DE1100640B - Process for the preparation of basic substituted alkylxanthine derivatives - Google Patents

Process for the preparation of basic substituted alkylxanthine derivatives

Info

Publication number
DE1100640B
DE1100640B DEC13727A DEC0013727A DE1100640B DE 1100640 B DE1100640 B DE 1100640B DE C13727 A DEC13727 A DE C13727A DE C0013727 A DEC0013727 A DE C0013727A DE 1100640 B DE1100640 B DE 1100640B
Authority
DE
Germany
Prior art keywords
derivatives
alkylxanthine
preparation
basic substituted
salts
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
Application number
DEC13727A
Other languages
German (de)
Inventor
Dr Erwin Kohlstaedt
Dr Karl-Heinz Klingler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CHEMIEWERK HOMBURG
ZWEIGNIEDERLASSUNG DER DEUTSCH
Evonik Operations GmbH
Original Assignee
CHEMIEWERK HOMBURG
ZWEIGNIEDERLASSUNG DER DEUTSCH
Deutsche Gold und Silber Scheideanstalt
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by CHEMIEWERK HOMBURG, ZWEIGNIEDERLASSUNG DER DEUTSCH, Deutsche Gold und Silber Scheideanstalt filed Critical CHEMIEWERK HOMBURG
Priority to DEC13727A priority Critical patent/DE1100640B/en
Priority to DEC13726A priority patent/DE1095285B/en
Priority claimed from DEC15043A external-priority patent/DE1100641B/en
Priority claimed from DEC15044A external-priority patent/DE1100642B/en
Publication of DE1100640B publication Critical patent/DE1100640B/en
Pending legal-status Critical Current

Links

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
    • C07D473/10—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 3 and 7, e.g. theobromine
    • 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 von basisch substituierten Alkylxanthin-Derivaten Zusatz zur Patentanmeldung C 13726 IVb /12p (Auslegeschrift 1 095 285) Gegenstand der Patentanmeldung C 13 726 IVb/12p ist ein Verfahren zur Herstellung von basisch substituierten Alkylxanthinen, oder deren Salzen, das dadurch gekennzeichnet ist, daß man Halogenalkylxanthine mit primären Oxyalkylaminen bei höheren Temperaturen, vorzugsweise zwischen 110 und 1700C zu Oxyalkylamino-alkylxanthinen umsetzt. Process for the preparation of basic substituted alkylxanthine derivatives Addition to patent application C 13726 IVb / 12p (Auslegeschrift 1 095 285) subject of patent application C 13 726 IVb / 12p is a process for the preparation of basic substituted alkylxanthines, or their salts, which is characterized by that haloalkylxanthines with primary oxyalkylamines at higher temperatures, converts preferably between 110 and 1700C to oxyalkylamino-alkylxanthines.

Es wurde nun gefunden, daß auch die Umsetzung von Halogenalkylxanthinen mit tertiären Aminen, deren Stickstoffatom Teil eines heterocyclischen Ringes ist, zu pharmakologisch wertvollen Verbindungen führt. It has now been found that the implementation of haloalkylxanthines with tertiary amines whose nitrogen atom is part of a heterocyclic ring, leads to pharmacologically valuable compounds.

Durch Erhitzen der Halogenalkylxanthine mit den entsprechenden heterocyclischen Basen, z. B. Pyridin, Chinolin oder Isochinolin oder deren Derivaten mit oder ohne Lösungsmittel, erhält man wasserlösliche quartäre Salze. Man verwendet äquivalente Mengen der Reaktionspartner oder auch Überschüsse der einen Komponente.By heating the haloalkylxanthines with the corresponding heterocyclic Bases, e.g. B. pyridine, quinoline or isoquinoline or their derivatives with or without Solvent, water-soluble quaternary salts are obtained. Equivalents are used Quantities of the reactants or excesses of one component.

Theophyllin enthalten auch die in der USA.-Patentschrift 2678 311 beschriebenen bisquartären Salze. Doch beruhen die pharmakologischen Eigenschaften dieser Verbindungen in erster Linie auf dem als sehr starken Ganglienblocker bekannten Hexan-1,6-bis-(trimethylammoniumhydroxyd). In den erfindungsgemäßen Produkten steht die milde blutdrucksenkende Wirkung bei geringer Toxizität im Vordergrund. Ein bekanntes vergleichbares Xanthinderivat mit quartärem Stickstoff in der Seitenkette ist beispielsweise das 7-(ig-Diäthylaminoäthyl) - theophyllin-j odmethylat der britischen Patentschrift 669070. Diese Verbindung besitzt zwar dieselbe blutdrucksenkende Wirkung wie das l-[ß-Theophyllinyl- (7') -äthyl] -3-carbaminyl-pyridiniumchlorid, hat aber bei einer LD50 von 132 mg/kg nahezu nur ein Drittel der therapeutischen Breite der erfindungsgemäßen Verbindung, deren LD50 357 mg/kg beträgt. Theophylline also contain that described in U.S. Patent 2,678,311 described bisquaternary salts. But the pharmacological properties are based these connections primarily to what is known as a very powerful ganglion blocker Hexane-1,6-bis (trimethylammonium hydroxide). In the products according to the invention stands the mild antihypertensive effect with low toxicity in the foreground. A well-known one a comparable xanthine derivative with quaternary nitrogen in the side chain is for example the 7- (ig-diethylaminoethyl) - theophylline iodomethylate of the British patent 669070. This compound has the same antihypertensive effect as that l- [ß-Theophyllinyl- (7 ') -äthyl] -3-carbaminyl-pyridinium chloride, but has one LD50 of 132 mg / kg is almost only one third of the therapeutic range according to the invention Compound whose LD50 is 357 mg / kg.

Beispiel 1 Ein Gemisch aus 37,6 g Nicotinsäureamid und 97,2 g 7-(p-Chloräthyl)-theophyllin wird 2112 Stunden auf 130 bis 160"C erhitzt. Nach dem Abkühlen wird die feste Masse mit Äthylalkohol verrieben und abgesaugt. Zur Entfernung des 7- (fl-Chloräthyl) -theophyllin-Überschusses kocht man das Reaktionsgemisch mit Chloroform aus und kristallisiert den Rückstand aus Wasser um. Man erhält so 62 g 1 -[fl-Theophyllinyl- (7') -äthyl] -3-carbaminylpyridiniumchlorid mit einem Zersetzungspunkt von 295"C. Example 1 A mixture of 37.6 g of nicotinic acid amide and 97.2 g of 7- (p-chloroethyl) -theophylline is heated to 130 to 160 "C for 2112 hours. After cooling, the solid mass rubbed with ethyl alcohol and sucked off. To remove the 7- (fl-chloroethyl) -theophylline excess is boiled the reaction mixture with chloroform and the residue recrystallizes from water. 62 g of 1 - [fl-theophyllinyl- (7 ') -ethyl] -3-carbaminylpyridinium chloride with a decomposition point of 295 "C.

Beispiel 2 Ein Gemisch aus 24,25 g 7-(p-Chloräthyl)-theophyllin und 24 g Nicotinsäure-diäthylamid wird 4 Stunden auf 125 bis 155"C erhitzt. Die noch heiße Masse verreibt man mit 30 ccm Äthylalkohol und saugt die gebildeten Kristalle ab. Zur Reinigung wird das Produkt mit 300 ccm Aceton ausgekocht und nach dem Abkühlen wieder abgesaugt. Man erhält so 25 g l-[p-Theophyllinyl- (7')-äthyl]-3-[N-diäthylcarbaminyl]-pyridiniumchlorid mit einem Schmelzpunkt von 215 bis 216O C. Example 2 A mixture of 24.25 g of 7- (p-chloroethyl) -theophylline and 24 g nicotinic acid diethylamide is heated to 125 to 155 "C for 4 hours. The still hot mass is rubbed with 30 cc of ethyl alcohol and the crystals formed are sucked off away. For cleaning, the product is boiled with 300 cc of acetone and allowed to cool sucked off again. 25 g of l- [p-theophyllinyl- (7 ') - Ethyl] -3- [N-diethylcarbaminyl] pyridinium chloride with a melting point of 215-216O C.

Beispiel 3 8,9 g Nicotinsäure-diäthylamid werden zusammen mit 12,1 g 1-(ß-Chloräthyl)-theobromin im Paraffinbad von 150 bis 1600C verschmolzen. Nach 3'/2 Stunden verreibt man das Reaktionsgemisch bis zur Kristallisation mit 20 ccm absolutem Äthylalkohol und saugt von nicht umgesetztem l-(ß-Chloräthyl)-theobromin (2,5 g) ab. Das Filtrat versetzt man mit dem gleichen Volumen Aceton und dann mit Äther, wobei 13,6 g l-[p-Theobrominyl-(l')-äthyl] 3-[N-diäthylcarbamiflyl] -pyridiniurnchlorid ausfallen. Zur Reinigung kristallisiert man aus einem Essigester-Äthylalkohol-Gemisch um. Der Schmelzpunkt beträgt 195 bis 197cC. Example 3 8.9 g of nicotinic acid diethylamide, together with 12.1 g 1- (ß-chloroethyl) -theobromine fused in a paraffin bath from 150 to 1600C. To The reaction mixture is triturated for 3 1/2 hours with 20 cc until crystallization absolute ethyl alcohol and sucks in unreacted l- (ß-chloroethyl) -theobromine (2.5 g). The filtrate is mixed with the same volume of acetone and then with Ether, with 13.6 g of l- [p-theobrominyl- (l ') - ethyl] 3- [N-diethylcarbamiflyl] pyridine chloride fail. For purification, it is crystallized from an ethyl acetate-ethyl alcohol mixture around. The melting point is 195 to 197cC.

Beispiel 4 21,7 g 7-(ß-Bromäthyl)-theophyllin werden zusammen mit 4,9 g Chinolin in 20 ccm absolutem Toluol 3 Stunden unter Rückfluß gekocht. Nach dem Erkalten saugt man ab und kocht den Rückstand zur Reinigung mit Chloroform aus. Man erhält so 4,9 g 1-[p-Theophyllinyl-(7') äthyl]-chinoliniumbromid mit einem Schmelzpunkt von 263 bis 266"C. Aus der Chloroform-Toluol-Mutterlauge läßt sich überschüssiges 7-(B-Bromäthyl) -theophyllin zurückgewinnen. Example 4 21.7 g of 7- (ß-bromoethyl) -theophylline are together with 4.9 g of quinoline were refluxed for 3 hours in 20 cc of absolute toluene. To it is filtered off with suction after cooling and the residue is boiled with chloroform for purification. This gives 4.9 g of 1- [p-theophyllinyl- (7 ') ethyl] -quinolinium bromide with a melting point from 263 to 266 "C. Excess Recover 7- (B-bromoethyl) -theophylline.

Claims (1)

PATENTANSPRUCH: Verfahren zur Herstellung von basisch substituierten Alkylxanthiu-Derivaten oder deren Salzen durch Umsetzung von Halogenalkylxanthinen mit basischen Stickstoffverbindungen nach Patentanmeldung C 13726 IVb/12p, dadurch gekennzeichnet, daß man Halogenallrylxanthine mit tertiären Aminen, deren Stickstoffatom Teil eines heterocyclischen Ringes ist, bei erhöhter Temperatur zu Dialkylxanthinalkylammoniumsalzen umsetzt. PATENT CLAIM: Process for the production of basic substituted Alkylxanthine derivatives or their salts by reacting haloalkylxanthines with basic nitrogen compounds according to patent application C 13726 IVb / 12p, thereby characterized in that one Halogenallrylxanthine with tertiary amines, whose nitrogen atom Part of a heterocyclic Ringes is, at elevated temperature, to dialkylxanthinekylammonium salts implements. In Betracht gezogene Druckschriften: Britische Patentschrift Nr. 669 070; USA.-Patentschrift Nr. 2678 311; Journal of the American Chemical Society, Brd. 48 (1926), S.2636 bis 2637 Documents considered: British Patent No. 669 070; U.S. Patent No. 2678,311; Journal of the American Chemical Society, Brd. 48 (1926), pp.2636 to 2637
DEC13727A 1956-09-25 1956-09-25 Process for the preparation of basic substituted alkylxanthine derivatives Pending DE1100640B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DEC13727A DE1100640B (en) 1956-09-25 1956-09-25 Process for the preparation of basic substituted alkylxanthine derivatives
DEC13726A DE1095285B (en) 1956-09-25 1956-09-25 Process for the preparation of basic substituted alkylxanthine derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DEC13727A DE1100640B (en) 1956-09-25 1956-09-25 Process for the preparation of basic substituted alkylxanthine derivatives
DEC13726A DE1095285B (en) 1956-09-25 1956-09-25 Process for the preparation of basic substituted alkylxanthine derivatives
DEC15043A DE1100641B (en) 1956-09-25 1956-10-22 Process for the preparation of basic substituted alkylxanthine derivatives
DEC15044A DE1100642B (en) 1956-09-25 1957-06-22 Process for the preparation of basic substituted alkylxanthine derivatives

Publications (1)

Publication Number Publication Date
DE1100640B true DE1100640B (en) 1961-03-02

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Family Applications (2)

Application Number Title Priority Date Filing Date
DEC13726A Pending DE1095285B (en) 1956-09-25 1956-09-25 Process for the preparation of basic substituted alkylxanthine derivatives
DEC13727A Pending DE1100640B (en) 1956-09-25 1956-09-25 Process for the preparation of basic substituted alkylxanthine derivatives

Family Applications Before (1)

Application Number Title Priority Date Filing Date
DEC13726A Pending DE1095285B (en) 1956-09-25 1956-09-25 Process for the preparation of basic substituted alkylxanthine derivatives

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DE (2) DE1095285B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3028272A1 (en) * 1980-07-25 1982-02-25 Fa. Dr. Willmar Schwabe, 7500 Karlsruhe ALKYLAMINO-DESOXY-1.4; 3.6-DIANHYDRO-HEXIT-NITRATE SUBSTITUTED BY PURINE BASES, METHOD FOR THEIR PRODUCTION AND PHARMACEUTICAL PREPARATION

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB669070A (en) * 1948-06-28 1952-03-26 Alexis Jean Marie Moussalli Improvements in or relating to compounds of the dimethyl xanthine series and production thereof
US2678311A (en) * 1952-05-07 1954-05-11 Delmar Chem Theophylline salts

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB669070A (en) * 1948-06-28 1952-03-26 Alexis Jean Marie Moussalli Improvements in or relating to compounds of the dimethyl xanthine series and production thereof
US2678311A (en) * 1952-05-07 1954-05-11 Delmar Chem Theophylline salts

Also Published As

Publication number Publication date
DE1095285B (en) 1960-12-22

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