DE2246428C3 - - Google Patents
Info
- Publication number
- DE2246428C3 DE2246428C3 DE19722246428 DE2246428A DE2246428C3 DE 2246428 C3 DE2246428 C3 DE 2246428C3 DE 19722246428 DE19722246428 DE 19722246428 DE 2246428 A DE2246428 A DE 2246428A DE 2246428 C3 DE2246428 C3 DE 2246428C3
- Authority
- DE
- Germany
- Prior art keywords
- acid
- pharmaceutically acceptable
- compound
- addition salts
- compound according
- 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
- 150000001875 compounds Chemical class 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- -1 3-Trifluoromethylthio-anilino Chemical group 0.000 claims 2
- 239000000969 carrier Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000203 mixture Substances 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
- 238000003756 stirring Methods 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DVSUJRJYWLHXNW-UHFFFAOYSA-N 2-[3-(trifluoromethylsulfanyl)anilino]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(SC(F)(F)F)=C1 DVSUJRJYWLHXNW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000000114 Pain Threshold Diseases 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 230000001754 anti-pyretic Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 231100000926 not very toxic Toxicity 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000037040 pain threshold Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Description
Die Erfindung bezieh; sich auf den 2-(3-Trifkiormethylthioanilino)-nicotinsäure-2.3-dihulro\\prop\lestcr der FormelThe invention relates; refer to 2- (3-Trifkiormethylthioanilino) -nicotinic acid-2.3-dihulro \\ prop \ lestcr the formula
OCH2-CHOH-Ch2OHOCH 2 -CHOH-Ch 2 OH
SCF,SCF,
und dessen Additionssalze, die dieser mit pharmazeutisch geeigneten Mineral- oder organischen Säuren bildet.and its addition salts, which this with pharmaceutically suitable mineral or organic acids.
Derartige Nicoiinsäureester sowie deren Additionssalze mit Säuren sind Gegenstand der DT-AS 22 34 712. Damit werden weitere Verbindungen der eingangs erw ahnten Art zur Verfügung gestellt.Such niconic acid esters and their addition salts with acids are the subject of DT-AS 22 34 712. In this way, further connections of the type mentioned at the beginning are made available.
Die Erfindung betrifft auch ein Verfahren zur Ilerstclliing des 2-(3-TriHuormeihylthio-anilino)-nieoiinsäure-2.3-dihydiOxvpiOpylesters und seiner pharmazeutisch geeigneten Säureadditionssalze. das dadurch gekennzeichnet ist. daß man 2-Chlornicotinsäure-2.3-0-isopropvlidendioxypropvlestcr mit m-Trifliiornietlnlthio-anilin in an sieh bekannter Weise umsetzt.The invention also relates to a process for preparing the 2- (3-trihydromethylthio-anilino) -nieoiinsäure-2,3-dihydric hydroxide and its pharmaceutically acceptable acid addition salts. which is characterized by it. that 2-chloronicotinic acid-2.3-0-isoproplidendioxypropvlestcr with m-Trifliiornietlnlthio-aniline implemented in a known manner.
Die Reaktion wird im sauren Medium, vorzugsweise in Gegenwart von Wasser, unter einem Slickstoffstrom bei RückflußtemperaUir des Reaktionsgemisches durchgeführt, wobei etwa während 2 Stunden gerührt w ird.The reaction is carried out in an acidic medium, preferably in the presence of water, under a stream of nitrogen carried out at the reflux temperature of the reaction mixture, stirring for about 2 hours.
Das Reaktionsprodukt wird in Form der freien Base isoliert, die man gewünschienfalls durch bekannte Verfahren mittels pharmazeutisch geeigneter bzw. verträglicher Säure in das Salz überführt.The reaction product is isolated in the form of the free base, which, if desired, can be obtained by known ones Process converted into the salt by means of a pharmaceutically suitable or compatible acid.
Die Erfindung betrifft weiterhin Arzneimittel, die aus einer erfindungsgemäßen Verbindung und den pharmazeutisch üblichen Hilfsmitteln bestehen.The invention also relates to medicaments that consist of consist of a compound according to the invention and the usual pharmaceutical auxiliaries.
'5 Die erfindungsgemäße Verbindung weist wem olle pharmakologische Eigenschaften auf. Obwohl wenig toxisch (der DLin-Wert bei der Maus beträgt p. o. bl() [Verirauensgrenze 95%: 490 bis 725] mg/kg), weist sie entzündungshemmende und antipyretische Eigenschaften auf. die zumindest so wirksam wie die der 2-(3-TiiNuormethylthio-anilino)-nicotinsäure (Dl.,.,-Weπ bei der Maus p. o. 465 mg/kg, vgl. DT-AS 22 34 7 12) und deren Methyl- und Äthylesier sind. '5 The compound according to the invention has some pharmacological properties. Although it is not very toxic (the DLin value in the mouse is po bl () [Verirauensbegrenz 95%: 490 to 725] mg / kg), it has anti-inflammatory and antipyretic properties. which is at least as effective as that of 2- (3-TiiNuormethylthio-anilino) nicotinic acid (Dl.,., - Weπ in the mouse po 465 mg / kg, cf. DT-AS 22 34 7 12) and its methyl and Ethylians are.
Von letzteren unterscheidet sie sich vorteilhaft durch eine etwa dreimal stärkere Wirkung auf den enizüiidunasbedingien Schmerz (Test von LO. Randall und ]. ). Sclilio. vgl. Arch. int. Pharm. 111. [1957]. S. 409 bis 418).It differs from the latter in that it has an approximately three times stronger effect on the pain caused by the disease (test by LO. Randall and]. ). Sclilio. see Arch. int. Pharm. 111. [1957]. Pp. 409 to 418).
Die nachstehende Tabelle gibt die Mittelwerte von Ergebnissen aus drei durchgeführten Versuchen mit der crfindiingsgemäßen Verbindung (Verbindung I) und mit 2-(3-Trifluormethylthioanilino)-nicotinsäure (Verbindune T), die als Bezug dient, wieder.The table below gives the mean values of Results from three experiments carried out with the compound according to the invention (compound I) and with 2- (3-Trifluoromethylthioanilino) nicotinic acid (Compound T), which serves as a reference, again.
Dosis
mg/k|!dose
mg / k |!
e Prozentsatz der Anhebung des Schmerzschwellcnweries.
der durch die Verbindungen hervorgerufen wird (bezüglich eines Versuchstiersatzes)*)
Verbindung I Verbindung T e Percentage of increase in pain threshold. caused by the connections (with regard to an experimental animal set) *)
Connection I Connection T
150
310150
310
6060
147147
*) Messungen 3 Stunden nach Injektion von Bierhefe.*) Measurements 3 hours after injection of brewer's yeast.
Aus der Tabelle geht hervor, daß die erfindungsgemäße Verbindung bei einer Dosis von 9 mg/kg eine genau gleiche Wirkung aufweist, wie sie bei der Verabreichung von 27 mg/kg bei Verbindung T erhalten wird.From the table it can be seen that the inventive Compound at a dose of 9 mg / kg has exactly the same effect as when administered of 27 mg / kg for compound T is obtained.
Das nachstehende Beispiel veranschaulicht die Herstellung der erfindungsgemäßen Verbindung.The following example illustrates the preparation of the compound of the invention.
In einem 500-ml-Dreihalskolben. der mit einem Kühler, einem Rührer und einem Einlaßrohr ausgerüstet ist, werden 17,5 g (0,063 Mol/g) 2-Chlornicotinsäure-2.3-O-isopropylidendioxypropylester. 140ir,l Wasser und 20 ml konzentrierte Salzsäure eingebracht. Man erhitzt dieses Gemisch während einer Stunde unter Rückfluß, wobei unter einem Stickstoffstrom gerührt wird. Man fügt 38,6 g (0.2 Mol/g) m-Trifluormethylihio-anilin hinzu und beendigt die Reaktion nach einstündigem Erhitzen auf Rückflußtemperatur unter einem Stickstoffstrom.In a 500 ml three-necked flask. the one with a Equipped with a condenser, a stirrer and an inlet pipe, 17.5 g (0.063 mol / g) of 2-chloronicotinic acid-2,3-O-isopropylidenedioxypropyl ester are obtained. 140ir, 1 water and 20 ml concentrated hydrochloric acid were introduced. One heats up reflux this mixture for one hour while stirring under a stream of nitrogen. Man adds 38.6 g (0.2 mol / g) of m-trifluoromethylihio-aniline and terminated the reaction after heating at reflux temperature for one hour under a stream of nitrogen.
Man filtriert heiß über pflanzlicher oder tierischer Kohle, kühlt die Lösung ab, filtriert das ausgefallene m-TrifluorniethvIthioanilin ab und macht das Filtrat mil einer 20%igen Amoniaklösung basisch. Das abgeschiedene Öl wird mit Äther extrahiert, der ätherische Extrakt mit Natriumsulfat getrocknet, filtriert, der Äther vertrieben, und man fügt der zurückbleibenden Masse 200 ml X>lol zu. Man kühlt während einiger Stunden, l'ilir en die abgeschiedenen Kristalle ab und kristallisiert diese aus Toluol um.It is filtered hot through vegetable or animal charcoal, the solution is cooled and the precipitated product is filtered off m-TrifluoroniethvIthioanilin and makes the filtrate mil a 20% ammonia solution basic. The separated oil is extracted with ether, the essential one Extract dried with sodium sulfate, filtered, the ether expelled, and 200 ml of X> lol are added to the remaining mass. One cools for a few hours, l'ilir en the deposited crystals from and crystallized this from toluene.
Man erhält 7 g (Ausbeute 29%) 2-(3-Trifluormethyl-7 g (yield 29%) of 2- (3-trifluoromethyl-
thioanilino)-nicotinsäure-2.3-dihydroxyptOpylesier. Sch nelzpunkt 102 C.thioanilino) nicotinic acid 2,3-dihydroxyptOpylesier. Melting point 102 C.
Aiiiilyse fürCK1IIi-,FiN-KXS (Molgewicht = 388):Aiiiilyse for CK 1 IIi -, FiN-KXS (molecular weight = 388):
Berechnet: C 49.50, f I 3,86. F 14.75, N 7.21%:Calculated: C 49.50, f I 3.86. F 14.75, N 7.21%:
gefunden: C49.54, 113.95. I" 14.50, N 7.15%:found: C49.54, 113.95. I "14.50, N 7.15%:
C 49.41, H 4,07. F 14.57. N 7.18%.C 49.41, H 4.07. F 14.57. N 7.18%.
D;is 2-(3-Tnfluormeihylthio-anilini))-niciiiinsiiiirc-2.J-dihjdroxy
prupylcMcr-hydrochlorid, uinkrisnillisien ;uis
einem Äihylaceiai/Alkoholgemisch (9: 1). sehinil/i bei
Ib5 C.
Analyse für CmHmf- iCINbO-iS(Molgewicht = 424.5):D; is 2- (3-Tnfluormeihylthio-anilini)) - niciiiinsiiiirc-2.J-dihjdroxy prupylcMcr-hydrochloride, uinkrisnillisien; uis an Äihylaceiai / alcohol mixture (9: 1). sehinil / i at Ib5 C.
Analysis for CmHmf- iCINbO-iS (molecular weight = 424.5):
Herechnei:Here:
C 45,27, H i,80, Cl 8,36. F-" 13,42, N 6.60%:C 45.27, H i, 80, Cl 8.36. F- "13.42, N 6.60%:
gefunden:found:
C 44,73, H 3,88. Cl 8,42, F 13.58. N 6.43.C 44.73, H 3.88. Cl 8.42, F 13.58. N 6.43.
C 44.71. H 3.96, Cl 8,38, i" 13.45, NC 44.71. H 3.96, Cl 8.38, i "13.45, N
Claims (3)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7135156 | 1971-09-30 | ||
| FR7135156A FR2154330A1 (en) | 1971-09-30 | 1971-09-30 | 2'-(3'-trifluoromethylthio-aniline)-glycerol nicotinate - anti -anflammatory and antipyretic |
| FR7335155A FR2201208B1 (en) | 1972-10-02 | 1973-10-02 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE2246428A1 DE2246428A1 (en) | 1973-04-12 |
| DE2246428B2 DE2246428B2 (en) | 1976-04-29 |
| DE2246428C3 true DE2246428C3 (en) | 1976-12-09 |
Family
ID=26216640
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19722246428 Granted DE2246428B2 (en) | 1971-09-30 | 1972-09-21 | 2- (3-TRIFLUOROMETHYLTHIO-ANILINO) -NICOTIC ACID-2,3-DIHYDROXYPROPYLESTER |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2246428B2 (en) |
-
1972
- 1972-09-21 DE DE19722246428 patent/DE2246428B2/en active Granted
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