OHOH
CH2-CH-CH2-N-CH-C-^CH 2 -CH-CH 2 -N-CH-C- ^
-CH--CH-
OHOH
CHCH
N-CHN-CH
I II I
CH2 R
QH5 CH 2 R
QH 5
Il οIl ο
OHOH
worin R die obengenannte Bedeutung hat in an sich bekannter Weise katalytisch hydriert und gegebenenfalls die erhaltenen Verbindungen mit einer Säure in die Salze oder aber die erhaltenen Racemate über die Salze optisch aktiver Säuren in die optisch aktiven Formen überführt.in which R has the abovementioned meaning and, if appropriate, catalytically hydrogenated in a manner known per se the compounds obtained into the salts with an acid or else the racemates obtained via the salts optically active acids converted into the optically active forms.
Die Erfindung betrifft basisch substituierte Alkyltheophyllinderivate der allgemeinen Formel IThe invention relates to basic substituted alkyl theophylline derivatives of the general formula I.
OH
CH, — CH — CH, — NH — CH — CH-/~\-0HOH
CH, - CH - CH, - NH - CH - CH- / ~ \ -0H
H,C -N-C = OH, C -N-C = O
O = CO = C
H3C-N-C-NH 3 CNCN
CH — CH2 — NH — CH — CH-OH- R OHCH - CH 2 - NH - CH - CH-OH- R OH
CHCH
in der R ein Wasserstoffatom oder eine niedermolekularcAlkylgruppe mit 1 bis 6 Kohlenstoffatomen bedeutet, und ihre Salze und optisch aktive Formen und ein Verfahren zu deren Herstellung, das dadurch gekennzeichnet ist, daß man in an sich bekannter Weise Ketone der allgemeinen Formel IIin which R denotes a hydrogen atom or a low molecular weight alkyl group having 1 to 6 carbon atoms, and their salts and optically active forms and a process for their preparation, which is characterized by is that in a known manner ketones of the general formula II
OHOH
H,C — N — C = OH, C-N-C = O
O=C C-NO = C C-N
H3C — N — C — NH 3 C-N-C-N
CH2 — CH — CH2 — N — CH — CCH 2 - CH - CH 2 - N - CH - C
OHOH
OHOH
CHCH
worin R die obengenannte Bedeutung besitzt, katalytisch hydriert und gegebenenfalls die erhaltenen Verbindungen mit einer Säure in die Salze oder aber diein which R has the abovementioned meaning, catalytically hydrogenated and, if appropriate, the compounds obtained with an acid in the salts or else the
CH2 R
C6H5 CH 2 R
C 6 H 5
erhaltenen Racemate in an sich bekannter Weise über die Salze optisch aktiver Säuren in die optisch aktiven Formen überführt. Hierzu eignen sich z. B. die Tar-racemates obtained in a manner known per se via the salts of optically active acids into the optically active ones Forms transferred. For this purpose, z. B. the tar
träte. Die Ausgangsprodukte der allgemeinen Formel II können in an sich bekannter Weise durch Umsetzung der in der deutschen Patentschrift 224 159 beschriebenen Benzylaminoderivate der allgemeinen Formelwould occur. The starting materials of the general formula II can be converted in a manner known per se the benzylamino derivatives of the general described in German Patent 224 159 formula
Theophyllinyl-(7) —CH2-CH-CH2-NHTheophyllinyl- (7) -CH 2 -CH-CH 2 -NH
OH CH2C6H5 OH CH 2 C 6 H 5
mit Halogenketonen der allgemeinen Formelwith halogen ketones of the general formula
OHOH
durch Histamin erzeugten Spasmus nach der Methode von Castillo und de B e e r (J. Pharm. Therap., 90 [1947], S. 104) durchgeführt: Die Wirkung wurde in Relation zur broncholytischen Wirkung des Papaverins bestimmt. Gleichzeitig wurde die akute Toxizität (LD50) nach intraperitonealer Injektion nach der Methode von Miller und Tainter (Proc. Soc. Biol. and Med., 57 [1944], S. 261) an der Maus bestimmt.Spasm generated by histamine was carried out according to the method of Castillo and de Beer (J. Pharm. Therap., 90 [1947], p. 104): the effect was determined in relation to the broncholytic effect of papaverine. At the same time, the acute toxicity (LD 50 ) after intraperitoneal injection was determined in the mouse using the Miller and Tainter method (Proc. Soc. Biol. And Med., 57 [1944], p. 261).
Die Ergebnisse sind in der nachstehenden Tabelle zusammengefaßt. Wenn nicht anders angegeben, wurden jeweils die Hydrochloride verwendet.The results are summarized in the table below. Unless otherwise stated, were each used the hydrochloride.
HaiShark
OHOH
erhalten werden.can be obtained.
Die erfindungsgemäßen Verbindungen zeichnen sich durch starke Herz-Kreislauf-Wirkung und broncholytische Wirkung aus.The compounds according to the invention are notable for their strong cardiovascular and broncholytic effects Effect.
Die überlegene broncholytische Wirkung der erfindungsgemäßen Verbindungen gegenüber den bekannten Broncholytika Papaverin und 7-(ß-Oxypropyl)-theophyllin) sowie einer aus der deutschen Patentschrift 1119 868 bekannten Verbindung zeigt der folgende Versuchsbericht:The superior broncholytic effect of the compounds according to the invention over the known ones Broncholytics papaverine and 7- (ß-oxypropyl) -theophylline) and a compound known from German Patent 1119 868 is shown in the following test report:
Die Untersuchungen wurden am isolierten Trachealringpräparat des Meerschweinchens gegenüber demThe investigations were on the isolated tracheal ring preparation of the guinea pig compared to the
Verbindungconnection
Broncholy-Broncholytic
tischetables
Wirkungeffect
Papaverin = 1Papaverine = 1
7-(2-Hydroxy-3-2'-3",4"-dihydroxyphenyl-2'-hydroxyäthylamino-propyl)- theophyllin (erfindungsgemäß)7- (2-Hydroxy-3-2'-3 ", 4" -dihydroxyphenyl-2'-hydroxyethylamino-propyl) - theophylline (according to the invention)
Papaverin (Base) Papaverine (base)
7-(/S- Oxypropyl-theophyllin
(Base) 7 - (/ S-oxypropyl-theophylline
(Base)
7-(2-2'-3",4"-Dihydroxyphenyl-2'-hydroxy-äthyl-
amino-äthyl-theophyllin
(Racemat) (deutsche
Patentschrift 1 119 868)...7- (2-2'-3 ", 4"-dihydroxyphenyl-2'-hydroxy-ethyl-
amino-ethyl-theophylline
(Racemate) (German
Patent specification 1 119 868) ...
500
1500
1
0,220.22
0,770.77
Toxizitättoxicity
(Maus)(Mouse)
LD50 mg/kgLD 50 mg / kg
480
104480
104
505505
600600
7-(2-Hydroxy-3-2'-3",4"-dihydroxyphenyl-2'-hydroxy-äthylamino-propyl)-theophyllin7- (2-Hydroxy-3-2'-3 ", 4" -dihydroxyphenyl-2'-hydroxy-ethylamino-propyl) -theophylline
OHOH
Theophyllinyl-(7) — CH2 — CH — CH2 — NH — CH2 — CHTheophyllinyl- (7) - CH 2 - CH - CH 2 - NH - CH 2 - CH
OH OHOH OH
OHOH
40 g 7 - (2 - Hydroxy - 3 - 2' - 3",4" - dihydroxyphenyl-2'-oxoäthyl-benzylamino-propyl)-theophyllin-hydro- chlorid werden in 1280 cm3 50%igem wäßrigem Methylalkohol warm gelöst und unter Zusatz von 3,5 g 10%igem Palladium-Kohle-Katalysator bei 50° C hydriert. Nachdem nach Aufnahme von etwa 1 Mol H2 die Wasserstoffaufnahme fast zum Stillstand gekommen ist, filtriert man und hydriert unter Zugeben von weiteren 3,5 g Katalysator zu Ende. Anschließend wird filtriert und im Vakuum eingedampft. Man kocht den Rückstand mit Äthylalkohol, wobei Kristallisation erfolgt. Nach dem Abkühlen wird abgesaugt und getrocknet. Man erhält 26,9 g des Hydrochlorids vom Schmelzpunkt 209 bis 21Γ C.40 g of 7 - (2 - hydroxy - 3 - 2 '- 3 ", 4" - dihydroxyphenyl-2'-oxoethyl-benzylamino-propyl) -theophylline-hydrochloride are dissolved warm in 1280 cm 3 of 50% aqueous methyl alcohol and hydrogenated at 50 ° C. with the addition of 3.5 g of 10% palladium-carbon catalyst. After the uptake of hydrogen has almost come to a standstill after the uptake of about 1 mol of H 2, the mixture is filtered and hydrogenated to the end with the addition of a further 3.5 g of catalyst. It is then filtered and evaporated in vacuo. The residue is boiled with ethyl alcohol, whereupon crystallization occurs. After cooling, it is filtered off with suction and dried. 26.9 g of the hydrochloride with a melting point of 209 to 21 ° C. are obtained.
Herstellung des AusgangsketonsProduction of the starting ketone
Zu einer Lösung von 66,0 g 7-(2-Hydroxy-3-benzylamino-propyl)-theophyllin in 195 cm3 25%igem Äthylalkohol wird im Stickstoffstrom unter Rühren bei 80° C Wasserbadtemperatur eine Lösung von 17,9 g S^-Dihydroxy-cu-chlor-acetophenon in 100 cm3 Äthylalkohol innerhalb von 2 Stunden zugetropft. Man rührt noch 2 Stunden bei dieser Temperatur, säuert mit alkoholischer Salzsäure an und versetzt mit 870 cm3 Äthylalkohol. Nach 24 Stunden wird das ausgefallene Hydrochlorid des überschüssigen 7-(2-Hydroxy-3-benzylamino-propyl)-theophyllins abgesaugt (35,3 g) und das Filtrat eingedampft. Der Rückstand wird mit Aceton aufgenommen und das nach einigem Stehen auskristallisierte 7-(2-Hydroxy-3-2'-3",4"-dihydroxyphenyl - 2' - oxoäthyl - benzylamino - propyl)-theophyllin-hydrochlorid abgesaugt. Zur Reinigung wird mit Äthanol ausgekocht. Ausbeute: 40,0 g; Schmelzpunkt: 185 bis 188°C.To a solution of 66.0 g of 7- (2-hydroxy-3-benzylamino-propyl) -theophylline in 195 cm 3 of 25% ethyl alcohol, a solution of 17.9 g of S ^ is added in a stream of nitrogen with stirring at 80 ° C. water bath temperature Dihydroxy-cu-chloro-acetophenone in 100 cm 3 of ethyl alcohol was added dropwise within 2 hours. The mixture is stirred for a further 2 hours at this temperature, acidified with alcoholic hydrochloric acid and treated with 870 cm 3 of ethyl alcohol. After 24 hours, the precipitated hydrochloride of the excess 7- (2-hydroxy-3-benzylamino-propyl) -theophylline is filtered off with suction (35.3 g) and the filtrate is evaporated. The residue is taken up in acetone and the 7- (2-hydroxy-3-2'-3 ", 4" -dihydroxyphenyl - 2 '- oxoethyl - benzylamino - propyl) theophylline hydrochloride which has crystallized out after standing for a while is filtered off with suction. For cleaning, it is boiled with ethanol. Yield: 40.0 g; Melting point: 185 to 188 ° C.
Claims (1)
O = C C-N OH R OH"Ch 2 -CH-CH 2 -NH-CH-CH
O = C CN OH R OH "
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DED0048167 | 1965-09-09 | ||
| DED0048167 | 1965-09-09 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1545749A1 DE1545749A1 (en) | 1972-03-30 |
| DE1545749B2 DE1545749B2 (en) | 1973-02-01 |
| DE1545749C true DE1545749C (en) | 1973-08-23 |
Family
ID=
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2716210A1 (en) * | 1976-04-15 | 1977-11-03 | Degussa | BASIC SUBSTITUTED XANTHIN DERIVATIVES |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2716210A1 (en) * | 1976-04-15 | 1977-11-03 | Degussa | BASIC SUBSTITUTED XANTHIN DERIVATIVES |
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