CH549570A - Salts of nicotinic acid N-oxide - with sympathomimetic amines, with circulatory activity - Google Patents
Salts of nicotinic acid N-oxide - with sympathomimetic amines, with circulatory activityInfo
- Publication number
- CH549570A CH549570A CH1562670A CH1562670A CH549570A CH 549570 A CH549570 A CH 549570A CH 1562670 A CH1562670 A CH 1562670A CH 1562670 A CH1562670 A CH 1562670A CH 549570 A CH549570 A CH 549570A
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- oxydnicotinic
- methyl
- aminoheptane
- amines
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 6
- FJCFFCXMEXZEIM-UHFFFAOYSA-N oxiniacic acid Chemical class OC(=O)C1=CC=C[N+]([O-])=C1 FJCFFCXMEXZEIM-UHFFFAOYSA-N 0.000 title abstract description 3
- 230000000694 effects Effects 0.000 title description 3
- 239000000150 Sympathomimetic Substances 0.000 title 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- -1 alkali metal salt Chemical class 0.000 claims abstract description 8
- 150000001412 amines Chemical class 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- LREQLEBVOXIEOM-UHFFFAOYSA-N 6-amino-2-methyl-2-heptanol Chemical compound CC(N)CCCC(C)(C)O LREQLEBVOXIEOM-UHFFFAOYSA-N 0.000 claims description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 150000001447 alkali salts Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- QNIVIMYXGGFTAK-UHFFFAOYSA-N octodrine Chemical compound CC(C)CCCC(C)N QNIVIMYXGGFTAK-UHFFFAOYSA-N 0.000 claims description 4
- 230000000144 pharmacologic effect Effects 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 229910001514 alkali metal chloride Inorganic materials 0.000 claims description 2
- 230000008033 biological extinction Effects 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000002349 favourable effect Effects 0.000 claims description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims description 2
- 230000031700 light absorption Effects 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- HHAVHBDPWSUKHZ-UHFFFAOYSA-N propan-2-ol;propan-2-one Chemical compound CC(C)O.CC(C)=O HHAVHBDPWSUKHZ-UHFFFAOYSA-N 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 230000000750 progressive effect Effects 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 230000002490 cerebral effect Effects 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract 1
- 229910052783 alkali metal Inorganic materials 0.000 abstract 1
- 230000004855 vascular circulation Effects 0.000 abstract 1
- 150000001414 amino alcohols Chemical class 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000010339 dilation Effects 0.000 description 2
- 230000005923 long-lasting effect Effects 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- SUHBASJODSAWBQ-UHFFFAOYSA-N 6-aminononan-2-ol Chemical compound CCCC(N)CCCC(C)O SUHBASJODSAWBQ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229950005065 oxiniacic acid Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000002315 pressor effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
Salts of nicotinic acid N-oxide (I) with amines of formula (II): Me2CR-(CH2)n-CHMe-NHR1 (II) (where R is H, OH or SH; R1 is H (prefd.) Me or Et; n = 1-4, pref. 3) are prepd. by reacting (II) or its hydrochloride with (I) or its alkali metal salt, pref. in MeOH or EtOH when (I) and (II) are used or in H2O when their salts are used. Salts increase vascular circulation, esp. in cerebral areas, without increasing the heart frequency.
Description
Die Erfindung betrifft die Herstellung bisher unbekannter therapeutisch wirksamer Verbindungen der N-Oxydnikotinsäure mit aliphatischen Aminen der allgemeinen Formel
EMI1.1
in der R Wasserstoff oder eine Hydroxyl- oder Sulfhydrylgruppe, Rl Wasserstoff oder eine Methyl- oder Äthylgruppe und n eine ganze Zahl zwischen 1 und 4 bedeutet.
Es ist bekannt, dass niedere aliphatische Amine und Aminoalkohole sympathikomimetische Eigenschaften besitzen und konstitutionsabhängig in unterschiedlichem Ausmass den Blutdruck beeinflussen. Insbesondere die Aminoalkohole, z.B.
das 6- M ethyl-6-hydroxyl-2-amino-heptan, verursachen strophantinartige Effekte am Herzen. Die pressorische Wirkung hat ihre Ursache teils in einer Konstriktion der Gefässe und andererseits insbesondere bei den Aminoalkoholen durch eine cardiotonische Wirkung. Andererseits bewirkt die Nikotinsäure insbesondere in der oberen Körperhälfte eine Gefässdilatation mit gleichzeitiger Verbesserung der Durchblutung.
Der Blutdruck hat hierbei sinkende Tendenz.
Es wurde nun gefunden, dass sich durch Umsetzung von Aminen der allgemeinen Formel
EMI1.2
in der R, Rl und n die oben angegebenen Bedeutungen ha ben, oder der entsprechenden Amin-Hydrochloride, mit N Oxydnikotinsäure bzw. deren Alkalisalz, neue Verbindungen herstellen lassen, die sich nicht nur fqr die lokale und perorale, sondern vor allem auch für die parenterale Applikation eignen und sich ausserdem durch eine besonders lang anhaltende Wirkung auszeichnen.
Die auch lokal sehr gut verträglichen Substanzen führen durch Vergrösserung des Minutenvolumens des Herzens und gleichzeitige mässige Gefässdilatation zu einer echten Mehrdurchblutung der Gefässe. von der u.a. besonders auch cerebrale Areale betroffen sind. Der Mitteldruck bleibt im allgemeinen praktisch unverändert; desgleichen wird die Herzfrequenz nicht erhöht. Der Energieverbrauch des Herzens ist im Vergleich zur geleisteten Arbeit verringert, so dass von einer Ökonomisierung der Herztätigkeit gesprochen werden kann.
Diese Eigenschaften, verbunden mit der besonders lang anhaltenden Wirkung durch die semipolare Sauerstoffbindung und die dadurch allmählich erfolgende Umwandlung des Nikotinsäureoxyds in Nikotinsäure stellen eine therapeutisch wichtige Erweiterung des Arzneimittelschatzes dar.
Die Darstellung der neuen Verbindungen erfolgt durch Umsetzung der Amine mit N-Oxydnikotinsäure in einem organischen Lösungsmittel, vorzugsweise Methanol oder Ätha- nol zu salzartigen Verbindungen nach folgendem Reaktionsschema:
EMI2.1
Man kann jedoch auch die Hydrochloride der Amine mit wässrigen Lösungen der Alkalisalze, insbesondere der Natriumsalze der Säuren zur Reaktion bringen. Nach Entfernung des Wassers werden die neuen Verbindungen mit Lösungsmitteln von den Alkalichloriden abgetrennt und auf übliche Weise gereinigt.
Beispiel I
Darstellung von 6-Methyl-6-hydroxy-2-aminoheptan N-Oxydnikotlasäure
In einem 500 ml Becherglas werden 29 g (0,2 M) 6-Methyl-6-hydroxy-2-amino-heptan (in den obigen allgemeinen Formeln also mit R = OH, Ri = H und n = 3) in 150 ml Methanol gelöst. Unter Rühren setzt man eine Suspension von 27,2 g (0,2 M) N-Oxydnikotinsäure in 150 ml Methanol zu.
Nach kurzer Zeit bildet sich eine klare Lösung. Diese wird in einem 500 ml Rundkolben überführt und 1 Stunde zum Sieden unter Rückfluss erhitzt. Dann destilliert man das Lösungsmittel ab und entfernt letzte Reste im Wasserstrahlvakuum. Es hinterbleibt ein zerfliessliches Salz, dessen genauer Schmelzpunkt nicht bestimmt werden kann.
Ausbeute: 51 g (90% der Theorie)
Lichtabsorption: Eine 0,002%ige Lösung in Wasser weist Absorptionsmaxima bei 258 und 214 nm und ein Minimum bei 233 nm auf. d = 1 cm.
Sep. Extinktion: E t % = 198, gemessen bei 258 nm in Wasser.
Brechungsindex: nE20 = 1,352 (20%ige wässrige Lösung).
Beispiel 2
Entsprechend wird die nur einfach methylsubstituierte 6-Methyl-2-aminoheptan N-Oxydnikotinsäure (also mit R = H) aus äquimolaren Mengen der Komponenten hergestellt; dabei kann nach Entfernen des Lösungsmittels der gelblich gefärbte Sirup mit Petroläther verrührt werden, wobei langsam Kristallisation erfolgt. Die farblosen, kleinen Kristalle lassen sich aus wenig Isopropanol-Aceton umkristallisieren.
Auch dies Produkt weist gleichfalls günstige pharmakologische Eigenschaften der genannten Art auf.
Die vorstehend beschriebenen Darstellungsbeispiele betreffen Heptylverbindungen, bei denen also n = 3 ist. Die mit entsprechend abgewandelter Ausgangskomponente dargestellten niedrigeren (n = 1 oder 2) und höheren (n = 4) Homologen der substituierten Nikotinsäure-Verbindungen versprechen nach den bisherigen Prüfungsbefunden gleichfalls vorteilhafte und fortschrittliche pharmakologische Eigenschaften.
PATENTANSPRUCH 1
Verfahren zur Herstellung von Verbindungen der N Oxydnikotinsäure mit aliphatischen Aminen der allgemeinen Formel
EMI2.2
**WARNUNG** Ende DESC Feld konnte Anfang CLMS uberlappen**.
The invention relates to the preparation of previously unknown therapeutically active compounds of N-oxydnicotinic acid with aliphatic amines of the general formula
EMI1.1
in which R is hydrogen or a hydroxyl or sulfhydryl group, Rl is hydrogen or a methyl or ethyl group and n is an integer between 1 and 4.
It is known that lower aliphatic amines and amino alcohols have sympathomimetic properties and, depending on their constitution, influence blood pressure to different degrees. In particular the amino alcohols, e.g.
6 M ethyl-6-hydroxyl-2-amino-heptane, cause strophantine-like effects on the heart. The pressor effect has its cause partly in a constriction of the vessels and on the other hand, especially with the amino alcohols, by a cardiotonic effect. On the other hand, nicotinic acid causes vascular dilation, especially in the upper half of the body, with a simultaneous improvement in blood flow.
The blood pressure has a decreasing tendency.
It has now been found that by reacting amines of the general formula
EMI1.2
in which R, Rl and n have the meanings given above, or the corresponding amine hydrochloride, with N-oxydnicotinic acid or its alkali salt, new compounds can be produced which are not only suitable for local and oral, but above all also for parenteral application and are also characterized by a particularly long-lasting effect.
The substances, which are also very well tolerated locally, lead to a real increased blood flow in the vessels by increasing the minute volume of the heart and simultaneous moderate vascular dilation. from the i.a. cerebral areas are particularly affected. The mean pressure generally remains practically unchanged; likewise the heart rate is not increased. The energy consumption of the heart is reduced compared to the work performed, so that one can speak of an economization of the heart's activity.
These properties, combined with the particularly long-lasting effect due to the semi-polar oxygen bond and the gradual conversion of nicotinic acid oxide into nicotinic acid, represent a therapeutically important addition to the range of medicines.
The new compounds are prepared by reacting the amines with N-oxydnicotinic acid in an organic solvent, preferably methanol or ethanol, to form salt-like compounds according to the following reaction scheme:
EMI2.1
However, the hydrochlorides of the amines can also be reacted with aqueous solutions of the alkali salts, in particular the sodium salts of the acids. After the water has been removed, the new compounds are separated from the alkali metal chlorides with solvents and purified in the usual way.
Example I.
Preparation of 6-methyl-6-hydroxy-2-aminoheptane N-oxydnicotlasic acid
In a 500 ml beaker, 29 g (0.2 M) 6-methyl-6-hydroxy-2-amino-heptane (in the above general formulas with R = OH, Ri = H and n = 3) in 150 ml Dissolved methanol. A suspension of 27.2 g (0.2 M) N-oxydnicotinic acid in 150 ml of methanol is added with stirring.
A clear solution forms after a short time. This is transferred to a 500 ml round bottom flask and refluxed for 1 hour. The solvent is then distilled off and the last residues are removed in a water jet vacuum. A liquid salt remains, the exact melting point of which cannot be determined.
Yield: 51 g (90% of theory)
Light absorption: A 0.002% solution in water has absorption maxima at 258 and 214 nm and a minimum at 233 nm. d = 1 cm.
Sep Extinction: E t% = 198, measured at 258 nm in water.
Refractive index: nE20 = 1.352 (20% aqueous solution).
Example 2
Correspondingly, the 6-methyl-2-aminoheptane N-oxydnicotinic acid, which is only mono-methyl-substituted (that is, with R = H), is produced from equimolar amounts of the components; after removing the solvent, the yellowish syrup can be stirred with petroleum ether, slowly crystallizing. The colorless, small crystals can be recrystallized from a little isopropanol-acetone.
This product also has favorable pharmacological properties of the type mentioned.
The illustration examples described above relate to heptyl compounds in which n = 3. The lower (n = 1 or 2) and higher (n = 4) homologues of the substituted nicotinic acid compounds shown with a correspondingly modified starting component also promise advantageous and advanced pharmacological properties according to the test results so far.
PATENT CLAIM 1
Process for the preparation of compounds of N-oxydnicotinic acid with aliphatic amines of the general formula
EMI2.2
** WARNING ** End of DESC field could overlap beginning of CLMS **.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1562670A CH549570A (en) | 1970-10-22 | 1970-10-22 | Salts of nicotinic acid N-oxide - with sympathomimetic amines, with circulatory activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1562670A CH549570A (en) | 1970-10-22 | 1970-10-22 | Salts of nicotinic acid N-oxide - with sympathomimetic amines, with circulatory activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH549570A true CH549570A (en) | 1974-05-31 |
Family
ID=4410636
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1562670A CH549570A (en) | 1970-10-22 | 1970-10-22 | Salts of nicotinic acid N-oxide - with sympathomimetic amines, with circulatory activity |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH549570A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2707077A1 (en) * | 1976-07-21 | 1978-01-26 | Tmc Corp | SKI BOOT |
-
1970
- 1970-10-22 CH CH1562670A patent/CH549570A/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2707077A1 (en) * | 1976-07-21 | 1978-01-26 | Tmc Corp | SKI BOOT |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUE | Assignment |
Owner name: DR. KARL-HEINZ JAEGER |
|
| PL | Patent ceased |