DE1194422B - Process for the production of azonia spironortropane derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07d

German class: 12 ρ-13

Number: 1194422

File number: P 31263IV d / 12 ρ

Filing date: March 5, 1963

Opening day: June 10, 1965

The implementation of nortropine or its derivatives with suitable dihalides was surprisingly found that not only the expected bistertiary bis-nortropin derivatives, but hitherto unknown azoniaspironortropane derivatives can also be obtained in good yield, the excellent Have spasmolytic properties and quaternary tropine derivatives known for their potency surpass. The antispasmodic effect of these compounds is similar to the effect of atropine comparable (see Table I), but the undesirable side effects of atropine are weakened are or are completely absent (see Table II). Also, the toxicity of these compounds is about of the same order of magnitude as the known quaternary tropine derivatives (see Table III).

The invention relates to a process for the preparation of azoniaspironortropane derivatives general formula

• ° - <D

R ₃

R ₂

in which R is a hydrogen atom or an acid radical of the general formula RiCO -, in which Ri is alkyl, aryl or an arylated and / or aralkylated alkanol radical, R2 and R3 are water atoms or alkyl groups, Z is an alkylene, azaalkylene , Oxaalkylene radical with at least 2 carbon atoms or the o-phenylene radical, X ^{- is} a halogen ion, and is characterized in that compounds of the general formula

N-H

in the presence of polar solvents at elevated temperatures within one to several days with dihalides of the general formula

X - CH ₂ \

\ r

X-CH ⁷ "
R ₂

R ₃

in which X denotes halogen atoms, reacts, optionally treating the reaction products obtained with acid chlorides of the general formula RiCOCl and optionally treating the reaction products obtained with a process for the preparation of
Azonia spironortropan derivatives

Applicant:

Dr. Robert Pfleger,

Chemical factory, Bamberg

Named as inventor:
Dr. Heinz Bertholdt, light oak;
Dr. Robert Pfleger, Bamberg;
Dr. Wolfram Schulz,
Griesheim near Darmstadt

fixed on acidic ion exchangers and then fractionally eluted with organic acids.

A preferred embodiment for the implementation of nortropine or pseudonortropine with dihalides is that they in the presence of water-based solvents and Executes alkali hydroxides or strongly basic ion exchangers.

One can thus either Nortropin- Pseudonortropinester or obtained by known procedures, in polar solvents, preferably in a mixture of acetonitrile and methanol, with suitable dihalides, such as 1,4-dibromobutane, spirozyklisieren by several days heating to 6O ⁰ C, or nortropine or Pseudonortropin in polar solvents, preferably in aqueous alcohol to implement and, with suitable dihalides in the presence of alkali metal hydroxide or a basic ion exchanger by 6- to for 8 hours heating at 40 to 8O ⁰ C esterify the umkristallisierbare from absolute alcohol Azoniaspirohalogenid in manner known per se .

The isolation of the esterified azoniaspironortropane derivatives is expediently carried out by fixation of the reaction product on an acidic ion exchanger and subsequent elution with formic acid of suitable strength.

The residue of the eluate can after the addition of hydrohalic acids from organic solvents

509 579/413

solvents, preferably from alcohols, are recrystallized.

The ion exchangers used are acidic ion exchange resins, for example by Formaldehyde condensation of polyphenols, phenol carboxylic acids or phenolsulfonic acids or by Sulfurization of suitable masses, such as cross-linked! Polystyrene, or basic ion exchange resins, ζ. B. from condensation products of amines or polyamines with aldehydes, ins- ro special formaldehyde; they are z. B. from "Die Pharmazie", Vol. 8 (1953), pp. 547 to 555, Angewandte Chemie, Vol. 63 (1951), pp. 450 to 457, and Chemiker-Zeitung, Vol. 79, (1955), pp. 733 to 737, known.

The invention is illustrated below with the aid of tables and examples.

Atropine sulfate

Scopolamine bromobutylate

Azoniaspiro- [3a-tropoyloxynortropane-8.1 '-pyrrolidine] chloride

Azoniaspiro- [3a-tropoyloxynortropane-8, r-piperidine] chloride

Azoniaspiro- [3a-diphenylglycoloyloxy-nortropane-8.1 '-pyrrolidine] chloride

Azoniaspiro- [3a-diphenylglycoloyloxy-nortropane-8.1 '-piperidine] chloride

Azoniaspiro- [3a-phenylglycoloyloxy-nortropane-8.1 '-pyrrolidine] chloride

Mydriask *)

50 ₇ / kg

2210/0

185%

145% 117%

100 _r / kg

260% 123%

207%

245%

118%

*) Pupil size of the untreated animal corresponds to 100 ⁿ / o (P. P u 1 ewka, A method for the quantitative determination of the smallest amounts of atropine and other mydriatics; Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol., 168 [1932], p. 306).

IS

Table I.
Spasmolysis in an isolated guinea pig small intestine

Spasmolysis *) (atropine sulfate = 100)

Atropine sulfate 100

Scopolamine bromobutylate 10

Azoniaspiro- [3a-tropoyloxy-nortropan-

8, r-pyrrolidine] chloride 110

Azoniaspiro- [3a-tropoyloxy-nortropan-

8,1'-piperidine] chloride 11

Azoniaspiro- [3a-diphenylglycoloyloxy-

nortropan-8, r-pyrrolidine] chloride .. 29 Azoniaspiro- [3a-diphenylglycoloyloxy-

nortropane-8, l'-piperidine] chloride ... 29 Azoniaspiro- [3a-phenylglycoloyloxynortropane-8, r-pyrrolidine] chloride .. 25

*) About 50% attenuation of the acetylcholine spasm on the isolated Guinea pig small intestine (R. Magnus, experiments on the surviving small intestine of mammals; Pflügers Arch. Physiol. People Animals, 102 [1904], p. 123).

Table II
Mydriasis on the mouse eye

Table III
Toxicity (LD50; mouse; i. Ν.)

Atropine sulfate 69.6 mg / kg

Scopolamine bromobutylate 16.3 mg / kg

Azoniaspiro- [3a-tropoyloxy-nortropan-

8, r-pyrrolidine] chloride 17.3 mg / kg

Azoniaspiro- [3a-tropoyloxy-nortropan-

8, r-piperidine] chloride 10.9 mg / kg

Azoniaspiro- [3a-diphenylglycoloyloxy-

nortropan-8, l'-pyrrolidine] chloride .. 12.3 mg / kg Azoniaspiro- [3a-diphenylglycoloyloxy-

nortropan-8, r-piperidine] chloride ... 11.6mg / kg Azoniaspiro- [3a-phenylglycoloyloxy-

nortropan-8, l'-pyrrolidine] chloride .. 24.9 mg / kg

example 1

Azoniaspiro- [3a-phenylglycoloyloxy-nortropane-8.1 '-pyrrolidine] chloride

2.16 g norhomatropin (10 mmol) and 1.90 g 1,4-dichlorobutane (15 mmol) are in 50 ml Acetonitrile-methanol (1: 1) warmed to 60 ° C for 14 days. After the solvent has been distilled off in a vacuum and the addition of dilute ammonia liquid is several times with ether extracted, the remaining water phase brought to dryness in vacuo and the residue crystallized from methanol-acetone.

F. 196 to 198 ⁰ C. Yield about 60% of theory.

Example 2

a) Azoniaspiro- [3a-hydroxy-nortropane-8,1 '-pyrrolidinj chloride

12.7 g of Nortropin (0.1 mol) and 21.6 g of 1,4-dibromobutane (0.1 mol) are stirred in 200 ml of 70% alcohol in the presence of a strongly basic ion exchanger based on polystyrene compounds containing quaternary ammonium groups hours heated to 38 to 4O ⁰ C. The filtrate is adjusted to pH 4 to 5 by adding dilute hydrochloric acid, brought to dryness in vacuo and the residue is crystallized from ethanol-ether.

F. 294 to 297 ^C C (decomposition). Yield 51% of theory.

b) Azoniaspiro- [3a-phenylglycoloyloxy-nortropane-8,1'-pyrrolidinj chloride

2.17 g of azoniaspiro- [3a-hydroxy-nortropane-8,1'-pyrrolidine] chloride (10 mmol) and 4.24 g of acetylmandelic acid chloride (20 mmol) are in vacuo (12 Torr) Heated to 100 ° C for 6 hours. After adding 40 ml of water, the mixture is repeatedly extracted with ether. the Water phase adjusted to pH 6.7 to 6.8 and

extracted continuously with chloroform for 24 hours. The residue of the chloroform extract remains after the addition of 20 ml of concentrated hydrochloric acid Stand at room temperature for 15 hours; the hydrochloric acid is removed in vacuo, the residue in

<\ s absolute alcoholic solution is adsorptively filtered through aluminum oxide, the filtrate residue crystallizes from methanol-acetone.
F. 197 to 198 ° C. Yield about 20% of theory.

35

45

Example 3

a) Azoniaspiro- [3jS-hydroxy-nortropane-8.1 '-pyrrolidine] bromide

12.7 g of pseudonortropine (0.1 mol) and 32.4 g of 1,4-dibromobutane (0.15 mol) are heated ^{to 60 ° C. in 100 ml of acetonitrile-methanol (1: 1) for 8 days.} After the solvent has been distilled off in vacuo and dilute ammonia liquid has been added, the mixture is extracted with ether a few times, the water phase is brought to dryness in vacuo and the residue is recrystallized from ethanol-ether.

M.p. 313 to 315 ° C (decomposition). Yield about 45% of theory.

b) Azoniaspiro- [3β-tropoyloxy-nortropane-8,1 '-pyrrolidinj chloride

2.17 g azonia spiro- [3 / S-hydroxy-nortropan-8,1 '-pyrrolidine] bromide (10 mmol) and 3.39 g Acetyltropasäurechlorid (20 mmol) are heated for 3 hours at 100 to 110 ⁰ C. After adding 10 ml of water, the aqueous phase is repeatedly extracted with ether, and the aqueous phase is placed on an acidic ion exchanger based on polyacrylic compounds containing carboxyl groups, then washed with 3 η-formic acid and, after 24 hours' exposure to 12 η-formic acid, eluted with formic acid of the same strength on the acetyltropic acid ester fixed on the ion exchanger . The eluate is brought to dryness in vacuo, the residue, after the addition of a small excess of dilute hydrochloric acid, is again gently brought to dryness in vacuo and crystallized from alcohol by adding ether.

F. 212 to 215 ^° C. Yield about 20% of theory.

Example 4

Azoniaspiro- [3 a -benzoyloxy-nortropane-8.1 '- (2'-methyl) pyrrolidine] bromide

9.24 g of benzoic acid nortropinester (4OmMoI) and 4.6 g of 1,4-dibromopentane (20 mmol) are dissolved in 100 ml of acetonitrile and heated for 2 days at 80 ⁰ C. After the solvent has been distilled off in vacuo, the residue is mixed with highly dilute ammonia liquid and ether. After the phases have separated, the aqueous phase is extracted a few times with ether, then weakly acidified with dilute hydrobromic acid and, after treatment with activated charcoal, distilled to dryness in vacuo. The residue is dissolved in absolute alcohol and fractionally crystallized by adding ether.

Mp 234-237 ° C (decomposition). Yield about 80% of theory.

Example 5

a) Azoniaspiro- [3a-hydroxy-nortropane-8,2'-isoindoline] bromide

1.27 g nortropine (10 mmol) and 3.94 g of o-xylylene dibromide (15 mmol) are dissolved in 25 ml acetonitrile-methanol: heated for 16 days at 60 ⁰ C (1: 1). After distilling off the solvent in. In vacuo and after adding dilute ammonia liquid, the mixture is repeatedly extracted with ether, the remaining aqueous solution is brought to dryness in vacuo and the residue is crystallized from absolute alcohol after the addition of ether.

F. 254 to 256 ⁰ C (decomposition). Yield about 50% of theory.

b) Azoniaspiro- [3a-diphenylglycoloyloxy-

nortropane-8,2'-isoindoline] chloride (monohydrate)

Azoniaspiro - [3a - hydroxy - nortropane - 8,2 '- isoindoline] bromide is first obtained in aqueous solution by treatment with a basic ion exchanger based on polystyrene compounds containing aliphatic amino groups into the base form convicted. The eluate is weakly acidified with dilute hydrochloric acid, in a vacuum Distilled dry and the residue crystallized from ethanol with the addition of ethyl acetate.

1.33 g azonia spiro- [3a-hydroxy-nortropan-8,2'-isoindoline] chloride (5 mmol) and 2.65 g a-Chlordiphenylessigsäurechlorid (10 mmol) are heated for 6 hours at 160 to 165 ⁰ C. The cooled melt is dissolved in 10 ml of methanol, after the addition of 50 ml of water, the solution is freed from methanol in vacuo and then repeatedly extracted with ether. The aqueous phase becomes continuous

extracted with ethyl acetate, the ethyl acetate phase dried with sodium sulfate and the filtrate up to Crystalline deposition concentrated. The crystals are recrystallized from ethanol with the addition of ether.

F. 265 to 267 ° C (decomposition). Yield about 18% of theory.

Example 6

a) Azoniaspiro- [3a-hydroxy-nortropane-8,4'-morpholine] chloride

12.7 g of Nortropin (0.1 mol) and 28.6 g of β, β'-Όϊ-chlorodiethyl ether (0.2 mol) are dissolved in 50 ml of alcohol and, after adding 100 g of 16% sodium hydroxide solution (0, 4 mol) 2 ¹ J heated to 100 ⁰ C for _{2 hours.} Before and after neutralization with dilute hydrochloric acid, the mixture is repeatedly extracted with ether, the aqueous solution is freed from the solvent in vacuo and the residue is extracted with hot absolute alcohol. The residue of the alcoholic solution is crystallized from isopropanol.

F. 280 ⁰ C (decomposition). Yield about 70% of theory.

b) Azoniaspiro [3a-benzoyloxy-nortropane-8,4'-morpholine] chloride

2,33gAzoniaspiro- [3a-hydroxy-nortropan-8,4'-morpholine] chloride (10 mmol) and 2.8 g of benzoyl chloride (2OmMoI) for 2 hours at 110 ⁰ C are heated. The crystalline product which separates out during the reaction is separated off after cooling, repeatedly triturated with ether and recrystallized a few times from isopropanol.

F. 258 ⁰ C (decomposition). Yield about 70% of theory.
6o

Example 7

a) Azoniaspiro- [3a-hydroxy-nortropane-8.1 '- (4'-methyl) -piperazine] -chloride-hydrochloride

3.3 g of bis-\ ß- chloroethyl] methylamine (21 mmol) are mixed with a solution of 2.54 g of nortropine (20 mmol) in 60 ml of water and, after the addition of a strongly basic ion exchanger, on

Based on polystyrene compounds containing quaternary ammonium groups, stirred vigorously for 3 to 4 hours. The filtrate is then shaken out repeatedly with ether, then weakly acidified with hydrochloric acid and distilled to dryness in vacuo. The residue is fractionally crystallized from absolute alcohol.
F. 27O ⁰ C (decomposition). Yield 75% of theory.

b) Azoniaspiro- [3a-acetoxy-nortropane-8,1 '- (4'-methyl) -piperazine] -chloride-hydrochloride

2.8 g of azoniaspiro- [3a-hydroxy-nortropane-8,1 '- (4'-methyl) -piperazine] -chloride-hydrochloride (10 mmol) are refluxed for 3 hours in 50 ml of acetyl chloride. After the main amount has been distilled off 100 ml of ether are added to the excess acetyl chloride; the precipitate becomes taken up with a little water and the resulting solution shaken out repeatedly with ether. the aqueous phase is distilled to dryness in vacuo and the residue from absolute alcohol crystallized with the addition of ether.

F. 239 to 241 ⁰ C (decomposition). Yield 95% of theory.

Claims (2)

Patent claims: 1. Process for the preparation of azoniaspironortropane derivatives of the general formula R — o z — R ₃ χ R ₂ in which R is a hydrogen atom or an acid radical of the general formula RjCO—, in which Ri is alkyl, aryl or an arylated and / or aralkylated alkanol radical, R ₂ and R3 are hydrogen atoms or alkyl groups, Z is an alkylene, azaalkylene, oxaalkylene radical with at least 2 carbon atoms or the o-phenylene radical, X ~ is a halogen ion , characterized in that one compounds of the general formula R -O Ν —Η in the presence of polar solvents at elevated temperatures within one to for several days with dihalides of the general formula X - ZR ₃ X-CH ^ R ₂ in which X denotes halogen atoms, converts, if appropriate, the reaction products obtained treated with acid chlorides of the general formula RiCOCl and optionally the obtained Reaction products fixed on acidic ion exchangers and then with organic Acids eluted fractionally. 2. The method according to claim 1, characterized in that the Nortropin or the Pseudonortropine with the dihalide in the presence of aqueous solvents and Reacts alkali hydroxides or strongly basic ion exchangers.