DE1001991B - Process for the preparation of new derivatives of theophylline - Google Patents
Process for the preparation of new derivatives of theophyllineInfo
- Publication number
- DE1001991B DE1001991B DESCH17824A DESC017824A DE1001991B DE 1001991 B DE1001991 B DE 1001991B DE SCH17824 A DESCH17824 A DE SCH17824A DE SC017824 A DESC017824 A DE SC017824A DE 1001991 B DE1001991 B DE 1001991B
- Authority
- DE
- Germany
- Prior art keywords
- theophyllinyl
- preparation
- theophylline
- new derivatives
- acetone
- 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.)
- Pending
Links
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical class O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Chemical compound CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- -1 diacetone alcohols Chemical class 0.000 description 2
- 229960000278 theophylline Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung neuer Derivate des Theophyllins Die [Theophyllinyl-(7)]-acetone, insbesondere der Stammkörper dieser Reihe, besitzen wertvolle pharmakologische Eigenschaften. Ihre pharmazeutische Verwertbarkeit ist jedoch durch die geringe Wasserlöslichkeit erschwert. So ist z. B. schon das einfache unsubstituierte [Theophyllinyl-(7)]-aceton nur zu etwa 21/, °/o in Wasser löslich.Process for the preparation of new derivatives of theophylline Die [Theophyllinyl- (7)] - acetones, in particular the main body of this series have valuable pharmacological properties. However, their pharmaceutical usability is due to their low water solubility difficult. So is z. B. even the simple unsubstituted [Theophyllinyl- (7)] - acetone soluble in water to the extent of only about 21%.
Es wurde nun gefunden, daß man zu neuen Theophyllinderivaten gelangt, die dem Theophyllin entsprechende wertvolle pharmazeutische Eigenschaften, aber in Verbindung mit einer wesentlich erhöhten Wasserlöslichkeit, aufweisen, wenn man die obengenannten [Theophyllinyl-(7)]-acetone in ihre entsprechenden Diacetonalkohole überführt.It has now been found that new theophylline derivatives are obtained, the valuable pharmaceutical properties corresponding to theophylline, but in connection with a significantly increased water solubility, if one the above [theophyllinyl- (7)] acetones into their corresponding diacetone alcohols convicted.
Letzteren ist aus Analogiegründen die Formel zuzuschreiben, in der R, R' und R" ein Wasserstoffatom oder einen Kohlenwasserstoffrest bedeuten.The latter is the formula for reasons of analogy in which R, R 'and R "represent a hydrogen atom or a hydrocarbon radical.
Zu dieser Überführung kann man sich der zur Ketolbildung aus Ketonen und insbesondere der zur Herstellung von Diacetonalkohol aus Aceton gebräuchlichen Arbeitsweisen bedienen (vgl. G. M. Schwab, Handbuch der Katalyse, Bd. VI, Die Katalyse in der organischen Chemie, 2. Hälfte, S. 372 bis 374, Wien, Springerverlag, 1943).For this conversion one can refer to the one for ketol formation from ketones and especially those commonly used to make diacetone alcohol from acetone Use working methods (cf. G. M. Schwab, Handbuch der Katalyse, Vol. VI, Die Katalyse in organic chemistry, 2nd half, pp. 372 to 374, Vienna, Springerverlag, 1943).
Beispiel 20 g [Theophyllinyl-(7)]-aceton werden in 100 ccm 1 n-Natronlauge über Nacht bei Zimmertemperatur geschüttelt. Man erhält so eine bräunliche Lösung, die mit Salzsäure auf einen pH-Wert von 7 neutralisiert und im Vakuum bei einer Badtemperatur von höchstens 50' zur Trockne eingedampft wird. Der trockne Rückstand wird zweimal mit je 250 ccm trocknem Tetrahydrofuran ausgekocht, vom ungelösten Natriumchlorid abgesaugt und das Filtrat auf ca. 50 ccm eingeengt. Über Nacht kristallisierte 6 g reines 1, S-Bis-[theophyllinyl-(7')]-2-methyl-2-oxy-pentanon-(4) vom F. 131 bis 132' (geringe Zersetzung) aus. Aus der Mutterlauge konnten weitere 12 g etwas unreineres Produkt mit Petroläther gefällt werden. Die Löslichkeit in Wasser übersteigt 600/,. Example 20 g of [theophyllinyl (7)] acetone are shaken in 100 cc of 1N sodium hydroxide solution overnight at room temperature. This gives a brownish solution which is neutralized with hydrochloric acid to a pH of 7 and evaporated to dryness in vacuo at a bath temperature of at most 50 '. The dry residue is boiled twice with 250 ccm of dry tetrahydrofuran each time, undissolved sodium chloride is filtered off with suction and the filtrate is concentrated to about 50 ccm. 6 g of pure 1, S-bis- [theophyllinyl- (7 ')] - 2-methyl-2-oxy-pentanone- (4) with a melting point of 131 to 132' (slight decomposition) crystallized out overnight. A further 12 g of somewhat impure product could be precipitated with petroleum ether from the mother liquor. The solubility in water exceeds 600 / ,.
Molekulargewicht Das Molekulargewicht wurde nach der kryoskopischen Methode in Wasser bestimmt. 0,9522 g Substanz in 15 ccm Wasser ergaben eine Gefrierpunktserniedrigung von 0,25°. Hieraus errechnet sich ein Molekulargewicht von 472,3 (± 5 °/o).Molecular Weight The molecular weight was determined according to the cryoscopic Method determined in water. 0.9522 g of substance in 15 ccm of water resulted in a lowering of the freezing point of 0.25 °. A molecular weight of 472.3 (± 5%) is calculated from this.
Mischschmelzpunkt mit 7-Acetonyltheophyllin 7-Acetonyltheophyllin F. 163 bis 164°. 1, 5-Bis-[theophyllinyl-(7')]-2-methyl-2-oxy-pentanon-(4) F.131 bis 132° (Zers.). Mischschmelzpunkt 120 bis 128°, nach vorausgehendem Sintern bei 110°.Mixed melting point with 7-acetonyltheophylline 7-acetonyltheophylline F. 163 to 164 °. 1,5-Bis- [theophyllinyl- (7 ')] - 2-methyl-2-oxy-pentanone- (4) F.131 up to 132 ° (decomp.). Mixed melting point 120 to 128 °, after previous sintering at 110 °.
Analyse des Oximderivates, F. 204 bis 205°: berechnet für C2oH"OBN9: C 49,3°/-,; H 5,10/0; N 25,90/0, gefunden C 49,10/,; H 5,10/,; N 25,4°/o.Analysis of the oxime derivative, m.p. 204-205 °: calculated for C2oH "OBN9: C 49.3 ° / -; H 5.10 / 0; N 25.90 / 0, found C 49.1% ; H 5.10%; N 25.4%.
Das zum Vergleich herangezogene, dem 1, 5-Bis-[theophyllinyl-(7')]-2-methyl-2-oxy-pentanon-(4) der Zusammensetzung nach am nächsten kommende bekannte 1, 3-Bis-[theophyllinyl-(7')]-propanon-(2) (vgl. Comptes rendus hebdomadaises des seances de 1'academie des sciences, Bd. 236 [1953], S. 2520) weist nur eine geringe Wasserlöslichkeit auf (vgl. »Contribution ä 1'etude de la chimie des purines. Nouveaux derives de synthäse de la theophylline<<, Dissertation von Raymond Z e 1 n i k, Universität Paris, 1955, S. 76 und 77).The used for comparison, the 1, 5-bis [theophyllinyl- (7 ')] - 2-methyl-2-oxy-pentanone- (4) the composition of the closest known 1, 3-bis- [theophyllinyl- (7 ')] -propanone- (2) (cf. Comptes rendus hebdomadaises des seances de 1'academie des sciences, vol. 236 [1953], p. 2520) has only a low solubility in water (cf. »Contribution ä 1'etude de la chimie des purines. Nouveaux derives de synthäse de la theophylline <<, Dissertation by Raymond Z e 1 n i k, University of Paris, 1955, pp. 76 and 77).
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DESCH17824A DE1001991B (en) | 1955-04-25 | 1955-04-25 | Process for the preparation of new derivatives of theophylline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DESCH17824A DE1001991B (en) | 1955-04-25 | 1955-04-25 | Process for the preparation of new derivatives of theophylline |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1001991B true DE1001991B (en) | 1957-02-07 |
Family
ID=7428044
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DESCH17824A Pending DE1001991B (en) | 1955-04-25 | 1955-04-25 | Process for the preparation of new derivatives of theophylline |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1001991B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1238035B (en) * | 1959-05-05 | 1967-04-06 | Chemiewerk Homburg | Process for the preparation of a new theophylline compound |
-
1955
- 1955-04-25 DE DESCH17824A patent/DE1001991B/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1238035B (en) * | 1959-05-05 | 1967-04-06 | Chemiewerk Homburg | Process for the preparation of a new theophylline compound |
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