DE1963597C3 - New neriifolin derivatives, processes for producing the same and pharmaceuticals containing them - Google Patents
New neriifolin derivatives, processes for producing the same and pharmaceuticals containing themInfo
- Publication number
- DE1963597C3 DE1963597C3 DE19691963597 DE1963597A DE1963597C3 DE 1963597 C3 DE1963597 C3 DE 1963597C3 DE 19691963597 DE19691963597 DE 19691963597 DE 1963597 A DE1963597 A DE 1963597A DE 1963597 C3 DE1963597 C3 DE 1963597C3
- Authority
- DE
- Germany
- Prior art keywords
- neriifolin
- derivatives
- chloroform
- new
- processes
- 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
- VPUNMTHWNSJUOG-BAOINKAISA-N neriifolin Chemical class O[C@H]1[C@H](OC)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@H](CC[C@H]2[C@]3(CC[C@@H]([C@@]3(C)CC[C@H]32)C=2COC(=O)C=2)O)[C@]3(C)CC1 VPUNMTHWNSJUOG-BAOINKAISA-N 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 4
- 239000003814 drug Substances 0.000 title claims description 3
- VPUNMTHWNSJUOG-ZGEFSCNOSA-N 17beta-Neriifolin Natural products O(C)[C@@H]1[C@@H](O)[C@@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@@](C)([C@H](C6=CC(=O)OC6)CC5)CC4)CC3)CC2)O[C@@H](C)[C@@H]1O VPUNMTHWNSJUOG-ZGEFSCNOSA-N 0.000 claims description 8
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 229940079593 drugs Drugs 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000005712 crystallization Effects 0.000 description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- QVQLCTNNEUAWMS-UHFFFAOYSA-N Barium oxide Chemical compound [Ba]=O QVQLCTNNEUAWMS-UHFFFAOYSA-N 0.000 description 2
- DMXVDFPEGANQNY-UHFFFAOYSA-N O.OC.ClC(Cl)(Cl)Cl.CCOC(C)=O Chemical compound O.OC.ClC(Cl)(Cl)Cl.CCOC(C)=O DMXVDFPEGANQNY-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- ANPYLYUCGAFKNQ-UHFFFAOYSA-N ethoxymethoxymethoxyethane Chemical compound CCOCOCOCC ANPYLYUCGAFKNQ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940100198 ALKYLATING AGENTS Drugs 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N Dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N Dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N al2o3 Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000007928 imidazolide derivatives Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Description
OCH,OCH,
in der jeweils einer der Reste Ri und R2 eine niedere Alkyl- oder Alkoxyalkylgruppe und der andere ein Wasserstoffatom oder eine niedere Acylgruppe darstellt, ferner Verfahren zur Herstellung derselben sowie diese enthaltende Arzneimittel.in each of which one of the radicals Ri and R2 is a lower one Alkyl or alkoxyalkyl group and the other represents a hydrogen atom or a lower acyl group, also processes for the production of the same as well as medicaments containing them.
Es wurde gefunden, daß diese Verbindungen eine überraschend hohe Resorption aufweisen und dadurch für eine perorale Applikation zur Therapie der Hei zinsuffizienz bestens geeignet sind.It has been found that these compounds have a surprisingly high absorption and thereby are ideally suited for peroral application for the treatment of heating insufficiency.
Das Verfahren zur Herstellung der Substanzen der Formel I ist dadurch gekennzeichnet, daß man in an sich bekannter Weise Neriifolin alkyliert und gegebenenfallsThe process for the preparation of the substances of the formula I is characterized in that in per se known way neriifolin alkylated and optionally
Gegenstand der vorliegenden Erfindung sind neue Neriifolin-Derivate der allgemeinen Formel IThe present invention relates to new neriifolin derivatives of the general formula I
anschlieCend O-acyliert. Die Alkylierung erfolgt durch Umsetzung mit geeigneten Alkylierungsmitteln, insbesondere Alkylhalogeniden, Dialkylsulfaten und Diazoalkanen. then O-acylated. The alkylation occurs through Reaction with suitable alkylating agents, in particular alkyl halides, dialkyl sulfates and diazoalkanes.
Die O-Acylierung kann mit allen in der Zuckerchemie üblichen Acylierungsmitteln wie Säureanhydriden, Säureimidazoliden, Säurechloriden gegebenenfalls unter Zusatz eines tertiären Amins oder mit der freien Säure durchgeführt werden.The O-acylation can work with everyone in sugar chemistry customary acylating agents such as acid anhydrides, acid imidazolides, acid chlorides, if appropriate below Addition of a tertiary amine or can be carried out with the free acid.
In den nachfolgenden Beispielen ist die Herstellung der neuen Verbindungen näher erläutert.The preparation of the new compounds is explained in more detail in the following examples.
Beispiel 1
Neriifolin-mono-methyiätherexample 1
Neriifolin mono methyl ether
1 g Neriifolin wird in 8 ml Dimethylformamid gelöst, mit 8 ml Toluol verdünnt und nach Zugabe von 0,58 g Bariumhydroxyd und 0,2 g Bariumoxyd unter Rühren bei Raumtemperatur innerhalb 60 Minuten tropfenweise mit einer Lösung von 0,82 ml Dimethylsulfat in 8 ml Toluol versetzt. Nach 4 Stunden Rühren bei Raumtemperatur wird mit 150 ml Chloroform verdünnt, abgesaugt, mit Chloroform nachgewaschen, das Filtrat mit 3 ml Pyridin versetzt und im Vakuum eingeengt. Der Rückstand wird in Chloroform aufgenommen, mit Wasser ausgeschüttelt und die Chloroformphase nach Trocknen über Natriumsulfat im Vakuum eingeengt. Mit dem Rückstand wird eine multiplikative Verteilung mit dem Phasengemisch Tetrachlorkohlenstoff-Essigester-Methanol-Wasser 3:1 :2 :2 durchgeführt. Die eingeengte organische Phase wird einer weiteren multiplikativen Verteilung mit dem Phasengemisch Tetrachlorkohlenstoff-Essigester-Methanol-Wasser 9:1 :6 :4 unterworfen. Die wäßrige Phase liefert nach Ausschütteln mit Chloroform, Einengen und Kristallisation aus Chloroform-Äther 280 mg Neriifolin-mono-methyläther;Fp. 194-198°C.1 g of neriifolin is dissolved in 8 ml of dimethylformamide, diluted with 8 ml of toluene and, after the addition of 0.58 g Barium hydroxide and 0.2 g of barium oxide with stirring at room temperature within 60 minutes a solution of 0.82 ml of dimethyl sulfate in 8 ml of toluene is added. After stirring for 4 hours at room temperature is diluted with 150 ml of chloroform, filtered off with suction, washed with chloroform, the filtrate with 3 ml of pyridine are added and the mixture is concentrated in vacuo. The residue is taken up in chloroform, with Shaken out water and the chloroform phase, after drying over sodium sulfate, concentrated in vacuo. With the residue is given a multiplicative distribution with the phase mixture carbon tetrachloride-ethyl acetate-methanol-water 3: 1: 2: 2 carried out. The concentrated organic phase becomes another multiplicative one Distribution with the phase mixture carbon tetrachloride-ethyl acetate-methanol-water 9: 1: 6: 4 subject. The aqueous phase yields after shaking out with chloroform, concentration and crystallization from chloroform-ether 280 mg neriifolin-mono-methyl ether; mp. 194-198 ° C.
Beispiel 2
Monoacetyl-neriifolin-monomethylätherExample 2
Monoacetyl neriifoline monomethyl ether
500 mg des gemäß Beispiel 1 hergestellten Neriifolinmonomethyläthers werden in 5 ml Pyridin gelöst mit 2,5 ml Essigsäureanhydrid versetzt 24 Stunden bei Raumtemperatur stehengelassen. Danach wird mit Wasser verdünnt, mit Chloroform ausgeschüttelt, die Chloroformphase mit 2 η-Schwefelsäure und Wasser gewaschen, über Natriumsulfat getrocknet und im Vakuum eingeengt. Nach Kristallisation aus Chloroform-Äther-Petroläther erhält man 390 mg Monoacetyl-neriifolin-monomethyläther; Fp. 103- 1070C.500 mg of the neriifolin monomethyl ether prepared according to Example 1 are dissolved in 5 ml of pyridine, mixed with 2.5 ml of acetic anhydride, and left to stand for 24 hours at room temperature. It is then diluted with water, extracted with chloroform, and the chloroform phase is washed with 2η-sulfuric acid and water, dried over sodium sulfate and concentrated in vacuo. After crystallization from chloroform-ether-petroleum ether, 390 mg of monoacetyl-neriifoline-monomethyl ether are obtained; Mp. 103-107 0 C.
Neriifolin-mono-äthoxymethylätherNeriifolin monoethoxymethyl ether
1 g Neriifolin wird in 10 ml Dimethylformamid und 10 ml Dimethylanilin gelöst, mit 1,5 g Äthylchlormethyläther versetzt und 20 Stunden auf 400C erwärmt. Das Reaktionsgemisch wird mit 300 ml Wasser verdünnt und mit Petroläther und Chloroform extrahiert. Die Chloroformextrakte werden im Vakuum eingeengt und mit Petroläther, Benzol und Chloroform-Methanol 1 :1 über 100 g Aluminiumoxyd fraktioniert. Der Rückstand der Chloroform-Methanol (1 :1)-Fraktion wird mit Benzol-Essigester über Silicagel fraktioniert. Die Fraktionen mit 40% Essigester liefern nach Einengen und Kristallisation aus Chloroform-Petroläther 280 mg Neriifolin- mono-äthoxymethyläther; Fp. 88 - 91 ° C.1 g Neriifolin is dissolved in 10 ml of dimethylformamide and 10 ml of dimethylaniline, treated with 1.5 g Äthylchlormethyläther and heated for 20 hours at 40 0 C. The reaction mixture is diluted with 300 ml of water and extracted with petroleum ether and chloroform. The chloroform extracts are concentrated in vacuo and fractionated with petroleum ether, benzene and chloroform-methanol 1: 1 over 100 g of aluminum oxide. The residue of the chloroform-methanol (1: 1) fraction is fractionated over silica gel with benzene-ethyl acetate. The fractions with 40% ethyl acetate yield, after concentration and crystallization from chloroform-petroleum ether, 280 mg neriifolin mono-ethoxymethyl ether; M.p. 88-91 ° C.
Claims (3)
1. Neriifolin-Derivate der allgemeinen Formel IPatent claims:
1. Neriifolin derivatives of the general formula I.
H3C^ CH 3
H 3 C
Priority Applications (22)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19691963597 DE1963597C3 (en) | 1969-12-19 | New neriifolin derivatives, processes for producing the same and pharmaceuticals containing them | |
| US00094210A US3753974A (en) | 1969-12-19 | 1970-12-01 | Neriifolin derivatives |
| CS8435A CS163235B2 (en) | 1969-12-19 | 1970-12-14 | |
| DK636470AA DK123096B (en) | 1969-12-19 | 1970-12-15 | Analogous process for the preparation of neriifoline derivatives. |
| ES386465A ES386465A1 (en) | 1969-12-19 | 1970-12-15 | Neriifolin derivatives |
| RO7065343A RO76964A (en) | 1969-12-19 | 1970-12-16 | PROCESS FOR THE PREPARATION OF NERIIFOLINE DERIVATIVES |
| CH1866870A CH540899A (en) | 1969-12-19 | 1970-12-16 | Process for the preparation of new neriifolin derivatives |
| BG016344A BG17559A3 (en) | 1969-12-19 | 1970-12-17 | METHOD FOR OBTAINING NEW NERINFOLINE DERIVATIVES |
| YU3095/70A YU34141B (en) | 1969-12-19 | 1970-12-17 | Process for preparing digitoxigenin alfa -l-thevetoside derivatives |
| CA100,976,A CA950898A (en) | 1969-12-19 | 1970-12-17 | Neriifolin derivatives, process for their preparation and compositions thereof |
| NL7018392A NL167970C (en) | 1969-12-19 | 1970-12-17 | PROCESS FOR PREPARING NERIIFOLINE DERIVATIVES AND THERAPEUTIC PREPARATIONS CONTAINING SUCH DERIVATIVES AND FORMED THERAPEUTIC PREPARATIONS. |
| IL35870A IL35870A (en) | 1969-12-19 | 1970-12-17 | Neriifolin derivatives and process for their preparation |
| GB60001/70A GB1272340A (en) | 1969-12-19 | 1970-12-17 | Derivatives of neriifolin |
| SE17121/70A SE366036B (en) | 1969-12-19 | 1970-12-17 | |
| ZA708566A ZA708566B (en) | 1969-12-19 | 1970-12-18 | New derivatives of neriifolin and the preparation thereof |
| PL1970145097A PL81431B1 (en) | 1969-12-19 | 1970-12-18 | |
| IE1616/70A IE34826B1 (en) | 1969-12-19 | 1970-12-18 | New derivatives of neriifolin |
| FI703425A FI47763C (en) | 1969-12-19 | 1970-12-18 | Process for the preparation of new neriifoline derivatives. |
| SU1499893A SU451240A3 (en) | 1969-12-19 | 1970-12-18 | The method of obtaining derivatives nereyfolin |
| AT1145270A AT301036B (en) | 1969-12-19 | 1970-12-18 | Process for the preparation of new neriifolin derivatives |
| FR7045727A FR2081385B1 (en) | 1969-12-19 | 1970-12-18 | |
| JP45114055A JPS5118426B1 (en) | 1969-12-19 | 1970-12-18 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19691963597 DE1963597C3 (en) | 1969-12-19 | New neriifolin derivatives, processes for producing the same and pharmaceuticals containing them |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1963597A1 DE1963597A1 (en) | 1971-06-24 |
| DE1963597B2 DE1963597B2 (en) | 1977-03-10 |
| DE1963597C3 true DE1963597C3 (en) | 1977-10-20 |
Family
ID=
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