DE1667893A1 - New anthelmintics - Google Patents

Description

Ntua complete registration documents

P 16 67 893.6
Case 565/579

IiAY AND BAKER LIMITED, Dagenham, Essex, England

New anthelmintics

The present invention relates to new means of controlling are determined by helminthes.

These new compositions contain as an effective product at least one quaternary ammonium compound of the formula

. r (D

In this formula, the symbols have the following meanings:

a) R represents a phenyl radical or a mononuclear heterocyclic radical A radical with 5 or 6 chain links which contains one or two oxygen, nitrogen or sulfur atoms in the ring and to group A through one of its carbon atoms is bound, (e.g. a 2-puryl, 2-thienyl, 3-thienyl, 2-pyridyl or 4-thiazolyl radical). These radicals can by one or two substituents from the group of halogen atoms

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and the alkyl, alkoxy, hydroxy, nitro, dialkylamino and Acylamino radicals (e.g. acetamido) may be substituted;

A means the grouping - CH = CH -;

Z, together with the nitrogen atom to which it is attached, denotes a mononuclear heterocyclic group with 5 or 6 chain links or a bicyclic heterocyclic group, which groups contain a quaternized tertiary nitrogen and wherein these heterocyclic groups also include or can contain two additional heteroatoms from the group of oxygen, nitrogen and sulfur atoms and v / obei these Groups optionally one or two substituents from the group of alkyl, phenyl, 4-thiazolyl, 2-furyl, 2-thienyl, Formyl-, hydroxyiminomethyl- (also called oxirainomethyl-), May have acyl, amino and acetamido radicals.

As examples, one can use the following quaternized heterocyclic Name groups:

Pyridinium, 2-l.Ie thy! Pyridinium, 2-ethylpyridinium, 4-ethyl-3-methylpyridinium, 2- (3- or 4-) Hydroxyiminoniethyl-pyridinium (also called Oximinomethyl-pyridinium), 4-Arainopyridinium, 4-acetamidopyridinium;

1,2-Mhydro-1-methylpyridinium, 1-methyl-1,4,5,6-th trahydropyridinium, Thiazolium, 2-methylthiazolium, 2-ethylthiazolium, 2-isopropylthiazolium, 4-methylthiazolium, 5-methylthiazolium;

Isoquinolinium;

1-He thylimidazolium;

1-methylpyrazolium;

Pyridazinium;

N-Me thy lpiperidinium;

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1-alkyl-2-phenyl-benzimidazolium, such as 1-methyl-2-phenyl-benzimidazolium, 1-alkyl-2- (4-thiazolyl) - and 1-alkyl-2- (2-furyl) - or 1-alkyl-2- (2-thienyl) benzimidazolium;

1-methyl-1,4, 5, 6-tetrahydropyrimidinium.

b) R denotes a mononuclear heterocyclic radical with 5 or 6 chain links, which has one or two heteroatoms from the group of oxygen, nitrogen and sulfur atoms and attached to group A through one of its carbon atoms is (e.g. 2-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 4-thiazolyl), where this radical is optionally on one or two carbon atoms by one or two substituents from the group of Halogen atoms and the alkyl, alkoxy, hydroxy, ITitro, dialkylamino and acylaraino radicals (e.g. acetamido) may be substituted;

A represents the group - CH ₂ - CH ₂ -;

Z, together with the nitrogen atom to which it is bonded, has the same meaning as under a).

c) R has the meanings as under a); A represents the group - CH ₉ CO -;

C.

Z together with the nitrogen atom to which it is attached means a pyridinium, 3- (or 4-) aminopyridinium, 3- (or 4-) acetamido-pyridinium-, 2- (3- or 4-) hydroxyiminomethyl-pyridinium-, 1-alkyl-1,2-dihydropyridinium (such as for example 1-methyl-1,2-dihydropyridinium-), 1-alkyltetrahydropyridinium- (such as for example 1-Hethyltetrahydropyridinium), Pyridazinium, 1- (or 2-) alkylpyrazolium (e.g. 1-methylpyrazolium), i-alkyl-2-phenylbenzimidazolium (e.g. i-methyl-2-phenylbenzimidazolium-) or 1-alkyl-2- (4-thiazolyl) -, 1-alkyl-2- (2-furyl) or 1-alkyl-2- (2-thienyl) benzimidazolium radical.

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d) R has the same meaning as under b); A represents the group - CHpCO -;

Z with the nitrogen atom to which it is attached represents a pyrazinium radical or a 2-alkylpyrazinium radical (e.g. 2-methylpyrazinium).

e) R has the same meaning as under a); . A represents the group - CH ₂ CO -;

Z means with the nitrogen atom to which it is attached, a pyridine group;

In all of these cases, X denotes a pharmaceutically acceptable anion.

The term "pharmaceutically acceptable anion" means a Anion that is used in the dosages used for the treatment of infections by helminth with the agents according to the invention is not toxic.

The "pharmaceutically acceptable anions" can be the halogen ions (bromide, chloride, iodide), the anions of the formula Q - SO ₂ O "or QSOO" (in which Q is an alkoxy, alkyl, hydroxyalkyl or mononuclear aryl radical), such as methyl sulfate, ethyl sulfate, methanesulfonate, ethanesulfonate, ß-hydroxyethanesulfonate (also called isethionate), benzenesulfonate, p-toluenesulfonate and p-chlorobenzene sulfinates, the embonate ions (anions of the 2,2'- Dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylic acid), the 2-hydroxy-3-naphthoate ions, the amsonate ions (anions of 4,4'-diaminostilbene-2,2'-disulfonic acid) as well as the anions, which themselves have anthelmintic activity (e.g. those derived from 4-cyano-2-iodo-6-nitrophenol and 3,3 ', 5,5', 6,6'-hexachloro-2,2'-dihydroxydiphenylmethane) , to name.

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Contain the alkyl, hydroxyalkyl and alkoxy radicals mentioned here at most 6 carbon atoms, and the acyl groups are, unless otherwise specified, those acyl groups derived from aliphatic carboxylic acids having at most 6 carbon atoms come.

The compound for which A is the group - CH = CH -, R is a thienyl radical, X "is a bromine ion and Z is with the nitrogen atom to which it is attached is a pyridinium residue means, i.e. 1 - </ 2 * - (2-thienyl) -vinyl7-pyridinium bromide, can be isolated in two isomeric forms. These are called Form A and Form B.

The compositions which contain at least one product of the formula I, as defined below, are preferred:

a) The group (+) means a pyridinium, pyridazi-

nium, 1-methylimidazolium or 1-methylpyrazolium radical; A represents the group -CH ₂ - CHg-; R represents a 2-thienyl group;

and in particular 1- / 2 * - (2-thienyl) ethyl7 ~ pyridinium bromide fX 'which is also called N- (2,2'-thenethyl) pyridinium bromide

and 1- / 2- (2-thienyl) ethyl7-pyridazinium bromide; A represents the group - CH = CH -; R denotes a phenyl or 2-thienyl radical;

and in particular the 1-styrylpyridinium salts or 1- / 5- (2-thienyl) vinyl7-pyridinium salts, such as the chlorides, bromides, p-chlorobenzenesulfinates, p-chlorobenzenesulfonates and smbonates; and the 1,2-dihydro-1-methyl-1-styryl

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pyridinium salts, especially amsonate, and the 2-methyl-3-styrylthiazolium salts, especially the broraid.

b) The group (+) represents a pyridinium, 2- or 4-

Hydroximinomethyl pyridinium, pyridazinium or 1-methylpyrazoliniurarest dar;

A means the group -CHpCO -;

R represents a phenyl, 2-furyl or 2-thienyl radical;

especially the salts, especially the bromides, of 1-phenacyl-pyridinium, 1- (2-furoylmethyl) -pyridinium (which can also be called IT- (2-puracyl) pyridinium '); 1- (2-Thenoylmethyl) -pyridinium, which can also be called N- (2-thenacyl) -pyridinium_7i 1-Phenacylpyridazinium, 1- (2-Thenoylmethyl) -pyridazinium / which also N- (2-5) henacyl ) -p'yridazinium can be called_7> 2- (or 4-) Hydroxyiminomethyl-i-phenacyl-pyridinium / Kas can also be called 2- (or 4-) oximinomethyl-F-phenacyl-pyridinium /; 2-Hydroxyiminomethyl-1 - (2-thenoylmethyl) -pyridiniura ^ 3as also called 2-0ximinomethyl-N- (2-thenacyl) -pyridinium can be grounded_7

The products of formula I can be used to treat infections caused by helminths, such as infections of the gastrointestinal tract used by llematodes or cestodes parasites. In particular, the above can be preferred for this purpose specified products are used.

For the treatment of infections caused by nematodes and in particular those belonging to the order Strongyloides and Ascaroides are preferred those products in whose formula the symbols have the following meanings:

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The group (+) is a pyridinium or 2-I.Iethylthiazo-

lium radical, while A is a group - CH ₂ - CH ₂ -, - CH = CH -

or represents -CH ₂ CO -; or a 1-methylpyrazolium radical, while A represents a group - CH = CH - or - CH ₂ CO -; or a 1,2-dihydro-i-methylpyridinium radical, while A represents the group - CH = CH -.

For the treatment of infections caused by Cestodes, those products are preferred in whose formula the symbols have the following meanings have: ™

The group ( ⁺ y ^ - ^s ^ ^e ^ - ⁿ 2- or 4-Hydroxyiminomethyl-pyridiniumrest, and A represents the group - OH ₂ CO -.

The amounts of active substance of the formula I to be administered will of course vary depending on the particular product considered for the particular case and in particular depending on the severity of the infection, the intended duration of treatment and the type of administration considered. Generally, doses of active cation 10-500 mg per kilogram of body weight for administration by the oral route satisfac- lend Λ. Most frequently, the treatment, especially with the preferred products, is carried out by administering 25-250 mg v / active cation per kg of body weight.

Of course, the doses indicated may vary depending on the circumstances in the form of a single dose or several doses, which may extend over a certain period of time, administered v / ground.

Of course, it is not possible to list all the helminths that can be fought with the products of formula I.

The following can be mentioned as examples: Roundworms, such as Syphacia olvelata, Aspiculuris tetraptera,

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Nematospiroides dubius, Hippostrongylus brasiliensis, Toxocara canis, Toxascaris leonina, Ancylostoina canium, Hoemonchus contortus, Ostertagia ostertagi, Gooperia punctata, or flatworms such as Hymenolepis nana.

The products of the formula I are normally used for normal use used in the form of compositions of which they at least partially form the effective part.

Me compositions according to the invention contain as effective Product of at least one of the quaternary ammonium derivatives of the formula I with the desired amount of a pharmaceutical usable excipients or coating.

The compositions include in particular the compositions which are intended for oral administration, such as lozenges, tablets, cachets, pills, capsules, BoIi, pastes, jelly or any liquid composition.

The solid form compositions include the troches, tablets, pills, pellets and granules, optionally with are coated with a pharmaceutically acceptable coating stable to acids or alkalis (for example with Enteral coatings), as well as the dispersible powders.

In such compositions, the active product or products are, with one or more inert diluents, such as starch, alginic acid, sugar, lactose or resins, mixed.

According to normal practice, these compositions can also contain products other than the inert diluents, such as, for example Contain lubricants, e.g. magnesium stearate.

Among the semi-solid compositions for oral administration include the pastes and jellies or jellies that contain the active product (s) together with an inert diluent

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medium, such as polyethylene glycol (6000) contain. The liquid compositions for administration Orally can be presented in the usual forms of emulsions, solutions, suspensions, syrups and elixirs, which contain the commonly used diluents, such as, for example, water or paraffin oil. Besides these Diluents, the compositions can also contain compatible adjuvants, such as, for example, wetting agents and suspending agents and emulsifiers, stabilizers, thickeners, sweeteners or flavoring agents and antioxidants, such as ascorbic acid.

The compositions for oral sweeping administration comprise also capsules made from absorbable products, such as gelatin capsules, which contain one or more effective Products together with or without diluents or excipients contain.

To compositions for administration by the parenteral route include aqueous, aqueous-organic or organic sterile solutions, suspensions and emulsions.

Examples of organic solvents or organic suspending media can be propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable esters, such as ethyl oleate.

The compositions can also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifiers, Contains dispersants and antioxidants.

They can be found, for example, by filtering them through a bacteria restrained filter, by introducing sterilizing Products into the composition or by heating sterilize.

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They can also be in the form of sterile solid compositions which are dissolved at the time of use.

The content of the quaternary ammonium derivative of the formula I can of course vary. It is sufficient that the quantitative proportion is a such is that one can achieve the desired effect.

In general, compositions containing 5-90% by weight of active product is satisfactory.

The products of the formula I in the feed or the fluids made by the animals-ordinary be absorbed, or also bring into compositions in which the active product in each physiologically an inert and orally administrable diluent or carrier is dispersed or admixed.

Under "physiologically inert" diluent or carrier one understands the products that do not react noticeably with the active substance and no harmful effect when administered on animals.

These compositions can be presented in the form of powders, granules, solutions, suspensions and emulsions contain the desired dose of the products of the formula I and administered to the animals or used as concentrates or additives be put in an additional diluent, the feed, the drinking water, or any other, normally introduces fluid taken up by the animal.

As an inert diluent of this type, one can use the flours or coarse grains, corn gluten, lactose, glucose, sugar, talc, kaolin, Calcium phosphate, potassium sulfate and diatomaceous earths, such as kieselguhr, name.

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The concentrates or additives that are to be incorporated into the Drinking water or other water normally consumed by animals Liquids to form solutions, dispersions, emulsions and suspensions that are stable, can be provided In addition to the active substance, surface-active agents and dispersants and emulsifiers such as higher secondary ones Alkyl sulfonates (trade name Teepol), polyoxyethylene (20) sorbitan monooleate and condensation products of β-haphthalenesulfonic acid with formaldehyde. You can also use one or more carriers or one or more diluents, which are preferably soluble in water, such as sugar and glucose, and inorganic salts such as Potassium sulphate. These concentrates or additives can also be in the form of dispersions or solutions by mixing the above concentrates with water or other harmless inert diluents or carriers or mixtures thereof.

The compositions described above can be prepared, by mixing the quaternary ammonium derivative (s) with the carrier (s) or diluents in the usual manner mixes.

The solid compositions can conveniently be prepared by intimately uniformizing the quaternary ammonium derivative mixed with feed or other solid products or distributed in them, e.g. by rubbing, stirring, grinding or mixing, or by adding the quaternary aramonium derivative this solution dissolves in a solvent such as, for example, water or a suitable organic solvent distributed in the solid products and then the solvent removed, working according to the usual procedures.

The foods containing the active product can also be prepared by adding them to these concentrates, which have a higher proportion of effective product

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contained in order to finally obtain mixtures in which the quaternary ammonium derivative in the desired concentration is uniformly distributed.

The feed materials that contain the quaternary ammonium derivative in an amount of 0.001-3 wt .- ^ correspond to a normal one Dose of active product.

The concentrates and additives normally contain between 5 and 90 wt .- ^, preferably between 5 and 50 wt .- ^, of quaternary ammonium derivative. You can do them if you want dilute appropriately to obtain a desired dosage.

The feed, drinking water or other liquids normally ingested by the animals, as well as all compositions, the at least one of the said quaternary ammonium salts, dispersed in or mixed with any diluent, as mentioned above, including concentrates and additives, belong to the range of Invention.

The compositions according to the invention can also Contain bacteriostatic, bactericidal, sporicidal agents and approved dyes.

The compositions can also be others if desired therapeutic agents, such as the following, contain:

4-cyano-2-iodo-6-nitrophenol,
2- (4-thiazolyl) benzimidazole,

5- (or 6-) butylbenzimidazole-2-carbamic acid methyl ester,

6-phenyl-2,3,5,6-te trahydro-iraidazo / 5-1, b_7thiazole, trans-1,4,5,6-tetrahydro-1-methyl-2- (2-thien-2'-ylvinyl) pyrimidine,

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Phenthiazine,
Cyanoacethydrazide,
Hexachloroethane,

Piperazine and its salts, such as piperazine adipate and 1-methylcarbamoyl-4-methylpiperazine adipate,

Carbon tetrachloride,

3,3 ', 5,5' »6,6 · -hexachloro-2,2'-dihydroxydiphenylraethane, Tetrachlorethylene,

4,4 »- ^ chloro-2,2'-di-hydroxydiphenylmethane, N- (2-chloro ~ 4-nitrophenyl) -5-chlorosalicylamide, N, N-dibutyl-4-hexyloxy-naphtamidine, trans-1,4-bis (2-isothiocyanato-ethyl) -cyclohexane, 2,2'-dihydroxy-3,3 ', 5,5', 6-pentachlorobenzanilide, 2,2 · -dihydroxy-3,3'-dinitro-5,5'-dichlorodiphenyl, 2-acetoxy-4'-chloro-3,5-diiodobenzanilide.

The following examples explain the compositions according to the invention:

BeisOJel 1

10 g of 2-methyl-3-styrylthiazolium bromide are dissolved in 100 ml Water.

The solution thus obtained can be used for oral administration,

Example 2
Lozenges

- {p.- (2-thienyl) -vinyl7-pyridinium bromide-

raonohydrate (Form A) 250 mg

Lactose 200 mg

Strength 50 mg

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-H-

Polyoxyethylene sorbitan monolaurate ................. 0.5 mg

Magnesium xearate 5 rag

for a lozenge.

Mix the pyridinium compound and the lactose with one Part of the starch and granulated with a 5 ^ strength starch paste, which contains the polyoxyethylene sorbitan monolaurate.

The mixture is sieved through a sieve 20 (British sieve size), dried and the rest of the starch and the magnesia stearate are set to. It is sieved again through a sieve of the same size and compressed.

Example 3

Injectable or potable solution

Dissolve 2 g of 1-phenacyl-pyridazinium bromide in 100 ml of water, the 1 ral higher secondary alkyl sulfonate (trade name Teepol) contains.

Sterilize through a bacteria-retaining filter.

ψ A solution is obtained which is suitable for administration by both the parenteral route and the oral route.

Example 4

Injectable or drinkable solution

One solves:

i-Styryl-pyridinium - ^ - cyano ^ -jod-ö-nitro-

phenolate 1.63 g

1-styryl pyridinium bromide monohydrate 2.69 g

in

Dimethyl sulfoxide 10 ml

One sterilizes over a bacteria-retaining filter,

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A solution is obtained which is suitable for parenteral administration üege or oral route is usable.

Example 5
Drinkable suspension

Mix 10 g of 1-styryl-pyridinium embonate dihydrate, the previously had been sieved through a sieve 60 (British sieve size) with 100 ml of water and 1 ml of polyoxyethylene sorbitan monooleate (Trade name Tween 80),

A drinkable suspension is obtained.

Example 6

Mix at 50 ⁰ O:

1-styryl pyridinium bromide nonohydrate 1 g

Water 5 ml

Polyethylene glycol 6000 10 g

It is cooled to 25 ° C. A gel is obtained which can be used for administration by the oral route.

Example 7
solution
One solves:

1-styryl pyridinium bromide monohydrate 10 g

- Y / ater 100 ml

Propylene glycol 7.5 ml

Filter through a bacteria-retaining filter.

The solution obtained can be used for oral or parenteral administration «

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Example 8
Capsules

Sieve through a sieve 40 (British sieve size) 1-styrylpyridinium bromide monohydrate *

It is distributed in gelatin capsules in an amount of 1 g per capsule.

Example 9
solution

One solves:

1-styryl pyridinium bromide monohydrate 2 g

Ascorbic acid 0.1 g

in

Water 20. ml

It is sterilized by filtering through a bacteria retardant Filter to obtain a solution that can be used for oral or parenteral administration.

Example 10
solution

One solves:

3,3 ', 5,5', 6,6'-hexachloro-2,2 ♦ -dihydrodiphenyl-

methane 7 _f 5 g

1-styryl pyridinium bromide monohydrate 38.5 g

in

I ¹ T-Me thylacetamide 60 ml

and adds:

IT-Me thylac et amid Q. s. 100 ml

A solution which can be administered orally is obtained.

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Example 11
Tjö sung
One solves:

1-styryl pyridinium chloride monohydrate 10g

in

V / ater 100 ml

A solution which can be used orally is obtained.

Example 12
solution
One solves:

1- / 5- (2-thienyl) vinyl7-pyridinium chloride-

monohydrate 10 g

in

Water 100 ml

A solution which can be used by the oral route is obtained. The products of formula I can be manufactured:

1) The products for which A represents a group - CH ₂ , by reacting a compound of the formula

R - CH ₉ CH ₉ X ₁ (II)

C. C.

in .der R has the meaning given above and X ₁ denotes a halogen atom (bromine, iodine, chlorine) or a methyl sulfate, ethyl sulfate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate or p-chlorobenzenesulfonate radical with a compound of the formula

C)

(in)

which the heterocycle eats, which the cation

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it was defined above, corresponds to, and

benenfalla subsequent transfer of X * "" into the received Product in another anion X "*, as it is defined above, according to known methods and in particular those mentioned below.

Me reaction can take place at a temperature between 0 and 20O ⁰ C, preferably between 20 and 100 ⁰ C, optionally in the presence of an inert solvent such as an ether (e.g. diethyl ether), an alcohol (e.g. ethanol) or a liitrile (e.g. acetonitrile) , or in the presence of an excess of the heterocycle of the formula III.

2) The products of the formula I for which A is the remainder

- CH = CH means, from compounds of the formula

- CH ₀ - CH - R 'X "" (IV)

in which Z, R and X ″ ″ have the meanings given above and Y is hydroxy, acyloxy, derived from carboxylic acid (e.g. benzoic acid), lower aliphatic acid (e.g. acetic acid), or represents a Halogenaton, produced by removing the I.Ioleküls HY.

If Y represents a hydroxy radical, the removal of HY, i.e. of water, can be carried out according to the known methods are, for example, by the action of an acyl halide such as benzoyl chloride or benzoyl bromide, by the action of a

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Acid or a mixture of acids, such as oxalic acid or a mixture of acetic acid and sulfuric acid, by action a salt such as anhydrous zinc bromide or a mixture of anhydrous zinc bromide / acetic acid, or by Exposure to an anhydride such as acetic anhydride in the presence of acetic acid.

The dewatering is at an appropriate! Temperature between 20 and 200 ⁰ C, if appropriate in the presence of, preferably jedoc in the absence of a suitable solvent is performed.

If Y is an acyloxy radical, the removal of HY, i.e. a molecule of the acid, can be carried out:

a) By heating under reduced pressure with increased tempering + ur, for example at 100 ⁰ C, if Y represents an acetoxy radical,

b) by heating in the presence of reagents and at temperatures, as previously for the removal of water from the compounds of the formula IV, for which Y represents a hydroxy radical, were described.

When Y represents a halogen atom, removal of HY, i.e., one molecule of hydrohalic acid, is accomplished by a dehydrohalogenation reaction under the action of an alkali base, for example alcoholic potassium hydroxide solution at ordinary temperature, performed.

The starting materials or intermediates used in these reactions can be made as follows:

I) The starting products of the formula IV, for which Y represents a hydroxy radical, can be prepared:

a) By reacting an aldehyde of the formula RCHO, in which R has the meaning given above, with a quaternary one Ammonium derivative of the general formula

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χ "(ν)

in which X "~ and Z have the meanings given above,

b) by reacting an aldehyde of the formula ROHO in which

R has the meaning given above, with a quaternary φ ammonium derivative of the general formula I, for which A is the Represents group OHpCO and which is produced as described later,

c) if the anion X ~ is a chloride, bromide or iodide anion represents, by reacting a heterocyclic compound of the general formula III with a compound of the formula

RCH (OH) CH ₂ X '. (VI)

in which R has the meaning given above and X ^{1 represents} a chlorine, bromine or iodine atom.

These reactions are carried out according to the known methods j for example:

For procedure a) by heating the reaction components in a suitable solvent, such as, for example, anhydrous Ethanol, in the presence of an organic base such as a secondary amine, e.g. piperidine,

for procedure b) by reaction at a temperature below room temperature in the presence of an inorganic Base, such as sodium hydroxide, in a suitable one Solvents, such as aqueous ethanol,

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for procedure c) by heating the reaction components in the presence or absence of a suitable solvent,

II) The starting products of the formula IV, for which Y represents an aeyloxy group, can be obtained by heating the products of formula IV, for which Y is a hydroxyl group, with an anhydride or a halide of a suitable carboxylic acid and, if necessary, a subsequent transfer the ester obtained can be converted into an ester of the desired carboxylic acid,

III) The starting products of the formula IV, for which Y is a halogen atom represents, can from the corresponding compounds of the formula IV, for which Y is a hydroxy radical, according to the known methods, for example by the action of thionyl chloride, thionyl bromide or phosphorus oxychloride will.

3) The products of formula I, for each A the remainder

- CH ₂ CO -

means v / grounding by reacting a compound of the formula

X ₁ CH ₂ COR (VII)

in which R and X «have the meanings given above, with a tertiary heterocycle of the formula III for which Z has the meaning given above, and optionally subsequent conversion of the anion X ~ into the one obtained quaternary derivative into another anion X "*, v / whether X has the meaning given above, by using known methods, in particular the one described below.

The reaction is carried out at a temperature between 0 and 200 ⁰ C, preferably between 20 and 10O ⁰ C, optionally in the presence

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means an inert solvent, such as an ether, e.g. diethyl ether, an alcohol, e.g. ethanol, or a hitrile, e.g. acetonitrile, or in the presence of a Excess of the heterocyclic compound of the formula III carried out.

Yfenn in the products of the formula I ₁ for which A represents the radical - CHpCO -, the symbol X ~ is intended to represent an iodide anion, these products can be obtained by reaction of a ketone of the formula

RCOCH ₃ (VIII)

in which R has the meaning given above, with an equimolecular amount of iodine and two molar equivalents of tertiary heterocyclic compound of formula III are prepared.

The reaction can be carried out by heating the mixture, preferably at about 100 ^° C., preferably in the presence of an excess of the tertiary heterocyclic compound,

If in the products of the formula I for which A represents the radical —CHpCO -, the symbol R denotes a phenyl group 'should, i.e. the products of the formula

- CH ₉ CO - // v>. X "(IX)

in which Z and X have the meanings given above, these products can be prepared by reacting a diazoacetophenone with the corresponding salt of the tertiary heterocyclic compound of the formula III, i.e. one containing the anion X ~ Compound of this formula.

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The reaction can be carried out by refluxing the reactants in an inert solvent such as an ether, e.g. diethyl ether, an alcohol, e.g. ethanol, or while keeping the reaction components under reflux in The presence of an excess of tertiary heteroylclic compound of the formula III can be carried out.

4) The compounds of the formula I for which the group (+ /

is substituted by an alkyl group on the nitrogen atom connected to the group -A- can by Quaternization of a compound of the general formula

-MT- A - R (X)

in the () corresponding to the cation (+)

Represents heterocycle and A and R have the meanings given above with a compound of the formula

R ₁ X ₁ (XI)

in which R _{1 is} an alkyl radical and X _{1 has} the meaning given above.

This reaction is carried out according to the known methods and preferably ^{between 0 and 200 °} C., in particular between 20 and 100 ^° C., optionally in the presence of an inert solvent such as an ether (eg diethyl ether), an alcohol (eg ethanol), a nitrile (For example acetonitrile) or in the presence of an excess of the tertiary heterocycle of the formula X carried out.

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5) The compounds of the formula I can be converted into other products of the formula I which contain the same cation but different anions th, by applying known methods, in particular using ion exchange resins or the double conversion procedures, be transferred.

The compounds of the formula I, for which A _{denotes the group - CH 2} CO -, on treatment with weak alkalis, v / ie, for example, alkali metal carbonates, give tautomeric betaines O ^ and C® of the formulas

XN 11

(XII)

- CH = C - R «-

in which Z and R have the meanings given above, which on treatment with acids of the formula HX, in which X the above Has given meaning, other compounds of the formula I provide.

The following examples explain the manufacture of the products ■ self:

Example 15

A solution was heated from 4 g of 1- (2-Hydroxy-2-o ~ fluorphenäthyl) pyridinium bromide in 16 ml of benzotrichloride 2 1/2 hours in an oil bath at 180 - 19O ⁰ C. The mixture is cooled to ⁰ ° C, sets 10 ml of acetone are added and the solid substance formed is obtained by filtration. After recrystallization from 25 in a mixture of equal volumes ml of isopropanol, ethanol and diethyl ether to obtain 2.55 g of 1-o-fluorostyryl pyridiniumbroinid of F = 166-167 ⁰ C, which, after stabilization in a humidistat over a saturated aqueous sodium nitrite solution for 24 Hours the monohydrate of F = 90-92 ⁰ C delivers.

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The 1- (2-hydroxy-2-o-fluorophenethyl) pyridinium broraide used as the starting product was made as follows:

10 ml of oxobenzaldehyde are added to a stirred solution of 10 g of phenacylpyridinium bromide in 100 ml of ethanol and 10 ml of water. It is cooled to -10 ⁰ O and 5 »6 ml of 1On sodium hydroxide solution are added dropwise over the course of 5 minutes. The mixture is left to stand for 5 days at ⁰ 0 C, then the mixture is acidified at ^{0 0} C with 6.5 ml of dilute 50 # Lger (weight per volume) hydrobromic acid and then diluted with an equal volume of diethyl ether.

The precipitate obtained is filtered off and recrystallized from 250 ml of ethanol. This gives 6.3 g of 1- (2-hydroxy-2-ofluorphenäthyl) pyridinium bromide from P = 248-260 ⁰ G.

By working in the same V / eise, but replacing the 1- (2-hydroxy-2-o-fluorophenethyl) pyridinium bromide with the corresponding hydroxy compounds one obtains the following products:

a) 1-p-methylstyryl pyridinium that with decomposition at 258 - 26O ⁰ C melt / "" from 1- (2-hydroxy-2-p-tolyläthyl) pyridinium bromide from I ¹ = 214-216 ⁰ C, which for his part, according to Kröhnke, Ber. (1934) 67, 661 is produced_J7.

b) 2-methyl-1 «styryl-pyridinium bromide from P = 225-228 ⁰ C / from 2-methyl-1- (2-hydroxy-2-phenethyl) -pyridinium bromide from P = 231-233 ⁰ C, which in turn after Kröhnke, Ber. (1935) 68, 1359 7.

c) 4-ethyl-3-methyl-1-styryl-pyridinium bromide from P = 220 224 ⁰ C / from 4-ethyl-3-methyl-1- (2-hydroxy-2-phenethyl) pyridinium bromide from P = 162-165 ⁰ C, which in turn A'thyl-4-3-methylpyridine and wirdj Styrolbromhydrin according Kröhnke, Ber, (1935) 68, "1359 produced ⁷ ·

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α) 2-ethyl-1-styryl-pyriäiniunbromid from P = 212-215 ⁰ C / "from 2-ethyl-1- (2-hydroxy-2-phenethyl) -pyridiniumbromid from P = 196-199 C, which in turn from 2-ethylpyridine and styrene bromohydrin according to Kröhnke, Ber. (1935) J58, 1559 prepared

e) 3-Styryl-thiazoliunbromid from P = 229-231 ⁰ C / "from 3- (2-hydroxy-2-phenethyl) -thiazoliuinbromid-monohydrate from P = 124 128 ⁰ C, which in turn from thiazole and styrene bromohydrin according to King and Brownell J. Am. Chem. Soc. (1950) JJ2, 25077

Example 14

A solution was heated from 25 g of 1 ~ (2-hydroxy-2-pheriäthyl) -pyridiniurachlorid in 50 ml of benzoyl chloride 1 hour on an oil bath at 180 - 19O ⁰ C. The mixture is cooled to ⁰ ° C from. One is to 500 ml of anhydrous diethyl ether and left to stand ⁰ C overnight Lei O. The pest substance obtained is filtered off, washed with anhydrous ether and crystallized from a mixture of equal volumes of anhydrous ethanol and anhydrous diethyl ether. After stabilization in air for 24 hours to obtain 17 »g of 1-5-styryl pyridiniumehlorid ~ monohydrate from P = 98 to 100 ⁰ C.

As a starting substance in this preparation verv / ended 1- (2-hydroxy-2-phenethyl) pyridinium chloride which melts with decomposition at 212 ⁰ C, according to Gautier, Comptes-Itendus Acad. Sciences Paris (1934) 198 , 1430 produced.

Example 15

A solution was heated of 9.7 g of 1- / 2-hydroxy-2- (3-thienyl) -äthyl7-pyridinium bromide in 19.4 ml of benzoyl chloride for 1 hour in an oil bath at 180-190 ⁰ C. The mixture is cooled to ⁰ C off, rub the whole thing with anhydrous ether and dissolve the residue in 100 ml of ether. Sodium bicarbonate is added until neutrality towards Congo red is achieved, and 10 g of potassium iodide are then added. The precipitate obtained is filtered off,

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washes it, rait ice water and recrystallizes it from ethanol. Ilan 5.8 g 1 - ^ - (3-thienyl) -viny] / - pyridinium) iodide-inonohydrat of P = 180-182 ⁰ C (softening at 165 ⁰ C).

Used as a starting product, 1- _</ 5-hydroxy-2- (3-thienyl) -äthyl7-pyridiniumbroHiid P = 183-185 ⁰ C was prepared from thiophene-3-aldehyde / "after Compaigne and Ie Suer, J. Am Chera Soc. (1948) 70, 1577_7 and Phenacylpyridiniunibromid geraäss Kröhnke, Ber. (1934), £ 7, 661 produced.

By working in the same way, but using 3 - ^ '2-Hydroxy-2- (2-thienyl) -äthyl7-1 -methyl-imidazoliumchlorid from P = 194 - 196 ⁰ C, which in turn from 1-Kethylimidazol and 2-chloro-1-hydroxy-1- (2-thienyl) ethane / "produced according to Hopff and Wandeler HeIv. ^G him. Acta. (1962) 45., 992_7 according to the method of Kröhnke, Ber. (1945) 68 , 1359 is produced, 1-Methy1-3- / 3- (2-thienyl) -viny ^ -imidazolium iodide monohydrate of P = 185 - 187 ⁰ C.

Example 16

A solution of 11.1 is heated g of 1- / 2-hydroxy-2- (2-thienyl) -äthyl7-pyridinium bromide in 21 nl of benzoyl chloride for 1 hour in an oil bath at 180-190 ⁰ C. The mixture is cooled to ⁰ ° C. , add 15 ml of acetone and allow to crystallize. The pests are filtered off, washed with acetone and recrystallized from 100 ml of a gel of equal volumes of ethanol and diethyl ether. After stabilization in a hygrostat for 24 hours a saturated aqueous IJatriumnitritlösung 4.5 g 1 is - / 2 '- (2-thienyl) -viny ^ pyridinium bromide monohydrate, Form A, P = 98 to 101 ⁰ C.

The product is dried 24 hours over phosphorus pentoxide at room temperature under 0.05 mm Hg, to yield the anhydrous salt from P = 170 -... 180 ⁰ C (King and Brownell loc cit, to give 98-100 ⁰ C as the melting point for the monohydrate and 180 - 181 ⁰ C for the anhydrous salt).

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Used as a starting product 1 - ^ / 2 * Hydroxy-2- (2-thienyl) -äthylT-pyridinium of F = 238-239 ⁰ C was to King and Brov / nmeil, loc. cit., produced.

Example 17

A solution of 60 g of 1- _< / 2 * -hydroxy-2- (2-thienyl) -ethyl7-pyridinium bromide in 600 ml of acetic anhydride and 600 ml of acetic acid is kept under reflux ^{in an oil bath at HQ 0 C for 3 hours.} Han pours the genic in 1.2 1 7 / water and then concentrates it under reduced pressure. A pale red smear is obtained. 350 ml of acetone are added. A yellow solid substance separates out. The mixture is left to stand for 3 hours at room temperature and the solid substance is then filtered off. They are washed with acetone and crystallized from 135 ml of isopropanol. 233 g of 1 - / ^ - (2-thienyl) vinyl7-pyridinium bromide, form B, of F = 177 17Q ⁰ C. are obtained.

The monohydrate, which ^{melts at 96-105 0} O, is obtained by letting the anhydrous product stand in a hygrostat over an aqueous saturated sodium nitrite solution for 72 hours.

Operating as described above, one obtains the 4-acetamido-1-styryl-pyridinium bromide of F = 331-333 ⁰ C, from 4-acetamido-1- (2-hydroxy-2-phenethyl) -pyridiniunbromid of F = 235-236 ⁰ C, which in turn is made from 4-acetamidopyridine and styrene bromohydrin by the method of King and Brownell, loc. cit., is produced. The reaction with the acetic anhydride-acetic acid mixture was
leads.

was stirred at 22O ⁰ C in a sealed Carius tube carried

Example 18

Heating a mixture of 10 g of 3- (2-hydroxy-2-phenethyl) -2-methyl-thiazolium bromide and 40 g of oxalic acid dihydrate in an oil bath for 3 hours at 140-145 ⁰ C. It is cooled to 20 ⁰ C, and adds 100 ml of acetone. It is cooled for 2 hours at ⁰ ° C. and filtered. The solid substance is washed with 50 ml of ice-cold

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Acetone. Han solves the! Pestsubstanz in 100 ml of water at 50 ⁰ C and the pH value of the solution A with sodium bicarbonate to 6-7. 10 g of potassium bromide are added, the mixture is cooled to about ⁰ ° C. and the precipitate is filtered off. Bine Umkris tallisation from Xthanol gives 4.7 g of 2-methyl-3-styryl-thiazolium bromide as pale red crystals of F = 227-229 ⁰ C.

The 3 ~ (2-hydroxy-2-phenethyl) -2-methyl-thiazolium bromide used as the starting product was made as follows:

18 g of 2-IIethylthiazole / manufactured according to Didier and Metzger, Compte-Rendus (1961) .2Ju !, 1619_7 and 36.5 g of styrene bromohydrin are heated for 3 days on a steam bath. It is cooled to 20 ⁰ C and triturated with 100 ml acetone. The solid substance is filtered off and crystallized from methanol. This gives 25.15 g of 3- (2-hydroxy-2-phenethyl) -2-methyl-thiazolium bromide in the form of crystals, blassmalvenfarbigen F = 253 - 255 ⁰ C.

By working in an analogous way, the following products are obtained:

a) 1-methyl-2-styryl-pyrazolium bromide of F = 195 - 196 ⁰ C from 2- (2-hydroxy-2-phenethyl) -1-methyl-pyrazolium bromide of F = 234 - 236 ⁰ C, which in turn from 1 -Methylpyrazole (manufactured according to Knorr, Ber. 1895, 28, 716) and styrene bromohydrin was manufactured,

b) 4 - !. Iethyl-3 ~ styryl-thiazolium bromide, which at 237 - 239 ⁰ C melts with decomposition, from 3- (2 ~ hydroxy-2-phenethyl) -4-methyl-thiazolium bromide from F = 176-178 ⁰ C, which in turn is made from 4-methylthiazole / Manufactured according to Clarke and Gurin J.Ara.Chem. Soc. (1935) j> 7, 1879_7 and styrene bromohydrin is produced.

Example 19

An alcoholic 10% (weight per volume) potassium hydroxide solution is used to a solution of 2.5 g of 2- (2-chloro-2 ~ phenethyl) -1-methylpyrazolium bromide in 250 ml of ethanol until obtained

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a permanent pH of 8-9. Leave for 1/2 hour stand. An inorganic layer precipitates out and is removed by filtration. The filtrate is acidified with concentrated Hydrobromic acid up to p} I 5. The suspension is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in 25 ml of acetone. The addition of diethyl ether leads to a pale red solid precipitate. They are recovered by filtration and crystallized from a mixture equal volumes of ethanol / diethyl ether.

0.4 g of i-methyl-2-styryl-pyrazolium bromide of F = is obtained 196 - 198 C, the same as that described in Example 18 a) Product is identical.

Used as a starting product, 2- (2 ~ chloro-2-phenethyl) -1-methyl-pyrazoliumbr.or; iid, which with decomposition at 165 - 167 ⁰ C melts, v / urde to King and Brov / nell, loc. cit., obtained by reacting 2- (2-hydroxy-2-phenethyl) -1-methyl-pyrazolium bromide (prepared as in Example 18) with thionyl chloride.

Example 20

3 »6 g of N-styrylpiperidine are heated. Manufactured according to Krb'hnke and Vogt, Liebigs Ann. (1954) .582., 52.J and 3.6 ml of methyl iodide in 15 ml of acetonitrile for 1 hour under reflux. The solvent is removed by distillation under reduced pressure and the residue is extracted four times with 25 ml of water each time. The aqueous extracts are combined, washed with diethyl ether, filtered and treated with 25 ml of 1N-amino acid. A brown precipitate forms, which is filtered off, washed with water and dried in vacuo over concentrated sulfuric acid. This gives N-methyl-H-F = styrylpiperidiniumamsonat from 221-224 ⁰ O.

Example 21

7.55 g of 3-thenoyl methyl bromide are used, manufactured according to Mac Dowell and Greenwood, J. Heteroc.Ohem. (1965) 2. » 46_7 to 3 ml

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to anhydrous pyridine with stirring. It is allowed the exothermic reaction to develop, and the mixture then crystallize by standing at room temperature I-Ian is 25 ml of diethyl ether to and filtered off the solid, Kan washed with diethyl ether and dried at 9O ⁰ C. Sine! ^ Crystallization a.us ethanol provides 6.6 g of 1- (3-thenoyl-methyl) -pyridinium bromide in the form of white platelets with an F = 181 - 183 ⁰ C.

By working in an analogous manner, the following compounds are made from:

a) 1-phenacyl-pyridazinium bromide, which decomposes at 237-238 ° C., (from phenacyl bromide and pyridazine, which in turn is produced according to Tetsinger and Lasco J.Org.Chem., 1956, 2A_, 746);

b) 1 ~ (2-furoyl-methyl) -pyridaziniumbromid, located at 214 ⁰ C decomposed (2-furoyl methyl bromide and pyridazine);

c) 1- (2-Thenoyl-methyl) -pyridazinium bromide, which is at 212 213 ° C decomposed, from 2-thenoyl-methylbromide and pyridazine;

d) 1-Iuethyl-3-phenacyl-2-phenyl-benzimidazolium bromide of F = 256-259 ⁰ C (decomp.) from phenacyl bromide and 1-methyl-2-phenyl-benzimidazole, which in turn is according to Fischer, Ber. (1892) 25 , 2842;

e) 1 -Lie thy 1-3- (2-thenoyl-methyl) -1,4,5,6-tetrahydropyrimidinium bromide of F = 185 - 186 ⁰ C from 2-thenoyl-methyl bromide and 1-I.Iethyl-1, 4,5t 6-tetrahydropyrimidine, which in turn according to Jantzsch and Seefelder, Ber. (1965), S> 8, 1342;

f) 1- ^ 2 "- (2-thienyl) -äthyl7-pyridiniunbromid of F = 186-188 ⁰ C; the reaction mixture is brought to reflux here 1 1/2 hours before standing; one goes from 2- (2- Bromoethyl) thiophene, which in turn is prepared according to Blick and Burckhalter, J. Am. Chem. Soc. (1942) 64, 477, and pyridine from;

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g) 1- / 2- (2-thienyl) ethyl7-pyridazinium bromide of F = 170 -

173 ⁰ C of 2- (2-bromoethyl) thiophene and pyridazine, wherein the reaction mixture is brought to reflux for 1/2 hour before allowing to stand;

h) iI.Iethyl-2-phenacyl-pyrazoliumbromid extending C decomposed liethylpyrazol 1-of phenacyl bromide and wherein the reaction mixture is brought to reflux before allowing to stand for 8 hours at 206 ^0;

i) 1-methyl-2- (2-thenoyl-methyl) pyrazolium bromide, which is decomposed at 202 - 2O5 ° C, from 2-thenoyl-methylbromide and 1-methylpyrazole, the reaction mixture refluxing for 8 hours is heated;

j) 2- (2-puroylmethyl) -1-methyl-pyrazolium bromide, which is found in 207 ° C decomposed, from 2-furoyl-methylbromide and 1-methylpyrazole, the reaction mixture being refluxed for 8 hours;

k) 2-hydroxyimino-1- (2-theno3 ^r l-methyl) pyridinium bromide, located at 188 - decomposes 190 ⁰ C, from 2-thenoyl methyl bromide and pyridine aldoxime 2, wherein the reaction mixture before allowing to stand 1 / Is refluxed for 2 hours;

1). S-Hydroxylminonethyl-i-phenacyl-pyridinium bromide, located at 239 - 240 ⁰ C decomposed, aldoxime-3-pyridine from phenacyl bromide and wherein the Reaktionsgemiech is brought to reflux before allowing to stand 16 hours.

Example 22

The procedure is as in Example 21, but using 2-furoyl methyl tosylate instead of 3-thenoyl methyl bromide. One receives 1- (2-Puroyl-methyl) -pyridinium tosylate in the form of white needles from F = HO - H1 ° C from 1,2-dichloroethane, whereby the 2-Furojrl-methyl tosylate used as the starting product as follows was obtained:

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6.9 g of 2-furoyl-methylbromia in solution in 50 ml of anhydrous acetonitrile are added to a suspension, kept in motion, of 11.8 g of silver p-toluenesulfonate in 50 ml of anhydrous acetonitrile. The mixture is stirred for 1 hour at room temperature, refluxed for 16 hours and cooled to room temperature. The silver bromide formed is removed by filtration and the filtrate is concentrated under reduced pressure. A grease is obtained which is dissolved in 100 ml of diethyl ether. Then filtered . Man - (60 ⁰ G 40 boiling range) solidifies is recrystallized from 80 ml of anhydrous diethyl ether by cooling to -5o ⁰ C to one the filtrate is concentrated under reduced pressure and give a red oil which on trituration with petroleum ether.. receives 7.8 g of 2-furoyl methyl tosylate in the form of white crystals of F = 58 ⁰ G.

Example 23

16.6 g of anhydrous pyridine in 100 ml of anhydrous diethyl ether are added dropwise to a suspension, kept in motion, of 30 g of 4-bromoacetylthiazole hydrobromide in 270 ml of diethyl ether. The reaction is slightly exothermic and, after stirring overnight at room temperature, the solid fraction is isolated by filtration and washed thoroughly with anhydrous diethyl ether. Then you dissolve it in 158 ml of water. The aqueous solution is filtered and 32 g of potassium iodide are then added. It is cooled to ⁰ ° C., the precipitate is filtered off and recrystallized from 50 ml of water / water. This gives 17.35 g of 1- (4-ThIazolylcarbonylmethyl) -pyridiniumjodid in the form of cream colored prisms, which are at 217 - 218 ⁰ G decompose.

The 4-BroEiaeetyl-thiazole-hydrobromide used as the starting product was made as follows!

2.5 g of dioxane dibroraide are added to a solution of 1.3 g 4-Acetylthiazol ^ / Manufactured according to Brlenmeyer and Überwasser, Helvet. Chim, Acta, (1940) £ 2, 1977 in 10 ml of carbon tetrachloride to. The mixture is refluxed for 1 hour. Crystals separate out. It is cooled and filtered. You get

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a grayish solid that is washed with methyl ether. This gives 2.6 g of 4-bromoacetyl-thiazol-hydrobroraid that with decomposition at 160 - 167 ⁰ C melts,

Example 24

5 »2 g of 2-thenoyl methyl bromide in 20 ml of anhydrous benzene are added to a suspension of 2.4 g of 4-aminopyridine in 20 μl of anhydrous benzene. The mixture is refluxed for 2 hours, cooled and filtered. The precipitate is washed with benzene and with acetone and recrystallized from 250 ml of ethanol. There is obtained 4 _f 3 g of 4-Anino-1- (2-thenoyl-rnethyl) -pyridiniumbrornid in the form of pink prisms which decompose at 292 G.

Example 25

While stirring, 2.1 g of sodium 2-hydroxy-3-naphthoate in 25 ml of water / water are added to a solution of 2.78 g of 1-phenacyl-pyridiniurabromide in 10 ml of water. An oil separates out and crystallizes. The solid substance is recovered by filtration, washed with ice water and dried in vacuo. 3.2 g is obtained i-phenacyl-pyridinium ^ -hydroxy ^ naphthoate, which after recrystallization from ethanol in the form of cream-colored needles, F = 201 - 202 ⁰ C is present.

Example 26

The procedure is as in the previous example with 2.1 g of sodium 2-hydroxy-3-naphthoate in 25 ml of water and 2.84 g of 1- (2-thenoylmethyl) pyrldinium bromide in 5 ml of water. This gives 2.6 g of 1- (2-thenoyl-methyl) pyridinium-2-hydroxy-3-naphthoate, which after recrystallization from ethanol in the form of platelets from the chamois f - is present 181 ⁰ C - 180th

example 27

127.6 g of silver p-chlorobenzenesulfinate are added to a solution of 119 g of 1-styryl-pyridiniurabromide-raonohydrat in 1.2 l of methanol while stirring,

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I.Ian refluxes for 3 hours, removes the silver bromide by filtering and concentrating the filtrate under reduced pressure. The remaining solid substance is dissolved in 600 nl ethanol solved. It is filtered in the heat at 40 C and then set 1.2

Diethyl ether too. It is cooled to 0 G and the orange crystals obtained are filtered off. They are washed with diethyl ether and obtained 148.5 g i-styryl-pyridinium-p-chlorbenzolsulfinatmonohydrat, decomposes the Bich above 18O ⁰ G.

By working in an analogous manner using the appropriate silver salts, the following salts of 1-styrylpyridinium are prepared from:

Chloride monhydrate from F = 98 - 100 ⁰ C sulfate hexahydrate from F = 79 - 84 ⁰ C tosylate from F = 211 - 213 ° C

Benzoate monohydrate from F = 98 - 101 ⁰ C (decomp.) Methanesulfonate senihydrate from F = 90 ⁰ C Succinate tetrahydrate, which ^{decomposes at 113 0} C Tartrate dihydrate, which ^{decomposes at 155 0} C Salicylate monohydrate, which decomposes at 146 ⁰ C cinnamate dihydrate from F = 87-88 ⁰ C. Treat adipate of F = 133-135 ⁰ C. Treat maleate from F = 122-124 ⁰ C.

Example 28

A solution of 30 g of ammonium isethionate in 200 ml of v / water is passed through a. 30 g Amberlite IRA 400, hydroxy form, filled ion exchange resin column, until the sluat ceases to be alkaline to litmus. Han then elutes with 500 ml of water and then with 250 ml of methanol and then passes through a solution of 2 g of 1-styryl-pyridinium bromide monohydrate in 50 ml of methanol. The eluate is concentrated in vacuo and 1.7 g of 1 is obtained -Styryl pyridinium isethionate of F = 118 - 12O ⁰ C.

One works in the same way, but replaces the ammonium isethionate by ITatriumbenzenesulfonat and receives so

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1-styryl-pyridiniumbenzenesulfonate from ϊ ¹ = 203 - 207 ⁰ O.

Example 29

1.9 g of ammonic acid in 10 ml of an in sodium hydroxide solution are added to a solution of 2.8 g of 1-styryl pyridiniuribromide monohydrate in 20 ml of water. Filtered the resulting .roten precipitate off, washed with water and dried at 90 ⁰ C. .lan 3.3 g 1-styryl pyridiniumamsonat monohydrate, located at 325 - 328 ⁰ C decomposes.

Kan works in an analogous way, but replaces the amsonic acid by the appropriate acid and thus obtain the following salts of 1-styrylpyridiniura:

4-cyano-2-; iodo-6-nitrophenolate from P = 155 - 157 ⁰ C (from 4-cyano-2-iodo-6 ~ nitrophenol, prepared according to French patent specification 1 375 311)

Pamoate dihydrate, located at 153 - 156 ⁰ C decomposed naphthalene-2-sulfonate of F = 173-175 C naphthalene - ^, 5-disulfonate ~ dihydrate from P = 354 ⁰ C.

1-aminonaphthalene-4,6,8-trisulfonate hexahydrate P = 162-168 ⁰ C.

Naphthalene-1-sulfonate P = 176-177 ⁰ C Chiniofonat dihydrate P = 120-150 ⁰ C 5-chlorosalicylate hydrate P = 45 - 50 ⁰ C naphthalene-2,7-disulfonate tetrahydrate P = 218 - 230 ⁰ C p-chlorobenzosulfonate from P = 245 - 247 ⁰ C.

Example 30

1.9 g of ammonic acid in 10 ml of 1N sodium hydroxide solution are added to a solution of 2.68 g of 1- (2-furoylmethyl) pyridinium bromide in 5 ml of water. Oak red crystals form, which are filtered off, washed with water and dried in vacuo. This gives 3.6 g 1_ (2-Puroyl-methyl) -pyrialniumamsonat, which decomposes at 221-223 ⁰ C.

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Example 3-1

I.Ian loot 4.85 g of the glucamine salt of 4-cyano-2-3od-6-nitrophenol (manufactured according to Belgian patent specification 673 993) in 40 ml of water and puts this solution in a solution of 2.78 g of i-phenacyl -pyridiniuinbronid in 10 ml 'Yasser too. The precipitate formed is recovered by filtration, washed with water and recrystallized from methanol. 1-Phenacyl-pyridinium-4-cyano-2 -;) od-6-nitrophenolate is obtained in the form of yellow prisms with a temperature of ^{157 ° C}

Example 32

A solution are added 2.78 g of 1-phenacyl-pyridinium bromide in 5 ml water to a solution of 10 g of potassium carbonate in 30 ml water at 0 - 2 ⁰ O under stirring. A pale red greasy substance separates out and is extracted with chloroform. The uhloroform solution is dried over sodium sulfate and concentrated in vacuo. The residue is treated with 25 ml of a solution of gaseous hydrogen chloride in diethyl ether. A pest substance forms, which is filtered off. They were crystallized twice from a mixture of equal volumes of ethanol-ethyl ether, thus obtaining 1.6 g of 1-Phenacylpyridiniumchlorid of F = 196-198 ⁰ C.

Example 33

A solution of 1.3 g of 1-styryl-pyriniunbromide-monohydrate in 20 ml v / ater is stirred for 1 hour with 1 g of Amberlite resin (IR 120, O? Yp 11, which passes through a sieve 200, British sieve size) 1 hour. The resinate obtained (1.5 g) is filtered off, washed with water and dried over concentrated sulfuric acid. The resinate contains 43 fi active cations.

Example 34

It is 2.5 g of 3,3 '5.5 _t ^f, 6,6'-hexachloro-2,2'-dihydroxydiphenyl methane (hexachlorophene) to a solution of 0.14 g of sodium in 12 ml of anhydrous ethanol to. A solution of 1.6 g of 1-styryl-pyridinium bromide-raonohydrat in 15 ml of ethanol is added and

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dilute the resulting red solution with 70 ml of water. A yellow pest substance (3.43 g) crystallizes out. They are filtered off, washed with water and recrystallized from ethanol. This gives 2.6 g of 1-styryl-pyridinium-monohexachlorophen salt of P = 182-184 ⁰ C.

Example 35

5 »8 g of 1,2-dihydro-i-styrylpyridine are dissolved in 85 ml of acetonitrile and 2.5 ml of methyl iodide are added. I-Ian is left to stand overnight and the pest substance formed is filtered off. An equal volume of water is added to the piltrate and it is carefully washed with methyl ether. The solution is filtered and a 1N solution of sodium amsonate is added until the precipitation has ended. Filtered the precipitate off, washed with V ^r ater and dried over concentrated sulfuric acid. 0.9 g of 1,2-Mhydro-1-methyl-1-styryl-pyridiniunamsonat of P = 306 308 ⁰ G (decomp.) Are obtained.

The 1,2-dihydro-i-styrylpyridine used as the starting product is made as follows:

4-15 g of sodium borohydride are dissolved in 125 ml of a saturated aqueous sodium bicarbonate solution. This solution is added dropwise and with stirring to a solution of 10 g of 1-styrylpyridinium bromide monohydrate in 300 ml of v / water. The mixture is stirred for 1/2 hour and the pest substance is filtered off. It is washed with water and dried in vacuo over concentrated sulfuric acid. Men 5.8 g of 1,2-dihydro-1-styrylpyridin P = 103-107 ⁰ C after softening at 98 ⁰ C.

example 36

8 g of silver chloride are added to a solution of 15 g of 1- ^ 2- (2-thienyl) vinyl7-pyridinium broraide (form A) (prepared as in Example 16) in 250 ml of methanol with stirring. The mixture is refluxed for 3 hours, the silver bromide formed is filtered off and the residue is concentrated in vacuo. That with 100 ml of acetone

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Stirred remaining oil solidifies. Kan filtered the solid substance is washed off with acetone and crystallized from a mixture of equal parts isopropanol / diethyl ether. You get 10.8 g! - ^ - (^

Dra.t from F = 98 - 99 ° C.

An analogous product is obtained by using the pyridinium salt, Form B, produced according to Example 17, goes out.

By working in ^{analogy to V.:} eise, jeooch, by replacing the silver chloride with silver p-chlorobenzenesulfinate, one obtains the 1- / 5- (2-thienyl) vinyl7-pyridiniiim-p-chlorobenzene sulfinate monohydrate, which is at 177-179 ⁰ C decomposes.

Example

A solution are added 2.25 g ITatrium p-chlorobenzenesulfonate in 20 ml ^{v, r} ater to a solution of 3 g of 1- / 5- (2-thienyl) -vinyl7-pyridinium bromide, Form A, v manufactured; ie in Example 16, in 20 ml of water. IDs a yellow precipitate forms, which is obtained by filtration, washed with water and crystallized from ethanol. This gives 3.4 g of 1 ~ / S- (2-thienyl) -vinyl7 pyridinium p-chlorobenzenesulfonate of F = 210-212 ⁰ C.

By working with the product of Form B, prepared as in Example 17, an analogous product is obtained.

One works in the same way, but replaces the sodium pchlorobenzenesulphonate by the sodium or aramonium salt of the

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- 4ό -

suitable acid to obtain the corresponding salts of the 1 - [?. ·· (2-thienyl) -vinyl] -pyridiniums, wherein the monohydrate of the embonate at 124 - 152 ⁰ C and decomposes the monohydrate of Amsonats above 350 ⁰ C.

Example 38

59.8 g of sodium N-benzoylsulfanilate (prepared according to Schroeter, Chem. Ber., 1906, J5 £, 1565) are dissolved in 600 ml of warm water, and a portion (100 ml) is placed in a 2 liter beher. The remaining solution and a solution of 52.4 g of 1-styrylpyridiniutnbromid in 500 ml of warm water are added to the reaction mixture at the same time with rapid stirring. Mechanical stirring is continued for an additional hour with ice cooling. The pale yellow precipitate is filtered off, washed with warm water and dried at 80.degree. Are thus obtained 88.6 g of 1-Styrylpyridlnlum-N-benzoylsulfanilat from P = 244 246 ⁰ C.

Example 39

A solution of 1.5 g of 1- (2-hydroxy-2-phenethyl) pyridinium pchlorbenzolsulfonat in 3 ml of benzoyl chloride for 1 hour in an oil bath at I80 - heated 190 ⁰ C and then cooled to 0 ⁰ C. 10 ml of acetone are added and the pest substance is filtered off and crystallized from 12 ml of water. Are thus obtained 1.1 g of 1-p-chlorobenzenesulfonate styrylpyridinium P = 245-247 ⁰ C.

The 1 - (2-hydroxy-2-phenethyl) pyridinium p-chlorobenzenesulfonate used as the starting material in the above preparation was manufactured as follows:

A solution of 2.8 g of 1- (2-hydroxy-2-phenethyl) pyridinium bromide in 28 ml of warm water is at once with 2.2. treated g of sodium p-chlorobenzenesulfonate in 10 ml of water. The precipitate is filtered off, washed with water and dried at 90 ⁰ C. This gives 3.3 g of 1- (2-hydroxy-2-phena * thyl) -pyridiniump-chlorbenzolsulf onate P "240-241 ⁰ C.

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Example 4P

A solution of 15 g of 1- (2-hydroxy-2-phenethyl) -pyridiniumnaphthalin-1,5-disulfonate in 3 mL of benzoyl chloride is on an oil bath at 18O 1Hour - heated 190 ⁰ C and then cooled to O C ^6. 10 ml of acetone are added. The solid substance is filtered off and recrystallized from 1 ^ 0 ml of water. There are thus 1.2 g of 1-styrylpyridinium-naphthalene ~ 1,5-disulfonate dihydr. t obtained from P = 354 ⁰ C.

The 1- (2-hydroxy-2-phenethyl) pyridinium naphthalene-1,5-disulfonate used as the starting material in the above preparation was made as follows:

A solution of 2.8 g of 1- (2-hydroxy-2-phenethyl) -pyridlniunibromid in 28 ml of warm water is treated all at once with 1.7 g of dinatrium naphthalene-1,5-disulfonate in 20 ml of water. The precipitate is filtered off, washed with water and dried at 90 ⁰ C. This gives 5.4 g of 1- (2 ~ hydroxy-2-phenethyl) -pyridiniumnaphthalin-1,5-disulfonate from P = 265 ⁰ C.

Example 41

1 * 8 g of 1- (2-hydroxy-2-phenethyl) pyridinium p-chlorbenzolsulfο-, nat and 7 * 2 g of oxalic acid dihydrate are 1 hour on an oil bath at 14O - retained 145 ⁰ C. After cooling to 20 ^° C., 15 ml of acetone are added to the reaction mixture. The suspension is ^{cooled to 0} ° C. for 2 hours and filtered, and the pest substance is washed with 15 ml of ice-cold acetone and crystallized from 20 ml of water. This gives 1.2 g of 1-Styrylpyridiniump-chlorobenzenesulfonate P = 240-241 ⁰ C.

Example 42

10 # (weight / volume) ethanolic potassium hydroxide becomes a solution of 4 g of 1- (2-chloro-2-phenethyl) pyridinium bromide (prepared according to Carroll, King and Brownwell, J.Am. Chem. Soc,

109843/1700

1950, 72, 2507) In 34 ml of ethanol added until the solution a Has a permanent pH of 8 to 9. After standing for 10 minutes, the inorganic precipitate is filtered off and the Piltrate with 10% (weight / volume) aqueous N-Benzoylsul- · fanilic acid (prepared according to Schroeter, Chem. Ber., 1906, J59, 1565) acidified to pH 4. The solution is reduced under reduced The pressure is concentrated, and the residue is triturated with 10 ml of ice-water. The pest substance is filtered off and extracted from 175 ml of water crystallized. 3.85 g of i-styrylpyridinium-N-benzoylsulfanilate are obtained from P = 244 - 246 ° C

Example 43

The procedure is as in Example 42, but acidified with 10 # (weight / volume) aqueous ρ-chlorobenzenesulfonic acid (prepared according to Cook and Cook, J. Am. Pharm. Ass.-Sci. Edn., 1949, J58, 239) . A pest substance separates from the reaction mixture. After 2 hours cooling at 0 ⁰ C, the solid is filtered off and crystallized from 50 ml of water. J3.6 g of 1-styrylpyrldinium p-chlorobenzenesulfonate with a melting point of 240 ° -241 ° C. are obtained.

Example 44

The procedure is as in Example 42, but acidified with a 10 % (weight / volume) aqueous suspension of ammonic acid. A solid substance separates out of the reaction mixture. The solid is filtered off, triturated with previously by the addition of N / 10 ammonium hydroxide to pH 8.5 basified water, filtered again, washed with water and dried at 90 ^e C. Is obtained), 1 g of 1-Styrylpyridiniura-amsonat monohydrate, located at 325 - 328 ⁰ C decomposed.

109843/1700

Claims (1)

Patent claim anthelmintic compositions in concentrated or ready-to-use form, optionally together with at least one diluent or a coating agent, characterized by a content of at least one quaternary Aiamoniura compound of the formula "Irkstoff", where in this formula the symbols have the following meanings: a) R represents a phenyl radical or a mononuclear heterocyclic radical with 5 or 6 chain members which contains one or two oxygen, nitrogen or sulfur atoms in the ring and is bonded to group A through one of its carbon atoms, these radicals optionally being represented by one or two substituents from the group of halogen atoms and alkyl, alkoxy, hydroxy, nitro, dialkylamino and acylamino radicals can be substituted; A means the grouping - CH = CH -; Z together with the nitrogen atom to which it is bonded denotes a mononuclear heterocyclic group with 5 or 6 chain links or a bicyclic heterocyclic group, these groups containing a quaternized tertiary nitrogen and these heterocyclic groups also containing 1 or 2 additional heteroatoms from the group the oxygen, nitrogen and sulfur atoms and these 109843/1700 groups optionally one or two substituents from the group of alkyl, phenyl, 4-thiazole, 2-furyl, 2-i1hienyl, formyl, Hydroxyiminomethyl (also called oximinomethyl), acyl, aryino and acetamido radicals can have; b) R denotes a mononuclear heterocyclic radical with 5 or 6 chain links, which has 1 or 2 hetero atoms from the group of oxygen, nitrogen and sulfur atoms and is bonded to group A through one of its carbon atoms, this radical optionally being to one or two of its carbon atoms can be substituted by one or two substituents from the group of halogen atoms and alkyl, alkoxy, hydroxy, nitro, dialkylamino and acylamino radicals; A represents the group - CHp - CH2 -; Z, together with the nitrogen atom to which it is bonded, has the same meaning as under a) j c) R represents the group -CH2CO-; Z, together with the nitrogen atom to which it is attached, denotes a pyridinium, 3- (or 4-) aminopyridinium, 3- (or 4-) acetamidopyridinium, 2- (3- or 4-) hydroxyiminomethyl-pyridiniuia- , 1-alkyl-1,2-dihydr ο pyridinium, 1-alkyl-tetrapyridinium, pyridazinium, 1- (or 2-) alkylpyrazolium, 1-alkyl-2-phenylbenzimidazolium or 1-alkyl-2- ( 4-thiazolyl), 1-alkyl-2- (2-furyl) or 1-alkyl-2- (2-thienyl) benzimidazolium radical; d) R has the same meaning as under b); A represents the group - CH2 - CO -; With the nitrogen atom to which it is bonded, Z denotes a pyrazinium radical or a 2-alkylpyrazinium radical; 109843/1700 e) R has the same meaning as under a); A represents the group -CH2CO -; Z with the nitrogen atom to which it is attached represents a pyridiniuing group; In all of these cases, X ~ means "a pharmaceutically acceptable anion. 1.0-9 * 44/174) 4