CS219841B1 - Esters of terebic acids and method of making the same - Google Patents
Esters of terebic acids and method of making the same Download PDFInfo
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- CS219841B1 CS219841B1 CS713981A CS713981A CS219841B1 CS 219841 B1 CS219841 B1 CS 219841B1 CS 713981 A CS713981 A CS 713981A CS 713981 A CS713981 A CS 713981A CS 219841 B1 CS219841 B1 CS 219841B1
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- Prior art keywords
- ethyl
- terebic
- formula
- esters
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- 150000002148 esters Chemical class 0.000 title claims description 10
- 239000002253 acid Substances 0.000 title claims 2
- 150000007513 acids Chemical class 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 title 1
- -1 4-acetaminophenyl Chemical group 0.000 claims description 15
- UZBOWOQARWWIER-UHFFFAOYSA-N 2,2-dimethyl-5-oxooxolane-3-carboxylic acid Chemical class CC1(C)OC(=O)CC1C(O)=O UZBOWOQARWWIER-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 3
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960001680 ibuprofen Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 1
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960005387 etofylline Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Předmětem vynálezu jsou estery kyseliny terebové (2,2-dimethyl-5-oxo-tetrahydrofuran-3-karboxylovéj, obecného vzorce I ( CHó)2 The present invention provides esters of terebic acid (2,2-dimethyl-5-oxo-tetrahydrofuran-3-carboxylic acid of formula I (CH 6 ) 2 )
C-CHCOO# i I O CH.C-CHCOO # 10 CH.
CO (I) ve kterém R je 4-acetaminofenyl, 2-diethylaiminoethyl, 2- (1 -methylpiperazin-4-yl)ethyl, 2- (theof ylin-7-yl J ethyl, 2- (4-oxo-3H-chinazolin-3-yl) ethyl a 2-(7-chlor-4-oxo-3H-chinazolin-3-yl)ethyl a způsob jejich přípravy.CO (I) wherein R is 4-acetaminophenyl, 2-diethylaiminoethyl, 2- (1-methylpiperazin-4-yl) ethyl, 2- (theophyl-7-yl) ethyl, 2- (4-oxo-3H- quinazolin-3-yl) ethyl and 2- (7-chloro-4-oxo-3H-quinazolin-3-yl) ethyl and a process for their preparation.
Látky se připravují tak, že se kyselina terebová převede v prostředí dichlormethanu pří teplotě místnosti N,N‘-karbonyldiimidazolem na imidazolld, který reaguje, aniž by se izoloval, s příslušnými alkoholy.The compounds are prepared by converting terebic acid in dichloromethane at room temperature with N, N‘-carbonyldiimidazole to imidazole, which reacts without isolation with the corresponding alcohols.
Látky byly testovány ,na protizánětlivou účinnost a ve srovnávacích testech s ibuprofenem prokázal derivát 2-diethylaminoethanolu a 7-chlor-3-(2-hydroxy)ethyl-4(3H)chinazolinonu v obou prováděných typech experimentálního zánětu významnou účinnost.The compounds were tested for anti-inflammatory activity and in comparative tests with ibuprofen, the 2-diethylaminoethanol and 7-chloro-3- (2-hydroxy) ethyl-4 (3H) quinazolinone derivative showed significant efficacy in both types of experimental inflammation.
Vynález se týká esterů kyseliny terebové (2,2-dimethyl-5-oxo-tetrahydrofuran-3-karboxylové) obecného vzorce I (ChLL c-CHCOOÍ?The present invention relates to esters of terebic acid (2,2-dimethyl-5-oxo-tetrahydrofuran-3-carboxylic acid) of the general formula I (CHLL c-CHCOOH2).
I II I
OO
CO (I) ve kterém R značí 4-acetaminofenyl, 2-diethylaminoethyl, 2- (l-methylpiiperazin-4-yl) ethyl, 2-(theofyllin-7-yl)ethyl, 2-(4-oxo-3H-chinazolin-3-yl)ethyl a 2-(7-chlor-4-oxo-3H-chinazolln-3-yl) ethyl.CO (I) wherein R is 4-acetaminophenyl, 2-diethylaminoethyl, 2- (1-methylpiiperazin-4-yl) ethyl, 2- (theophylline-7-yl) ethyl, 2- (4-oxo-3H-quinazoline) -3-yl) ethyl and 2- (7-chloro-4-oxo-3H-quinazolin-3-yl) ethyl.
Látky obecného vzorce I, které jsou nové, byly testovány na protizánětlivou účinnost ve srovnávacích testech se známým preparátem ibuprofenem [kyselina 2-(4-isobutylfenyl)propionová] a u některých byla zjištěna významná účinnost, což dokládá tabulka:The compounds of the formula I which are novel have been tested for anti-inflammatory activity in comparative tests with the known preparation ibuprofen [2- (4-isobutylphenyl) propionic acid] and some have been found to have significant activity, as shown in the table:
Tabulka protizánětlivé účinnostiTable of anti-inflammatory activity
Procento inhibice zánětuPercent inhibition of inflammation
Látka podle Kaolin FASubstance according to Kaolin FA
+ statisticky významné oproti neléčené kontrole + statistically significant versus untreated control
Srovnáním výsledků z tabulky vyplývá, že zvláště sloučeniny, připravené podle vynálezu v příkladech 1 až 3, jsou protizánětlivě účinné, i když ne tolik jako ibuiprofen.A comparison of the results in the table shows that, in particular, the compounds prepared according to the invention in Examples 1 to 3 are anti-inflammatory, although not as much as ibuiprofen.
Pokud látky obecného vzorce I mají bazickou povahu, aplikují se s výhodou ve formě solí s fyziologicky přijatelnou anorganickou nebo organickou kyselinou, např. citrónovou, vinnou, maleinovou, fumarovou a podobně.When the compounds of formula (I) are basic in nature, they are preferably applied in the form of salts with a physiologically acceptable inorganic or organic acid, for example citric, tartaric, maleic, fumaric and the like.
Hodnocení látek bylo provedeno na krysách po podání dávek 25 a 100 mg/kg ve dvou modelech experimentálního zánětu (kaolinový a adjuvantní edém). Statisticky významnou protizánětlivou účinnost v obou typech experimentálního zánětu prokázal citrát esteru 2-diethylaminoethanolu a ester 7-chlor-3- (2-hydroxy) ethyl-4 (3H) chinazollnonu.Substance evaluation was performed in rats at doses of 25 and 100 mg / kg in two models of experimental inflammation (kaolin and adjuvant edema). 2-Diethylaminoethanol ester citrate and 7-chloro-3- (2-hydroxy) ethyl-4 (3H) quinazollnone ester citrate showed statistically significant anti-inflammatory activity in both types of experimental inflammation.
Vynález se týká také způsobu výroby těchto derivátů. Podle vynálezu se nové estery kyseliny terebové obecného vzorce I připravují tak, že se na Imidazolid kyseliny terebové, připravený in šitu z kyseliny N,N‘-karmonyldiimidazolem , působí alkoholem obecného vzorce IIThe invention also relates to a process for the preparation of these derivatives. According to the invention, the novel terebic acid esters of the formula I are prepared by treating an imidazolide of terebic acid prepared in situ from N, N‘-carmonyldiimidazole with an alcohol of the formula II
ROH (II), ve kterém R značí totéž co ve vzorci I.ROH (II), in which R denotes the same as in formula I.
Příprava nových látek se výhodně provádí tak, že se kyselina terebová převede ekvivalentem N,N‘-karbonyldlimidazolu v dichlormethanu na imidazolid, který reaguje při teplotě místnosti, aniž by se izoloval, s ekvivalentem příslušného alkoholu na žádaný ester.The preparation of the novel compounds is preferably carried out by converting terebic acid with an equivalent of N, N‘-carbonyldlimidazole in dichloromethane to an imidazolide which reacts at room temperature without isolation, with the equivalent of the corresponding alcohol, to the desired ester.
Všechny použité alkoholy obecného vzorce II jsou známé a lze je připravit známými postupy.All alcohols of the formula II used are known and can be prepared by known methods.
Podrobnosti způsobu provedení jsou uvedeny v následujících příkladech provedení.Details of the embodiment are given in the following examples.
Příklad 1Example 1
K roztoku 3,34 g N,N‘-karbonyldiimidazolu ve 40 ml bezvodého dlchlormethanu se přidá při teplotě místnosti 3,16 g kyseliny terebové, směs se míchá 5 min a k takto připravenému imidazolidu se přidá 2,34 g 2-diethylaminoethanolu. V míchání při teplotě místnosti se pokračuje 6 h, směs se ponechá do příštího dne, zředí se dichlormethanem, roztok se promyje vodou a rozpouštědlo se odidestiluje za sníženého tlaku k suchu. Odparek (4,5 g) se rozpustí v 10 ml ethanolu, k roztoku se přidá roztok 3,3 g kyseliny citrónové v 10 ml ethanolu, směs se zahřeje krátce k varu a ponechá 16 h při teplotě místnosti. Vyloučená krystalická látka se odsaje a překrystaluje z,e směsi ethanolu a etheru. Získá se 2,88 g citrátu odpovídajícího esteru, t. t. 98 až 99 °C.To a solution of 3.34 g of N, N‘-carbonyldiimidazole in 40 ml of anhydrous dichloromethane was added at room temperature 3.16 g of terebic acid, the mixture was stirred for 5 min, and 2.34 g of 2-diethylaminoethanol were added to the thus prepared imidazolide. Stirring at room temperature was continued for 6 h, the mixture was left until the next day, diluted with dichloromethane, washed with water, and the solvent was distilled to dryness under reduced pressure. The residue (4.5 g) was dissolved in 10 ml of ethanol, a solution of 3.3 g of citric acid in 10 ml of ethanol was added, the mixture was heated briefly to boiling and left at room temperature for 16 h. The precipitated crystalline solid is filtered off with suction and recrystallized from a mixture of ethanol and ether. 2.88 g of the corresponding ester citrate are obtained, m.p. 98-99 ° C.
Příklad 2Example 2
Stejným způsobem, jak je popsáno v příkladu 1, se z 3,16 g kyseliny terebové a 2,88 g l-methyl-4-(2-hydroxy)ethylpiperazinu získá 4,9 g citrátu odpovídajícího esteru,In the same manner as described in Example 1, 4.9 g of citrate of the corresponding ester are obtained from 3.16 g of terebic acid and 2.88 g of 1-methyl-4- (2-hydroxy) ethylpiperazine,
1.1. 162 až 163 °C (ethanol).1.1. Mp 162-163 ° C (ethanol).
Příklad 3Example 3
Stejným způsobem, jak je popsáno v příkladu 1, se z 3,16 g kyseliny terebové a 4,48 g 7-chlor-3-(2-hydroxy)ethyl-4(3H)chinazolinonu získá 5,76 g odparku, který krystalizací z 2-propanolu poskytne 4,3 g žádaného esteru, t. t. 127 až 128 °C.In the same manner as described in Example 1, 5.76 g of a residue are obtained from 3.16 g of terebic acid and 4.48 g of 7-chloro-3- (2-hydroxy) ethyl-4 (3H) -quinazolinone, which is crystallized from 2-propanol gave 4.3 g of the desired ester, mp 127-128 ° C.
Příklad 4Example 4
Stejným způsobem, jak je popsáno v příkladu 3, se získají z 3,16 g kyseliny terebové a ekvivalentního množství alkoholu odpovídající estery.In the same manner as described in Example 3, the corresponding esters are obtained from 3.16 g of terebic acid and an equivalent amount of alcohol.
Ester Výtěžek T. t. °C aj paracetamolu 67 % 155 až 158Ester Yield of m.p. and paracetamol 67% 155-158
b) 7-(2-hydroxy jethyltheofyllinu 68 % 151 až 152b) 7- (2-hydroxyethyltheophylline) 68% 151-152
c) 3-(2-hydroxy jethyl-4(3H)- 70'% 106 až 107 chinazolinonuc) 3- (2-hydroxyethyl-4 (3H) -70% 106-107 quinazolinone)
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS713981A CS219841B1 (en) | 1981-09-30 | 1981-09-30 | Esters of terebic acids and method of making the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS713981A CS219841B1 (en) | 1981-09-30 | 1981-09-30 | Esters of terebic acids and method of making the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS219841B1 true CS219841B1 (en) | 1983-03-25 |
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ID=5419960
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS713981A CS219841B1 (en) | 1981-09-30 | 1981-09-30 | Esters of terebic acids and method of making the same |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS219841B1 (en) |
-
1981
- 1981-09-30 CS CS713981A patent/CS219841B1/en unknown
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