New méthoxy-5 alcoyl ommonium tétrahydrofuranes and tétrahydrothiophénes, a process for their preparation and compositions therapeutic while containing.
The invention has legal rights to novel raéthoxy-s-alkyl ammonium salts of general formula tetrahydrothiophenes tetrahydrofurans and: - a pyridinium salt, of formulae: 9 ΛNR/ F. R , Z- WITH % THE N ^ S R ! where R represents H or CH3 - ammonium salt, of formulas; % HC3 0 nüch3 X hM3 ^% 0 IC I-J(HM3 ) 3, 2 A Z " is a pharmaceutically acceptable anion. The compounds are in the form of stereoisomers separated or any mixture thereof " These compounds are particularly useful as an anti-PAF(PAF-signifies factor d * platelet aggregation) with the corresponding activity as anti-anaphylactic, anti-thrombotic agents, anti-ischemic, immunosuppressants and acting against the corruption of kidneys, against various impacts, allergy skin and intestinal ulcers caused by endotoxin for example. The invention also relates to a process for preparing these compounds by reacting a compound of formula I: with a compound of the formula II: The II NaOB wherein b is the precursor-containing an amino group, or b=a. The reaction is carried out in a solvent such as dimethylformamide, at a temperature of 60 to 80 °c. The conversion of b in a is carried out by known methods. The starting compounds of the formula I can be prepared by reacting a compound of formula III: hM3 (hM2 ) i2 X hM2 THE OH THE III with methanesulfonyl in the benzènepyridine, followed by a conventional treatment. The compound of formula II is prepared by reacting of 1 'sodium hydride on 1 'amino-alcohol BOH corresponding in DMF to 50 and 60 degrees Celsius. The invention relates, finally, therapeutic compositions containing the compounds. EXAMPLE 1 Iodide (terdécyle-a 2 'tetrahydrofuran methyloxy-a 5') ethyl -2 triméthy1ammonium. © Θ X=o, m=2, the n - - has=(HM3 )3 , THE I Transportable : Preparation of the terdécyle-to-2 ethoxy methyl tetrahydrofuran diméthy1amino and 5. (Α ¾)=has 2n (HM3 )2 • Added 0.51 grams (12.7 mmol) of NaH (oil dispersion to 60%) to a mixture of 1.13 grams (12.7 mmol) of dimethylaminoethanol and 100 ml dry dimethylformamide. The mixture is stirred for 30 min, to 60 °c, then adding 2.3 grams (6.35 mmol) of terdécyle-to-2 tetrahydrofuran methanol-5 methane sulfonate. After again stirred for two hours at 80 °c, the mixture is cooled and 1' excess of NaH is decomposed by addition of 5 ml MeOH. After evaporation of most of the DMF, the residue that is obtained is diluted into L-.' water and that is extracted three times with 1' ethyl ether compounds. The organic layer is washed with water until neutral, then dried and evaporated (mgs04) vacuum. The crude compound of interest is then purified by chromatography at silica gel using 5% MeOH in .1 to the CHClo as eluent to obtain 0.9 grams (40%) of the desired compound as an oil. iRNMR (80 megahertz, CDC13 , HMOS) Step b : preparation of 11 iodide (terdécyle-to-2 tetrahydrofuran methyloxy and 5) ethyl trimethylammonium -2. Stirred, during 2 hours at room temperature, 0.5 grams (1.4 mmol) of the compound prepared in step a) above with an excess of d " methyl iodide (2 grams, 14 mmol) in ml acetone 5q dry. After removal of the solvent and the excess mel, the residue is chromatographed on silica gel column using 20% MeOH in 5 to the CHC13 as eluent " to give the desired compound as a yellow solid that melts at 104 °c. An IR (on KBr) 2940, 2860 (C_H), 1120, 1070 (COC-) centimeters "1 . iHNMR (80 ΜΗΖ, CDC13 , HMOS) 3.77 (m-, 3:00, ch-ch 0 +2 N), 3.56 (e, 9:00, the n (HM3 )3 ), 2, 25 - 1, 50 (the m, 6 Η, ch2 c-0), 1.25 (wide O, 22:00, (HM2 )X1 ), 0.85 (a T, 3:00, hM3 ) the O EXAMPLE 2 Iodide (terdécyle-a 2' tetrahydrofuran methoxy-51 ) -2-tolyl p-trimethylammonium © Θ X=0, m=l, β=^HM 3^3 Proceeding as in the example 1 has) and b), starting from the same compound methanesulfonyl and alcohol P-dimethyl aminobenzyl prepared by reducing NaBH ^ p-dimethylaminobenzaldehyde in solution in ethyl the alcohol to obtain the desired compound as a yellow solid that melts at 124 - 126" C.. (COC-) cm.-1 . 1 © HNMR (80 MEGAHERTZ, CDC13 , HMOS) 2 Θ Η, HC=activated c-c), 4.65 (e, 2 Η, O CHj ft-) , 4.05 (wide O, 11 Η, Ν, (CK3) 3 + CH-O), 3.49 (d-, Η 2, EXAMPLE 3 Iodide (terdécyle-a 21 tetrahydrofuran methyloxy-to-51 ) methyl a pyridinium methyl-3n This preparation is carried out as in the example L has) and b), starting from the same compound methane sulfonyl chlorides and pyridyl-3 methanol to obtain the desired compound as a yellow solid that melts at 76 °c. An IR (on KBr), 3080, 3060 (aromatic C-H), 2940, 2870 (-CH), 1645 Θ (On), 1130, 1080 (COC-) - cm.-1 . 1HNMR (80mhz, CDCI3, HMOS) Hi, 8.57 (d-, 1:00, hr7 ), 8.17 (t-, 1:00, hi, 4.90 (e, 2:00, 0 CH2 - pyridin), 4.68 (e, 3:00, HC3 The n -), 4, 36 - 3, 72 (w, 2:00, ch-O), 3.62 (D., 2:00, 0" HM2 " C 0), 2, 21 - 1, 55 (m-, 6:00, FS - ^ the C-O), 1.25 (s-wide, 22:00, (HM2 )]] L. ), 0.82 (t-, 3:00, ^ HC EXAMPLE 4 Chloride (terdécyle-a 28 tetrahydrofuran roéthyloxy-a 5') -6 a pyridinium hexyl Proceeding as in 11 example 1, starting from the same compound methane sulfonyl chloride and pyridinio-6 hexanol for obtaining the desired compound in the form of a hygroscopic oil. 1HNMR (80mhz, CDCL3 , HMOS) © © Hr), 8.17 (T-, 2:00, © HC=c-n), 4, 47 - 3, 67 (m-, 4:00, ch 0 HMthe O 0), 2, 2 - 1, 32 (w, 10:00, HM - C-G-) 26:00, (HM2 )the I; L. + 0-C.2 - (CH22 )2 - C.2 THE N -), + 0 CH2 - C 0), 3.33 (m-, + HC2 ~C-n), 1.2 (broad s at, 0.82 (t-, 3:00, HC3 )" 2:00, The compounds of 1' invention have been administered to the mouse to determine the value of the dl50. For all compounds according to the invention, has been greater than 300 mg dl50/kilograms (the IP or SC)/kg to 600 mg and (in.)" The pharmaceutical interest compounds of the invention has been highlighted by the following pharmaceutical experiment. Inhibition of platelet aggregation on the rabbit lipped. The experiment was performed on wafers, from rabbit plasma lipped. The blood samples were picked by the hepatic artery and put into a citrate buffer solution (3.8%; at pH 7.4); the blood was then centrifuged for 15 min at 1200/min T-. The test sample was prepared in DMSO, then poured onto platelet rich plasma with which it has been left in contact for 1 min, and a dose of 2.5 nm PAF has been added. The determination is made on an apparatus that determines the percentage CronologCoultronics transmission corresponding to the maximum value of the peak before pulping. The percentage of change of the inhibition, with respect to the percent transmission, is calculated (witness: pure DMSO in). The method is described in detail in-laboratory investigation, flight. 41, Number 3, 275 P, 1973, jeans sling CAZENAVE, Dr.MED., scallops benvenist, Dr.MED., and J. Dr. Fraser Mustard, m d, "Visualization d' Garajonay Platelets bypass Derived-to-Activating compete in a the Independent of imprinted release polymers reacting NDA tea arachiodonate Pathway NDA flaws bypass membrane activates on Drugs". The results demonstrate that the compounds inhibit the aggregation induced by PAF 2.5 nm. five test, to kits for each five rabbits, enabled to calculate the ci50 of various compounds using the linear regression method. For the compounds of the various examples, the following values of ci50 were found: Example NO 1; 2.66. 106 Example no. 10 2: 1.27. 105 Example no. 10.3: 1.1. 10-6 Example NO 4: 2.8. 10~5 . This invention relates to new tetrahydrofurans and tetrahydrothiophenes of the general formula: <IMAGE> wherein X stands for O or S, m is an integer from 1 to 12 and A is a pyridinium or an ammonium salt, to a preparation process of said compounds and to therapeutic compositions of matter containing the same. CLAIMS 1 Degrees) novel methoxy-5 - alkyl ammonium-tetrahydrofurans tetrahydrothiophenes of general formula: HM3 (HM2 )12 HM2 - CH2 - O-<2 )W. - HAS in which X is O or s; A is: - a pyridinium salt, of formulas; θ R , Z- WITH ■&© ii R Θ , z- ' F. θ where R represents H or CH3 , - ammonium salt, of formulae: ©hM 3 Θ - N-CH3 the Rz or -N(HM3 ) 3, Z- HM3 θ Θ Z is a pharmaceutically acceptable plaarraaceutiquement mercy. 2 Degrees) - a method for preparing the compound according to claim 1, by reacting a compound of formula I: with a compound of the formula II I The II NaOB wherein b is the precursor-containing an amino group, or b=a, the reaction being carried out in a solvent such as dimethylformamide, at a temperature of 60 to 80 °c. 3 Degrees) - a therapeutic composition comprising, as active principle, an effective amount of at least one of the compounds according to claim 1, associated with a suitable carrier.TOXICOLOGY
PHARMACOLOGY