DE3531747C2 - - Google Patents

Description

The invention relates to 1,3-dihydro-6-aminomethyl-7-hydroxy furo- (3,4-c) -pyrine derivatives, a process for their preparation position and pharmaceutical manufacture containing these ver bonds.

DE-OS 28 50 948 and DE-OS 32 04 596 1.3- Dihydro-7-hydroxy-furo- (3,4-c) pyridine derivatives known, which, however, in contrast to the 6-amino methyl compounds, in the 6-position by a methyl group are substituted.

The invention relates to 1,3-dihydro-6-aminomethyl 7-hydroxy-furo- (3,4-c) -pyrine derivatives of the general form mel I

in which A₁ and A₂ each independently represent a hydrogen atom, a straight-chain saturated or unsaturated hydrocarbon radical having 1 to 5 carbon atoms or a phenyl radical, the radicals represented by A₁ and A₂ each being unsubstituted or by a chlorine or fluorine atom, a trifluoromethyl group, an alkyl radical with 1 to 5 carbon atoms, an alkoxy radical with 1 to 5 carbon atoms, an alkylthio radical with 1 to 5 carbon atoms, a dialkylamino radical each with 1 to 5 carbon atoms in the alkyl radicals, a dialkyl aminoalkoxy radical with 1 to 5 carbon atoms in each of the two alkyl radicals and in the alkoxy radical or an α - or β- alkoxy-N-pyrrolidinyl radical having 1 to 5 carbon atoms in the alkoxy radical, and also pharmaceutically acceptable salts of these compounds.

The invention further provides 1,3-dihydro-6-amino-methyl-7-hydroxy-furo- (3,4-c) pyridine derivatives of the general formula I ', in which A₁ and A₂ have the following meanings:
Hydrogen and 3,4,5-trimethoxyphenyl-ethyl, hydrogen and cyclohexyl, hydrogen and α- thienyl, hydrogen and 2,3-dichlorophenyl, hydrogen and 3,4,5-trimethoxyphenyl, methyl and α- thienyl, p-methylthiophenyl and α- furyl, α -furyl and α- furyl or cyclohexyl and 2,3-dichlorophenyl.

The one from the two aforementioned publications Known 6-methyl-furo- (3,4-c) pyridine derivatives are diuretics. The compounds according to the invention also have therapeutic ones Effect. In contrast to the known compounds the compounds according to the invention, however, as antiallergics be used.  

The invention also relates to a method for the production provision of the aforementioned compounds by implementation a 1,3-dihydro-6-formyl-7-hydroxy-furo (3,4-c) pyridine derivative of general formula II

in the A₁ and A₂ have the above meanings with a stoichiometric amount of hydroxylamine and NaOH in Water at room temperature and subsequent hydrogenation of the oxime obtained at room temperature under normal pressure in acetic acid with hydrogen in the presence of a Pd / C catalyst lysators according to the following reaction scheme:

The 1,3-dihydro-6-formyl-7-hydroxy-furo- (3,4-c) pyridine derivatives of general formula II can be derived from the corresponding 1,3-dihydro-6-methyl-7-hydroxy-furo (3,4-c) pyridine derivatives of general formula III

in which A₁ and A₂ have the meanings given above have, according to the following reaction sequence:

The compounds of the general formula III are in the DE-OS 32 04 596.4 and 34 12 885.9.

The following is the preparation of a starting compound namely of 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy- furo- (3,4-c) pyridine explained in more detail. The remaining Aus corridors can be connected in a corresponding manner hold.

(a) In a 1 liter reaction vessel equipped with a stirring, Heating and cooling devices were equipped 22.3 g 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) pyridine at 0 ° C in the presence of 300 ml of methylene dichloride with 18.2 g of slowly added m-chloroperoxydbenzoic acid treated. After stirring overnight at room temperature 150 ml of a 10 percent sodium sulfate solution was added. After stirring and decanting, the methylene dichloride phase with the same amount of sodium sulfate solution, 2 times with 150 ml of sodium bicarbonate solution and 3 times with Washed 10 ml of water each and then over anhydrous Dried sodium sulfate. By evaporation to dryness you kept a beige precipitate, the petrol ether washed, filtered and dried. Man he held 22.9 g (96 percent) 1,3-dihydro-3-p-chlorophenyl-6- methyl-7-hydroxy-furo- (3,4-c) pyridine-N-oxide.

(b) In the reaction vessel described above, 22.9 g the compound obtained above at 0 to 5 ° C in counter wait for 175 ml of methylene dichloride with 4.3 ml of trifluor Acetic anhydride treated dropwise with stirring. The Mixture was stirred at room temperature overnight then cooled and treated dropwise with 95 ml of methanol. To Evaporation to dryness the residue was in 300 ml chloro form, 2 times with 75 ml each with 10 percent sodium hydrogen carbonate solution and 3 times with 100 ml of water wash and dry over anhydrous sodium sulfate.  

The chloroform phase was evaporated. The residue was washed with diethylene ether and under reduced pressure dried. 21.3 g (93 percent) of 1,3-dihydro- 3-p-chlorophenyl-6-hydroxymethyl-7-hydroxy-furo- (3,4-c) - pyridine.

(c) In a 2 liter reaction vessel 21.3 g of the compound obtained in the above step in the presence of 0.9 liters of chloroform for 3 hours while stirring with 27 g Manganese dioxide treated at 28 to 30 ° C. After detaching, filtration Wash and wash with chloroform and then with vinegar Acid ethyl ester, the solution was evaporated to dryness. The pulp-like mass obtained was treated with isopropyl oxide and then treated with pentane. 20.1 g (95 percent) were obtained 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) - pyridine.

Finally, the invention also relates to medicinal products agent containing a 1,3-dihydro-6-aminomethyl 7-hydroxy-furo- (3,4-c) pyridine derivative of the above defi ned general formula I or on a pharmacological compatible salt thereof mixed with a therapeutic compatible diluent or carrier.

The invention will be explained in more detail below with the aid of examples explained.

Example 1 1,3-dihydro-3-methyl-6-aminomethyl-7-hydroxy-furo (3,4-c) pyridine

In a 2 liter reaction vessel was at room temperature 71.2 g (0.4 mol) of 1,3-dihydro-3-methyl-6-formyl 7-hydroxy-furo- (3,4-c) pyridine, 270 ml of 1N sodium hydro xid solution and then dropwise a solution with stirring  of 27.8 g (0.4 mol) of hydroxylamine hydrochloride in 200 ml Given water. After stirring for 10 hours, the reaction filtered mixture. After washing with water and drying 74 g (96 percent) of the corresponding 6-oxime were obtained derivatives.

The 6-oxime derivative (74 g) was then mixed with 0.9 liters of vinegar acid in a closed reaction vessel, which with a Gas circulation device was given. To Nitrogen circulation was 15 g palladium on carbon Catalyst added to the reaction vessel. The mixture was in An for 4 hours at room temperature under normal pressure presence of a measured amount of hydrogen.

The reaction mixture was then filtered and dried evaporated. The residue was treated with toluene and then with Treated methanol. 70 g (76 Pro cent) of the acetate of 1,3-dihydro-3-methyl-6-aminomethyl 7-hydroxy-furo- (3,4-c) pyridine recrystallized. It acted is a beige product of F. 167 ° C, whose analysis works well with the empirical formula C₉H₁₂N₂O₂ · C₂H₄O₂ matched. The compound was insoluble in water.

Since all other connections are based on the same manufacturer position received are given in the following Examples details about the manufacturing conditions not repeated. The corresponding bases (without acetic acid rest) and other salts from these bases were made in the usual way Way get.

Example 2 1,3-dihydro-3-propyl-6-aminomethyl-7-hydroxy-furo (3,4-c) pyridine

Using 1,3-dihydro-3-propyl-6-formyl-7-  hydroxy-furo- (3,4-c) pyridine was obtained as the starting product a pale beige, 77% yield product insoluble in water with a melting point of 187 ° C., whose analysis works well with the empirical formula C₁₁H₁₆N₂O₂ · C₂H₄O₂ matched.

Example 3 1,3-dihydro-3- (3 ′, 4 ′, 5′-trimethoxyphenyl) ether-6-amino- methyl-7-hydroxy-furo- (3,4-c) pyridine

Using 1,3-dihydro-3- (3 ′, 4 ′, 5′-trimethoxy- phenyl) -ethyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine as Starting product was obtained in 61 percent yield a white, water-insoluble product from F. 140 to 144 ° C, whose analysis works well with the empirical formula C₁₉H₂₄N₂O₅ · C₂H₄O₂ matched.

Example 4 1,3-dihydro-3-cyclohexyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) pyridi-n

Using 1,3-dihydro-3-cyclohexyl-6-formyl-7- Hydroxy-furo- (3,4-c) -pyridine was obtained in 67 percent Yield a white, water-insoluble product of F. 173 to 177 ° C, its analysis well with the Molecular formula C₁₄H₂₀N₂O₂ · C₂H₄O₂ matched.

Example 5 1,3-dihydro-3-α -thienyl-6-aminomethyl-7-hydroxy-furo (3,4-c) pyridine

Using 1,3-dihydro-3- α- thienyl-6-formyl-7-hydroxy-furo- (3,4-c) pyridine as the starting compound, a yellowish, water-insoluble product of F was obtained in 58 percent yield 148 ° C, the analysis of which was in good agreement with the empirical formula C₁₂H₁₂N₂O₂S₁ · C₂H₄O₂.

Example 6 1,3-dihydro-3-phenyl-6-aminomethyl-7-hydroxy-furo (3,4-c) pyridine

Using 1,3-dihydro-3-phenyl-6-formyl-7-hydroxy furo- (3,4-c) pyridine was obtained in 82 percent prey a pale beige, water-insoluble pro product of F. 188 ° C, the analysis of which goes well with the Molecular formula C₁₄H₁₄N₂O₂ · C₂H₄O₂ matched.

Example 7 1,3-dihydro-3-p-chlorophenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c-pyridine)

Using 1,3-dihydro-3-p-chlorophenyl-6-formyl 7-hydroxy-furo- (3,4-c) -pyridine as the starting product one held a pale beige in 86 percent yield colored, water-insoluble product from F. 204 to 206 ° C, whose analysis works well with the empirical formula C₁₄H₁₃ClN₂O₂ · C₂H₄O₂ matched.

Example 8 1,3-dihydro-3- (2 ', 3'-dichlorophenyl) -6-aminomethyl-7-hydroxy-furo- (3, -4-c-pyridine

Using 1,3-dihydro-3- (2 ′, 3′-dichlorophenyl) - 6-formyl-7-hydroxy-furo-3,4-c) pyridine was obtained in 72 percent yield a pale yellow, insoluble in water product from F. 193 to 196 ° C, whose Ana lyse well with the empirical formula C₁₄H₁₂Cl₂N₂O₂ · C₂H₄O₂ agreed.

Example 9 1,3-dihydro-3-p-fluorophenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) pyrid

Using 1,3-dihydro-3-p-fluorophenyl-6-formyl  7hydroxy-furo- (3,4-c) -pyridine was obtained in 69 percent Yield a pale beige, water-insoluble pro ducts from F. 183 to 187 ° C, whose analysis well with the empirical formula C₁₄H₁₃FN₂O₂ · C₂H₄O₂ matched.

Example 10 1,3-dihydro-3-p-tolyl-6-aminomethyl-7-hydroxy-furo (3,4-c) pyridine

Using 1,3-dihydro-3-p-tolyl-6-formyl-7- hydroxy-furo- (3,4-c) pyridine was obtained as the starting product a 78% yield of a pale beige, product insoluble in water from F. 158 to 160 ° C, whose analysis works well with the empirical formula C₁₅H₁₆N₂O₂ · C₂H₄O₂ matched.

Example 11 1,3-dihydro-3-p-methoxyphenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -p-yridine

Using 1,3-dihydro-3-p-methoxyphenyl-6- formyl-7-hydroxy-furo- (3,4-c) -pyridine was obtained in 62pro percent yield a pale beige in water insoluble product from F. 144 to 149 ° C, the Analysis agrees well with the empirical formula C₁₅H₁₆N₂O₃ · C₂H₄O₂ agreed.

Example 12 1,3-dihydro-3- (3 ', 4', 5'-trimethoxy) phenyl-6-aminomethyl-7-hydroxy-f-uro- (3,4-c) pyridine

Using 1,3-dihydro-3- (3 ′, 4 ′, 5′-trimethoxy) - phenyl-6-formyl-7-hydroxy-furo- (3,4-c) pyridine was obtained whitish in 49 percent yield, water un soluble product from F. 137 to 141 ° C, the Ana lyse well with the empirical formula C₁₇H₂₀N₂O₅ · C₂H₄O₂ agreed.  

Example 13 1,3-dihydro-3-m-trifluoromethylphenyl-6-aminomethyl-7-hydroxy- furo- (3,4-c) pyridine

Using 1,3-dihydro-3-m-trifluoromethylphenyl 6-formyl-7-hydroxy-furo- (3,4-c) pyridine was obtained in 84 percent yield a white, water-insoluble Product from F. 197 to 203 ° C, the analysis of which is good matched the empirical formula C₁₅H₁₃F₃N₂O₂ · C₂H₄O₂.

Example 14 1,3-dihydro-3-p-dimethylaminoethoxyphenyl-6-aminomethyl-7- hydroxy furo (3,4-c) pyridine

Using 1,3-dihydro-3-p-dimethylaminoethoxyphenyl 6-formyl-7-hydroxy-furo- (3,4-c) pyridine was obtained a pale yellow, water-insoluble in 46 percent yield Product from F. 160 to 164 ° C, its analysis well matched the empirical formula C₁₉H₂₃N₃O₂ · C₂H₄O₂.

Example 15 1,3-dihydro-3-methyl-3- α- thienyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) pyridine

Using 1,3-dihydro-3-methyl-3- α- thienyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine gave a white, slightly insoluble in water in 66 percent yield Product from F. 206 to 208 ° C, the analysis of which was in good agreement with the empirical formula C₁₃H₁₄N₂O₂S · C₂H₄O₂.

Example 16 1,3-dihydro-3-ethyl-3-phenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) pyridine

Using 1,3-dihydro-3-ethyl-3-phenyl-6-formyl  7-hydroxy-furo- (3,4-c) -pyridine was obtained in 80 percent Yield a white, water-insoluble product of F. 207 ° C, its analysis well with the empirical formula C₁₆H₁₈N₂O₂ · C₂H₄O₂ matched.

Example 17 1,3-dihydro-3-phenyl-3-p-trifluoromethylphenyl-6-aminomethyl 7-hydroxy-furo- (3,4-c) pyridine

Using 1,3-dihydro-3-phenyl-3-p-trifluoromethylphenyl- 6-formyl-7-hydroxy-furo- (3,4-c) pyridine was obtained a white, water-insoluble in 65 percent yield Product of F. 221 ° C, the analysis of which is good matched the empirical formula C₂₁H₁₇F₃N₂O₂ · C₂H₄O₂.

Example 18 1,3-dihydro-3,3-di-p-flourphenyl-6-aminomethyl 7-hydroxy-furo- (3,4-c) pyridine

Using 1,3-dihydro-3,3-di-p-fluorophenyl-6- Formyl-7-hydroxy-furo- (3,4-c) pyridine was obtained in 81 percent Yield a pale yellow, water-insoluble Product of F. 214 ° C, the analysis of which well with the Molecular formula C₂₀H₁₆F₂N₂O₂ · C₂H₄O₂ matched.  

Example 19 1,3-dihydro-3-α-furyl-3-p-methylthiophenyl-6-aminomethyl-7-hydroxy-furo (3,4-c) pyridine

Using 1,3-dihydro-3- α- furyl-3-p-methylthiophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, a whitish, in water was obtained in 63 percent yield Insoluble product of F. 153 to 157 ° C, the analysis of which was in good agreement with the empirical formula C₁₉H₁₈M₂O₃S · C₂H₄O₂.

Example 20 1,3-dihydro-3,3-di- α- furyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) pyridine

Using 1,3-dihydro-3,3-di- α- furyl-6-formyl-7-hydroxy-furo- (3,4-c) pyridine, a white, water-insoluble product was obtained in 72 percent yield of F. 178 ° C, whose analysis agreed well with the empirical formula C₁₆H₁₄N₂O₄ · C₂H₄O₂.

Example 21 1,3-dihydro-3-cyclohexyl-3- (2 ′, 3′-dichlorophenyl-6- amino-methyl-7-hydroxy-furo (3,4-c) pyridine

Using 1,3-dihydro-3-cyclohexyl-3- (2 ′, 3′- dichlorophenyl) -6-formyl-7-hydroxy-furo- (3,4-c) pyridine was obtained in 59 percent yield a yellow, in Water-insoluble product of F. 213, the Analysis agreed well with the empirical formula C₂₀H₂₂Cl₂N₂O₂ · C₂H₄O₂.

Example 22 1,3-dihydro-3-vinyl-3-p-methylthinophenyl-6-aminomethyl-7- hydroxy furo (3,4-c) pyridine

Using 1,3-dihydro-3-vinyl-3-p-methylthiophenyl  6-formyl-7-hydroxy-furo- (3,4-c) pyridine was obtained a beige color in water in 66 percent yield insoluble product of F. 155 ° C, its analysis well matched the empirical formula C₁₇H₁₈N₂O₂S · C₂H₄O₂.

Example 23 1,3-dihydro-3-dimethylaminopropyl-3-p-chlorophenyl-6-amino methyl-7-hydroxy-furo- (3,4-c) pyridine

Using 1,3-dihydro-3-dimethylaminopropyl-3- p-chlorophenyl-6-formyl-7-hydroxy-furo (3,4-c) pyridine a white one in water in 47 percent yield insoluble product of F. 169 ° C, its analysis well matched the empirical formula C₁₉H₂₄ClN₃O₂ · C₂H₄O₂.

toxicity

DL₅₀ values were obtained with oral and intraperitoneal administration determined on mice. These values were between 0.7 to over 2.4 g / kg (p. O.) And between 0.6 to 1.65 g / kg (i.p.).

pharmacology

The activity of the compounds of the invention was determined by Various tests have been demonstrated, of which below some are reproduced.

A. Passive cutaneous anaphylaxis

This experiment was carried out according to the information in Fiche Technique No. 48, J. Pharm. Paris, Vol. 10 (1), 1979, pp. 69-72.

Male Sprague-Dawley rats (180 to 200 g) were given 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 ovalbumin (5 mg / ml) and Evans blue (2.5 mg / ml). This caused the formation of Wheals around the injection sites are induced by immune serum. The wheals were removed 30 minutes after they were formed, measured and 24 hours at 65 ° C in 4 ml formamide (for the extraction of Evans blue). The optical The supernatant density was determined spectrophotometrically at 620 nm measured.

A first group of 8 rats was used as a control group used. A second group of 8 animals was also created with theophylline (25 mg / kg) as a comparison compound treated. 10 further groups of 8 animals each was dosed with 10 compounds of the invention each 25 mg / kg treated. The connection numbers correspond the numbers of the above examples. The latter 11 groups were given the corresponding connections for 1 hour orally before injection of the ovalbumin / Evans blue mixture administered. The percentage reduction in wheal formation in terms of size and color was compared determined with the control group. The results are summarized in the left half of the table below.

B. Antihistamine effect

This experiment was carried out according to W. Doepfner and A. Cerletti, Int. Arch. Allergy, Vol. 12 (1958), p. 89 and J. Pharmac. and Exp. Ther. (Vol. 191 (2), (1974), pp. 300-310).

Male Sprague-Dawley rats (140 to 160 g) were Held without water for 18 hours and then received 1 ml / kg Water (control) or 0.2 ml of an aqueous solution or  Suspension of the compounds to be examined. The volume the left hind paw was measured by plethysmography. Then 0.1 ml of 5% histamine hydrochloride was injected. The resulting inflammation became 1 hour later dimensioned by volume determination.

The following groups with 8 animals each were used: 1 control group, 10 groups for those to be examined Compounds (see section A) and 2 groups for the comparative compounds mequitazine and promethanzine, where the doses were 25 mg / kg each. The percentage Inflammation was reduced compared to the control group determined. The results are on the right Page of the table below.

These two studies clearly show that the compounds of the invention have potent antihistamine activity have.

Presentation - posology

Oral tablets are used for human therapy Gelatin capsules containing 0.20 g each Compound of the invention preferred. For the intravenous Ampoules are administered with the same amount of active ingredient, which are injected under perfusion. The daily doses for human therapy are 0.20 to 2 g p. o. and 0.20 to 1 g i. v.  

Claims (4)

1. 1,3-dihydro-6-aminomethyl-7-hydroxy-furo- (3,4-c) pyridine derivatives of the general formula I in which A₁ and A₂ each independently represent a hydrogen atom, a straight-chain saturated or unsaturated hydrocarbon radical having 1 to 5 carbon atoms or a phenyl radical, the radicals represented by A₁ and A₂ each being unsubstituted or by a chlorine or fluorine atom, a trifluoromethyl group, an alkyl radical with 1 to 5 carbon atoms, an alkoxy radical with 1 to 5 carbon atoms, an alkylthio radical with 1 to 5 carbon atoms, a dialkylamino radical with 1 to 5 carbon atoms in each of the alkyl radicals, a dialkylaminoalkoxy radical with 1 to 5 carbon atoms in each of the two alkyl radicals and in the alkoxy radical or an α - or β- alkoxy-N-pyrrolidinyl radical having 1 to 5 carbon atoms in the alkoxy radical are substituted,
as well as pharmaceutically acceptable salts of these compounds. 2. 1,3-dihydro-6-aminomethyl-7-hydroxy-furo- (3.4-c) pyridine derivatives of the general formula I ' in which A₁ and A₂ have the following meanings:
Hydrogen and 3,4,5-trimethoxyphenyl-ethyl, hydrogen and cyclohexyl, hydrogen and α- thienyl, hydrogen and 2,3-dichlorophenyl, hydrogen and 3,4,5-trimethoxyphenyl, methyl and α- thienyl, p-methylthiophenyl and a- furyl, α- furyl and α- furyl or cyclohexyl and 2,3-dichlorophenyl. 3. A process for the preparation of the compounds of claims 1 and 2, characterized in that 1,3-dihydro-6-formyl-7-hydroxy-furo- (3,4-c) pyridine derivatives of the general formula in which A₁ and A₂ have the same meaning as in claims 1 and 2, reacted with a stoichiometric amount of hydroxylamine and NaOH in water at room temperature and then the oxime obtained at room temperature under normal pressure in acetic acid with hydrogen in the presence of a Pd / C- Catalyst hydrogenated. 4. Medicines containing as an essential component at least one compound according to claim 1 or 2, together with a suitable diluent or carrier.