DE1470413C - Quaternary ammonium compounds and their preparation - Google Patents

Description

The invention relates to quaternary ammonium compounds of the general formula I and their preparation. It has been found that the compounds of general formula I

CHt CH-

CH ₂ - (CH ₂ ) /

A.

CH = CH

\ ch ₂ ); - ch ₂

in which η denotes the number 1 or 2, R ¹ either a methyl, ethyl, n-propyl or n-butyl group and X an equivalent of an anion, against Syphacia obvelata and Aspiculuris tetraptera in mice, Ancylostoma caninum, Toxocara canis and T. cati in mice and cats, Uncinaria stenocephala, Toxacaris leonina and Trichuris vulpis in dogs, and Trichuris trichiura, Oesophagostomun apiostomum and Physaloptera spp. are effective in monkeys and have particularly low oral toxicities in mice. -

The effectiveness of these compounds lies in the cation, while the equivalent anion, which is associated with the cation, is relatively unimportant for this. However, it is said to be pharmacological and pharmaceutically acceptable, i.e. e.g. a bromide, chloride, p-toluenesulfonate, methylsulfate or Be ethyl sulfate ion.

The table below shows the efficacies and toxicities as well as the respective therapeutic index of compounds of the general formula I and of the known, vermicidally active compounds pyrvinium pamoate and pyrvinium iodide. Pyrvinium is an abbreviation for the 6-dimethylamino-2- [2- (2,5-dimethyl-1-phenyl-3-pyrrolyl) -vinyl] -l-methylquinolinium ion. The compounds were administered orally to mice and the individual doses were measured in milligrams of cation per kilogram of body weight of the mice. The efficacy against Syphacia obvelata was measured by the percentage of worms removed. The toxicities were determined as LD ₅₀ = mg cation / kg body weight and the respective therapeutic index as LD ₅₀ / dose for 1007 ₀ ige (or with the ^{values marked with +} for 99% ige) effectiveness. It is clear from the table that the compounds of the invention have lower LD ₅₀ values and higher therapeutic indices than known pyrvinium compounds and are therefore superior to them.

Efficacy, Toxicity and Therapeutic Index of Compounds According to the Invention and of pyrvinium pamoate and iodide

60

connection
of the general formula I. η χ effectiveness . % 99 LD ₃₀ Thera.
more peutic R ¹ Γ 'J dose 100 index CH ₃ 20th 85 to > 1000 > 50 1 J 20th 100 QH ₅ 20th 100 1350 136 10 95 1 Cl 7.5 100 C ₂ H ₅ 10 100 600 120 5 90 2.5

connection
of the general formula I. π X Effectiveness % LD ₅₀ Ther · - '
"mixer '»» 1 J Dom 100 .Index ' nC, H ₇ 20th LQQ 1500 100 2 - r 15th 100 CH ₃ 20th 98 > 1000 > 50 -2 j 10 100 C ₂ H ₅ 20th 100 800 80 10 85 2 j 5 100 n-QH, 20th 98 450 22.5 2 j 10 99 n-QHg 20th 85 300 15 ⁺ Pyrvinium pamoate 10 100 10 99 14th 1.4 3 86 Pyrvinium iodide 2 99 20th 96 18th I ⁺ 10 65 5

The compounds of the Distilbazolkations corresponding to the general formula I are in itself known manner so prepared that a correspondingly substituted p-aminobenzaldehyde with a quaternary Salt of 2,6-lutidine of the general formula II

(H)

in which R ¹ and X have the abovementioned meaning, condensed and, if appropriate, the compound thus obtained is likewise converted in a manner known per se into the salt of another pharmaceutically or pharmacologically acceptable anion. The reaction is usually carried out in a solvent such as a lower alcohol in the presence of a catalyst such as a secondary amine, e.g. B. piperidine performed.

The equivalent anion of the quaternary salt of the general formula II should preferably be Anion of the same type or the same anion as that associated with the distilbazole cation in the General formula I to combine is desired because the compounds of the Distilbazolkations in the Most solutions are very sparingly soluble, and the compounds are converted twice to form salts of another anion is accordingly unsatisfactory.

To get the desired anion in the quaternary To obtain salt of the general formula II, the salt is quaternized by 2,6-lutidine with a Compound of the general formula III

R ¹ X ■. (III>

in which R ¹ has the abovementioned meaning and X represents one equivalent of the desired anion, or by transfer by means of double decomposition of the salt as prepared in the salt with the common _w desired anion. If z. B. R ^{1 is} an ethyl radical and X is an iodide or methyl sulfate ion, ethyl iodide or ethyl methyl sulfate is used for the quaternization of 2,6-lutidine; if z. B. "the iodide of the quaternary salt is present and the chloride is desired, the double reaction can be effected by heating the iodide with methanolic hydrogen chloride.

The chemistry of the preparation of the quaternary salt of the general formula II and of the compounds of the distilbazole cation corresponding to the general formula pretty much limits the nature of the group R ¹ in the compounds of the distilbazole cation. The usual decrease in the reactivity of alkyl halides with increasing size of the alkyl group is exacerbated by the steric hindrance of the two methyl groups in 2,6-lutidine. For this reason, R ^{1 is} not a branched alkyl group, but a low molecular weight alkyl group with no more than 4 carbon atoms.

The compounds of general formula I with pharmaceutically or pharmacologically acceptable Anions can be used as vermicidal agents.

The compounds of the distilbazol cation according to. general formula I are deeply colored Crystals whose surface color ranges from dark red to almost black and whose Solutions, when concentrated enough, range from pink to red. The connections however, are so insoluble in water that the water is not visibly colored. The color goes on intense but broad absorption band back; the maximum is around 495 πΐμ (Cm = 55,000 to 60,000), but the intense absorption (Cm = 40,000 or above) appears from about 460 to 530 ηΐμ.

The compounds of the general formula I according Distilbazolkations melt well above 200 ⁰ C. It probably melt, with decomposition, depending on the rate of heating in some way. Furthermore, the dark color of the compounds makes the precise determination of the melting points extremely difficult. Therefore, the details of the melting points in the following examples are only to be regarded as approximate. They are of little value for identification and of no value for the purity criterion.

The following examples illustrate the invention. All temperatures are given in degrees Celsius.

example 1

60

A mixture of 2,6-lutidine (107 g) and ethyl iodide (312 g) was placed on a steam bath Treated reflux for 24 hours. The precipitate formed was filtered off and the filtrate was further Treated under reflux for 24 hours; this procedure was repeated. After recrystallizing twice ethanol became pure N-ethyl-2,6-lutidinium iodide receive; the melting point is 212 to 214 °. : v

A mixture of 1,4-dibromobutane (216 g), methanol (500 ml) and aniline (465 g) were refluxed on a steam bath at 100 ° for 5 hours. The methanol was evaporated and a 40 to 50% aqueous sodium hydroxide solution (120 g hydroxide) added to residue. The organic layer was taken up with ether and washed over dried anhydrous potassium carbonate. The ether and potassium carbonate were removed and the excess aniline is distilled off in vacuo. This gave N-phenylpyrrolidine with a boiling point from 133 to 134 ° / 19 mm Hg.

To dimethylformamide (32 ml) cooled in an ice bath was added phosphorus oxychloride (9 ml; equivalent 16 g) over 10 minutes with stirring, and N-phenylpyrrolidine (15 g) was added dropwise over 15 to 30 minutes. The mixture was heated to 100 ° for 2 to 2 ¹ I ₂ hours, cooled and poured into ice (100 g). * - The aqueous solution was brought to a pH of 11 by adding a 40 to 50% strength aqueous sodium hydroxide solution (about 25 g of hydroxide). After ^{standing for 1} J ₂ to 1 hour, the p-pyrrolidine benzaldehyde was extracted with ether. The ether extract was dried over potassium carbonate, the carbonate removed and the dried ether solution concentrated; the aldehyde crystallized out on cooling. It was purified by recrystallization from ether, in which it is only sparingly soluble, from hexane, in which it is very slightly soluble, or from a mixture of both. It had a melting point of 85 to 86 ^° C. "· ■

A mixture of N-ethyl-2,6-lutidinium iodide (2 _f 6 g), methanol (100 ml), p-pyrrolidine benzaldehyde (4.2 g) and piperidine (1 ml) was refluxed on a steam bath. In less than an hour, solid 2,6-bis- (p-pyrrolidinostyryl) -l-ethylpyridinium iodide precipitated, and vigorous pounding began. After 2 hours the solids were collected and the filtrates were refluxed for a further 20 hours. A second serving was thus obtained and, after the filtrate had stood for another day, a third serving. The compound had a melting point of 282 to 283 °.

It was found to be almost insoluble in hot methanol and was washed several times with ether cleaned and then once or twice with ten or twenty times the amount by weight of hot methanol digested. Because recrystallization is difficult, largely all insoluble impurities, like dust and boiling stones, from the easy-to-clean reactants in the final condensation stage removed and then kept away as far as possible.

When carried out on a larger scale, the impact will occur in the final condensation stage significant problem. In either case, a powerful stirrer should be used or the reaction mixture at a temperature of 60 to 65 °, d. H. below the boiling point of methanol.

Example 2

N-ethyl-2,6-lutidinium iodide (10 g) was dissolved in methanol (200 ml) and bubbled hydrogen chloride until 20 g was absorbed. The solution was then heated on a steam bath, the

Most of the solvent was gradually distilled off; then methanolic hydrogen chloride became (100 ml; 10%) are added and the process is repeated. The flask was on a steam bath evacuated; the residue of N-ethyl-2,6-lutidinium chloride was suitable for synthetic purposes. N-ethyl-2,6-lutidinium chloride and p-pyrrolidine benzaldehyde were condensed in a manner similar to that described in Example 1. That so 2,6-bis (p-pyrrolidinostyryl-1-ethylpyridinium chloride) obtained decomposed above 270 °.

Example 3

The following compounds were prepared in a manner similar to that described in Examples 1 and 2, manufactured: .

a) 2,6-bis (p-pyrrolidinostyryl) -l -methylpyridinium iodide, which melts with decomposition at 295 to 297 ° ';

b) 2,6-bis (pyrrolidinostyryl) -l-n-propylpyridmium- ' iodide, which melts at 265 to 267 ° with decomposition, and

c) 2,6 - bis - (p- pyrrolidinostyryl) -1 - η - propylpyridinium p-toluenesulfate, which decomposes at 260 °.

* B e i s ρ i e 1 4

In a manner similar to that described in Example 1, N-phenylpiperidine was converted into p-piperidinebenzaldehyde, Melting point 63 to 64 °, converted and used to produce the following compounds:

a) 2,6-bis- (p-piperidinostyryl) -l -methylpyridinium iodide, which melts with decomposition at 222 to 225 °; .

b) 2,6 - bis - (p - piperidinostyryl) -1 - ethylpyridinium iodide, that with decomposition at 242 to 244 °

melts;

c) 2,6 - bis (p- piperidinostyryl) -1 - η - propylpyridinium iodide, which melts with decomposition at 228 to 229 °, and

d) 2,6-bis (p-piperidinostyryl) -1 -n-butylpyridinium iodide, which melts with decomposition at 245 to 247 °.

20th

Claims (2)

Patent claims: 1. Quaternary ammonium compounds of the general formula I CH, / V-CH = CH- r mts \ / in which η denotes the number 1 or 2, R ¹ denotes either a methyl, ethyl, n-propyl or n-butyl group and X denotes an equivalent of an anion. 2. Process for the preparation of compounds of the general formula, characterized in that in which R ¹ and X have the abovementioned meaning, condensed and, if appropriate, the compound thus obtained is also known per se CH ₂ CH (CH ₂ ), - CH ₂ net that one can use a correspondingly substituted p-aminobenzaldehyde in a manner known per se with a quaternary salt of the general formula ter way converted into the salt of another pharmaceutically or pharmacologically acceptable anion.