DE1570014C - Tetramcotinic acid ester of 2,2,6,6 Tetrahydroxymethylcyclohexanols and Ver drive for its production - Google Patents
Tetramcotinic acid ester of 2,2,6,6 Tetrahydroxymethylcyclohexanols and Ver drive for its productionInfo
- Publication number
- DE1570014C DE1570014C DE1570014C DE 1570014 C DE1570014 C DE 1570014C DE 1570014 C DE1570014 C DE 1570014C
- Authority
- DE
- Germany
- Prior art keywords
- acid ester
- cholesterol
- tetramcotinic
- tetrahydroxymethylcyclohexanols
- production
- 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
- 150000002148 esters Chemical class 0.000 title claims description 16
- 239000002253 acid Substances 0.000 title claims description 15
- ICVIFRMLTBUBGF-UHFFFAOYSA-N 2,2,6,6-tetrakis(hydroxymethyl)cyclohexan-1-ol Chemical class OCC1(CO)CCCC(CO)(CO)C1O ICVIFRMLTBUBGF-UHFFFAOYSA-N 0.000 title claims description 8
- 238000004519 manufacturing process Methods 0.000 title description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 238000003379 elimination reaction Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 229960003512 nicotinic acid Drugs 0.000 claims description 2
- 235000001968 nicotinic acid Nutrition 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- -1 nicotinic acid halide Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 claims 1
- 239000012433 hydrogen halide Substances 0.000 claims 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 30
- 229940107161 Cholesterol Drugs 0.000 description 15
- 235000012000 cholesterol Nutrition 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 210000002966 Serum Anatomy 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 210000004185 Liver Anatomy 0.000 description 2
- 150000001840 cholesterol esters Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- WXZMFSXDPGVJKK-UHFFFAOYSA-N 2,2-bis(hydroxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N Trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Description
Die Erfindung betrifft den Tetranicotinsäureester des 2,2,6,6-Tetrahydroxymethylcyclohexanols der folgenden Strukturformel:The invention relates to the tetranicotinic acid ester of 2,2,6,6-tetrahydroxymethylcyclohexanol of the following Structural formula:
<f S<f p
COOH2CCOOH 2 C
CH2OOCCH 2 OOC
<f<f
CH2OOC CH2 CH2 CH 2 OOC CH 2 CH 2
CH2 N
\CH 2 N
\
sowie ein Verfahren zu dessen Herstellung.and a method for its production.
Dieser Ester ist eine neue Verbindung, die in der Literatur noch nicht beschrieben worden ist. Er kann in an sich bekannter Weise.durch Umsetzung von 4 Teilen Nicotinsäurechlorid oder des chlorwasserstoffsauren oder eines anderen anorganischen Säuresalzes desselben in Gegenwart oder Abwesenheit eines Lösungsmittels mit 1 Teil 2,2,6,6-Tetrahydroxymethylcyclohexanol unter Abspaltung von Chlorwasserstoff hergestellt werden.This ester is a new compound that has not yet been described in the literature. He can in a manner known per se by reacting 4 parts of nicotinic acid chloride or of the hydrochloric acid or another inorganic acid salt thereof in the presence or absence of one Solvent with 1 part of 2,2,6,6-tetrahydroxymethylcyclohexanol with elimination of hydrogen chloride getting produced.
. Für das Verfahren eignen sich indifferente Lösungsmittel, wie wasserfreies Benzol oder Toluol. Geeignete Säurebindemittel sind Basen, wie Pyridin, Triäthylamin und Trimethylamin. Diese Basen können unter Umständen gleichzeitig als Säurebindemittel und als Lösungsmittel verwendet werden. Die Umsetzung erfolgt ohne Schwierigkeiten bei 2- bis 3stündigem Erhitzen der Reaktionsteilnehmer auf dem Wasserbad auf 70 bis 900C.. Indifferent solvents, such as anhydrous benzene or toluene, are suitable for the process. Suitable acid binders are bases such as pyridine, triethylamine and trimethylamine. Under certain circumstances, these bases can be used simultaneously as acid binders and as solvents. The reaction takes place without difficulty at 2 to 3 hours of heating the reactants on a water bath at 70 to 90 0 C.
Da die Hydroxylgruppe in Stellung 1 des 2,2,6,6-Tetrahydroxymethylcyclohexanols anderer Natur ist als die übrigen Hydroxylgruppen, reagiert sie auch dann nicht mit dem chlorwasserstoffsauren Salz des Nicotinsäurechlorids, wenn bei der Umsetzung 5 Teile dieses Salzes angewandt werden.Since the hydroxyl group in position 1 of the 2,2,6,6-tetrahydroxymethylcyclohexanol is of a different nature than the other hydroxyl groups, even then it does not react with the hydrochloric acid salt of nicotinic acid chloride, if 5 parts of this salt are used in the implementation.
Die erfindungsge'mäße Verbindung eignet sich zum Herabsetzen des Cholesterinspiegels im Blut.The connection according to the invention is suitable for lowering the cholesterol level in the blood.
Aus »Arzneimittelforschung«, Jg. 11 (1961) S. 110 bis 112, ist bekannt, daß der Hexanicotinsäureester von m-Inosit bei oraler Darreichung den Cholesterinspiegel des Blutserums herabsetzt. Eine ähnliche Wirkung ist aus der französischen Arzneimittelpatentschrift M 1629 für den Hexanicotinsäureester des Sorbits sowie aus der französischen Arzneimittelpatentschrift M 2046 für den Tetranicotinsäureester des Pentaerythrits bekannt.From "Arzneimittelforschung", Vol. 11 (1961) pp. 110 to 112, it is known that the hexanicotinic acid ester of m-inositol, when administered orally, lowers the cholesterol level in the blood serum. A similar effect is known from the French pharmaceutical patent specification M 1629 for the hexanicotinic acid ester of sorbitol and from the French pharmaceutical patent specification M 2046 for the tetranicotinic acid ester of pentaerythritol.
Die Wirksamkeit der erfindungsgemäßen Verbindung wurde im Vergleich zu derjenigen des Hexanicotinsäureesters von m-Inosit an Gruppen von Mäusen untersucht. Die Mäuse wurden 12 Tage mit einer Nahrung mit einem Cholesteringehalt von 1 Gewichtsprozent gefüttert,und zu Vergleichszwecken wurde eine Gruppe von Mäusen mit normaler Nahrung (ohne Cholesterinzusatz) gefüttert. Bestimmungen des Cholesteringehalts des Blutserums und der Leber der Mäuse ergaben die in der folgenden Tabelle genannten Werte. Die Spaltenüberschriften haben die folgenden Bedeutungen:The effectiveness of the compound according to the invention was compared to that of the hexanicotinic acid ester of m-inositol in groups of mice. The mice were used for 12 days fed a diet with a cholesterol content of 1 percent by weight, and for comparison purposes a group of mice was fed normal diet (without added cholesterol). Provisions of the cholesterol content of the blood serum and liver of the mice gave those in the following Values mentioned in the table. The column headings have the following meanings:
Normal = mit normaler Nahrung gefütterte Vergleichstiere; Normal = comparison animals fed with normal food;
Kontrolle = mit 1 % Cholesterin enthaltender Nahrung gefütterte Kontrolltiere;Control = with food containing 1% cholesterol fed control animals;
CTT = mit 1 % Cholesterin + 0,1 %ige wäßrigeCTT = with 1% cholesterol + 0.1% aqueous
Lösung des Tetranicotinsäureesters des 2,2,6,6, - Tetrahydroxymethylcyclohexanols enthaltender Nahrung gefütterte Tiere;Solution of the tetranicotinic acid ester of 2,2,6,6, - tetrahydroxymethylcyclohexanol animals fed containing food;
NS = mit 1 % Cholesterin + 0,1 %ige wäßrigeNS = with 1% cholesterol + 0.1% aqueous
Nicotinsäurelösung enthaltender Nahrung gefütterte Tiere;Feeded animals containing nicotinic acid solution;
IHN = mit 1 % Cholesterin + 0,1 %ige wäßrigeIHN = with 1% cholesterol + 0.1% aqueous
Lösung des Hexanicotinsäureesters von m-Inosit enthaltender Nahrung gefütterte Tiere.Food containing solution of the hexanicotinic acid ester of m-inositol Animals.
Normalnormal Kontrollecontrol
CTTCTT
NSNS
IHNHIM
Gewichtszunahme nach 12 Tagen, gWeight gain after 12 days, g
Peroral dargereicht, mg/kg/Tag Orally administered, mg / kg / day
. Irri Blutserum ' . Irri blood serum '
Gesamtcholesterin, mg% Total cholesterol, mg%
Cholesterinester, mg% Cholesterol ester, mg%
Ester zu Gesamtcholesterin Esters to Total Cholesterol
Triglycerid, mg% Triglyceride, mg%
Phosphatid zu Gesamtcholesterin In der Leber Phosphatide to Total Cholesterol In The Liver
Gesamtcholesterin, mg/g Total cholesterol, mg / g
Cholesterinester, mg/g Cholesterol ester, mg / g
Phosphatid, mg/g Phosphatide, mg / g
Ester zu Gesamtcholesterin Esters to Total Cholesterol
1,62 01.62 0
110,8 76,3 0,689 187,7 65,0 1,694110.8 76.3 0.689 187.7 65.0 1.694
5,0 2,0 34,1 0,400 2,9
05.0 2.0 34.1 0.400 2.9
0
358,3
279,2358.3
279.2
0,779
273,5
156,00.779
273.5
156.0
0,7630.763
20,0
15,0
36,3
0,75020.0
15.0
36.3
0.750
2,4
924,02.4
924.0
184,2
.143,3184.2
.143.3
0,778
164,0
66,0
0,8900.778
164.0
66.0
0.890
19,3
14,8
36,3
0,76719.3
14.8
36.3
0.767
1,31.3
738,5738.5
254,2
194,6254.2
194.6
0,766
204,0
108,00.766
204.0
108.0
0,8030.803
18,4
13,6
40,7
0,73918.4
13.6
40.7
0.739
3,6
919,03.6
919.0
320,1
250,4320.1
250.4
0,782
263,0
135,00.782
263.0
135.0
0,8220.822
15,9
11,2
37,0
0,70415.9
11.2
37.0
0.704
Fortsetzungcontinuation
LD50 für Mäuse
LD50 für Ratten Toxicity, g / kg (oral)
LD 50 for mice
LD 50 for rats
8,2517.8
8.25
.8,017.8
.8.0
Aus der obigen Tabelle ergibt sich, daß der erfindungsgemäße Ester bei gleicher Toxizität dem Hexanicotinsäureester des m-Inosits hinsichtlich der Herabsetzung des Cholesterinspiegels im Blutserum überlegen ist.The table above shows that the ester according to the invention has the same toxicity as the hexanicotinic acid ester des m-inositol in terms of lowering the cholesterol level in blood serum is.
Ein Gemisch aus 60 ml Benzol, 40 ml Pyridin und 17 g Nicotinsäurechlorid-hydrochlorid wird mit 4,5 g 2,2,6,6-Tetrahydroxymethylcyclohexanol versetzt und das Ganze 2,5 Stunden auf die Rückflußtemperatur von 75 bis 80°C erhitzt. Nach dem Erkalten wird ίο Wasser zugesetzt. Der Niederschlag wird abfiltriert, gründlich mit Wasser gewaschen und getrocknet. Durch Umkristallisieren aus verdünnter Essigsäure erhält man 14 g des Tetranicotinsäureesters des 2,2,6,6-Tetrahydroxymethylcyclohexanols; F. = 177 bis 1800C.A mixture of 60 ml of benzene, 40 ml of pyridine and 17 g of nicotinic acid chloride hydrochloride is mixed with 4.5 g of 2,2,6,6-tetrahydroxymethylcyclohexanol and the whole is heated to the reflux temperature of 75 to 80 ° C. for 2.5 hours. After cooling down, ίο water is added. The precipitate is filtered off, washed thoroughly with water and dried. Recrystallization from dilute acetic acid gives 14 g of the tetranicotinic acid ester of 2,2,6,6-tetrahydroxymethylcyclohexanol; F. = 177 to 180 0 C.
Berechnet
gefunden .Calculated
found .
C 63,74, H 5,04, N 8,74%;
C 63,42, H 5,11, N 8,58%.C 63.74, H 5.04, N 8.74%;
C 63.42, H 5.11, N 8.58%.
Claims (2)
1. Tetranicotinsäureester des 2,2,6,6-Tetrahydroxymethylcyclohexanols der StrukturformelPatent claims:
1. Tetranicotinic acid ester of 2,2,6,6-tetrahydroxymethylcyclohexanol of the structural formula
Family
ID=
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