SE461394B - 6-AMINOMETHYL-FURO- (3,4-C) -PYRIDINE DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

461 394 The compounds of the invention are of interest for their therapeutic activity. mainly in the field of antiallergic effect.

According to the invention there is also provided a process for the preparation of the above-mentioned compounds. which process comprises reacting 6-formyl-7-hydroxy-furo- (3,4-c) -pyridine derivatives of the general formula II II II QHC or M'-CHO wherein A1 and A2 have the above meaning, with a stoichiometric amount of hydroxylamine and of NaOH in water at room temperature. after which the oxime thus obtained is hydrogenated at room temperature under normal pressure in acetic acid with hydrogen in the presence of a Pd / C catalyst according to the following reaction scheme: Nnzon 'H2 M-cno ---> M-cu = N-OH -š- dzP I 6-Formyl-7-hydroxy-furo- (3,4-c) -pyridine derivatives II can be obtained from the corresponding 6-methyl-7-hydroxy-furo- (3,4-c) -pyridine derivatives of the general formula III . wherein Al and A ion sequence HO-CH 2 2 have the meanings above.

(CF MnO OHC CO) by the following reaction M-chloro-eroxibersoe 'Sm fl fä O 461 394 L.

I '461 394 Compounds III are described in our patent applications 8200744-4 and 8401841-5.

The production of only one of the starting compounds. 1,3-Dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine is now described in more detail. whereby other starting materials are obtained in the same way. a) In a 1 liter reactor with stirring, heating and cooling devices, 22.3 g of 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) were treated. -pyridine at 0 ° C in the presence of 300 ml of methylene dichloride with 18.2 g of m-peroxybenzoic acid, which was added slowly. After stirring overnight at room temperature, 150 ml of 10% sodium sulfate solution was added. After stirring and decanting, the methylene dichloride phase was washed with the same amount of sodium sulfate solution. twice with 150 ml of sodium bicarbonate solution and three times with 100 ml of water. after which it was dried over anhydrous sodium sulfate. After evaporation to dryness, a beige precipitate was obtained. which was washed with petroleum ether. filtered and dried, Yield 22.9 g (96% 9 of 1,3-dihydro-3-p-chlorophenyl-6-methyl-7-hydroxy-furo- - (3,4-C) -Pyridine-N-oxide. b) I the same reactor as above, 22.9 g of the obtained compound in the previous step were treated at 0 DEG-5 DEG C. in the presence of 175 ml of methylene dichloride with 4.3 ml of difluoroacetic anhydride, added dropwise with stirring. The mixture was stirred overnight at room temperature and then cooled and treated dropwise with 95 ml of methanol. After evaporation to dryness, the residue was taken up in 300 ml of chloroform, washed twice with 75 ml of 10% sodium bicarbonate solution and three times with 100 ml of water and dried over anhydrous sodium sulfate. The chloroform was evaporated, and the residue was washed with diethyl ether and dried under reduced pressure. Yield 21.3 g (93 t) of 1,3-dihydro-3-p-chlorophenyl-6-hydroxymethyl-7-hydroxy-furo- (3,4-c) -pyridine. . c) In a 2 l reactor, 21.3 g of that compound were treated. with 27 g of manganese dioxide in the presence of 0.9 l of chloroform at 28-30 ° C with stirring for 3 hours. After separation, filtration, washing with chloroform and then with ethyl acetate the solution was evaporated to dryness and the paste was treated with isopropyl oxide then with pentane to give 1 g (95%) of 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy - -furo- (3.4-c) -pyridine.

According to the invention there is further provided a pharmaceutical composition containing a 1,3-dihydro-6-aminomethyl-7-hydroxy-furo- - (3,4-c) -pyridine derivative of the general formula I, as defined above. or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable excipient or carrier.

The invention is described by the following examples.

Example 1 1,3-Dihydro-3-methyl-6-aminomethyl-7-hydroxy-turo- (3,4-c) -Dyridine In a 2 L reactor, 71.2 g (0.4 mol) of 1,3-dihydro-3 were poured at room temperature. -methyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine. 270 ml of 1N sodium hydroxide and then. dropwise with stirring. 27.8 g (0.4 mol) of hydroxylamine hydrochloride dissolved in 200 ml of water. Stirring was maintained for 10 hours. and the reaction mixture was filtered to give, after washing with water and drying, 74 g (96%) of the corresponding 6-oxime derivative.

The 74 g of the 6-oxime derivative was then poured with 0.9 l of acetic acid into a sealed reactor equipped with a gas circulator. normal pressure for 4 hours.

After filtering the reaction mixture, it was evaporated to dryness. The residue was treated with toluene and then with methanol. from which 70 g (76 2) of the acetate of 1,3-dihydro-3-461,394-methyl 6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine were recrystallized. a beige product, melting at 167 ° C (Tottolí), the analysis of which showed a good agreement with the formula CQHIZNZOZ. CZHÅOZ. This compound was insoluble in water.

The same route was used for all the synthesized compounds. and procedure details will not be repeated in the following examples. The corresponding hashes (without acetic acid moiety) and other salts of said bases are obtained in the usual way. Example 2 1,3-Dihydro-3-propyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine Starting from 1,3-dihydro-3-propyl-6-formyl-7-hydroxy- turo- - (3,4-c) -pyridine was obtained (yield 77 l) a pale beige product, melting at 187 ° C (Tottoli). insoluble in water. whose analysis showed a good agreement with the formula C11H16N2O2.

C H O. Example 1 1,3-Dihydro-3- (3 ', 4'.S'-trimethoxyphenyl) -ethyl-6-aminomethyl-7-: hydroxy-furo- (3,4-c) -pyridine Starting from 1,3-Dihydro-3- (3 ', 4', 5'-trimethoxyphenyl) -ethyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine was obtained (yield 61 X) but white product, melting at 140-144 ° C (Tottolí). insoluble in water. whose analysis showed a good agreement with the formula CHNO .CHO 19 24 2 5 2 4 2 'Example 4 1,3-Dihydro-3-cyclohexyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine Starting from 1.3 -dihydro-3-cyclonexyl-6-formyl-7-hydroxy-furo- - (3,4-c) -pyridine a white product was obtained (yield 67 2). melting at 173-177 ° C (Tottoli). insoluble in water, whose analysis II 461 394 showed a good agreement with the formula ClqH20N2O2.C2H402.

Example 5 1,3-Dihydro-3-α-thienyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -gyridine Starting from 1,3-dihydro-3-α-thienyl46-formyl-7- hydroxy- furo- - (3,4-c) -pyridine was obtained (yield 58 h) a yellowish product, melting at 148 ° C (Tottoli). insoluble in water. whose analysis shows a good agreement with the formula C12H12N2Q2S1'c2H4O2. formyl-7-hydroxy-furo- (3,4--C) -pyridine was obtained (yield 82 2) a pale beige product. melting at 188 ° C (Tottoli). insoluble in water. whose analysis showed a good agreement with the formula C -3-p-Chlorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine was obtained (yield 86%) a pale beige product. melting at 204 ~ 206 ° C (Tottolí). insoluble in water. whose analysis showed a good agreement with the formula C H CINZO .CZH 0. 14 13 2 4 2 Example gel B 1,3-Dihydro-3- (2'.3'-dichlorophenyl) -6-aminomethyl-7-hydroxy-furo- - (3,4-c) -gyridine Starting from 1,3-dihydro-3 (2 ', 3'-dichlorophenyl) -6-formyl-7-hydroxy-furo- (3,4-c) -pyridine was obtained (yield 72%) a pale 461,394 l yellow product, melting at 193- 196 ° C (Tottoli). insoluble in water, the analysis of which showed a good agreement with the formula C H C12N O .C H O. 14 12 2 2 2 4 2 Example gel ii 1,3-dihydro-3-p-fluorophenyl-6-aminomethyl-7-hydroxy-furo- (3.G- -c) -gyridine Starting from 1,3-dihydro-3 -p-fluorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine was obtained (yield 69 l) a pale beige product, melting at 183-178 ° C (Tottoli). insoluble in water, the analysis of which showed a good agreement with the formula C H FN202.C H 0. 14 13 2 4 2 Example 10 1,3-dihydro-3-p-toluyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -gyridine Starting from 1,3-dihydro-3-p-toluyl-6 -formyl-7-hydroxy-furo- - (3,4-c) -pyridine was obtained (yield 78 2) a pale beige product. melting at 158-160 ° C (Tottoli). insoluble in water, the analysis of which showed good agreement with the formula CHN 0 .CH 0 16 2 2 2 4 2 'Example 11 1,3-dihydro-3-p-methoxyphenyl-6-aminomethyl-7-hydroxy-furo- (3, 4- -c) -gyridine Starting from 1,3-dihydro-3-p-methoxyphenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, a pale beige product was obtained (yield 62 2). melting at 144-149 ° C (Tottoli). insoluble in water, the analysis of which showed a good agreement with the formula C15H16N2O3.C2H402.

Example 12 1,3-Dihydro-3- (3 °, 4 ', 5'-trimethoxy) -phenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine Starting from 1 -Dihydro-3- (3 ', 4', 5'-trimethoxy) -phenyl-6-h.

In 46 DEG-394-formyl-7-hydroxy-furo- (3,4-c) -pyridine was obtained (yield 49 3) a white active product, melting at 137 DEG-141 DEG C. (Tottoli), insoluble in water. analysis showed a good agreement with the formula Cl7H2ON205.C2HqO2.

Example 13 1,3-Dinhydro-3-m-trifluoromethylphenyl-6-aminomethyl-7-hydroxy-furo-§3,4-C) -gyridine Starting from 1,3-dihydro-3-m-trifluoromethylphenyl-6-formyl- 7-Hydroxy-furo- (3,4-c) -pyridine was obtained (yield 84%) of a white product. melting at 197-203 ° C (Tottolí). insoluble in water. whose analysis showed a good agreement with the formula Cl5H13F3N2O2.C2H4O2.

Example Gel 14 1,3-Dihydro-3-p-dimethylaminoethoxyphenyl-6-aminomethyl-7-hydroxy-furo-§3,4-c) -pyridine Starting from 1,3-dihydro-3-p-dimethylaminoethoxyphenyl-6-formyl-7 -hydroxy-furo - (}. 4-c) -pyridine was obtained (yield 46%) a pale yellow product, melting at 160-164 ° C (Tottoli). insoluble in water, the analysis of which showed a good agreement with the formula Cl9H23N302.C2H4O2.

Example 15 - 1,3-Dihydro-3-methyl-31-thienyl-6-aminomethyl-7-hydroxy-furo- - (3,4-c) -pyridine Starting from 1,3-dihydro-3-methyl-3-α- thienyl-6-formyl-7-hydroxy-Euro- (3,4-c) -pyridine was obtained (yield 66 X) a white product, melting at 206-208 ° C (Tottoli). slightly soluble in water, the analysis of which showed a good agreement with the formula Cl3H14N2O2S.C2H402.

Example 16 1,3-Dihydro-3-ethyl-3-phenyl-6-aminomethyl-7-hydroxy-furofig, 4-c) -gyridine Starting from 1,3-dihydro-3-ethyl-3-phenyl-6-formyl -7-hydroxy- 461 394 -furo- (3.4-c) -pyridine was obtained (yield 80%) a white product, melting at 207 ° C (Tottoli). insoluble in water. whose analysis showed a good agreement with the formula Cl6H18N2O2.C2HqO2.

: F- I? Example gel 17 '1,3-dihydro-3-phenyl-3-p-trifluoromethylphenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine Starting from 1,3-dihydro-3-phenyl- 3-p-Trifluoromethylphenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine was obtained (yield 65 h) a white product. melting at 22l ° C (Tottolí), insoluble in water. whose analysis showed a good agreement with the formula C21H1vF3N2 ° 2'CzH4 ° 2 'Example 1g 1,3-dihydro-3-phenyl-3-a> methoxypyrrolidinyl-6-aminomethyl-7-hydroxy-furo- (3,4- c) -pyridine Starting from 1,3-dihydro-3-phenyl-3-α-methoxyyrrolidinyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine. was obtained (yield 41 2) a yellowish product, melting at 132 DEG-132 DEG C. (Tottoli). insoluble in water, the analysis of which showed a good agreement with the formula C19H22N3O3.C3H402. gyemgel 19 1,3-dihydro-3,3-di-p-fluorophenyl-6-aminomethyl-7-hydroxy-furo-44,4-c-ridin Starting from 1,3-dihydro-3,3-di-p-fluorophenyl-6 -aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine was obtained (yield 81 2) a pale yellow product. melting at 214 ° C (Tottoli), insoluble in water. whose analysis showed a good agreement with the formula C20H15SF2 "z ° 2 '° 2H4 ° 2' <Exemgel 20 1,3-dinydro-3-α-furyl-3-p-thiomethylphenyl-6-aminomethyl-7- -nydroxy-furo - (3,4-c) -pyridine * LM Starting from 1,3-dihydro-3-α-furyl-3-p-thiomethylphenyl-6,461,394 11-formyl-7-hydroxy-furo- (3.4'c) - pyridine was obtained (yield 63 h) a white product, melting at 153 DEG-157 DEG C. (Tottoli). insoluble in water, the analysis of which showed a good agreement with the formula CHNO SC HO _ 19 18 2 3 2 4 2 Example gel Z1 1,3-dihydro-3,3-di-difuryl-6-aminomethyl-7-hydroxy-furo-L3 A- -c) -gyridic starting from 1,3-dihydro-3,3-di-u-furyl-6-formyl-7-hydroxy-Euro-(3,4-c) -pyridine a white product was obtained (yield 72 l). melting at 178 ° C (Tottoli). insoluble in water. whose analysis showed a good agreement with the formula C16H14N2O4'C2H4O2 'Example 22 1,3-dihydro-3-cyclohexyl-3- (2', 3'-dichloro) -phenyl-6-aminomethyl- -7-hydroxy-furo- ( 3,4-c) -pyridine Starting from 1,3-dihydro-3-cyclohexyl-3- (2'3'-dichlorophenyl) -6-formyl-7-hydroxy-furo- (3,4-c) -pyridine was obtained (yield 59 X) a yellow product, melting at 230 ° C (Tottoli). insoluble in water. whose analysis showed a good agreement with the formula C20H22C12N2O2.C2H402.

Example 23 1,3-Dihydro-3-vinyl-3-p-B-methylmethylphenyl-6-aminomethyl-7-hydroxy-furo-g3,4-c) -gyridine Starting from 1,3-dihydro-3-vinyl-3-p -thiomethylphenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine was obtained (yield 66 h) a beige product, melting at 15 ° C (Tottoli). insoluble in water, the analysis of which showed a good agreement with the formula C17H18N2O2s'C2H402 'Example 24 1,3-Dihydro-3-dimethylaminopropyl-3-p-chlorophenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine Starting from 1,3-dihydro-3-dimethylaminopropyl-3-p-chlorophenyl-461 394 12 -6-formyl »7-hydroxy-furo- (3,4-c) -pyridine a white product was obtained (yield 47 2). . melting at 169 ° C (Tottoli). insoluble in water, the analysis of which showed a good agreement with the formula Cl9H2qClN3O2.C2H4O2.

I ° __X__i __ <= _ i_2e_t DL50 was determined per os and I.P. in mice. Depending on the compounds, the value ranged from 0.7 to over 2.4 g / kg (per os) and 0.6 to 1.65 g / kg I.P.

Pharmacology A complete pharmacological study was performed and the following tests are reported below.

A - Passive cutaneous anaphylaxis This experiment was performed as described in Fiche Technique No. 48 by J.Pharm. Paris 1979 lg (l), p. 69-72.

Male Sprague-Dawley rats (180-200 g) received two intradermal injections of immune serum in the back. 72 hours later, they received an intravenous (penile vein) injection of 1 ml of a mixture of egg albumin (5 mg / ml) and Evans blue (2.5 mg / ml): This induced the formation of bulges around the sites of injection of immune serum. The bumps were removed for 30 min. after the formation. was measured and then incubated for 24 hours at 65 ° C in 4 ml of formamide (for extraction of Evans blue). Optical density was determined on the supernatant at 620 nm with a spectrophotometer.

A first group of 8 rats was used for control. A second group (8) was used for treatment with a reference substance (theophylline. 25 mg / kg) and ten other groups (all with 8 rats) were used for the treatment with ten of the compounds of the present invention (all at 25 mg / kg). . identified by their sample number. For these eleven groups, the appropriate compound was administered per os one hour before the injection of the egg albumin / Evans blue mixture. The percentage reduction of the rings with respect to surface area and color was determined by comparison with the control. The results are reported in the left part of the table below. k) 10 461 394 13 B - Anti-histamine action This experiment was performed as described by Doepfner W. and Cerletti A., Int. Arch. Allergy lg. 89 1958, and J.Pharmac. and exp. ther. (1974) lgl, p. 300-310.

Male Sprague-Dawley rats (140-160 g) were subjected to water resistance for 18 hours before receiving 1 ml / kg of water (for control), 0.2 of an aqueous solution or suspension of the tested compounds. The volume of the left hind paw was measured by plethysmography, after which 0.1 ml of 5% histamine hydrochloride was injected. The response to inflammation was evaluated with a subsequent volume determination one hour later. Groups of 8 animals were used: one for control, ten for tested compounds (same as in A above) and two for the reference compounds mequitazine and promethazine. all in a dose of 25 mg / kg.

The percentage reduction in the inflammatory response was obtained by comparison with the control. The results are summarized in the right part of the following table.

From these two experiments it is clear that the compounds according to the invention have a strong anti-histamine effect. Gresentation - Dosage For human use via oral administration, tablets or gelatin capsules containing 0.20 g of a compound of the invention are preferred. For intravenous administration, ampoules containing the same amount to be injected by perfusion were used. Daily doses in human therapy are from 0.20 to 2 g per os and 0.20 to 1 g I.V. 461 594 14 2 reduction of Histamine-induced edema '15 bulnad% reduction of the inflammation Compounds Surface Color Theophylline -60 -62 - EX. 1 -77 -86 -48 EX. 2 -58 -60 -77 EX. 4 -61 -66 -59 EX. 5 -49 -60 -68 EX. 6 = 75 -84 -79 EX. 9 -68 - 72 -83 EX. 10 -68 »72 -66 EX. 14 -71 ~ 8l -Sl EX. 16 -53 -59 -54 EX. 18 -65 -69 -62 Mequitazine - - »-60 Promatazine - - -41 (k Om

Claims (3)

10 15 20 25 30 35 461 394 Patent claims A 1,3-dihydro-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine derivative of the general formula I wherein each of A1 and A2 independently of one another denotes a hydrogen atom. a straight, saturated or unsaturated hydrocarbon group having from 1 to 5 carbon atoms. a thienyl, pyrrolidinyl or a furyl group, a cyclohexyl group: a phenyl group: or a phenylethyl or a toluyl group, each of those groups. represented by A1 and A2, are unsubstituted or are substituted by one or more chlorine or fluorine atoms. trifluoromethyl groups, alkyl groups having from 1 to 5 carbon atoms, alkoxy groups having from 1 to 5 carbon atoms. alkylthio groups having from 1 to 5 carbon atoms. dialkylamino groups. wherein each alkyl group has from 1 to 5 carbon atoms, dialkylaminoalkoxy groups, wherein each of the two alkyl groups and the alkoxy groups has from 1 to 5 carbon atoms or u- or α-alkoxy-N-pyrrolidinyl groups. wherein the alkoxy group has from 1 to 5 carbon atoms. and pharmaceutically acceptable salts of these compounds. A process for the preparation of 1,3-dihydro-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine derivatives according to claim 1 having the general formula I wherein each of A and A 1 2 a straight, saturated or unsaturated hydrocarbon group having from 1 to 5 carbon atoms, cyclohexyl-. independently denote a hydrogen atom. and tieny1 ~. pyrrolidinyl-. furyl-, phenyl-. phenylethyl or a toluyl group wherein each of the groups represented by A and A is unsubstituted or is substituted by one or more chlorine or fluorine atoms. trifluoromethyl groups. alkyl groups having from 1 to 5 carbon atoms, alkoxy groups having from 1 to 5 carbon atoms. alkylthio groups having from 1 to 5 carbon atoms. dialkylamino groups, wherein each alkyl group has from 1 to 5 carbon atoms. dialkylaminoalkoxy groups, wherein each of the two alkyl groups and the alkoxy groups has from 1 to 5 carbon atoms or u- or fialkoxy-N-pyrrolidinyl groups. wherein the alkoxy group has from 1 to 5 carbon atoms, and pharmaceutically acceptable salts of these compounds, characterized in that the 6-formyl-7-hydroxy-furo- (3,4-c) -pyridine derivatives of the general formula wherein Al and A2 has the meanings given above. is reacted with a stoichiometric amount of hydroxylamine and of NaOH in water at room temperature. after which the oxime thus obtained is hydrogenated at room temperature under normal pressure in acetic acid to hydrogen in the presence of a Pd / C catalyst. 3. Therapeutic composition. characterized in that it contains as active ingredient an effective amount of a compound according to claim 1, wherein each of A1 and A2 is a hydrogen atom. and straight. saturated or unsaturated hydrocarbon group independently representing from 1 to 5 carbon atoms. and thienyl-. Pyrrolidinyl or a furyl group; a cyclohexyl group: a phenyl group: or a phenylethyl or a toluyl group wherein each of the groups. which are represented by A1 and A2, are unsubstituted or are substituted by one or more chlorine or fluorine atoms, trifluoromethyl groups. alkyl groups having from 1 to 5 carbon atoms. alkoxy groups having from 1 to 5 carbon atoms. alkylthio groups having from 1 to 5 carbon atoms, dialkylamino groups. wherein each alkyl group has from 1 to 5 carbon atoms, dialkylaminoalkoxy groups. wherein each of the two alkyl groups and the alkoxy groups has from 1 to 5 carbon atoms or α- or fialkoxy-N-pyrrolidinyl groups, wherein the alkoxy group has from 1 to 5 carbon atoms. and pharmaceutically acceptable salts of these compounds together with a suitable excipient or carrier.