DE1915644A1 - Basic 1: 2 benzoisothiazole and 1: 2 benzoisoxazole ethers and processes for their preparation - Google Patents

Description

The invention relates to various basic Ij2-Benzoiso · thiazole and l: 2-benzoisoxazole ethers, suitable for use as local anesthetics, antihistamines, as anti-inflammatory, analeptic and antispasmodic agents which act generally on the cardiovascular system and at the same time on the nervous system act "The invention also relates to a process for the production of such basic ethers"

The basic ethers prepared according to the invention are encompassed by the following general formula

909841/1749

in the

X an atom eir? Ej a " ^r . ^; Oxygen • -io-uv ^ / c: .-.-Rivnpe selected elements: .. r, ο,

Y is a substituent '3V: Jcr group of the alkyl radicals, halogens, -aryl and aralkvl-la ^ ikc-le, or hyoj o> .yl , aldehyde and carboxyl groups it>' .: ·. »

η is an integer equal to or greater than one and

R is a nitrogen group substituent selected from the group Monoalkylarnino-, DiaUQ-'lamino-, pirrolidixi-, piperidine-, Morpholine and quaternary ammonium groups "

The compounds represented by the general formula (1). can be prepared according to the invention by first adding the carbonyl compound (a> 01inon) : ai.z of the formula

k where Y and X have the meanings explained above, with phosphorus oxychloride (POCl -,) 'in the presence of pyridine at a temperature from 120 C to 140 react for at least two hours * The resulting / 5-chlorobenzoisothiazole (or as Alternative: ^ -Chlorobenzoisoxazol) is then at the boiling point for at least 15 minutes of a reaction with an alkaline Alkoxide (alcoholate) is subjected to the following formula as an alkylaminoalcohol

MO- (

Θ09841 / 17Α9 BATH

-5-- '1915544

in which the characters R and η have the meanings given above « ■ The thereby achieved product vrJrd collected and in a known manner converted into the corresponding hydrochloride, which is then recrystallized from a with the corresponding hydrochloride compatible solvent is cleaned *

It is also possible, starting from the hydrochloride, to prepare a series of salts of the basic ethers according to the Japanese, for example sulphates, titrates,. ^c , Jsc from orgjr iscbjn and sulphonic acids "Many of these salts are ranjerloci.ii more often therapeutically well-leveled by injection"

Follow! is fen -eir. ^ rn ho j game. - ' ¹ Ii-. ".i; ^r -, ·. ·» "·· '. ^ CiLv'. .v-.öiFchc '; ■ Ether according to ü.ev h: -f Xi-CW- ^ iv-tficv. ei-.v .- :. i, ^l . _w j ^

Example It

Preparation of Di-η 3uty3 aniipoätavl ÄV ::. Er -'Vr, g 1 t2-3enzoisothiazole

First of all, Ben: ⁷ .oisvithiar.oiyl- (chloride in the following manner is shown: 0.1 mol of bezoisothia ^ olinone, 0.1 mol of anhydrous pyridine and 0.15 mol of phosphorus oxychloride for a period of about 5 hours Heated between 0 ° C and 140 ° C. »After cooling, the mixture is poured onto iced water, on which an oily product is separated, which hardens immediately and consists of unpurified 3-chlorobenzoisothiazole» This product is purified by steam distillation, whereby the yield is ÖO % to 90 % *

u; the ether is now prepared in the following way: 0.02 mol of finely powdered sodium in ^ O ml of xylene 0.03 mol of 2-di-n-butylaminoethanol was added, whereupon the mixture is slowly warmed up, forming the corresponding sodium- ■ alkylamino-alkoxide »This compound now becomes one Reaction with the jS-chlorobenzoisothiazole shown above (0.02 mol) and placed in a water bath for JO to 40 Minutes warmed up »The oily product is now the raw one

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Di-n-Butylaminoäthyl-A'ther des 1 ^ -Benzoisothiazol * which is purified by repeated washing with water and then converted into the hydrochloric acid by means of gaseous hydrochloric acid, whereupon the hydrochloride is purified by recrystallization Hydrochlcrid is about $ 70, "the melting point of the hydrochloride · is 10ö ° to 109 ⁰ C ₀ the formula of the hydrochloride is obtained from the appended at the end of the description table 1 under the number" VIII "

Another way of representing the 1i2-benzoisothiazole and li2-benzoisoxazole ether according to the invention consists in the. Alkylation of the bidentate chelate complex of the benzothiazolinone or of the benzoisoxazolinone, whereupon the isomers are obtained by fractional crystallization or by chromatography, preferential

wisely using

, separates »

This reaction takes roughly the following course

C-O

) _n -ci

- 0 (CH ,.) -R

and the following Example 2 shows the practical implementation;

Example 2

0.04 mol of the sodium salt of benzoisothiazolinone, dissolved in 100 ml of dimethy lsulf oxide, and 0.04 mol of 2 ~ diethylaminoethyl chloride are heated for 3 hours in a boiling water bath »Now sodium chloride is separated off, and after expelling of the solvent, the residue is under vacuum

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BATH

distilled " whereby the isomeride mixture accumulates at 110 C to 130 ° C under an absolute pressure of 0.1 mm Hg (yield - Ö5 ^; ratio of nitrogen derivatives to oxygen derivatives = 2: 3) *

A portion of the fraction obtained by the process described above is converted into the hydrochloride in a solution in methanol & After the solvent has been eliminated, the residue is repeatedly crystallized from absolute ethanol and ether 3 (2-Diethylaminoethoxy) Benzoisothiazole is (Compound No., IV in Table I) ₀

A second portion of the distillate is 3 ~ to ^ times Volume of chloroform dissolved, the solution in passage through

a column made of aluminum oxide (Merck, standardized according to Brockmann) is rinsed with chloroform. The oxygen-containing derivative is present in the first fractions, from which it can be separated in a sufficiently pure state by evaporation of the solvent, the boiling point being 110 ° to 112 ° C (at a pressure of 0.15 mm Hg) «For C ₁ ^ H ₁ O, NgOS the following analysis resulted

formula

This alternative method is based on the bidentate chelate complex of benzoisothiazolinone (or Benzoisoxazolinone) which reacts with an alkylamino halide is subjected «This gives you on the one hand the metal halide and - on the other hand, a mixture of isomers, which are split up in a suitable manner, e.g. by factional Crystallization or by chromatographic processes *

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gef * = 62 , 36 ; H = 7, 30; 12th , 66 about » 62 7, 25th 12th _S 8o

BATH

In addition, there are cases in which the 1: 2-benzoisothiazolamine- Ether or the 1: 2 benzoisoxazole amine ethers according to the invention must undergo further chemical processing for representation of derivatives or, for example, to the transition from a monoalkylamine ether On the corresponding dialkylamine ether · Ks sirü, applications are also conceivable in which further processing steps are required, for example if the basic ethers according to the invention contain a quaternary ammonium radical » The following examples show additional reaction stages «

Example 3

If the 3 ~ (2-monomethylethoxy) -Benzoisothiazole according to the above Process has been prepared and now the corresponding dimethyl derivative is to be presented, namely the 3- (2-dimethylaminoethoxy) -benzoisothiazole, methylation takes place according to the following reaction scheme »

^ ^H 3 CO-CH ₀ -CH ₀ -NKCH ^ (Z ^ \ -CO-CH ₂ -CH ₂ -N ₁₁

H-CH0 + H-C00H

One leaves 1.3 g of 35 ^ strength formaldehyde and. 1.6 g of oil formic acid (formic acid) react under suitable conditions with 1.0 g of 3 ~ (2-methylaminoethoxy) -benzoisothiazole, which has previously been shown according to the method in Example 1 * The methylation reaction is carried out by boiling the three components over a period of 15 hours * The product obtained is converted into the corresponding hydrochloride, which ^{melts at 177 0} to I78 ⁰ C *

In Table 1 attached at the end of the description, the chemical and physical values or * constants listed, also the formulas for the hydrochloride of the initial monomethylamine derivatives (Compound No. * I, Table 1) as well as the

- / w

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ORIGINAL BATHROOM

Formulas of the corresponding dimethylamine derivatives (compound no. T, II, table 1), which are represented in the manner described below *

If it is necessary to use the general formula (1) as the radical R To introduce a quaternary ammonium group, first an amino ether according to the instructions described above shown, whereupon the quaternization with methyl iodide is carried out «The following example explains these additional procedural steps *

example H- Quaternization of ^ ~ (2 ~ dimethylaminoethoxy) -Benzolsothiazole

First, the j5- (2 ~ dimethylaminoethoxy) -3enzoisothiazole is shown according to the method described above (the compound II in Table 1 relates to the corresponding hydrochloride), of which .0.01 mol are dissolved in 20 ml of ethyl ether and ' this solution is completed by 0.03 mol of methyl iodide «. The mixture is allowed to react for 10 to 12 hours at room temperature, whereupon a solid substance separates out, namely trimethyl-benzoisothiazolylhydroxyethylammonium iodide. This raw product is recrystallized from methanol and has its melting point at about 192 ° C to 193 ° C * The yield is approx. 85 %, and the result is the compound XXII in Table 1, '

Table 1 shows a complete series of basic bezoisothiazole ethers with their physicochemical and analytical details, so that the various compounds with Determination can be recognized «Those with Roman numerals Compounds designated I to XXI are the hydrochlorides of the basic ones represented by the general formula (1) Ether »For the quaternary ammonium bases given, the constants relate to the iodides of these ammonium bases · Der Substituent Y in the general formula (1) has been appropriately modified; namely, it is a

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BATH ORIGINAL

Alkyl radical in compounds from XXII to XIX, while in in all other cases a hydrogen atom is present. If none Hydrogen is present., The position is indicated at which the substitution has taken place «In the preparation of the compounds I to XXI, the solvent for the crystallization was ethanol ether, while for the other compounds XXII to XXIV methanol was used «-. _

In contrast, Table 2 shows the physico-chemical properties of some basic esters of benzoisoxazole »In In all of the compounds listed in Table 2, the substituent Y is always "hydrogen, the value of the index η changing will »The compounds XXV to XXXI inclusive are hydrochlorides, while the remaining compounds XXXII to XXXIV ammonium iodides are * ·.

The ones used to crystallize the compounds according to Table 2 Solvents were formed by a mixture of absolute ethanol and ethyl ether for the compounds XXVIII and XXX, while for all other compounds - absolute ethanol was used «* _ ■■

The pharmacological tests already carried out with some of the compounds k prepared according to the invention were consistently successful and promising. Surface anesthesia was carried out on the cornea of rabbits according to the Chance and Lobstein method, and tests with the retraction reflex on the hind leg of decapitated frogs were carried out according to the method of Bulb * -ing and Wajda. The effectiveness of the various compounds according to Table 1 was compared It was possible to confirm that the compounds according to the invention, in particular lobsters I, IV, VII, IX and XXI (1 solution) have an anesthetic effectiveness which can be compared at any time with the effectiveness of lidocaine "" ·

9098 417 1 74 9 BATH

In the investigations with the corneas of rabbits, the compounds IV, IX, λVIII "and XXI proved to be special effective for external anesthesia, more effective than Lidocaine under the same experimental conditions, while im '/ ersuch with the sciatic nerve of frogs, the compounds IV, II and xIX showed an activity comparable to that of lidocaine

The compounds showed considerable antihistamine activity IX, II, XVI, III, I and VII with the corresponding concentrations of 0.005, 0.01, 0.05, 0.25> 0.5 or 1.0 mg / cnr in experiments with intestinal obstruction (isolated terminal xELus) of Guinea pigs according to the method of Bertaccini and Zamboni * The compounds IX, XXI and XXVIII, which with concentration were used in the range between 0.5 and 1.0 rag / cnr, showed an aspecific spasmoethic activity without antihistaminic activity Effect* . .

Very good anti-inflammatory properties were found for the Compounds IX, XXI, XXVIII and IV of Tables 1 and 2 at Try, in which the emergence of edema on the balls of the feet of rats according to the method of Van-Arman et al 'to prevent' was «

Intensive analeptic efficacy was found with conventional methods for examining breathing and arterial pressure, especially when testing on dogs for the compounds XXXII and XXlI * The critical amount for respiratory stimulation resulted at 5 mg / kg body weight for compound XXXII and at 30 mg / kg Body weight for compound XXII *

Taking into account the already tried and tested and still in careful and extensive investigations found the versatile effectiveness of the basic ethers produced according to the invention there is already a wide therapeutic application, area «■. . - -. -

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TABELI £

Y- n-

-3

II B 2 -K

Π Η 2

T H 2

TI I 2

Till B Z

IX H 2

B 2

η ΐ2

III K 2 -S

VII H 2 -B

CJLCn)

v W »

Melting point formula

ο.

174-173

177-178

'.65-171

165-187

1S3-1S9

'.68-109

1SS-1TO

108-109

172-173

2Cl-SO ANALYSIS

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13.70 -

10.8t -

f.ae'T _t sr u, je - β.

n, u n, m

«5.54 ßi?, S> 7.S4 7.82 10.34 10.47 β, 17- $, S5

* t, C2 £ 4.97 Ö.OS β, 04 £ 1, 4S 12.4 £ 9.63 - 11, £ 1

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909841/1749

BATH

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909841/174

BAD ORfGlNAI.

Claims (1)

In basic ethers <iu. '.> 1: 2 ~ benzoisothiazole and des Ii2-benzoisoxazole according to the general formula C-O ( (D in the X is an atom of an element from the oxygen-sulfur group is,
Y is a substituent from the group of alkyl radicals, halogens, aryl and aralkyl radicals, nitro groups or hydroxyl, Aldehyde and carboxyl groups, η is an integer equal to or greater than one and R is a nitrogen substituent group selected from the group the monoalkylamine, the dialkylamine, pirrolidine, piperidine, Morpholine and quaternary ammonium arrangements is selected » 2β Process for the preparation of the compounds according to claim 1 _p, characterized in that first a Corbonyl * compound (3-olinone) with the general formula with phosphorus oxychloride in the presence of pyridine at a Temperature from 120 ° to 140 ° C for at least two hours j Reaction can be brought about, whereupon the resultant 9098 4 1/1749 191S 6 A 4 at 3-chlorobenzoisothiazole (hzw * jJ-chlorobenzoisoxazole) at boiling temperature can react with an alkali metal and an alkylamine alcohol of the formula M - .0 - (CHp) - R and then that. resulting product collects and enters the corresponding hydrochloride transferred, which is purified by recrystallization from a compatible solvent. 2 «Process for the preparation of basic ethers of Ij2-Benzoisothiazole and des_l: 2-benzoisooxazole with the general formula (D • x
characterized in that the bidentate chelate complex of olinone is formed with an atom of a metal corresponding to the Äthej? Crystallization or is broken down by chromatography * 4 «Process for the preparation of alkyl derivatives of the basic ethers according to claim 1, characterized in that free ether according to its representation by formaldehyde and porminic acid alky-P is lated to introduce an additional alkyl radical that is bound to the substituent (R) according to claim 1 * 5 * Process for the production of quaternary ammonium derivatives of the basic ethers according to Claims 1 to 4, characterized in that that an alkylamine ether reacts with methyl iodide is brought » 909841/1749 BATHROOM OFlIGINAL,