DE3531747A1 - 6-AMINOMETHYL-FURO- (3,4-C) -PYRIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL COMPOUNDS - Google Patents

Description

RS Cas 109

The invention relates to 6-aminomethyl-furo- (3,4-c ^ pyridine derivatives, a process for their preparation and pharmaceuticals containing these compounds.

The invention relates to 1, S-dihydro-ö-aminomethyl -? - hydroxy-furo- (3,4-c ^ pyridine derivatives of the general formula I.

.0

(I)

H ₂ N - CH ₂

in which A ₁ and Ap each independently represent a hydrogen atom, a straight-chain saturated or unsaturated hydrocarbon radical with 1 to 5 carbon atoms, a heterocyclic radical with up to 6 ring atoms, a cycloalkyl radical, a phenyl radical or a phenylalkyl radical, where the denoted by A ₁ and Ap each unsubstituted or by one or more chlorine or fluorine atoms, trifluoromethyl groups, alkyl radicals with 1 to 5 carbon atoms, alkoxy radicals with 1 to 5 carbon atoms, alkylthio radicals with 1 to 5 carbon atoms, dialkylamino radicals with 1 to 5 carbon atoms in the alkyl radicals, dialkylaminoalkoxy radicals 1 to 5 carbon atoms in each of the two alkyl radicals and in the alkoxy radical or ex- or ß-alkoxy-N-pyrrolid ± nyl radicals are substituted with 1 to 5 carbon atoms in the alkoxy radical, as well as pharmaceutically acceptable salts of these compounds.

The compounds of the invention are therapeutic by virtue of their being Effect of interest, mainly in the field of antiallergic drugs.

RS Cas 109

3531 7-7

The invention also relates to a process for the preparation of the aforementioned compounds by reaction of a 6-formyl-7-hydroxy-furo- (3,4 ~ c) -pyridine derivative of the general formula II

(ID

or M-CHO for short

OHC

in which A. and A »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 cat. lysators according to the following reaction scheme:

M- CHO

NH ₂ OH

■ * M-CH = N-OH

Pd / C

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

(III)

RS Cas 109

in which A ₁ and A _{2 have} the meanings given above, prepare according to the following reaction sequence:

m-chloroperoxybenzoic acid

(CF ₃ CO) ₂ 0

MnO,

HIGH

OHC

The compounds of the general formula III are described in DE-OSes 3204596.4 and 3412885-9.

The following describes the preparation of a starting compound, namely 1, S-dihydro-S-p-chlorophenyl-o-formyl-i-hydroxyfuro- (3,4-c) pyridine explained in more detail. The other starting compounds can be obtained in a corresponding manner.

(a) In a 1 liter reaction vessel equipped with stirring, heating and cooling devices, 22.3 g of 1, S-dihydro-Sp-chlorophenyl-ö-formyl-T-hydroxy-furo- (3, Treated 4-c) pyridine at ⁰ ° C. in the presence of 300 ml of methylene dichloride with 18.2 g of slowly added m-chloroperoxybenzoic acid. After stirring overnight at room temperature, 150 ml of a 10 percent strength sodium sulfate solution were 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 hydrogen carbonate solution each time and 3 times with 100 ml of water each time and then dried over anhydrous sodium sulfate. Evaporation to dryness gave a beige precipitate which was washed with petroleum ether, filtered and dried. 22.9 g (96 percent) 1, S-dihydro-Sp-chlorophenyl-omethyl-7-hydroxy-furo- (3,4-c) -pyridine-N-oxide were obtained.

(b) In the reaction vessel described above, 22.9 g of the compound obtained above were ^{treated dropwise at 0 to 5 °} C. in the presence of 175 ml of methylene dichloride with 4.3 ml of trifluoroacetic anhydride with stirring. The mixture was stirred at room temperature overnight, 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 percent sodium hydrogen carbonate solution each time and 3 times with 100 ml of water each time and dried over anhydrous sodium sulfate.

The chloroform phase was evaporated. The residue was washed with diethyl 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-e) -pyridine were obtained.

(c) In a 2 liter reaction vessel
^{21.3 g of the compound obtained in the above step are treated with 27 g of manganese dioxide at 28 to 30 °} C. for 3 hours with stirring in the presence of 0.9 liter of chloroform. After separation, filtration and washing with chloroform and then with ethyl acetate, the solution was evaporated to dryness. The slurry obtained was treated with isopropyl oxide and then with pentane. 20.1 g (95 percent) of 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine were obtained.

Finally, the invention also relates to medicaments containing a 1, S-dihydro-o-aminomethyl-7-hydroxy-furo- (3,4-c) pyridine derivative of the general formula I defined above or on a pharmacologically acceptable salt thereof in admixture with a therapeutically compatible diluent or carrier.

The invention is explained in more detail below by means of examples explained.

example 1

1,3-Dihydro-3-methyl-6-aminomethyl-7-hydroxy-furo- (3> 4-c) -pyridine

71.2 g (0.4 mol) of 1, S-dihydro-S-methyl-ö-formyl-7-hydroxy-furo- (3,4-c) -pyridine, 270 ml of 1 η sodium hydroxide solution and then a solution dropwise with stirring

of 27.8 g (0.4 mol) of hydroxylamine hydrochloride in 200 ml of water. After stirring for 10 hours, the reaction mixture was filtered. After washing with water and drying 74 g (96 percent) of the corresponding 6-0xime derivative were obtained.

The 6-oxime derivative (74 g) was then mixed with 0.9 liters of acetic acid placed in a closed reaction vessel equipped with a gas circulation device. To Nitrogen circulation was added 15 g of palladium-on-carbon catalyst added to the reaction vessel. The mixture was in the presence of 4 hours at room temperature under normal pressure stirred a measured amount of hydrogen.

The reaction mixture was filtered and evaporated to dryness. The residue was treated with toluene and then with methanol. 70 g (76 percent) of the acetate of 1, S-dihydro-S-methyl-6-aminomethyl-7-hydroxy-furo- <3, 4-c) -pyridine were recrystallized from the methanol. It was a beige-colored product with a temperature of 167 ° C. (Tottoli), the analysis of which was in good agreement with the empirical formula CqH ₁₂ N ₂ O ₂ -C ₂ HJuO ₂ . The compound was insoluble in water.

Since all other connections are made in the same way details of the manufacturing conditions are shown in the examples below not repeated. The corresponding bases (without acetic acid residue) and other salts from these bases were based on the usual Way received.

Example 2

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

Using 1,3-dihydro-3-propyl-6-formyl-7-

RS Cas 109 - 9 - 3θ3Ί / 4 /

hydroxy-furo-0, 4-c) -pyridine as starting material was obtained in 77 percent yield of a pale tan, water-insoluble product, mp 187 ⁰ C (Tottoli), the analysis of well with the molecular formula C. EL gNp Op. CpH ₂ . Op matched.

Example 3

1,3-Dihydro-3- (3 ', 4', 5 '-trimethoxyphenyl) -ethyl-6-aminomethyl-7-hydroxy-furo- (3 , 4-c) pyridine

Using 1,3-dihydro-3- (3 '., 4 ·, 5 »-trimethoxyphenyl) -ethyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine as the starting product was obtained in 61-percent yield a white, water-insoluble product, mp 140-144 ⁰ C (Tottoli), the analysis of which was in good agreement with the molecular formula C.qlipuNpO -.CpHj _1, Op.

Example 4

1, S-dihydro-S-cyclohexyl-S-aminomethyl ^ -hydroxy-furo- (3,4-c) -pyridine

Using 1, S-Di
hydroxy-furo (3,4-c) -pyridine was obtained in a 67-percent yield a white, water-insoluble product, mp 173 to 177 ⁰ C (Tottoli), the analysis of well with the molecular formula C.2.Hp ₀ NpOp.C ₂ H ₁ .Op matched.

Example 5

1,3-Dihydro-3-X-thienyl-δ-aminomethyl-1-hydroxy-furo- (3,4-c) -pyridine

Using 1,3-dihydro-3-C-thienyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine as the starting compound gave a yellowish, water-insoluble product in 58 percent yield * ^C 2 ^H 4 ° ^{übereinstimmfee} 2 2 ^N 2 ° 2 ^S 1 · | - mp 148 ° C (Tottoli), the analysis of well with the molecular formula C ₁₂ ^H

Example 6

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

Using 1, S-di furo- (3,4-c) pyridine, a pale beige-colored, water-insoluble product with a melting point of 188 ° C. (Tottoli) was obtained in 82 percent yield, the analysis of which was compatible with the Molecular formula C ₁ J ₁ , H _{1 2.NpO 2} .CpH ₁ .0 ₂ matched.

Example 7

1, S-dihydro- ^ - p-chlorophenyl-o-aminomethyl-Y-hydroxy-furo - (3,4-c) -pyridine

Using 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo- (3, ⁱ ^ -c) -pyridine as the starting product, a pale beige colored in Water-insoluble product with a temperature of 204 to 206 ° C (Tottoli), the analysis of which was in good agreement with the empirical _{formula C 1} ^ H _{1 -ClN 2} O ₂ -C ₂ Hj ₊ O ₂ .

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, ⁱ tc) -pyridine gave a pale yellow in water in 72 percent yield Insoluble product with a temperature of 193 to 196 ° C (Tottoli), the analysis of which was in good agreement with the empirical _{formula C 1 JiH 12} Cl ₂ N ₂ O ₂ -C ₂ H ^ O ₂ .

Example 9

1,3-Dihydro-3-p-fluorophenyl-o-aminomethyl ^ -hydroxy-furo- (3,4-c) -pyridine

Using 1, S-dihydro-S-p-fluorophenyl-o-formyl-

RS Cas 109 - 11 - 3o3 1 /.47

7-hydroxy-furo- (3,4-c) -pyridine was obtained in 69 percent yield, a pale beige-colored, water-insoluble product with a melting point of 183 ° to 187 ° C. (Tottoli), the analysis of which is good with the empirical formula C. .. ^ H ..-, FNpOp. CpH ₂ , Op matched.

Example 10

1, B-dihydro-S-p-toluyl-o-aminomethyl-T-hydroxy-furo- (3> 4-c) pyridine

Using 1, S-dihydro-Sp-toluyl-ö-formyl -? - hydroxy-furo- (3,4-c) -pyridine as starting material, a pale beige-colored product insoluble in water was obtained in 78 percent yield from 158 to 160 ° C (Tottoli), the analysis of which agreed _{well with the empirical formula C 1} ^ HLgNpOp.CpH _{1 .CL.}

Example 11

1, S-dihydro-S-p-methoxyphenyl-S-aminomethyl-T-hydroxy-furo- (3,4-c) -pyridine

Using 1,3-dihydro-3-p-nlethoxyphenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine gave a pale beige product insoluble in water in 62 percent yield from 144 to 149 ° C (Tottoli), the analysis of which works well with the _{empirical formula C 1} , -Η. gNpO- .CpH ₁ .0 »matched.

Example 12

1,3-dihydro-3- (3 ^!, 4 ', 5'-trimethoxy) -phenyl-6-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine

Using 1,3-dihydro-3- (3 ', 4', 5'-trimethoxy) -phenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine gave in 49- percent yield a whitish, water-insoluble product vom F. 137 to 141 ⁰ C (Tottoli), the analysis of which works well with the _{empirical formula C. “H 20} NpCv. CpH ₁ . Op matched.

RS Cas 109 - 12 -

Example 13

1,3-Dihydro-3-m-trifluoromethylphenyl-o-aminomethyl ^ -hydroxy furo- (3,4-c) -pyridine

Using 1, S-dihydro-Sm-trifluoromethylphenyl-6-formyl-7-hydroxy-furo- (3j4-c) -pyridine, a white, water-insoluble product with a melting point of 197 to 203 was obtained in 84 percent yield ° C (Tottoli), the analysis of which agreed well with the empirical formula C .., - H., ο ^F oNpOp .CpH ^ Op.

Example 14

1, S-Dihydro-S-P-dimethylaminoethoxyphenyl-o-aminomethyl ^ - hydroxy-furo- (3,4-c) pyridine

Using 1, S-dihydro-Sp-dimethylaminoethoxyphenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, a pale yellow, water-insoluble product with a melting point of 16O was obtained in 46 percent yield to 164 ⁰ C (Tottoli), the analysis of which agreed well with the empirical formula C ^ Hp-NoOp.CpHiiOp.

Example 15

1, S-Dihydro-S-methyl-S- <* -thienyl-α-aminomethyl ^ -hydroxyfuro- (3,4-c) -pyridine

Using 1,3-dihydro-3-methyl-3-oC-thienyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine a white product which was sparingly soluble in water and had a melting point of 206 ° to 208 ° C. (Tottoli) was obtained in 66 percent yield, the analysis of which was good matched the empirical formula C-oH..j, NpOpS.CpHj.Op.

Example 16

1, S-Dihydro ^ -ethyl-S-phenyl-o-aminomethyl ^ -hydroxy-furo- (3> 4-c) -pyridine

Using 1,3-Di:

7-hydroxy-furo- (3,4-c) -pyridine was obtained in 80 percent yield, a white, water-insoluble product with a melting point of 207 ° C. (Tottoli), the analysis of which was good with the empirical _{formula C-IgH 1 QNpOp} .CpHuOp matched.

Example 17

1, B-Dihydro-B-phenyl-Bp-trifluoromethylphenyl-S-aminomethyl- 7- hydroxy-furo- (3> 4-c) -pyridine

Using 1, S-dihydro-S-phenyl-Sp-trifluoromethylphenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, a white product insoluble in water was obtained in 65 percent yield vom F. 221 ⁰ C (Tottoli), the analysis of which agreed well with the empirical formula C ₂₁ H ₁₇ F ^ N ₂ O ₂ .C ₂ H ^ O ₂ .

Example 18

1, S-dihydro-S-phenyl-S- = x-methoxypyrrolidinyl-o-aminomethyl-7-hydroxy-furo- (3,4-c) -pyridine

Using 1, S-Di

received

one in 41-percent yield a yellowish, water-insoluble product, mp 129 to 132 ⁰ C (Tottoli), the analysis of which was in good agreement with the molecular formula C.qHppN-, 0 ".C ₂ H ₁ 0. ₂

Example 19

1,3-dihydro-3,3-di-p-fluorophenyl-o-aminomethyl-1-hydroxyfuro- (3,4-c) pyridine

Using 1,3-dihydro-3,3-di-p-fluorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine gave a pale yellow in water in 81 percent yield insoluble product, mp 214 ⁰ C (Tottoli), the analysis of which was in good agreement with the molecular formula C q H ^ _1, -FpNpOp.CpH _1, Op.

RS Cas 109 - 14 -

Example 20

1, S-Dihydro-B - ^ - furyl-S-p-thiomethylphenyl-o-aminomethyl - 7-hydroxy-furo- (3,4-c) pyridine

Using 1, S-phenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine a whitish, water-insoluble product with a melting point of 153 ° to 157 ° C. (Tottoli) was obtained in 63 percent yield Analysis agreed well with the empirical formula C.QH ^ MpO ^ S.CpH ^ Op .

Example 21

1,3-Dihydro-3,3-di-cc-furyl-6-aminomethyl-7-hydroxy-furo- ( 3,4-c) -pyridine

Using 1,3-dihydro-3,3-di-oC-furyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine gave a white in water in 72 percent yield insoluble product, mp 178 ⁰ C (Tottoli), the analysis of which was in good agreement with the molecular formula C.gH .. ηNpO _2, .CpH ₁ .0 '.

Example 22

1,3-Dihydro-3-cyclohexyl-3- (2 ^> , 3'-dichloro) -phenyl-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 gave 59 percent strength yield a yellow, water-insoluble product, mp 213 ⁰ C (Tottoli), the analysis of well with the empirical formula Cp _Q HppClρNpOp .CpHj. Op matched.

Example 23

1, S-dihydro ^ -vinyl-S-p-thiomethylphenyl-o-aminomethyl -? - hydroxy-furo- (3 »4-c) pyridine

Using 1,3-dihydro-3-vinyl-3-p-thiomethyl-

RS Cas 109 - 15 -

phenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine was obtained in 66 percent yield, a beige-colored, water-insoluble product of F. 155'c (Tottoli), the analysis of which works well with the Molecular formula C ₁₇ H gN ^ O ^ S.CpH ₁ , 0 "matched.

Example 24

1, S-dihydro-S-dimethylaminopropyl-B-p-chlorophenyl-o-aminomethyl-7-hydroxy-furo- (3, 4-c) -pyridine

Using 1, S-dihydro-S-dimethylaminopropyl-Sp-chlorophenyl-δ-formyl-T-hydroxy-furo-CSj ^ -cJ-pyridine, a white, water-insoluble product of F. 169 ° C (Tottoli), the analysis of which agreed well with the empirical formula C-qHL ^ ClN-, CL.CpH ₁ .CL,

toxicity

^ were administered orally and intraperitoneally determined on mice. These values ranged from 0.7 to over 2.4 g / kg (p.o.) and between 0.6 and 1.65 g / kg (i.p.).

pharmacology

The activity of the compounds of the invention has been demonstrated by various tests, of which are 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) 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 device made of ovalbumin (5 mg / ml) and Evans blue (2.5 rag / ml). This induced the formation of wheals around the injection sites of immune serum. The wheals were removed 30 minutes after their formation, measured and ^{incubated for 24 hours at 65 °} C. in 4 ml of formamide (to extract Evans blue). The optical density of the supernatant was measured spectrophotometrically at 620 nm.

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

B. Antihistamine Action

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

Male Sprague-Dawley rats (140 to 160 g) were Maintained without water for 18 hours and then received 1 ml / kg of water (control) or 0.2 ml of an aqueous solution or

Suspension of the compounds to be investigated. The volume of the left hind paw was measured by plethysmography. 0.1 ml of 5% histamine hydrochloride was then injected. The resulting inflammation became 1 hour later measured by volume determination.

The following groups with 8 animals each were used: T control group, 10 groups for those to be examined Compounds (see. Under Section A) and 2 groups for the comparison compounds mequitazine and promethazine, where the doses were 25 mg / kg each. The percentage reduction in inflammation was compared to the control group determined. The results are shown on the right-hand side of the table below.

It is clear from these two studies that the compounds of the invention have potent antihistamine activity own.

Presentation - Posologi e

For human therapy by the oral route, tablets or gelatin capsules, each containing 0.20 g of a Compound of the invention preferred. For intravenous administration, ampoules with the same amount of active ingredient, which are injected under perfusion, provided. The daily doses in human therapy are 0.20 to 2 g p.o. and 0.20 to 1 g i.V.

RS Gas 109

links * Reduction of
Onadripl η coloring Decrease in histamine
induced edema Theophylline surface - 62 example - 60 - 86 - 48 example - 77 - 60 - 77 example
4th - 58 - 66 - 59 example - 61 - 60 - 68 example - 49 - 84 - 79 example
9 - 75 - 72 - 83 example
10 - 68 - 72 - 66 Gouge - 68 - 81 - 51 example - 71 - 59 - 54 Gouge - 53 - 69 - 62 Mequitazine - 65 X - 60 Promethazine - 41

Claims (3)

Claims 1. 1,3-Dihydro-6-aminomethyl-7-hydroxy-furo- (3, ¹ + -c) -pyridine derivatives of the general formula I (D in the A- and A "each independently of one another Hydrogen atom, a straight chain saturated or unsaturated hydrocarbon radical with 1 to 5 carbon atoms, a heterocyclic radical with up to 6 ring atoms, a cycloalkyl radical, a phenyl radical or a phenylalkyl radical, where the A- and Ag represented radicals in each case unsubstituted or by one or more chlorine or fluorine atoms, trifluoromethyl groups, Alkyl radicals with 1 to 5 carbon atoms, alkoxy radicals with 1 to 5 carbon atoms, alkylthio radicals, with München-Bogenhausen, Poschingerstraße 6 Telegram: Chemindus Munich - Telephone: (089) 98 32 22 Telex: 5 23 992 (abitz d) RS Cas 109 1 to 5 carbon atoms, dialkylamino radicals with 1 to 5 carbon atoms in the alkyl radicals, dialkylaminoalkoxy radicals with 1 to 5 carbon atoms in the two alkyl radicals and in the alkoxy radical or a (. - or ß-alkoxy-N-pyrrolidinyl radicals with 1 to 5 carbon atoms in the alkoxy radical are substituted, as well as pharmaceutically acceptable salts of these compounds. 2. Process for the preparation of the compounds according to Claim 1, characterized in that 6-formyl-7-hydroxyfuro- (3,4-c) pyridine derivatives are used the general formula OHC in which A ₁ and A ~ have the same meaning as in claim 1, reacted with a stoichiometric amount of hydroxylamine and NaOH in water at room temperature and then the resulting oxime at room temperature under normal pressure in acetic acid with hydrogen in the presence of a Pd / C catalyst hydrogenated. 3. Medicaments containing as an essential component at least one compound according to claim 1, together with a suitable diluent or carrier.