DE1518453A1 - Process for the preparation of o-aminoalkoxy-substituted dibenzylaethers - Google Patents

Description

o-amino alkoxy-substituted dibenzyl ethers.

The invention deals with the manufacture of novel o-aminoalkoxy-substituted dioenzyl ethers of the general formula

-CH ₂ -2-CB ₁ -, -

laa. >"- *

in which ΐί, and lip are identical or different to one another and are alkyl radicals or together with the amino nitrogen atom form a heterocyclic ring, R ,, R. and R ₁ - as being identical or different to one another , hydrogen, halogen, alkyl or alkoxy , Z oxygen or sulfur and η represent the integer 2 or 5.

There are so many different anti-spasmodic ones Compounds synthesized, their more active and therefore

209817 / U95

more suitable representatives generally have a complex molecular structure with at least one ester bond. For reasons of analogy with naturally occurring compounds of comparable effectiveness, which are related to the tropa and pseudotropa esters, the presence of this ester grouping has hitherto been regarded as important both for the degree of effectiveness and for the pharmaceutical compatibility. These compounds are, however, not entirely satisfactory because the ester grouping in the living organisms to which they are added can be modified in various ways, whereby the compounds are entirely or only briefly effective and irritating to possibly highly toxic.

It was found according to the invention that pharmaceutically effective dibenzyl ethers of novel composition can be produced which are free from the adverse properties of other known compounds of similar applicability.

Therefore, one aim of the invention is to create a series of synthetic compounds with physiological activity, which are generally not subject to the detrimental decomposition that is common for natural and synthetic esters with pharmacological Activity is typical.

The invention further aims at the production of o-aminoalkoxy-substituted ones Dibenzyl ethers with useful pharmaceutical activity.

Further objects of the invention and advantages are from the following Description visible.

209817 / U9S

BATH ORIGINAL

According to the invention, the novel compounds are described in the-Wei.-e produced that one initially in the sense of the equivalents

CHO

CEO

+ Cl- (CH ₂ ) - <. HCl

o-Hydroxybenzaldehyde at temperatures below 100 ° and preferably at 6o - 8o ° with the Hydrochlorld of a dialkylaminochloroalkane in the presence of e.g. at least two equivalents of an alkali metal carbonate and a suitable solvent, e.g. a lower alkanol, dimethylformamide, dimethylsulfoxide or tetrahydrofuran, to o-aminoalkoxy-benzaldehyde: then

this benzaldehyde derivative in the sense of the formula equation

CEO

0- (CH ₂ ). -Ν '

CH ₂ OH

0- (CH ₂ ) ^ -i

reduced to the corresponding benzyl alcohol, whereby the aldehyde residue is either chemically, e.g. using sodium borohydride, od ^ T catalytic me. Hydrogen preferably below 100 atm.

Dru-'kb ° i temperatures below about f5 ^and preferably about Γ-Ό - 4 t / "in G ^ ß'inwart a hydrogenation catalyst acidic: as Raney-131 ■■><* - 1 j, and slept ^ ·] i- h

209817 / U9S

BATH ORIGINAL

this o-amino (lower) alkoxy-benzyl alcohol in the sense of the formula equation

CH ₂ OH

- (CH ₂ J _n -N:

IU,

-CH ₂ -0-CH ₂ -

(CH ₂ ) -N

at temperatures between 30 ° and 100 ° in the presence of a strongly basic condensing agent, such as sodium amide or hydride, and using a suitable, preferably anhydrous solvent, such as benzene, toluene, dimethylformamide, dimethyl sulfoxide or the like, with one at none with those previously defined FU, R ^ and R ₁ - radicals and combined on the methyl radical with Y equal to halogen or p-toluenesulfonate substituted benzyl derivative to the dibenzyloxy ether.

- ¹ S-

209817 / U95 SAD ₀ RfGiNAL

According to a modified embodiment of the invention, can the ο-aminoalkoxybenzyl alcohol obtained according to reaction scheme II also first convert it into its corresponding thio compound, i.e. the mercaptan, and from this mercaptan finally build up the corresponding dibenzyl thioether according to reaction scheme III.

For this purpose, the benzyl alcohol from the chemical step is used II according to the reaction scheme

GHjOH

0- (CH ₂ ) -I

, CH ₂ Cl

+ SOCl ₂

■ «2

η \.

HCl

R ₂

at about 20 ° to about 60 ° in an organic solvent such as benzene, methylene chloride, chloroform or the like Thionyl chloride to the corresponding o-aminoalkoxy-benzyl chloride hydrochloride around and

then decreases this benzyl chloride

the reaction scheme

CH ₂ Cl

+ NaHS

0- (CHa) _n -N '

. HCl

CH ₂ SH

0- (CH ₂ ) _n -N;

under a HpS atmosphere at about 6o ° to about 100 ° in a suitable one Medium such as methanol, ethanol or isopropanol with over-

203817 / U9S

BATH ORIGINAL

Schüssigen, e.g. 2 equivalents of sodium hydrogen sulphide for o-Aminoalkoxy-benzyl mercaptan react.

This mercaptan is then condensed, as already mentioned, according to the reaction scheme '

CHj SH

O- (CH ₂ ) _{n -N}

under the same working conditions as in the previous synthesis step III benzyl chloride substituted with fU, R ^ and R ^ or -p-toluenesulfonate to the desired dibenzylthioether.

The o-aminoalkoxy-dibenzyloxy or thioether bases obtained in this way are converted in the usual way into their pharmacologically acceptable acid addition or quaternary ammonium salts.

209Ö17 / U95

Demriernäs: · The invention consists of a method of manufacture of o-aminoalkoxy-substituted dibenzyl ethers of the Pc ■ meI

in which R, and Rp as mutually identical or different are alkyl radicals or together with the amino nitrogen atom form a heterocyclic ring, R ,, R ₂ ^ and R ₁ - as mutually identical or different are hydrogen, halogen, alkyl or alkoxy radicals, Z oxygen or Sulfur and η represent the integer 2 or j5, and is characterized by the fact that one

1. o-Hydroxybenzaldehyde at temperatures below 100 ° and preferably at 60-80 ° with the hydrochloride a dialkylamino-chloroalkane in the presence of at least two equivalents of an alkali metal carbonate and a solvent such as lower alcohol, dimethylformamide, Dlmethylsulfoxyd or tetrahydrofuran for corresponding o-aminoalkoxy-benzaldehyde,

2. This o-aminoalkoxy-benzaldehyde preferably catalytically at temperatures below about 75 ° and preferably about 20 - 40 ° in the presence of a hydrogenation catalyst, preferably Raney nickel with compressed hydrogen corresponding o-aminoalkoxy-benzyl alcohol redude: t,

209817 / U9S ^ßAD ORlGiNAL

2a) optionally this o-aminoalkoxy-benzyl alcohol first with thionyl chloride in an organic solvent at 20 - 60 ° in the appropriate Benzyl chloride and then this with excess sodium hydrogen sulfide in an organic solvent at 6o - 100 to the o-aminoalkoxy-benzyl mercaptan implements,

3) the benzyl mercaptan from step 2a) or optionally the benzyl alcohol from step 2) at temperatures between 30 ° and 100 ° in the presence of a strongly basic condensing agent, preferably sodium hydride, in a preferably anhydrous organic Solvent with one on the core with the PU, Rj, and R, radicals and defined above substituted on the methyl radical by halogen or p-toluenesulfonate Benzyl derivative condensed to the corresponding dibenzyloxy or thio ether, and

4) if necessary, the Ktherbase from step 3) in itself in a known manner into a pharmaceutically acceptable acid addition or quaternary ammonium salt.

As far as they appear in the description and claims, "alkyl" mean UiId ¹¹ AlkOXy ¹¹ their representatives with straight or branched chain aliphatic groups each with 1 - 6 carbon atoms, "heterocyclic" radicals such as piperidyl, morpholinyl and piperazinyl and "halogen" Bromine, chlorine and iodine.

The following working examples: Sole, for further explanation serve the invention. g ^ p ORIGINAL

EXAMPLE 1 "

■ ο- (ft -diethylaminoethoxy) benzaldehyde 122 g (1 mol) of ο-hydroxybenzaldehyde are introduced into a suspension of 2 1/2 g KgCCU in 1.5 1 96% ethanol with vigorous turbination at 60 °. 1.2 g (1 mol) of Ν, Ν-diethyl- β- chloroethylamine are added within 20 minutes. HCl is added in larger proportions and the reaction mixture is then refluxed for hours. After cooling, it is filtered, the solvent is distilled off and the residue is partitioned between water and ether. The ether is dried, distilled off and the residue is distilled in vacuo. K ^ ₂ 123 ° C. Yield: - 152 g.

EXAMPLE 2

ο- ( ß- Diethylaminoethoxy) -benzyl alcohol 221 g (1 mol) of o-diethylaminoethoxy-benzaldehyde are dissolved in 1 liter of methanol, mixed with 20 g of Raney nickel and at about 20 ° under 80 atm. H ₂ pressure above 1.1 / 2 Hydrogenated for hours. After the pressure has been released, the nickel is filtered off and the piltrate is distilled 0.1 mm vacuum. The hydrochloride is obtained from the ethereal solution of the alcohol by adding HCl.

Kpo, l \ l21 - 122 °.

Yield} - 215 g.

Fp. Of the hydrochloride: - 123 - 124 ⁰ C.

Analysis of the hydrochloride: -

C H N Cl

Calculate: - 60.10 ^ 8.54 % 5.39 % $ 13.65

found :- βΟ, Ιβ 8,32 5, ^ 9 13, ^ 5

- 10 -

209817 / U95 ^mo original

EXAMPLE ? * V

ο- ([3 -N-Piperidlnj-ethoxy) -benzaldehy d.

122 g (1 mol) of ο-hydroxybenzaldehyde are introduced into a suspension of 233 g of Na ₂ CO in 2 liters of 96% strength ethanol with vigorous stirring at 70 °; 184 g (1 mol) of N-ß-chloroethylpiperidine.HCl are added in, for example, five portions over the course of 30 minutes, and the reaction mixture is then refluxed for 5 hours. After cooling, it is filtered, the solvent is distilled off and the residue is partitioned between ether and water. The ether is dried and distilled off and the residue is distilled in a high vacuum.

^K Λ

pool
Yield: - 168 g.

EXAMPLE 4

o- (| 3-N-piperidino-ethoxy) -benzyl alcohol 232 g (1 mol) of o - ((3 -N-piperidino-ethoxy) -benzaldehyde are dissolved in 1.5 l of ethanol, and 20 g of Raney-Niekel are added and hydrogenated at about 30 ° under 80 atm H ₂ pressure for 2 hours After the pressure has been released, the nickel is filtered off.

Pp. 85 -86 ⁰ C (from hexane).

Yield: - 212 g.

Analysis; - CHN 0

calculated; - 71, ^ 5 % 9.00 % 5.95 # 13.60 % found: - 71.65 9.02 6.23 13.30

EXAMPLE ft

ο- ( β -Dirnethylaminopropoxy) benzaldehyde

122 g (1 mol) o-Hydroxybei ^ kldehyd be entered into a suspension of 294 g of K ₂ CO · »in 2 ~ ^J γ'Tsopropanol. One turbines

^7th 2098T7 / U95

BATHROOM ORIGINAL - 11 -

strong and keeps the temperature at 60 °. 158 g (1 mol) of ^ -chloropropyl-dimethylamine HGl are added in large portions over the course of 30 minutes and the mixture is then heated to 80 ° for 5 hours. After cooling, it is filtered, the solution is distilled off and the residue is divided between ether and Jasner vei. The ethereal phase is dried and evaporated, and the residue is distilled in a high vacuum.

^Κρ · ο οι - " ^ö " ¹⁰⁰ ° ^G ·

Yield: - 148 g.

EXAMPLE 6

o- (v> -Dime thy I amino propoxy) -benzyl alcohol 20; g (1 mol) o - (- p -dimethylaminopropoxy) benzaldehyde are dissolved in 1.5 liters of methanol, mixed with 20 g of Raney nickel and at 20 ° below 70 atm. H _g pressure hydrogenated for 1.1 / 2 hours. After the pressure has been released, the nickel is filtered off and the filtrate is distilled under a vacuum of 0.01 mm.

^K P 0, Oi ^lo8 ° ^c

Yield: - Γ-Χ) g.

. Fp of HydT'ochlorides: - 131 ⁰ C.

Analysis of the hydrochloride: -

CHN Eq

calculated: - 58.64 55 8.20 # 5.69 ?? 14.42 %

found: - 58, ^ 9 7 * 9 / 5Wl 14.24

EXAMPLE 7

2- (jS -N-Piperidlno-ethoxy) -dibenzyloxyether.HCl ? 3 * 5 g (1/10 mol) o- ((3 -N-Piperidino-ethoxy) -benzyl alcohol in a suspension of J, ^ g (1/10 mol) NaNHp in? 00 t.-ii dry toluene at [0 ° in j -ο * .- ft. * I3-.h B ^ endi ^ iu

209817 / U95

the · NHp-'expansion one leaves quite a reading of τ-asnh 12.7 g (1/10 mol) of senzyl chloride in 20 ml of absolute toluene run off. The contents of the flask are refluxed for one hour. After cooling, ether is added, the mixture is filtered and the Piltrate saturated with HClr gas. The crystalline precipitate is recrystallized from isopropanol.

M.p. 172-175 ⁰ C. C. H 5. N Cl Yield:- 28 g. 69.69 $ 7.8O % 4th Qv 0 /
, O (ρ 9.79 % Analysis:- 69, Ql 7.77 , 15 9.88 Expected:- ß-N-pipei idino-ethoxy) -dibenzyloxy ether. HCl found:- EXAMPLE 8 4-chloro-2 ^! - (

25.5 g (1/10 mol) of o- (ρ -N-piperidino-ethoxy) -benzyl alcohol added dropwise to a suspension of 2.4 g (1/10 mol) of NaH in 100 ml of dimethylformamide at 60 °. This is followed by 1/2 hour stirred at 80 ° and cooled to 5 °. At this temperature adds 16.1 g (1/10 mol) of p-chlorobenzyl chloride are added dropwise with stirring added. Stirring is continued for 1 hour at 30 ° and 1/2 hour at 80 °. The solvent is distilled off in vacuo, the residue taken up in ether, the ethereal phase twice with; Washed water, dried and saturated with HCl gas. the crystalline filling is recrystallized from isopropanol.

M.p. 140 - 141 ⁰ C, C. H yield 52 g. 65.65 % 6.8? ■■; Analysis:- ■? 5, -V4 ■>, -'4 calculated K ^ found: -

N Cl

5.3U ■■ 17.8: '; ■■ 5.08 1, [\ 2

209817 / 1A95 BAD ORIGINAL

BSIS PIEL 9 fa

. 4-Chlar-2 ^> -fß-dintethylaminoethoxy) -dibenzyloxyether. HGl 19 * 5 g (1/10 mol) of ο- (β-dimethylaminoethoxy) benzyl alcohol are added dropwise at 80 ° to a suspension of 2.4 g (1/10 mol) of NaH in 100 ml of dimethylformamide. With vigorous stirring, 16.1 g (1/10 mol) of p-chlorobenzyl chloride are slowly added after the contents of the flask have cooled to 50 °. The mixture is then stirred for a further 1 hour at room temperature and 1 hour at 70-80. The solvent is distilled off in vacuo, the residue is taken up in ether, the ethereal phase is washed twice with a little water and dried. When HGl gas is introduced, the hydrochloride salt precipitates. It is recrystallized from isopropanol.

M.p. 167-169 ° G.

Yield: - 20.5 g

Analysis: - GHN Cl calculated: -

found:-

EXAMPLE 10

2-chloro-2 '- (g> dimethylaminoethoxy) dibenzyloxy ether. HGl 19 * 5 g (1/10 mol) o- (β-dimethylaminoethoxy) benzyl alcohol are added dropwise at 80 ° to a suspension of 2.4 g (1/10 mol) NaH in 100 ml dimethyl sulfoxide. The mixture is cooled 30 ° and slowly mixed with a solution of 16.1 g (1/10 mol) of o-chlorobenzyl chloride in 100 ml of dimethyl sulfoxide, stirring is continued for 1 hour at 30 ° and for 1 hour at 70 °. The mixture is then concentrated in vacuo , takes up the residue in ether, washes the ether with water and dries it over MgSO ^. The crystalline hydrochloride salt obtained when HCl gas is passed in is recrystallized from isopropanol.

209817/1495 bad ORIGINAL

6ο , 67 % 6th , 51 5 *. 3 , 93 % 19 78 60 , 68 6th , 64 4th , 05 19

Mp 131-132 ° C.

Yield: - 10 g.

Analysis: - CHN Cl

calculated: -60.67 % 6.51 % 3.93 % 19.90 % found: -60.85 * 6.55 4, 18 Iy, 74

EXAMPLE 11

2-methyl-2 ^f - (ft -diethylaminoethoxy) -dibenzyloxyether. HCl 22.3 g (1/10 mol) of o- (p -diethylaminoethoxy) benzyl alcohol are allowed to drop into a boiling suspension of 2.4 g of NaH (1/10 mol) in 200 ml of absolute toluene. After the evolution of hydrogen has ceased, 14 g (1/10 mol) of o-methylbenzyl chloride are quickly added and the mixture is refluxed for 4 hours. After cooling, it is diluted with 1 liter of ether, filtered off and HCl gas is passed into the filter. The precipitating hydrochloride salt is recrystallized from isopropanol.
Mp 135 ° C.
Yield: - 17.5 g
Analysis: - CHN Cl

calculated: - o9.50 % 8.31 % 3.85 % y,? 4 %

found: - 69.08 8.52 3.89 10.03

EXAMPLE 12

2-methoxy-2 '- ( ß- diethylaminoethoxy) -dibenzyloxyether. HCl 22.3 g (1/10 mol) of o- (β-diethylaminoethoxy) benzyl alcohol are added dropwise to a boiling suspension of 2.4 g (1/10 mol) of NaH in 200 ml of absolute toluene. After the NaH has been consumed, a solution of 15.6 g (1/10 mol) of o-methoxy-benzylchloride is added

BAD ORIGINAL 209817 / T495 " ¹⁵ ~

50 ml of absolute toluene are added and the reaction mixture is heated under reflux for 4 hours. After cooling, add 1 liter Aether is added, stirred with activated charcoal, filtered and the The filtrate is saturated with HCl gas. The unusual HydroChloridsalζ is recrystallized from ethyl acetate / isopropanol. M.p. 149-150 ° G.

Yield:- 14 g. C. H N Cl Analysis:- £ 66.38 7.96 % $ 3.69 9.33 % calculated:- 66.44 8.28 4.07 9.57 found:- EXAMPLE 13 4-methoxy-2 ^! - (ß-diethylaminoethoxy) -dibenzyloxyether. HCl

22.3 g (1/10 mol) of o- ( ρ- diethylaminoethoxy) benzyl alcohol, dissolved in 100 ml of absolute toluene, are added to a boiling suspension of 2.4 g (1/10 mol) of NaH in 100 ml of dry toluene. After the development of hydrogen has ended, 15.6 g (1/10 mol) of p-methoxy-benzyl chloride are added dropwise. The batch is refluxed for 5 hours. After cooling, it is diluted with 1 liter of ether, decolorized with activated charcoal, filtered and concentrated. The residue is distilled in a high vacuum at 0.01 mm.

^K P 0, Oi ^l64 ° ^c -

Yield: - 13 g.

Mp. Of the hydrochloride recrystallized from ethyl acetate: -133.5 ° C.

Analysis:- 66 C. 1 ? ', H N % Cl - 1 6 - calculated:- 66 .38 % 7, 96 f £ 3, o9 £ 9.33 found:- , 12 7 / 66 3.9V ORIGINAL 9.27 2098 U95 BATH

EXAMPLE 14 Λ

2 - (^ -Diethylaminoethoxy) -3'.4 * -dloxyroethylene-dibenzyloxyether.HCl 22.3 g (1 / 10 mol) o- (ß-diethylaminoethoxy) -benzyl alcohol and stir it for another 15 minutes. A solution of 17 g (1/10 mol) of piperonyl chloride in 50 ml of dry dimethylformamide is then added, with good cooling, and the mixture is slowly heated to 80 °. The mixture is stirred for a further 1 hour at this temperature and then the solvent is stripped off in vacuo. The residue is taken up in ether, washed with water and dried. When HCl gas is introduced, an oil precipitates which solidifies when rubbed with acetone. The resulting hydrochloride salt is recrystallized from acetone.

M.p. 116-117 ° C.
Yield: - 13 g.

Analysis: - CHN Cl

calculated: - 64.02 % 7.17 % 3.56 % 9.01 % found: - 63.92 % 7.16 3.50 8.84

EXAMPLE 15

2- ( fi-Dläthylaminoäthoxy ^ -g ', Λ'-dimethyl-dibenzyloxyether. Oxalate 22.3 g (1/10 mol) of o- (ρ -diethylaminoethoxy) -benzyl alcohol is added dropwise to a boiling suspension of 3 * 9 g NaNHp in 150 ml absolute toluene As soon as the evolution of ammonia has ended, a solution of 15.4 g (1/10 mol) 2,4-dimethylbenzyl chloride in 50 ml absolute toluene is slowly added and the reaction mixture is refluxed for 5 hours After cooling, 1 liter of ether is added, the color is decolorized with activated charcoal, the mixture is filtered and HGl gas is passed in. The precipitated product becomes

209817 / U95

BATH ORIGINAL -If-

separated off, decomposed with 2η NaOH and the deposited base taken up in ether. After drying, the oxalate is precipitated with the help of an ethereal oxalic acid solution. It is recrystallized from ethyl acetate / isopropanol.
M.p. 115.5-116.5 ° C.
Yield: - 19 g.

Analysis: - CHN

calculated: -66.80 % 7.71 % 3.25 # found: -66.77 7.63 3.44

EXAMPLE .16

2-fft-diethylaminoethoxy) -3 ', 4'-dimethyl-dibenzyloxyether _t oxalate A solution of 22.3 g (1/10 mol) o- ( β- diethylaminoethoxy) -benzyl alcohol in 50 ml of absolute toluene is $ £ j ? jü / in a boiling slurry of 2.4 g (1/10 mol) of NaH in 100 ml of dry toluene added dropwise. After the reaction has ended, a solution of 15.5 S (1/10 mol) of 3,4-dimethylbenzyl chloride in 20 ml of absolute toluene is slowly run in. The batch is refluxed for 4 hours. After cooling, 1 liter of ether is added, the mixture is filtered and saturated with HCl-Oas. The precipitated product is separated off, made alkaline with 2η NaOH and the separated oil is taken up in ether. The dried solution is concentrated and the residue is distilled in a high vacuum at 0.05 mm.

• 0.05
Yield: - 18 g.

Pp. Of the oxalate: - 110 - 111 ° C.

Analysis: - CHN O

calculated: -77.37 % 9.15 % 4.11 % 9.37 % found: -77.25 9.09 4.15 8.98

209817 / U95 " ^l8 "

EXAMPLE 17 "*

2 - (^ -Diethylamlnoathoxy) ^ ¹ ^ '- dimethyl-dlbenzyloxyether. HCl 22.3 g (1/10 mol) of o- (β-diethylaminoethoxy) benzyl alcohol are added to a suspension of 2.4 g (1/10 mol) of NaH in 100 ml of boiling absolute toluene. As soon as the evolution of hydrogen has ended, a solution of 15 * 4 g (1/10 mol) of 2,5-dimethylbenzyl chloride in 20 ml of dry toluene is added dropwise and the mixture is refluxed for a further 4 hours. The cooled reaction mixture is mixed with 1 liter of ether, decolorized with animal charcoal and filtered. When HCl is passed into the filtrate, the hydrochloride salt precipitates. It is recrystallized from ethyl acetate / isopropanol.

Pp. 154-155 ° 0.
Yield: - 21 g.

Analysis: - £ _ H N Cl

calculated: -69.92 % 8.53 % 3.71 % 9.38 % found: -69.54 8.44 3.89 9.27

EXAMPLE 18

2- ( (5-Diethylaminoethoxy) -2'.4 * -dichloro-dlbenzyloxyether. HCl 22.3 g (1/10 mol) o- (ρ -diethylaminoethoxy) -benzyl alcohol, dissolved in 20 ml of absolute toluene, become one A suspension of 2.4 g (1/10 mol) of NaH in 150 ml of absolute boiling toluene is added dropwise After the evolution of hydrogen has ceased, a solution of 19.5 g (1/10 mol) of 2,4-dichlorobenzyl chloride in 20 ml of absolute toluene are added and the contents of the flask are refluxed for 4 hours. After cooling, it is diluted with 1 liter of ether, stirred with activated charcoal, filtered and passed into the piltrate HCl-Oas. The precipitating hydrochloride salt is recrystallized from ethyl acetate / isopropanol.

209817/1495 _1Q

130.5-131 ° C.
Yield: - 18.5 g
Analysis: - C

calculated: - 57.35 % found: - 57.52

6.25 5.97

$ 3.35
3.39

Cl

25.40 % 25 * 23

EXAMPLE 19

2- ( -y-dimethylaminopropoxy) ~ 3 ^t , V-dioxymethylene-dibenzyloxyether. HCl

24.5 g (1/10 mol) of o- (-γ- dimethylaminopropoxy) benzyl alcohol are added dropwise at 80 ° to a suspension of 2.4 g (1/10 mol) of NaH in 150 ml of anhydrous dimethylformamide. After the evolution of hydrogen has ceased, the solution is cooled to 20, a solution of 17 g (1/10 mol) of piperonyl chloride in 50 ml of dimethylformamide is added and the mixture is stirred at this temperature for 1/2 hour. The mixture is then heated to 60 ° within half an hour and then concentrated in vacuo. The residue is taken up in ether, extracted with water, filtered, dried and saturated with HCl gas. The hydrochloride salt initially separates out as an oil, but solidifies after a few hours.
M.p. 105-106 ° C.

(Made from isopropanol). Yield: - 17 g. Analysis: - CH

calculated:-
found:-

Cl

63 , 23 % 6th , 90 % 3 , 69 % 9, 34 % 62 , 90 6th , 67 4th , 03 9, 37

-20 -

209817 / U95

bad original

EXAMPLE 20

2 ~ (ft -diethylaminoethoxy) -dibenzylthioether. Oxalate 22.3 g (1/10 mol) of o - ((i-diethylaminoethoxy) benzyl alcohol are dissolved in 100 ml of chloroform, 50 g of thionyl chloride are gradually added with occasional cooling ether is added to the cooled batch with stirring, the hydrochloride of o- (ß-diethylaminoethoxy) benzyl chloride precipitating in crystalline form.

Mp 135 ° C.

Yield; - 26 g.

4.6 g (2/10 mol) of Na are in 150 ml of absolute under nitrogen Dissolved ethanol. 6.8 g of hydrogen sulfide are introduced into the ethylate solution. Under a HpS protective atmosphere, under vigorous stirring, an ethanolic solution of 27 g (1/10 mol) of o- ((J-diethylaminoethoxy) -benzyl chlorine id. HCl was added dropwise When the addition is complete, the mixture is refluxed for a further hour, with a vigorous stream of HgS flowing through the solution leads. The ethanol is distilled off and the residue is partitioned between benzene and water. The benzene phase becomes dry brought, whereby care must be taken by adding enough benzene that the residue is anhydrous at the end.

The crude o- ( (b- diethylaminoethoxy) benzyl mercaptan (19.1 g) is added to a suspension of 1.9 g (8/100 mol) of NaH in absolute toluene under nitrogen at 60 ° Then 10.1 g (8/100 mol) of benzyl chloride are rapidly added and the mixture is heated under reflux for 2 hours. After cooling, the measurements are taken

209817 / U95

BADORlGiNAL - PL -

extracted with dilute hydrochloric acid, the extract with ether over- ■ layers and the base is set free with 4 η NaOH. The ether phase is dried, drawn off and dried. The residue distilled in a 0 ^ 5 mm vacuum.

^Κ Ρ · 0.5 mm ¹ ^ ² " ²⁰⁴ ° ^c ·
Yield: - 16 g.

Pp of the oxalate: -89-90 ° C.

Analysis: - CHNS

calculated:- 63.13 % 6; 3, 7, 66 % found:- 63.25 7 _p 3. 7, 46 EXAMPLE 21 2- ( ρ-diethylaminoethoxy) -2 ' »75 # .35 % -ohlor-dibenzylthioether , Oxalate 1O5 , 57

19.1 g (8/100 mol) o - ((2> -Diethylaminoethoxy) benzyl mercaptan, dissolved in 50 ml of benzene become a suspension of 1.9 g (8/100 mol) NaH in absolute benzene under nitrogen at 60 °. After the hydrogen evolution has stopped, drips a solution of 13 g (8/100 mol) of o-chlorobenzyl chloride in Add 20 ml of benzene and reflux for 3 hours. After cooling, the benzene phase is extracted with 2 η HGl, overlaid the aqueous extract with ether and makes alkaline with 4 η NaOH. The ether phase is drawn off, dried and evaporated. Of the The residue is subjected to vacuum distillation at 0.03 mm.

^κ Ρ 0.03 ^19β - ¹⁹⁸ °°
Yield: - 14.5 g #

Mp. Of the oxalate: - 114.5 - H5 ° C.

Analysis: - C HNS Cl

calc .: -58.33 % 6.01 % 3.09 % 7, O8 % 7.83 found:-58.08 6.25 3.01 6.79 7.61

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- 22 -

The o- (aminoethoxy) -dibenzyl ethers prepared according to the invention have interesting pharmacological properties, especially in salt form Activity. They express very strong spasmolytic, broncholytic, ahtitussive, analgesic, antiphlogistic, antipyretic, anticonvulsant and sedative effect with low toxicity. A particular advantage is the excellent solubility in water their salts, especially their hydrochlorides. Injection of the solutions does not cause irritation or tissue damage, The superiority of the compounds over common pharmaceuticals can be seen from the following comparisons: -

As comparison substances were used: -

material

A Dimethylaminophenyldimethylpyrazolone (e.g. known under the protected brand name "Pyramidon") - (for analgesic, anti-inflammatory and anti-pyretic activity.)

B Morphine hydrochloride (for analgesic activity).

C 2-methyl-3-o-tolyl-4 (3H) -quinazolinone (e.g. known under the protected brand name "Revonal" (for sedative activity)

D papaverine (for spasmolytic activity).

E 3,5,5-trimethyloxazoline-2,4-dione (e.g. known as the protected brand name "Tridion" (for anticonvulsive Activity)).

F Codeine (for antitussive activity).

4-0ΐ} θΓ-2 '- (ft -piperidinoethoxy) -dibenzyloxyether .HCl (referred to as I)

a) Toxicity: -
I: -
LD '»- 700 mg / kg sc (mouse)

ι 350 mg / kg so (mouse)
209817/1495

- 23 -

Ib) Analytical effect: -

. ba) test animals were male white mice (NMIR strain) weighing 1? - 20 g. There were 12 animals in each group. 15 minutes after subcutaneous application Phenyl-p-quinone was administered intraperitoneally to the substances to be examined or the corresponding control solution ■ administered. The observation time after the phenyl-pquinone injection was 20 minutes. The results are shown in the following table: -

n _llhqtfln7 dose number of animals ^{number of animals mlt positive} substance _{mg / kg} number of animals painful reaction

12th

9 4 0 2 4

bb) test animals as specified under ba). There were 10 animals in each group. The mice were placed on a glass plate set, which was heated to 60 ° with a thermostat. In an initial measurement, for each animal the time from placing it on the plate to the first pain reaction is measured. After that the substances were administered and at intervals of 30, βθ, 90 and 120 minutes further measurements carried out.

- 24 -

209817 / U95

NaCl solution 50 12th A. 100 12th A. 100 12th I. 100 12th I. 50 12th I. 12th

substance

Dose baseline
mg / kg = 100 %

Values after

min. βθ min. 9o min. 12o min. χ χ χ χ

NaCl (i.g.) -

B 25

(i.g.) 50

(i.g.) 100

9.2 sec. 9.9 +8 9.6 +4 11.8 +28 13.9 +51

9.8 sec. 16.8 +71 18.1 +85 13.6 +39 13.2 +35

8.8 sec. 16.5 +88 14.3 +63 15.3 +74 19.3 + 119

9.7 sec. 16.7 +72 15.4 +59 17.8 +84 16.4 +69

x column = change in response time in %

cj anti-inflammatory effect; -

Test animals were male rats (Wistar) weighing 100 to 130 g. The substances were found on the paw edema examined. There were 10 animals in each group. The paw edema was produced by ovalbumin or formalin. the Swelling of the paw was measured after 60 and 120 minutes with the apparatus described by Enders and Heidbrink. The results are shown in the following table: -

Dose AddI - starting substance *>% * ^ t ' worth
mg / kg art _{β 100} ^

Values after

min. 12o min.

Relat. values

Protein-

edema: - S. C. NaCl 100 S. C. A. 50 S. C. I. - S. C. NaCl 100 S. C. A. 100 G. C. I. Formalin edema:-

NaCl

100
100

sc
s. π.
s. α.

0.89 0.91 0.85 1.04 1.08 1.02

1.0 0.98

209817 / U9S

1.48

1.19
1.09
1.6

1.57

1.39

1.45
1.2?

100 % 42 % 40 fo

100 % 82 fo 61 %

100 pounds

63 ■ '■' ■

BATH ORIGINAL

Antipyretic effect: -

The test animals were rabbits (white New Zealanders) weighing 2.8 to 3.5 kg. The temperature rise was produced by iv injection of a therapeutic fever-inducing agent from non-pathogenic bacterial strains of the Goli group (e.g. known under the protected trade name ^tt Pyrifer ^ft ). After measuring the normal temperature, 30 minutes before the injection of the active ingredient, the substances to be tested were administered in this way.

substance

mg / kg

application

Output measurement

60 min. 120 min.

NaGl

I.
NaGl

50

40

so.

so.

S. C,

S.C,

39.9 ° C 39.8 ° C

39.7 ° C

39.

40.1 (+0.2)

40.0 (+0.2)

39.8 (+0.1)

39.4 (+ -ο)

41.3

40.5
(+0.7)

40.5
(+0.8)

39.5
(+0.1)

41.4 (+1.5)

40.5 (+0.7)

41.4 (+1.7)

39.7 (+0.3)

4-chloro-2 * -f / 3-diethylaminoethoxy) dibenzyloxy ether. HGl (referred to a) Toxicity; - Ili-

LDj-Qi- 400 mg / kg s.c. (Mouse)

Gi- s.c. not determinable due to unacceptability in water.

Di- 250 mg / kg s.c. (Mouse)

Anesthesia duration extension: -

Test animals were male mice weighing 17 to 23 g · The animals were given 30 minutes before the intravenous injection of mg / kg N-Methylcyclohexenylmethyl-barbituric acid (for example, known under the registered trade name ^M Evipan ") to be tested Sub-

- 26 -

209817 / U95

BATH

punch or the corresponding control solution subcutaneously or administered intragastrically. The time taken to spontaneously straighten up from the side position was rated as the duration of sleep.

substance rag / kf ^ζ number. tion type Average
Sleep duration in minutes NaCl 10 subcutaneous 18th II 75 10 η 164 NaCl - 10 Il 13th II 75 10 tr 106 NaCl
II 50 10
10 intra
gastral
W. 21
89 II 100 10 H 145 NaCl 10 Il 21 C. 40 10 η 84

In a second experiment, methyl isoamylthiobarbital sodium (e.g. known under the protected brand name "Pentothal").

NaCl

NaCl

NaCl

- 10 subcutaneous 50 10 Il 10 It 75 10 'Il 40 10 intragastric 100 10 Il 10 Il

91 24

539 130

> 355

Photoelectric motility measurement; -

Test animals as described under b). The animals came for 30 minutes after application of the substances in groups of 5 in the test cage · The number of light beam interruptions were registered for 30 minutes with an interval of 2 minutes *

209817 / U95

-27-

SAD ORIGINAL

substance

mg / kg

Animal application number of light beam shortage type refractions per 30 minutes

NaCl - 5 subcutaneous II 100 10 It II 50 5 dd II 25th 5 It NaCl - 5 dd NaCl
II 100 Ul U! intraga-
s tr al
It NaCl __ Ul It II 50 5 ti NaCl - 5 ti II 25th 5 dd NaCl - 5 dd II 10 5 ti NaCl __ 5 It C. 40 5 dd NaCl - 5 dd C. 30th 5 dd

809 O

35 250 701

541

104 532 134

527 194

522 222 52? 120

244

Motility measurement in the trembling cage; -

Test animals as described under b). The movement activity of the animals was recorded over 2 hours. Every attempt was made carried out on 27 mice. The following results were found: -

Substance mg / kg

Application type

Number of tremors within 2 hours

NaCl __ subcutaneous 15th 760 NaCl - dd 1? 4QO II 50 It 3 200 NaCl —— dd 15th 720 NaCl __ ti 14th 650 NaCl _ - intraeastral IG O6O C. 30th 10 620 NaOl —— dd 21 200

- 28 -

209817 / U95

BATH

e ) Spasmolytic effect: -

ea) On the isolated guinea pig large intestine according to Magnus.

The intestinal cramp was caused by acetylcholine (1: 5 x 10) and histamine (1: 5.3 χ 10).

II "solved the spasm completely in dilutions of 1: 5 χ 10 ^v . C only solved the spasm in concentrations of 1: 5 χ 10.

eb) Guinea pig asthma experiment according to Konzett and Rössler. Histamine (10 and 15 μg / kg iv.) Was used as a spasmodic. The bronchospasm was generated every 3 minutes. The substances were administered i.v. administered.

II: - Suppression of bronchospasm for 9.5 minutes after 2 mg / kg. Suppression of bronchospasm for more than 25 minutes after 5 mg / kg.

D: - Suppression of bronchospasm for 2 min. After 2 mg / kg. Suppression of bronchospasm for 5 min. After 5 mg / kg.

ec) Isolated guinea pig heart according to Langendorff. II: - Increase in the coronary flow by 100 %

during 3 minutes after 50 f .

D: Increase in the coronary flow by 50 % for 1 minute after 50 y .

2-chloro-2 '- (ft dlmethylamlnoethoxy ) -dibenzyloxyether. HGl

(referred as III)

a) Toxicity: - III: -

LDc ₀ ^: "^ ⁰⁰ rogAg ^s · ⁰ · (mouse)

ID ^ q: - see above cannot be determined because it is insoluble in water. 2000 mg / kg p.o. (Mouse)

209817 / 1A95 bad original -2

b) Anticonvul ^ ive Effect: -

To study the anticonvulsant effect, pentetrazole was used administered at a dose of 120 mg / kg s.c. The number of stretching convulsions and survivors was assessed, as well additionally the survival time. Served as experimental animals male mice weighing 18 to 22 g.

substance

Dose mg / kg

- Animal-

^{Number of number of}

Animals with

dead animals

^About> "vital

Time

NaCl - s.c. 12th 12th 12th 20 min III 50 s.c. 12th 0 10 50 min III 100 s.c. 12th 0 VJI 75 min E. 300 i.g. 12th 3 10 35 min

2- ( fb Diethylaminoethoxy) dibenzyloxy ether. HCl (referred to as IVi

a) Toxicity; - IV: -

LDc ₀ ^: ~ ² ° 0 rag / kg ^{s 0} (mouse)
P: -
!!) ": - 240 mg / kg sc (mouse)

effect '-

Guinea pigs weighing 250 to 350 grams were used. Each group included 6 animals, the guinea pigs were placed in a glass cage in which 1/3 η Hp SOj was sprayed to produce the cough. the Coughs were recorded over 3 minutes.

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209817 / U9S

% 0

substance

Dose mg / kg

Appl, art

Number of coughs per minute (average values)

NaCl - - S.C. P. 50 S.C. IV 20th S.C. IV 10 S.C. IV 5 S.C. NaCl __ S. C.

6 2 2

4 8

2- (ß-Diethylaminoethoxy) -dibenzylthioether. Oxalate (referred to as XX)

a) Toxicity:

XX: LD 50 600 mg / kg see above (mouse) Papaverine: 250 mg / kg see above (mouse)

b) Spasmolytic effect:

On the isolated guinea pig colon according to Magnus

ba) Spasmodicum: Acetyloholin spasmolysis in a concentration of 1: 25,000 according to papaverine 1: 500,000 according to XX 1: 25,000 according to papaverine 1: 1,000,000 according to XX

bb) Spasmodicum: BaCI p

Solution of the spasm in a concentration of 1: 50,000 according to papaverine 1: 250,000 after XX

209817 / U9S

BAD ORIGINAL ^ -

be) Spasmodicum: histamine

Spasmolysis at a concentration of

1: 25.OOO after Papaverine 1: 200,000 after XX

bd) Spasmolysis in situ

on the uterus of the rat. Spasm of the uterine muscles was caused by 1 int. U. / kg iv uterus-active pituitary posterior lobe hormone, as is e.g. B. under the protected brand name "Orasthin ¹¹ is commercially available, caused: spasmolysis by papaverine after 10 mg / kg iv spasmolysis by XX after 2 mg / kg iv spasmolysis by papaverine after 10 mg / kg iv spasmolysis by XX after 4 mg / kg iv

c) Broncholysis attempt according to Konzett and Rössler

ca) The bronchospasm was caused by acetylcholine . Broncholysis after

4 mg / kg i.v. Papaverine

2 mg / kg i.v. XX

cb) The bronchospasm was caused by histamine . Broncholysis after

8 mg / kg i.v. Papaverine. Duration of action: 9 min. 2 mg / kg i.v. XX duration of effect: > 25 min.

As can be seen from the test results below, the intermediate products from the synthesis step also already have therapeutic usefulness.

209817 / U95

1) ο- (ß-N-piperidino-ethoxy) -benzyl alcohol (see example 4)

Taking into account the toxicity, this compound is superior to codeine in their antitussive activity. There were guinea pigs with a body weight of 250 g to 350 g used. There were 6 animals in each group. The guinea pigs were placed in a glass cage to produce the cough, in which a mist of 1/3 η H ^ SOl · was sprayed. The coughs were recorded over 3 minutes.

Substance Dose Applica- number of coughs

mg / kg type of diet per minute (average values)

Tragacanth mucus - i.g. 6th Codeine 100 i.g. 3 o- (ß-N-piperidino-
ethoxy) benzyl
alcohol 150 i.g. 3 Tragacanth mucus i.g. 6th

-33-

209817/1 4 95

BAD oRIGINAL

-LD50 of ο- (ß-N-piperidino-ethoxy) -benzyl alcohol: 900 mg / kg i.g LD50 of odein: 425 mg / kg i »g.

2) o- (γ-Diinethylaminopropoxy) -benzyl alcohol (see example Ö) Taking into account the toxicity situation, this compound is clearly superior to preparation A in terms of its analgesic effect.

a) Test animals were male white mice (NMIR strain) weighing 17 to 20 g. There were 12 animals in each group. Preparation A was used as a positive comparison substance. 15 minutes after the subcutaneous application of the substances to be examined or the corresponding control solution vmrde phenyl-p-quinone administered intraperitoneally. the Observation time after phenyl-p-quinone injection 20 I-iinuteii. The results are shown in the following table emerge:

substance dose
mg / kg animal
number Number of animals with posi
tive pain reaction NaGl solution _ 12th 12th A. 75 s.c. 12th 6th A. 100 s.ο. 12th 2 o- (y-diraethyl-
aminopropoxy) -
benzyl alcohol 50 see above 12th 6th ο- (y-dimethyl-
aminopropoxy) -
benzyl alcohol 100 see above 12th 3 NaCl solution - 12th 12th

-34.-209817 / U95 ad ^oBlGlHAU

b) Test animals as specified under a). There were 10 animals in each group. The mice were placed on a glass plate, which was heated to 60 ° C with a thermostat. In an initial measurement, the time from Put on the plate measured until the first pain reaction. Thereafter, the substances were administered and at a distance Further measurements carried out after 30, 60, 90 and 120 minutes .

Dose Initial change in response time Substance mg / kg fourth in %

30 60 90 120 min.

NaGl i.g. A.

75 s.c.

+111

o- (γ-dimethylaminopropoxy) benzyl alcohol 75 sc

o- (γ-dimethylaminopropoxy) benzyl alcohol I50 s.c.

100 % +17 + ^ 9 +35 100 % +79 +77 +52

100 % +79 +69 +87 100 $ +109 +135 +120 +89

LD50 of o- (γ-dimethylaminopropoxy) benzyl alcohol : 600 mg / kg see above

LD50 from A

: 260 mg / kg s.c.

209817 / U95

ORIGINAL

Claims (4)

\ X ^> rST8453 patent claim ^^ Process for the preparation of o-aminoalkoxy-substituted dibenzyl ethers of the formula in which R. and Rp are identical or different to one another and are alkyl radicals or together with the amino nitrogen atom form a heterocyclic ring, R ^, Rj, and Rp - as being identical or different to one another, hydrogen, halogen, alkyl or alkoxy radicals, Z represent oxygen or sulfur and η represents the integer 2 or 3, characterized in that one 1. o-Hydroxybenzaldehyde at temperatures below 100 and preferably at 60-80 ° with the hydrochloride a dialkylamino-chloroalkane in the presence of at least two equivalents of an alkali metal carbonate and a solvent such as lower alcohol, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran for corresponding o-aminoalkoxy-benzaldehyde, 2. This o-aminoalkoxy-benzaldehyde preferably catalytically at temperatures below about 75 ° and preferably about 20 - ^J 10 in the presence of a hydrogenation catalyst, 209817 / U95 BAD ORIGINAL -56- preferably Raney nickel is reduced with compressed hydrogen to the corresponding o-aminoalkoxy-benzyl alcohol, 2a. optionally this o-aminoalkoxy-benzyl alcohol initially with thionyl chloride in an organic Solvent at 20 - 60 ° in the corresponding benzyl chloride and then with excess Sodium hydrogen sulfide in an organic solvent at 6o - 100 ° to the o-aminoalkoxy-benzyl mercaptan implements, 3. The benzyl mercaptan from step 2a) or optionally the benzyl alcohol from step 2) at temperatures between 30 ° and 100 ° in the presence of a strongly basic condensing agent, preferably sodium hydride, in a preferably anhydrous organic Solvent with one on the core with the above-defined FU, FU and FU radicals and substituted on the methyl radical by halogen or p-toluenesulfonate Benzyl derivative condensed to the corresponding dibenzyloxy or thio ether, and 4. if necessary, the ether base from step 3) in itself in a known manner into a pharmaceutically acceptable acid addition or quaternary ammonium salt. 209817/1495 ^ß AD ORJG »NAL