DE2251260A1 - PROCESS FOR PRODUCING BIGUANIDE COMPOUNDS - Google Patents

Description

William H. Rorer, Inc., Fort Washington (Pa., USA)

Process for the preparation of biguanide compounds

In order to inhibit gastric juice secretion and as a spasmolytisohe agent, one uses for example Atropine, homatropine, propanthellae bromide, dicyclomine hydrochloride, as well as other.Verbindungen, which the invention Biguanids are dissimilar in structure. But we know that because of the anticholinergic Properties of these compounds cause the same undesirable side effects, such as mydriasis, xerostomia, Cycloplegia, as well as other undesirable effects.

30th

It has now surprisingly been found that the 1-phenylbiguanides according to the invention are valuable pharmacological agents are those that increase gastric secretion have inhibitory and spasmolytic properties. ·

It was also found that the compounds according to the invention are practically not anticholinergic Exert side effects inherent in the gastric juice-inhibiting and antispasmodic agents.

Finally, it was also found that the compounds according to the invention have a low toxicity value exhibit.

It also became a simple and effective method for the treatment of gastrointestinal complaints and gastrointestinal diseases such as duodenal ulcers and peptic ulcer.

It was found that the in 1 position substituted phenyl biguanides of this invention also have an effective level of antihypertensive effect and have depressive effects on the central nervous system.

Finally, pharmaceutical preparations have also been created which contain at least one of the Phenylbiguanide substituted in the 1-position as an active ingredient and for the above therapeutic Applications are suitable.

The present invention describes a class

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of chemical compounds consisting of 1-phenyl biguanides. The invention also describes non-toxic
pharmaceutically acceptable salts and a method for that
Production and use of these 1-phenyl biguanide compounds.

The compounds according to the invention can generally be represented by the structural formula I and are suitable for the treatment of gastrointestinal complaints and diseases, which can be achieved by using a
active agents inhibiting gastric juice secretion or antispasmodic agents. The compounds of structural formula I moreover have an effective degree of antihypertensive properties and a depressive effect on the central nervous system and are therefore suitable for the treatment of elevated blood pressure and as mild tranquilizers.

The compounds according to the invention correspond to the following formula:

NH NH

IJL.

wherein R ₂ , R ,, R _21. , R ₁ - and R ^, which can be the same or different, hydrogen, lower alkyl, lower alkenyl, halogen, nitro, amino, di-lower alkylamino, halo-lower

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alkyl, halo-lower alkoxy, halo-lower alkanoyl, Hydroxyl, cyano, thiocyanate, carboxyl, carbo-lower alkoxy, Di-lower alkylsulphonamido, lower alkylsulphonyl, halo-lower alkylsulphonyl, Phenoxy, acyloxy, halophenoxy,

mean

Phenyl or halophenyi}. The invention also relates on the non-toxic acid addition salts of these compounds.

In the descriptive part, the following definitions should come into question:

The term "lower alkali" refers to a straight-chain or branched hydrocarbon radical having 1 to about 8 carbon atoms. ,

The "acyl" radical can be any organic radical which is derived from an organic acid, by removing the hydroxyl group, e.g. acetyl, propionyl, benzoyl, etc.

According to a preferred embodiment of this invention, it describes a class of new chemicals Compounds which contain a phenyl radical which has at least one alkyl radical and one halogen atom as substituents carries, this remainder at the 1-position on the Biguanide chain adheres.

These compounds correspond to the following structural formula;

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NH NH Il Il

NH-C-NH-C-NH ₂ Π

where η denotes the numbers 1 to 3, Alk, Hai and R each other can be in any position of the ring, Alk with a lower alkyl or lower alkenyl radical 1 to 7 carbon atoms, which is a straight chain or

represents, branched radical can be JTHal fluorine, chlorine, bromine or Iodine and R denotes hydrogen, fluorine, chlorine, bromine, iodine or a straight-chain or branched lower alkyl radical with 1 to 7 carbon atoms, with the proviso that Alk is a radical other than the 2-methyl radical if Hai represents the chlorine or 4-bromine atom and R at the same time denotes the hydrogen atom or when Hal and R denote 3j5-dichloro substituents, and that Alk neither denotes 4-methyl radical still represents the ^ -butyl radical when Hai den 3-chloro substituents and R are hydrogen. The non-toxic acid addition salts of these compounds fall also under this invention.

Of the compounds of the formula II, those are preferred in which η 1 or 2 and Alk is lower alkyl with 1 to 5 carbon atoms.

Another special embodiment of the invention describes a class of new chemical compounds that contain a phenyl radical * which by at least 2 halogen atoms is substituted and is connected to the biguanide chain at the! position "

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These compounds correspond to the following structural formula:

_γ j

.JÖSj V_ NH-C-NH-C-MH

wherein X, Y and Z can be located anywhere on the ring and X and Y are fluorine, chlorine, bromine or iodine, while Z is hydrogen, fluorine, chlorine, bromine or iodine, with the proviso that X or Y is not Represents 2-bromine substituents when the remaining symbol Y or X signifies the 4-chloro or 4-bromine substituents, while Z represents the hydrogen atom, and that in those cases in which X and Y represent chlorine atoms and are in positions other than in the 2- and 6-positions, Z does not represent a hydrogen atom, and in those cases in which X, Y and Z represent chlorine atoms and X and Y are in the J> and 4-positions, Z are in the 2-position is located. The non-toxic acid addition salts of these compounds are also included in this invention.

The particularly preferred compounds of this type according to structural formula III are those in which X and Y fluorine, chlorine or bromine and Z hydrogen, fluorine,

3 0 S 6 2 0 '/ 10 5 1

Chlorine or bromine.

Another special embodiment of this. Invention describes a class of new chemical Compounds / which contains a phenyl radical which at least one trifluoromethyl group or another fluorinated substituents and in the 1-position is connected to the biguanide chain.

These compounds correspond to the following structural formula:

NH NH HH

NH-C-NH-C-NH ₂ ^IV

where X 'is the 2-trifluoromethyl radical, provided that Y' is halogen, nitro or trifluoromethyl, or X 'is the' 3-trifluoromethyl radical, provided that Y 'is halogen, nitro or trifluoromethyl, provided that Y ^{1 is} not a 4-halogen or 4 -Nitro substituents, or X * denotes the 4-trifluoromethyl radical, provided that Y 'denotes nitro or trifluoromethyl, or X ^! represents the hydrogen atom if Y 'is trifluoromethoxy, difluoroacetyl, trifluoroacetyl or trifluorosulfonyl.

The particularly preferred compounds of this embodiment of the formula IV are those in which Y '

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Means fluorine, chlorine or bromine.

The present invention also relates to a new method for the treatment of gastrointestinal complaints and diseases and consists in the administration of 1-phenylbissuanide compounds of the structural formula I.

The present invention also describes a new method for the treatment of high blood pressure caused discomfort and consists in the administration of a therapeutically effective amount of the phenyl biguanide compounds the structural formula I.

The pharmacologist knows that non-toxic acid addition salts of pharmacologically active amine compounds do not differ from the corresponding free bases in terms of their effectiveness. The salts are only advantageous with regard to the solubility factor. ...

The amines according to the invention can be easily into the non-toxic acid addition salts thereof by conventional methods convict. The non-toxic salts of this invention are those salts whose acidic component pharmacologically at the dosages in question Allowed are «Such salts can be derived from inorganic acids, organic acids, higher fatty acids, high molecular weight Acids, etc., with the examples

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the following acids: hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, Malic acid, succinic acid, glycolic acid ,. Lactic acid, salicylic acid, Benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid, abietic acid, etc.

The compounds according to the invention can be obtained by the following methods:

One can use a cyanoguanide and a substituted aniline in the presence of an equimolar amount of a mineral acid condense to give the corresponding substituted phenyl biguanide.

The following reaction equation illustrates this synthesis:

N Il

HX + C-NH-C-NH ₂

NH NH

o v- ^nh - ^c - ^nh - ^c " ^nh 2 · ^hx Rb %

NH NH

if f!

.NH-C-NH-C-NK,

where HX is an acid, e.g. sulfuric acid, hydrochloric acid, hydrogen bromide acid, hydriodic acid, phosphoric acid, nitric acid, alkyl sulfonic acids, aryl sulfonic acids, or an acidic compound, e.g. monohydrogen sulfate, monoalkyl sulfate, Means dihydrogen phosphates, hydrogen alkyl phosphates, and similar strongly acidic compounds. Instead of a To add such acidic compound to the reaction mixture, one can also use the corresponding acid addition salts of the use substituted anilines.

The implementation is preferably carried out with the aid

or all one of an aniline salt either in a polar medium / and using elevated temperatures. Any acid addition salt of the amine can be used as the salt, but the salt of a mineral acid will preferably be used. An aqueous, partially aqueous or a non-aqueous solution can be used as the polar medium. A solvent will preferably be used which refluxes at the desired reaction temperature. Particularly preferred solvents are water or alcohol, but other solvents can also be used, such as, for example, DMSO, diethylene glycol, ethylene glycol, tetrahydrofuran, dimethylformamide, etc. The reaction should also be carried out at a temperature which is high enough for condensation to easily occur, but not so high that the bigua-

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does not decompose. The reaction temperature may vary between room temperature and about 250 ⁰ C, but it is preferably the reaction at temperatures in the range of about 50 to perform up to 150 ⁰ C. The biguanide salt formed can be converted into the free base with a metal hydroxide or alkoxide solution. The desired biguanide can be isolated in a manner known per se.

According to a specific embodiment of this invention, there is a new method of manufacture
of the biguanide compounds in question. It was surprisingly found that in the
Reaction of a substituted aniline with cyanoguanidine in a weakly acidic solvent which is not nucleophilic, the condensation occurs in high yield.

It was also found that this implementation works with both strong

/ sterically hindered as well as with very little reactive anilines takes place. A phenolic solvent, for example phenol, cresol, xylenol, etc., will preferably be used. The reaction can take place at temperatures between
Happen room temperature and about 150 ⁰ C, but it is preferably to use temperatures between 60'und 100 ⁰ C. The isolation of the reaction product can be based on

happen in a former or physical way. Preferably but if the salt of the product from the reaction

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mixed with the help of a non-polar solvent, e.g. ether, precipitate. But you can also use the reaction mixture make alkaline and extract with ether.

The anilines used as starting materials are either known or can be known per se Way to be made. For example, one can alkylate an acetanilide using a Alkyl halide and aluminum chloride according to the Friedel-Crafts method perform the desired sub-

ιί '

stitution in the o and p positions. The chlorination or bromination of an acetanilide or aniline can be carried out in acetic acid or in the presence of a small amount of iodine dissolved in an inert solvent, for example carbon tetrachloride. A chlorine or bromine solution is then added, the temperature being kept in the vicinity of ⁰ ° C. In this way halogenation occurs in the o- and / or p-positions. The desired alkyl haloanilides are obtained by alkylation or halogenation with subsequent halogenation or alkylation. Further alkylation or halogenation leads to the desired polysubstituted anilides. By deacylation with 50 fo sulfuric acid or alcoholic potassium hydroxide yields the aniline.

The iodination can also be carried out according to the methods known in the literature using iodine monochloride

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(ClJ) happen.

As mentioned above, an acetanilide can be alkylated and / or halogenated to form an o- and / or p-halogen and / or alkylacetanilide to obtain. A Friedel-Crafts reaction of this latter compound with acetyl chloride leads to the introduction of the acetyl group in the p-position of the acetanilide. The acetamido group can then desacy-

compound and then diazonium / deaminated, being the desired m-alkyl and / or halogen substitution achieved. The acetophenone can then be converted into the cocime, which is followed by a Beckmann rearrangement an acetamide can be obtained. The deacylation yields the aniline. Further alkylation and / or halogenation leads to ortho / para substitution.

By nitration of the above anilides and subsequent reduction to the amine, which then under Formation of the diazonium fluoroborate is diazotized and thermal is decomposed, the fluoranilide is obtained .. By diazotization and subsequent Sandmeyer reaction with cuprous chloride, The haloanilide is obtained from cuprobromide or cuprojödid.

The chlorination, bromination or iodination of an acetanilide or aniline can be carried out in acetic acid or in the presence a small amount of iodine * dissolved in an inert solvent, e.g. carbon tetrachloride will. A solution of chlorine is then added

Bromine or iodine monochloride, keeping the temperature close to ⁰ ° C. In this way there is a substitution in the o and p positions. The desired mixed haloanilides are obtained by halogenation and subsequent second halogenation. The desired polysubstituted anilides are obtained by further halogenation. Deacylation with 50% sulfuric acid or alcoholic potassium hydroxide leads to aniline.

If the halogenation is carried out according to the above information with acetophenone or an o- or p-halogen substituted If acetophenone is used instead of anilide, the substitution takes place in the m-position. The formation of an oxime and the subsequent Beckmann rearrangement leads to acetamide, which is then deacylated to aniline.

The nitration of the above anilides and the subsequent reduction to the amine, which you then to Diazonium fluoroborate diazotized and thermally decomposed, leads to the fluoranilide. By diazotization and then Sandmeyer reaction with cuprous chloride, cuprobromide or Cuproiodide is used to obtain the haloanilide.

Is a halogen compound, in which the halogen atom is chlorine, bromine or iodine, can be reacted with Cuprocyanid in quinoline at about 150 ⁰ C to give a cyano compound. But you can also use trifluor

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, as described in Tetrahedron Letters 47, 4095 (1959) implement methyljödid and copper powder at about 150 ⁰ C in dimethylformamide to obtain a trifluoromethyl compound.

A halogen atom can under the Rosenmund-Von Brown conditions with the formation of the nitrile compound are treated, which in turn can be hydrolyzed to form a carboxyl compound. The nitro group can be reduced to an amino group, which is alkylated with the introduction of the dialkylamino substituent can. A hydroxyl compound can be obtained by demethylating a methoxy substituent. The Sandmeyer reaction can take place with an amino compound, whereby a chlorine, bromine, xanthate, hydroxyl or introduces alkoxy substituents. The xanthate can then be converted into the meraapto compound by hydrolysis which, in turn, form an alkylthio-

can
group are alkylatedZ ~ .which in turn can be oxidized to alkylsulfinyl and alkylsulfonyl groups. A thiocyanato group can be reduced to a mercapto group. An iodine substituent can be removed by catalytic hydrogenation.

Reactions can also be carried out with the 1-phenylbigpsnide compounds perform, obtaining further substituted products. In this context, it was found

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that 1-phenyl biguanides are alkylated, halogenated, nitrated or thiocyanate to give the corresponding substituted products.

The compounds according to the invention have a valuable degree of inhibiting gastric juice secretion Efficacy and are effective in reducing the volume, ': and acidity of gastric juice in humans and mammals. Furthermore, these compounds produce a considerable spasmolytic effect on the gastrointestinal muscles, i.e. they reduce the peristalsis of the gastrointestinal muscles, which can be determined by a delay in gastric emptying. It should also be emphasized that these compounds are also characterized by an extremely low acute oral Distinguish toxicity.

In particular, those described in the present description are substituted in the 1-position Phenylbiguanide for the treatment of digestive disorders and diseases such as duodenal ulcers and ulcusbepticum, are valuable.

The present compounds can be used alone or in conjunction with other known anti-gastric acid agents, such as aluminum hydroxide, magnesium hydroxide, Magnesium trisilicate, aluminum glycinate, calcium carbonate etc., use.

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The compounds according to the invention have antihypertensive effects and are therefore also suitable as antihypertensive agents.

For all these purposes, the inventive Biguanides are usually administered orally or parenterally. Orally they can be taken as tablets, watery ones or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or Administer syrups or elixirs. The term "parenteral" as used in the present text includes the subcutaneous Injection, intravenous, intramuscular, or intrasternal injection, or the usual infusion methods *

Preparations intended for oral use can be prepared using a conventional method of pharmaceutical preparations. Such preparations may include one or more agents, e.g. Sweeteners> Flavor-correcting agents, coloring agents and preservatives, contain to a pharmaceutical grade to deliver cheap and edible preparation. An 'effective 1-aryl or 1-aralkyl biguanide in admixture with Tablets containing non-toxic pharmaceutically acceptable excipients are suitable for this purpose. Such excipients For example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and

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Disintegrants, e.g. corn starch or alginic acid, binders, e.g. starch, gelatin or acacia gum, and lubricants, e.g. magnesium stearate, stearic acid or talc. The tablets can be uncoated, or they can be coated by conventional methods in order to disintegrate and absorb in the gastrointestinal tract delay and thereby cause a protracted effect over a longer period of time.

For oral use you can also use hard gelatine capsules, in which the active substance is also used an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. Man can also produce soft gelatin capsules in which the active substance is mixed with an oil medium, e.g. peanut oil, liquid paraffin or olive oil.

Containing the active 1-aryl and 1-aralkyl biguanides aqueous solutions form a further embodiment of the invention. If necessary, you can also use watery Use suitable excipients for suspensions. Such exercises are suspending agents, e.g. sodium carboxymethyl cellulose, Methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidine, tragacanth gum and acacia gum. Dispersants or wetting agents can also be used, e.g. naturally occurring phosphatides, such as lecithin. Also condensation products

3 π :) e 2 o / 1 η f.

of an alkylene oxide with fatty acids, e.g. polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, e.g. heptadecaäthylenoxycetanol, or condensation products of ethylene oxide with partial esters, which differ from fatty acids and a Derive hexitol, e.g. polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial Esters derived from fatty acids and hexitol anhydrides, e.g. polyoxyethylene sorbitan monooleate, are possible candidates. These aqueous suspensions can also one or more. Preservatives, e.g. ethyl or n-propyl-p-hydroxybenzoate, one or more colorants, -contain one or more taste-correcting agents and one or more sweeteners, e.g. sucrose. ',.

Oily suspensions can be obtained in this way; that the active substance is suspended in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil, for example liquid paraffin. The oily suspensions can contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweeteners, for example those of the type mentioned above, and taste-correcting agents can be added in order to obtain an edible oral preparation. These preparations can by adding an antioxidant, for example

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Ascorbic acid.

Dispcrgable powder and granules, which are suitable for the preparation of an aqueous suspension Suitable for adding water, contain the active ingredient · in Admixture with a dispersant, wetting agent or suspending agent, being used as a suspending agent or wetting agent those already mentioned above can be considered. Additional excipient, e.g. sweeteners, pouch-correcting Agents and coloring agents can also be present.

The compounds according to the invention can also in the form of oil-in-water emulsions. The oily one Phase can be a vegetable oil], e.g. olive oil odor Peanut oil or a mineral oil such as liquid paraffin .; or mixtures thereof. Suitable emulsifiers can Naturally occurring gums, e.g. acacia gum or tragacanth gum, naturally occurring phosphatides, e.g. soybean lecithin, and esters or partial lister, derived from fatty acids and hexitanhydrides, e.g., sorbitan monooleate. The emulsions can contain sweeteners and contain taste-correcting agents.

Syrups and elixirs can contain nutrients such as glycerine, sorbitol or sucrose. Such preparations can also be a pain reliever, a preservative, and a taste-correcting and coloring agent contain. The pharmaceutical preparations can ■

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Be in the form of a sterile injectable preparation, e.g. in the form of a sterile injectable aqueous suspension. This suspension can be compiled in a known manner using such suitable dispersing agents or wetting agents and suspending agents as mentioned above. The sterile injectable preparations can also be in the form of sterile injectables Solutions or suspensions in a non-toxic, parenteral acceptable diluents or solvents, for example in the form of an aqueous solution which is buffered to a pH of 4.0 to 7 * O and moreover isotonic by adding sodium chloride.

Furthermore, these compounds can be tabletted or otherwise formulated so that on in each case 100 parts by weight of the preparation 5 to 95 parts by weight of active substance are present. The dosage unit form generally contains between approximately 1 mg and approximately 500 mg active substances according to the invention. The preferred one Dosage unit contains about 10 mg to about 100 mg.

The dosage is done so that the maximum te-Vapeutisohe Response is guaranteed until improvement has occurred, whereupon one has the minimum effective There is a dose which provides relief or relief. Thus, one will generally adjust the dosages

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choose so that they can be used therapeutically in the treatment of gastrointestinal disease states or symptoms, e.g. for duodenal ulcers and ulcers pepticum, and are effective for relieving discomfort caused by high blood pressure. in the in general, the daily dose can vary between approximately 0.5 mg / kg and 70 mg / kg (preferably 2-25 '"S / ^ gA'ag), whereby one should of course be careful ι that when determining the appropriate dosage for one specific case the patient's weight, general health, age and other factors, which may affect the response to the drug »should be considered.

Various animal experiments have been carried out to determine whether the inventive

probably
Compounds / are also effective in humans. These tests relate to the effect of phenylbiguanides substituted in the 1-position on gastric juice secretion, their spasmolytic effect, their mydriatic effect and the determination of their toxicity. It was found that the compounds according to the invention are extremely effective under the circumstances mentioned above.

One such test is the gastric juice secretion test. This test is carried out as follows: Shay rats are left Starve for 4 to 8 hours while

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Water ad lib. is made available. The rats are selected at random and divided into groups of 10 animals each. These animals are treated intraduodenally (ID) with the test compound or vehicle immediately after the stomach is ligated to the pyloric ring. The animals are then killed with chloroform after a period of h hours, the stomach taken out and tested for its content .in terms of volume, pH and acid content Gesarat.

A second gastric secretion test will be performed on

Dog carried. This test is described in the Handbook of Physiology, Section 6: Alimentary Canal, Volume I]: Secretion} American Physiology Society, Washington, D.C 1967 *.

It has been found that the compounds of the invention, when subjected to the gastric juice secretion tests mentioned above, show a pronounced ability to reduce gastric volume and gastric acidity. These tests _; correspond best to the effect on the stomach in humans and are therefore standard tests for determining the secretion-inhibiting properties.

To prove the anti-ulcer effectiveness, the following test is carried out. Male Wistar rats (130-150 g) are fasted for 2 hours,

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whereupon they were given 5 mg / kg reserpine intraperitoneally. The stomachs are removed after 24 hours and checked for ulcer formation. The ulcers were rated on a scale of 0 to 4 and the number of ulcers established. Pretreatment with the biguanide compounds according to the invention reduces the Degree and number of ulcerations compared to reserpine-treated control rats, achieved.

The determination of the antispasmolytic properties can be carried out according to the method of D.A. Brodle and S.K. Kundrats in "Effect of Drugs on Gastric Emptying in Rats," Fed. Proc. 24_, fl4 (1965).

The pupillary dilatation is done according to the method by R.A. Turner, Screening Methods in Pharmacology, Academic Press, New York and London, pp. 17 ^ -175 * 1965. The acute toxicity is determined according to the usual Litchfield-Wilcoxon method calculated.

In view of the results of such tests, the pharinakological data clearly show that the Phenyl biguanide substituted in the 1-position as an effective agent inhibiting magenta secretion] and Antispasmodics can be considered which are practical are free from anticholinergic side effects and moreover have a low toxicity.

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Tests were also carried out on animals to determine the ability of the compounds of the formula I to prevention of reactions, which may be present as side effects in people with high blood pressure, to “prove. One such test is by Ryo Tabei, Sydney Spector, William J, Louis and Albert Sjoerdsma in Clinical Pharmacology and Therapeutics, Vol. 11, No. 2,269-2γ4 (1970). This test method is known to have a good correlation with high blood pressure in humans, and it is considered the standard method for determining the blood pressure seri * properties. In view of the results of this test, the 1-phenyl biguanides of this invention be considered effective antihypertensive agents »

In order to determine the depressive effect of the compounds of the formula I on the central nervous system, the Suppression of spontaneous motor activity at normal ** len mice (18-22 g) and immature rats (90-100 g) according to the method of Dews, Brit »J. Pharmacol * J3, 46 (1953) determined »The results of this test show that a relative increase in the sedative effect is evident.

The following are detailed examples of the preparation of the compounds according to the invention is shown. They are not intended to be limiting in any way Be nature.

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Example 1 I- (p-Trifluoromethoxypheny1) -biguanid-dlhydrochlqri d

A mixture of 6.3 g (0.0296 mole) of p-Aminophenyltrifluormethyläther hydrochloride and 2.49 g (0.0296 fabi) cyanoguanidine is immersed with stirring in a heated oil bath at 210 ⁰ C for 15 minutes. The amber-colored, glass-like reaction product obtained is dissolved in 100 ml of water, made alkaline with 40% strength sodium hydroxide solution and extracted with 250 ml of ether. The ethereal layer is washed twice with 10 ml of water, dried over sodium carbonate and filtered, and the ethereal solution is made strongly acidic by adding a saturated, ethereal hydrochloric acid solution. The precipitate is collected on a filter, washed twice with 50 ml of anhydrous ether and dried at 25 ° C / 125 mm. Recrystallization from a mixture of isopropanol and cyolohexane (mixing ratio 1: 1) gives 1- (p-trifluoromethoxyphenyl) biguanide dihydrochloride.

Example 2

1- (p-Tolyl) biguanide dihydrochloride

A mixture of 4.3 g (0.03 mol) of p-toluidine

hydrochloride and 2.5 g (0.03 mol) of cyanoguanidine with stirring is immersed in a heated oil bath at 210 ⁰ C for 15 minutes. The amber-colored, glass-like reaction product obtained is in 100 ml

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placed and extracted with 250 ml of ether. The ethereal layer is washed twice with 10 ml of water, dried over sodium carbonate, filtered and the ethereal solution is made strongly acidic by adding a saturated, ethereal hydrochloric acid solution. The precipitate is collected on a filter, washed twice with 50 ml of anhydrous ether and dried in vacuo at .25 ⁰ C, to yield the l- (p-tolyl) -blguanid dihydrochloride.

Example 3 1- (2-chloro-4-methylphenyl) biguanide hydrochloride

To 0.05 mol of l- (p-tolyl) biguanide, dissolved in 75 ml of acetic acid, 9 ml of conc. Hydrochloric acid and then 1.7 g (0.0164 mol) of sodium chlorate in 4 ml of water. The temperature is maintained under stirring for 10 hours to less than 25 ⁰ C and then the mixture was cooled in an ice bath. 40% strength sodium hydroxide solution is added to the reaction mixture and the mixture is extracted with ether. The ether is treated with water, dried over magnesium sulfite and evaporated to dryness. The Chlorhydratsalζ is then prepared by addition of ethanolic hydrochloric acid to give the l- (2-chloro-4-me thy! Phenyl) -biguanide hydrochloride is obtained.

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Example * 4 l- (p-N, N ~ dimethylsulfamylphenyl) -biguanide

To 11 g (0.055 mol) ρ-Ν, Ν-dimethylsulfamylaniline 17.68 ml (0.055 mol) of 3.1N hydrochloric acid are added. This reaction mixture is then used on the steam bath with 15 ml of isopropanol and 4.62 g (0.055 mol) of cyanoguanidine heated for 18 hours. The alcohol is evaporated and the remaining product with 250 ml of 7.4 $ hydrochloric acid diluted. The mixture is then filtered, cooled and made alkaline with 10% sodium hydroxide solution. The precipitate is filtered off, stirred with 100 ml of boiling isopropanol and filtered, l- (p-N, N-dimethylsulfamylphenyl) biguanide being obtained receives.

■ Example 5

l-.f 3j5-Di- ( trii'luorrnethy 3 ) -phenyl! -biguani d

To 22.9 g (0.1 mol) of 3,5-di- (trifluortnethy.l) aniline, and 8, ^J lg (0.1 mol) are added Cyanoguanidjn 10 nu conc. Add hydrochloric acid and 20 ml of water. The solution was then heated on a water bath for 1 hour, until a solid precipitate formed. Dar Heaktioniigeriii sch wj rd to room temperature cooled with ^J t0 $ sodium hydroxide solution strongly nlkal: I asked 3Ch. And then mj t p ether .- trahJert?. The ether layer becomes Π1χ: γ potassium carbonate- ρ: - ·

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dries and evaporated in vacuo, leaving an oil behind. This residue is mixed with 500 ml of heptane rubbed and the solid product formed was recrystallized from methylene chloride, 1-f3J5-di- (trifluoromethyl) ~ phenyl] biguanide.

Example 6 1-( 2> 3 j 4j 6-tetrafluorophenyl) biguanide

A mixture of 7.0 g (0.035 moles) 2,3,4 * 6 - ^ - träfluoroaniline hydrochloride and 2.9 g (0.035 mol) cyano-guanidine is brought to melt by heating for 1 1/2 hours. The mixture is then cooled, heated with 25 ml of water until solution has occurred, whereupon this solution is treated with 4ü $ -iger Matronlauge alkaline. The solution is then extracted with ether and dried over potassium carbonate and evaporated to dryness. The residue is taken over silica gel Use of a mixture of isopropanol and ammonium hydroxide Ehromabographiert, l- (2,3,4,6-Tetrafluorophenyl) -biguanid receives.

Example 7
l - ^^ - DLchlorphenylJ-bifmanid

A mixture of 300 g (1.85 mol) of 2,6-dichloro

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aniline, 155 g (1.85 mol) of cyanoguanidine and 712 ml 2,6N hydrochloric acid (1.85 mol) is heated during several hours at ⁰ C 6o. The reaction mixture is then cooled, made alkaline with 10% sodium hydroxide and extracted with a mixture of ether and methanol in a mixing ratio of 1: 1. The extract is washed with a saturated saline solution and dried over sodium sulfate. The solvent is evaporated and replaced with benzene to give the crude product after concentration. The residue is dissolved in 100 ml of hot methanol and diluted with 200 nü. V / ater offset. The precipitate is isolated, washed with water and dried. The hydrochloride salt is then treated in alcohol to give 1- (2,6-dicftlorophenyl) biguanide.

Example 8
. l- (2,5-Dlohlor - ^ - f luorp henyl) -biguan.id- hyd> rochlorid

A mixture of Vf, 9 g (0.22 mol) of 2,5-dichloro-4-fluoroaniline hydrochloride and 19.4 grams (0.23 moles) of cyanoguanidines in 300 ml of m-cresol is on the V / asserbade during Heated for 1 hour. The reaction mixture is then cooled and charged with ether, a precipitate being formed will. This precipitate is filtered off and stored in v / poor

the filtrate dissolved water, treated with charcoal and filtered and / here-

chilled on in an ice bath. This is followed by 10 fi

BATH ORIGINAL

309820/1051

- "51 -

Sodium hydroxide solution to make the mixture strongly alkaline

with residue

to deliver. The mixture is then filtered and / with water washed. It is then dissolved in methanol and the pH is adjusted to 7 using methanolic hydrochloric acid

• r de Rü residue

and the mixture evaporated to dryness / rubbed with ether and filtered off, l- (2,5-dichloro-4-fluorophenyl) biguanide hydrochloride receives.

Example 9 l- (2-chloro-6-ethylphenyl) biguanide hydrochloride

A mixture of 3 g (0.0156 mol) of 2-chloro-6-ethylaniline hydrochloride and 1.35 g (0.16 moles) of cyanoguanidine in 25 ml of m-cresol is on the for 1 hour Steam bath heated. The reaction mixture is then cooled and 250 ml of ether are added. The precipitation is filtered off and dissolved in 100 ml of warm water, treated with charcoal and filtered and finally in one Chilled ice bath. 10 $ sodium hydroxide solution is then added, to make the mixture strongly alkaline

d lagging behind he R

place. The mixture is then filtered and / or washed with water. This product is then dissolved in methanol, the pH is adjusted to 7 by means of methanolic hydrochloric acid and the mixture is evaporated to dryness, triturated with ether and filtered, l- (2-chloro-6-ethy! Phenyl) -bluuanide-hydrochloride i d receives,

8ADÖR {GINAt 309820/1 OR 1

Example 10 1- (2,6-dichloro- ^j + -methylphenyl) -biguanide hydrochloride

35 ml of conc. Hydrochloric acid is added, whereupon 6.95 g (0.0653 mol) of sodium chlorate in 15 ml of water are added dropwise. The temperature is kept at less than 25 ^° C. for 15 hours while stirring. The reaction mixture is then mixed with high sodium hydroxide solution, with ice and with ether and extracted. The ether layer is washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is added to 75 ml of methanol and 75 ml of water and stirred in an ice bath and then filtered. The residue is added to ethanolic hydrochloric acid, l- (2,6-dichloro-4-methylphenyl) biguanide hydrochloride being obtained.

Example 11 1- (2,6-dibromo-t ^j-tri f trifluoromethyl phenyl) -biguanide

A suspension of 15 g (0.06 mol) of p-trifluoromethylphenyl chloride in 200 ml of water, 19.2 g (0.12 mol) of bromine are added dropwise over the course of 3 hours. Then the Roaktjonsgernirsoh is cooled and that is not converted bromine is eliminated by means of sodium sulfite. That

309820/10 61

Mixture is then made strongly alkaline and with Aether extracted. The ethereal layer is dried over sodium sulfate, treated with charcoal, filtered and evaporates. The solid residue is recrystallized from a mixture of dioxane and water, l- (2,6-dibromo-4-trifluoromethylphenyl) biguanide being obtained receives.

Example 12 1- (2-Bromo-4-methylphenyl) biguanide

To a suspension of 10 g (0.0523 mol) of 1- (p-tolyl) biguanide in 175 ml of water, 8.4 g (0.053 mol) of bromine are added dropwise over the course of 3 hours. The reaction mixture is cooled and the unreacted bromine is eliminated using sodium bisulfite. The mixture will then made strongly alkaline and extracted with ether. The ethereal layer is dried over sodium sulfate, treated with charcoal, filtered and evaporated to give 1- (2-bromo-4-methylphenyl) biguanide.

If 2 moles of bromine are used in the above example, 1- (2,6-dibromo-4-methylphenyl) biguanide is obtained.

Example I3 ! .- (2,6 ~ dichloro-4-thiocyanatophenyl) -biguanide

A solution of 1- (2,6-dichlorophenyl) biguanide

309820/1051

(28.0 g, 0.1 mol) in methanol (60 ml), which has previously been saturated with sodium bromide, is cooled ^{to 5 ° C. with stirring.} Sodium thiocyanate is then added and the mixture is stirred for 10 minutes. A solution of ± 1.6 g of bromine in 20 ml of methanol, which has previously been saturated with sodium bromide, is then added dropwise to the mixture, while stirring. After the reaction has ended, 300 ml of water are added and the mixture is adjusted to a pH of 12 using 40 # sodium hydroxide solution. The organic base is extracted with ether and the ethereal solution washed with brine, dried over sodium sulfate and evaporated to dryness. The residue is allowed to crystallize from aqueous methanol, l- (2,6-dichloro - ^ - thiocyanatophenyl) biguanide being obtained.

Example 1Λ l - (^ - Nitro-2,6-dichlorophenyl) -biguanide

lh g of l- (2,6-dichlorophenyl) biguanide hydrochloride are added to 18 ml of conc. Sulfuric acid was added and the reaction mixture was stirred for 5 minutes. Then 2.5 ml of conc. Nitric acid (specific gravity 1.51) while maintaining the temperature, if necessary, by cooling with water to 30 to ⁰ 4o C. After the addition of the nitric acid has ended, the mixture is stirred for 10 minutes and then poured into water. Then

309820/1051

22512S0

the mixture is made alkaline with sodium hydroxide and extracted with ether. The ether extract is washed, dried over sodium sulfate, evaporated and the residue allowed to crystallize from aqueous methanol, 1- (4-nitro-2,6-dichlorophenyl) biguanide is obtained.

Example 15 1- (2,6-Dibromopheny1) -biguanid-hydroiodide.

A solution of 1- (2,6-dibromo-4-iodophenyl) -biguanide (4γ g, 0, I ₁ mol) in methanol (500 ml) is in a hydrogen atmosphere in the presence of 5 $ palladium-on-carbon (lg) shaken. After an uptake of hydrogen of 2, 4l has determined at room temperature and atmospheric pressure, is interrupted, the shaking and the mixture filtered through diatomaceous earth. The piltrate is evaporated to dryness and the solid residue is dissolved in 100 ml of methanol. After adding 150 ml of ether with stirring, 1- (2,6-dibromophenyl) biguanide hydroiodide is obtained.

Example 16

According to the above methods using the chlorohydrate salt of

309820/1051

h -Vinyl-2-chloranill in,

^ t-Al lyl-2-chloroaniline,

^ l-Methallyl-2-chl orani lin,

4 - (^ - pentenyl) -2-ehloranil: in and

^J l-propargyl -2-chloranine is obtained

J- (I] -Vinyl -2-chloropheny 1) -biguanid,

l- ( ^; l-Λllyl-2-eh] orpheny]) -biguanid,

1 - ( l \ -Mothai 1 y1-2-chiorpheny]) -b if uanid,

] -f 4 - (^ - pentenyl) ~ 2 - ohlorpht! nyl! -biguanid and

] - (^ l-propargyl -2-chloropheny1) -biguanide.

D e i fH) i ej 1 <

If one works according to the biij in Examples 1
16 information given under Usage; the Aucnanfjijmsiterial ion, no f _{3 mentioned} below, one υλι the corresponding end products.
Aufp / rancmiiateria l final product

2,3-Di chi or / aniline 1 - (2,3-Di chi or / phenyl) - bi guan i d

2,4-Dichi or / ani 1 i η 1 - (2,4-Di chi or / phony 1 ^Y bigtiani d

2,1-difluor / anilii. 1- (2,4-difluoro / phenyl) biguanide

2,5-Di chi or / ani 1 i n 1- (?, I> -I) ichl or / phenylHngiuni d

2,5-Diil uor / anil in T - (2, B-Di f 1 uo rv ph eny I) - b i g u a η i d

2,6-dichloro / anil in 1- (?, F'-dichloro ^ phenyl) -biquatiid

2,6-difluoro / anil in 1- (2, f> - difluoro / phenyl) -biguanide

3,4-Dichlorx.inil in 1 "(3,4-dichloro / phenyl> -bigiianid

3,1) -Dichi or / anil i η 1 - (3,5-Dichio * vphenyI) -Liguani d

3 0 9 8 2 0/1 0 S 1 6AD ORtGtNAL

2,4-DiJοdvanil in
2,3,4-TriehlinvariiTin 2,3> 5 - Tnchloivanilin 2 »3 _V 6 - Trichloryani'iin 2,4 ,. 5- ^r i'r ic hi ο r / a π i 1 i η 2,4,6-trichloro / aniline 3,4 _f 5-trichlot - / 'dniltri 2,3-dibror; 5'anil in
2,4 - PH)) On! / A nil in
2 »S-D'ibrora / a η i 1 i η
2,6-dibroni / anil in
3,4-dibromo / aniline
3,5-dibroni'anil in
2,4,6-tribromo / anil in 2-chloro-3-brora / anil i η 2-chloro-4-broni / anil in 2-chloro-5-bromo / anil in 2-chloro-6-bronvanil in 3 -Chlor — 1 · bronvanil in 3-CJi 1 ο r — 5 - b \ on ν a η i 1 i η

4-Chior ~ 2-brom 'mi 1 in 4-chloro-3-b) Oiiv.in i 1 in 2-chloro-4-JO (1-mil in 4-Cti I or -—2-} often ^ an i 1 ι η • 1- (2,4-Dijod ^ phenylHiiguani d l- (2,3 _s 4-Trichlotvplienyi) -biguanid l- (2,3,5-Trichlor / 'phonyl) -bi (jLianid l - (2,3 _J 6-Trichlorophenyl) -biguairid 1- (2,4,5-Trichi or / phe ^ yD-biguani dl "(2,4,6-Trichloro / phenyl) -biguanid i" (3,4 , 5-trichloro / phenyl) -biguanide 1 - (2,3-di bromo / phenyl) -bi g uani ei T- (2,4-di brorii / phenyl) -bi g uani d 1- (2,5- Dibronvphenyl) kbiguanid

1 - (3,4-dibromo * phony l) -bi g ua ni d l- (3,5-dibronuphenyl) -biguanid 1 - (2,4,6-tri bromo'-pheny l) -bi guani d 1 - (2-ChI or — 3-bromine / phenyte) -biguanid 1 - (2-Chl or - 4-bronivph enyl) -bi guan id 1- (2-chloro- ^ 5-bröin4) henyl) -biguanid l- (2-chloro- "6-broin« 'phenyl) -big.uanid T- (3-Chi or-4-bj ^ oiii / -phenyl) -t) iguanid T - (v3-chloro-5-broni4) henyl) -biguanide 1- (3-chloro-6-bi ^% om ^ phenyl) -biguanide 1- (4-chloro-2-bronvphenyl) -biguanide 1- (1-chloro-S-bromo-'phenylJ -bi guani d T- (2-chloro-4-iodine>'|> hGriyl) -bigu.inid T- (4 -chloro-2-iodophenyl) -biguan id

SAD

2-CliI or —4- Π uorvani 1i η 2-Chl or — 5- Π uotν aniline 3-chlorine - 2-fluor.-anil in 4-ChI or — 2- f 1 uor ^ ani 1 i η 2, 4-dichloro-3-bronvanil in 2,4-di bromo-3-chloivaniline 2,5-dichloro-4-fluoro / anil in 2,6-dichloro-4-f 1 uor / a nil in 2,4 -Dichlur - 3-fluoro-anil in 3,4-dichloro-2-fluoro'anil in 2,6-dichloro-4-methyl anil in 2,6-dichloro-4-ethylaril in 2,6-dichloro- 4-propylaniline 2,6-dichloro-4-i-propylene Π in 2,4-di-fluoro-3-broni'anil in 2,6-dichloro -4-t-buty1anil in 2 | 4-di fluoro- 3-iodine "anil in 2-bromo-4-chloro-6-methylanil in 2-bromo-4-fluoro-6-chloro-anil in 2-chloro-3-bromo-4-fluorvani 1 in 2-chloro —4-methyl-6-broin ^ anil in 2-bruin-4-ynethy] anil in 2-Fl nor-4-mo thy lan Π in 2-chloro-4-methyl 3ni 1 in 2-chloro-4 -brom - 6-ine thy I an i 1 i η —4-fluoro'-phenyl) -biguanide 1- (2-chloro-5-fluoro ^ phenyl) -biguan1d l- (3-chloro-2-fluoro phenyl) -biguan1d ^r

1- (4-chloro-2-fluoro-phenyl) -biguanide 1- (2,4-dichloro-S-bronvphenylJ-biguanide 1- (2,4-dibromo-3-chloro-phenyl) -biguanide 1- (2 , 5-Di chi or-4-f 1 uoiv pheny l) -biguani d 1- (2, G-Di chi or-4-fluoivphenyl) -biguanid 1- (2,4-dichloro-3-fluorophenyl) -biguanide 1- (3,4-dichloro-2-fluoiv pheny!) - biguan id l- {2,6-dichloro-4-rnatliylphynyl) -biguanid l- (2,6-dichloro-4-ethylphynylH3igua ^ id 1- (2,6-DiChlor-4-propylphenyl) -biguanide 1 - ( 2 , 6 * Di chi or-4- i -propylphcnyl) -biguanid 1- (2,4-Difluoro-3-broni " phenyl) -biguanide 1- (2,6-dichloro-4-t-butylphenyl) -biguanide 1- (2,4-di-fluoro-3-iod'p! ienyl) -biguanide 1- (2-drom-4 -chlor- 6-methylphenyl) -biguanide 1-C2-bromo-4-fluoro-6-chloro-phenyl) -biguanide 1- (2-ChIor-3-bromo-4-fluoro-'phenyl) -biguanide 1 - (2-ChIor-4-methyl-6-bromo> phenyl) -biguanide 1 - (2-urünt -4-methyl-6-bromo-phenyl) -bi guarvid 1- (2-fluoro-4-methyl phenyiybiguan id

1- (2-ChUn 1-methy 1 phenyl biguanid

1- (2-ChI or-4-bromo-6-methylphenyT) -biguo.nid

IOSt

ÖAD OWGlNAU

2-chloro-5-trifluoro ^ methyl am '1 i η 4-bromo-2-tri f 1 uoiv methyl ani 1 i η 4-fluoro-2-trifluoromethylaniline 2-iodine- 4-methyl ani 1 i r. 3,5-dichloro-2-fluoro-aniline 3,5-dichloro-2-iodine-anil in 2,5-di-fluoro-3-bronvanil in 3,5-dibromo-2-iod'aniline 2-chloro-3-bromo-5-fluoro-anil in 2-bromo-3-f1uo r-5-c h1 o »ν a η i 1 i η 2-fluorine-5-tri f 1 uorvmethyl ani 1 i η

2-F1 uor-3-bromo-5-chloivanil in 2-chloro-3-fluoro-B-iod'-anil in 3,6-dibromo-2-chloivanil in 2,6-dichloro-3-jocbanil in 2-Tri f 1 uor ^ niethyl ani 1 i η

2-chloro-3-bromo -6-fl

2,4-dichloro-6-bronwniline 2, G-Di chi or— 4-bronvan i 1 i η 2,4-dichloro-6-iodine> -aniline 2,6-dichloro-4-iodine-aniline 2,4-dichloro-6-fluoivaniline 2-Cjilor-4-fluoro-6-iodo-aniline-2,4-Di bromine-6-chl or ^ aniline

- 39 -

1 - (2-Cin or-5-tri f 1 uor ^ methyl phenyl) -bi guani d 1 - (Ί-bromo-2-tri fluoiv methyl phcnyl) -bi guani d1- (4-fluoro-2 ~ trifluorxinethylphenyl) -bi9uanid 1- (2-iodine- 4-methylphenyl) -bi guani d 1 - (3,5-Di chi or-2-f 1 uor-'phenyl ^ bi guani d 1- (3,5- Dich! Or-2-, 5od-'phenyl) -biguanid 1- (2,5-Difluoro-3-brouKphenyl) -biguanid 1- (3,5-D "! Bromo-2- od« -phenyl) - biguanide 1- {2-chloro-3-bromo-5-fluoro ^ phenyl} -biguanide 1- (2-erom-5-trifluoro> -methylphenyl) -biguanide 1- (2-F] uo r - B- tri fluoro ^ methyl phenyl) biguanide

1 "(2-F1 uor -3-bromo-5-chlorophenyl) -bi guani d 1- (2-ChI or-3-f 1 uor - 5-iodophenyl> -bi guani d 1 - (3,6-di bromo- P-chi or ^ phenylH'igi'atii d 1- (2, C-Di chi (> r'-3-iodo ^ phenyl) 4) iguanide 1- (2-Tt i f 1 uorwnethyl-4-chTor -. PhGny1) -

biguanid

1 - (2-chloro-3-bromo-6-fluorine-phenyl) -biguanide

1 - (2 , 4-Όΐ chi or — G-bromo-phenyl} biguanid 1 - (2,6-Di chi oi — 4-bromo ^ phenyl) -bi guani d 1- (2,4-Di chi or— 6-iodo-phenyl) -biguanid 1- (2,6-dichloro-4-iod'-phenyl) -bigLianid 1- (2,4-di chi or-6-fluorophenyl) -bi guani dl - (2-chloro-4-fluoro-6-iodo-phenyl) -bi9ii <inid 1- (2,4-di-bromo-6-chloro-phenyl) -bigiianide

309820/1061

SAO ORIGINAL

2,5-dibromo-4-chloro-anil in 2,4-di bromo— 6-fluoro nile in 2,4-Dij od - 6-bronvanil in 2,4-difluoro-6-chloro- <aniline 2-chloro-4-bromo-6-iodine-aniliri 2-chloro-4-iodine-6-bronraniline 2-chloro-4-bromo-6-fluoro-anil in 2-chloro-r-4-fluor- 6-bronvanil in 2-bromo-4-chloro-G-fluoro-aniline 3,4-dichloro-5-bronvanil in 3,4-dichloro-5-fluoro-ranil in 3,4-Di Π uor — 5-chl or -anil in 3,5-Difluoro-4-ChIOr ^ aIiU in 3-chloro-4-bromo-5-fluoivanil in 3-chloro-4-fluoro-5-bromo-aniline 2-Xthyl-4-iodine ^ ani1 in 3-methy "! - 2,4,6-trichlotvanil in 2-methyl -3-chi or ^ arii 1 in 2-methyl-4-chloro'-anil in 2-methyl-5-chloro-ani 1 i η 2-methyl-6-chloro ^ anil in 3-methyl-2-chloro'-anil in S-methyl-'i-chior-'ann in 4-Methyl-2-clilo) vanil in 4 -Methyl -3- chi or- ^ a η i 1 i η 1- (2.6 "di-bromo-4-chloro-1-phenyl) -biguanide 1 - (2,4-Di bromo-6-f 1 uor ^ phenyl) -bi guani d 1- (2,4-Diiodo-6-broni'phenyl) biguanide 1- (2,4-D'fluoro-G-chloro-'phenylVbiguanide 1- (2-chloro-4-bromo-6-iodo-phenyl) -biguanide 1- (2-chloro-4-iodo-6-bromo'-phenyl) -biguanide 1- (2-ChI or -4-bromo-6-fluoro'-phenyl) -biguanide 1- (2-ChI or -4-fluoro-6-bromo 1-phenyl) -biguanide 1- (2-Bromo-4-chloro-6-fluoro-1-phenyl) -biguanide 1- (3,4-dichloro-5-bronphenyl) -biguanide 1- (3,4-Di chi or-5-fluoro'-phenyl) -biguanide 1- (3,4-difluoro-5-chl or ^ phenyD-biguanide 1- (3,5-Difluoro-4-chloro-1-phenyl) -biguanide 1- (3-ChI or -4-bromo-5-fluoro-1-phenyl) -biguanide 1- (3-chloro-4-fluoro-5-bromo-'phenyl) -biguanide l-0-WetJiyl-4-iodo-'phenyl) -biguanide 1- (3-methyl-2,4,6-trichloro ^ phenyl) biguanide 1 - (2-methyl -3-chloro "phenyl) biguanide 1 - (2-methyl -4-chloro-phenyl) -bi gua ni d 1- (2-Methyl-5-chloro-phenyl) -biguanide 1- (2-methyl-6-chloro-phenyl) -biguanide 1- (3-methyl-2-chloro'-phenyl) biguanide 1- (3-methyl-4-chloro- '' phenyl) -biguanide l- (1-methyl-2-ch "l or - phenyl Hiiguani'd ' 1- (4-Motliyl-3-chloro ^ phenyl) -bigu: uiid

BATH ORIGINAL

2-methyl-6-broiivanil in 4-methyl] -2-bromo-'an i 1 i η 2-i-methyl -3- f 1 uor-ani 1 in 2-methyl-4-fluoro "aniline 2-MebhyT"f; -nuor - anil in 2-Methyi -6- fl uorvanfl i η 3-Müthyl -Z- f 1 uor - ani 1 i η 3-Methyl-1-fluoro-'anilin 3-Methy! - 5- f 1 uor-- an Hin 3- Me thy1-6-fIu ora nil in 2-ethyl-4-chior ^ aniline 2-propyl-4-chl or ^ an'i! in 2-Butyl -4-chl or * -ani 1 in AK thy 1 - 2- ch 1 ο r-- a η i 1 i η 4-Profiyl -2-chl or ^ ani 1 in 4-Eii tyl -2 -ch 1 or-- ani 1 i η 4-) lthy1-2-bronwnil in 4-sec-BuLy-2-brom - aniline 4-Mi thy 1-2-f 1 uor ^ ani 1 ri η 2-methyl -4-iodine - dniline 2-tif: Lhy 1 - ¹ J-iodine- ^ an i 1 in 3-Me thy 1 "^ - JOcI - anil in l- (2-methyl
1- (4-methyl

l- (2-Metftyl
1- (2-methyl

1- (2-methyl
l- (2-methyl
l- (3-methyl
1- (3-Me thy!

6-bromo-phenyl) -biguanide 2 ~ bronvphenyl) biguanide

3-fluoro'phenyl) biguanide 4-fluoro (1) phenyl) biguanide.

5-fluo »vphenyl) biguanide 6-fluoro (1) phenyl) biguanide 2-fluoro-phenyl) -biguanide 4- Π uojvphenylVbiguanid

1- (3-MGthyl-6-nuor ^ phenyl) -biguam'd l- (2-Ä thy! -4-chl or ^ phenyl) -biguanide l- (2-propyl -4-chl or-phenyl) - biguanid 1- (2-butyl-4-chlor-phenyl) -biguanid 1- (4-kthyl-2-chlor.'phenyl) -biguanid 1- (4-propyl-2-chlorvphenyl> -biguanid l - (4-Eutyl-2-chloro-'phenyl) -biguanid 1- (4-Kthyl-2-broin / -phenyl) -biguanid 1- (4-sec-Butyl-2-bi'0 ₁ ii'phenyl) -biguanid 1- (4-methyl-2-tuoivphenyl) -biguanid 1 - ('2-Mc thy 1 -'hj od "phcnyl} -biguan id 1 - (2-Me Llivl -5-j od-'piienylj -b i giidti id 1 - (3-Fethyl -? .- jew'-phenyl) -biguanid I - (4-Me thy! -2-iodine-phe.nyl) -bi tjuani d

SAD OfMOINAL "

2251280

2,6-dichloro--ni troani1 in 2,6-dimelhoxyaniline

2,6-dichloro-4- (p-chloro-'phenyl) -anilirv

2,6-DifUior ^ aniline 2,6-Dinitroanil in 3 »4,5-T r imethoxyani1i η 3,5-1) i chi or -4-ine thoxyani 1 i η p-Dimetliylsul famylanil in 4-phenylanil in 2,6-dichloro-4-carbathoxyani1 in 2,6-dicarbethoxyaniline 4- (p-chloro- "phenoxy) -anil in

2,6-dichloro-4-dimethylamino anil in

2,6-di (trifluoro-methyl) aniline 2,4-dichloro'ani I in 2,4-dibroni ^ aniline 2,4-Di fluoro ^ anil in 2,3-Di fluoro ^ anil in 2,5-Di fluoro-'iinilin

p-Aniino-a, a, u-trifliioracctophcnon

p-Ai'iinopfuMiyl-fx, α, ctr ^ ri fluorine thy I sill ton

Di-3,5-tri fluoro - niothylani 1 in ö-Λιιιίiio-Z-bniiii-bfnzotri Πuarid 1- (2,6-Di-chloro-4-nitrophenyl) -bigu2nide 1 - (2,6-Di methoxypheny]) - b i guani d

- 4- (p-chloro-'phenyl) -phynyl] -

[
biguanid

1 - (2,6-Di f 1 nor "phenyl) -bi guan i d 1 - (2,6-Di nitrophenyl) -bi guani d 1- (3,4,5-trimethoxyphenyl) -bi guani d 1- (3,5-dichloro-4-methoxyphenyl) -bi guani d 1- (p-Dimethyl sulphamylphenyl) biguanide 1- (4-Bi phenyl yl) -bi guani d 1 - (2,6-Di chloro-4-carbethoxypheny! ^ Biguanide 1- (2,6-dicarbethoxyphenyl) biguanide i: ^ 4- (p-chloro <phenoxy) -phenyl] -biguanide

1- (2,6-dichloro-4-dimethylaminophenyl) biguanide

1- [2,6-DHtrifluoro-methyl) -phenyl} -biguanide 1- (2,4-Di chlorophenyl) -bi guani d 1- (2,4-dibromo-phenyl) -biguanide 1- (2,4 -Difluor ^ phenyl) -biguanid 1 - (2,3-Di f 1 uo rs phcnyl) -bi guani d 1- (2, B-Di fl uor-phonyl) -biguanid l- (p-'lrif luor ^ acetylphynyl) biguanide

1 - (p-Tri fluoro sulphonylphynyl) -bi guani ei

l- (f) i-3,5-tri uot> methylphcnyD-biguani (p 1- (4-Bromo-3-Li'i noι> methyl phenyl) -t> iyuanid

3 η 9 H 2 u / 1 η ρ ι

3-Atnino-4-chloro''benzotene fluoride

p-rAmino-aja-difluoro ^ acetophenone

2-amino-5-broni''benzotrifluoride 2-Araino-5-nitrobenzotrifluoride 4-Ami no-3-ni trobenzotri f 1 uori d 2-amino-5-fluotvbenzotrifluond

5-A mi no-2 ~ fluor- · benzo tri fluoric? S-amino - ^ - fluorobenzotrifluoride 3-Ami no-4-brorn. * Benzotri f 1 uori d 2-Amino-5-chloro ^ benzotrifluoride B-amino ^ chloro-benzotrifluoride

l- (o-tolyl) -bi guanide l ~ (m-Tolyl} -bi guanid 1- (2,4-xylyl) bigucinide 1- (2,6-xylyl) -bi guanide l- (o-ethylphenyl) -bi guanide 1 - (p-ltthyi phenyl) -biguani d 1 - (ni-butyl phenyl) -bi guani d 1- (p-P ropy! Pheny1) -bi guanid l- (p-i-propylpheny1) biguanide 1- (p-i-Butylphenyl) -biguanide 1- (p-t-Butylphenyl) -biguanide -1 - {2-Chi or-5-trifluoro-; methyl phenyl) -bi gua.ni d ! - (p-DifluotvacetylphenylVbiguanid

1- (4-bromine -2-trifluoro "methytpheny1) -bi guanide 1- (4-lUtio-2-trlfluoromethylphenyl) tiguanide 1- (2-Nitro-4-trifluoro 1-methylphenyl) biguanide

1- (4-fluorine-2-trifluoro / niethylphynyl) - biguanid

Ί - (4-Fl UOi-3-trif! Uo »methyl phenyl) -biguanide

1 "(2-fluoro-5-trifluoride methyl phenyl) -biguanide

1- (2-Bromo-5-trifluo) v-methylphenyl) biguanide

1 - (4-ehl or-2-tri f 1 uor ^ methyl phenyl) biguanide

1 - (4-ChI or -r-3-trifluoro- · methyl phenyl) -biguanide

1- (2-Methyl-6-chloro-phenyl) -biguanide 1- (2-c hi or-3-methylphenyl) -bi guanide 1- (2 ₃ 4-Dimethyl-6-chloro-'phenyl) -biguanide 1- (2,6-Dimethyl-4-chloro-'phenyl) -bi guanid 1- (2-Ethyl-6-chloro-'phenyl) -biguanid 1- (2-ChI or- 4-ethylphenyl) -biguanid 1- (2-ChI or-3-i-propylphenyl) -bi guanid 1 - (2-C hi or-4-propyl phenyl) -bi guani d 1 - (2-C hi or-4-i- propyl phenyl) - biguanide 1- (2-ChI or- 4-i -butyl phenyl) -bi guanide 1 - (2-C hi or-4-t-butylphenyl) -bi guanide

1- (2,4-Diethylphynyl) -biguanide 1- (2,4-Diethyl-6-chloro-phenyl} -biguanide

1- (2-Kethyl-4-chloro ^ phenyl) -1- (2-methyl-4,6-dichloro "phenyT) -biguarnd biguanid *. .

l- (2-methyl-5-bronvphenyD-biguanid l- (2-methyl-4-chloro-5-broni'phenyl) -

biguanid

1- (2-methyl-4-bromo'phenyl) - l- (2-methyl-4-bromo - 6 - chloro-'phenyl) -

biguanid biguanid

1- (2-M! thyl-6-fluoro / phenyl) - 1- (2-Kethyl-4-chloro-6-fluoro-phenyl) -

biguanid biguanid

1- (2-methyl-4-fluoro-phenyl) - 1- (2-Mgthy 1-4-fluoro-6-chloro-phenyl) -

biguanid biguanid

1- (3-methyl-2,4-dichloro-phynyl) -biguanide biguanid

1- (4-Methyl-2-chloro-phenyl) -1- (4-Methyl-2,6-dichlorophenyl) -biguanide biguanid

1- (2-methyl-3-bromo-phenyl-biguanide 1- (2-methyl-3-brcm- 6-

1- (2,6-DiniothylphGnyl) bicjuanide 1- (2,6-Dimethyl-4-chloro-'phenyl) -biguanide

l- (3,5-dimethyl-4-chloro * -phenyl) - l- (3 _J 5-dimethyl-2,4,6-trichloro ^ phenyl) -

biguanid biguanid

1- (2-Methyl-3-chloro-· phenyl) -1- (2-Mithyl-3-chloro-6-bromo "phenyl) biguanide biguanid

1- (2-methyl-6-chloro "phenyl) - 1- (2-methyl-4-bromo-6-chloro-phenyl) oliguanide biguanid

1- (2-methyl-4-fluoro-phenyl) -1- (2-methyl-1-4-fluoro-6-bromo-phenyl) -biguanide biguanid

1- (2-Methyl-4-iodo-phenyl) -biguanide 1- (2-methyl-4-iodo-6-broni "phenyl) -biguanide

1- (2,4-Dimethylphenyl) -biguanide 1 - (2,4-Dimethyl-6-bronophenyl) -biguanide

1- (2,6-Dimethylphcny1) -biguanide 1- (2,6-dimethyl-4-bronypheny / - biguanide

1- (4-trifluoro r ^ methyl phenyl) - 1- (2,6-di bromo - 4-trifluoro methyl phenyl) -

biguanid biguanid

1- (4-fluoro-1-phenyl) -biguanide 1- (2,6-dibromo-4-fluoro-1-phenyl) -biguanide

309820/1051

Ί- (2,6-Di chi or> phenyl) -bi guani d 1 - (4-Ni trophenyl) -bi guani d 1- (4 '-C hi or-4-biphenyl) -bi guanide Ί - (4-phenoxyphenyl) -bi guani d

1- [4- (4 ^L -chloro-'phenoxy) -phenyl] -biguanide

1- (2,4-Di chi or'phenyl) -bi guani d T- (2,4-dichloro''phenyl) biguanide

T- (4-TrifluorVmethyl phenyl) biguanide

1- (4-C.hlor "phenyl) biguanide l- (2,4-Di chi or ^ phenyl) ~ bi guani d l- (2, & - Dichlor ~ 4-brüm ^ phenyl) -biguanid 1 - (2,6-di-bromo-4-nitrophenyl) -bi guani d 1- (2,6-dibromo- ~ -4'-chi or -4-biphenyl) -bi guani d 1- (2,6-Dibromo-4-phenoxyphenyl) biguanide

1 - [2,6-dibromo-4- (4'-chloro-'phenoxyVphenyl] biguanide

1- (2,4-dichloro-6-bronvphenyl) biguanide

l- (2,4-dichloro-6-thiocyanatophenyl) " biguanid

1 - (2-Ni tro-4-tri f 1 uor-'methyl phenyl) -bi guani d

1- (2-Nrtro-4-chloro-'phenyl) -biguanide 1- (2,4-Di chi or-6-ni.trophenyl) -biguanide

Example l 8

There will be 10,000 tablets for oral use using the materials listed below prepared, each tablet 50 mg of 1- (2,6-dichlorophynyl) -biguanide hydrochloride contains:

Component "gram

500 350

1- (2, 6-Diehlorphenyl) -biguan Ld-hydroehlorid Lactose USP
Potato starch USP

This mixture is mixed with an alcoholic solution moistened by 20 g P.tearlnsäurci and pass through a sieve guided. Let dry ground the following materials

ü 9 FPO / 1 η Γ »

admitted:

Component gram

Potato starch U.S.P. 320

Talk. 400

Magnesium stearate 500

colloidal silicon dioxide. 64

The mixture is thoroughly mixed and closed Compressed tablets.

Example 19

There will be 500 ampoules with the following materials each of these ampoules containing 2 ml of a solution, many 15 mg of 1- (2,4,6-trichlorophenyl) biguanide hydrochloride contain:

Component gram

1- (2,4,6-Trichlorophenyl) biguanide hydrochloride 7 »5

Ascorbic acid 1

Sodium bisulfite 0.5

Sodium sulfite. 1

The above-mentioned ingredients are added to distilled water, the solution to one volume diluted by 1 liter and then mixed thoroughly. This solution is filled into ampoules, which are usually

309820/1 OB 1

rather hot sterilized.

Example 20

An elixir of which each 5 ml 50 mg l- (p-Trifluoromethylphenyl) -biguanid-hydrochloride are contained, is prepared by adding 750 ml of invert sugar diluted with 100 ml of water and this solution 0.3 g of benzoic acid and 10 g of l- (p-trifluoromethylphenyl) -biguanide hydrochloride adds. This is followed by adding 100 ml of alcohol (U.S.P.) containing 0.2 g of taste-correcting Medium, and then with water to obtain a total volume of 1 liter. The solution is mixed thoroughly, filtered and bottled.

Example 21
Capsules are made in the following way:

150 g of l- (2,4-dichlorophenyl) biguanide hydrochloride, 3 g of magnesium stearate,

2 grams of finely divided silica, branded "CAB-O-Sil", sold by Godfrey L. Cabot, Inc., Boston, Mass., And
234 g of lactose.

These ingredients are thoroughly mixed with one another mixed and the mixture filled into gelatin capsules. Each capsule contains 500 mg of the preparation and thus 150 mg 1- (2,4-dichlorophenyl) biguanide hydrochloride.

309820/1051

Example 22

Tablets are made in the following way:

100 g l- (2,6-dibromophenyl) biguanide hydrochloride, 20 g corn starch,
14 g calcium carbonate and
1 g of magnesium stearate.

The active ingredient and the starch are thoroughly mixed together with a 10 $ gelatin solution moistened and granulated by pressing the material through a sieve with a mesh size of 0.84 mm. the Granules are dried, mixed thoroughly with calcium carbonate and magnesium stearate and compressed into tablets, each tablet weighing approximately 125 mg and 100 mg of 1- (2,6-dibromophenyl) biguanide hydrochloride contains.

Example 23

A preparation of the following composition is made:

75 g 1- (2,5-dichloro-4-fluorophenyl) biguanide hydrochloride, 50 g microcrystalline cellulose,
10 g polyvinylpyrrolidine,
5 g magnesium stearate and
85 g starch.

309820 / 10R

The active substance and the cellulose are intimately mixed with one another, moistened with a polyvinylpyrrolidine solution in water and granulated by pressing through a sieve with a mesh size of 2.00 mm. The dried granules are mixed with starch and with magnesium stearate and compressed to form coated tablets weighing 225 mg each. These tablet cores are then provided with an elastic coating of an aqueous sugar solution containing 60 g of powdered acacia gum, 60 g of powdered gelatine and 600 g of sugar per liter of solution. A dust powder mixture of 180 g of powdered sugar, 60 g of powdered starch, 1 g of powdered talc and 1 g of powdered acacia gum is then applied to these tablet cores. This procedure, namely coating with a gelatin coating and dusting, is repeated about 5 times. The treated seeds are then coated in a coating pan with a 60 ^ strength sugar solution ₀ The coating with sugar, is repeated until each coated tablet having a weight of about 400 mg.

Example 24

The following components are used:

50 g of l- (2-bromine-4-methylphenyl) biguanide hydrochloride 200 g of magnesium hydroxide gel,
200 g aluminum hydroxide gel,

j O 9 8 2 0 / · ^f !! ~ 1

. _ 50 -

g sorbitol, '

10 g of p-IIydroxybenzoefjaureniothylester and Remainder to 5000 ml of distilled water.

The ingredients are thoroughly dissolved and suspended in the distilled water. If desired, can you add a taste-correcting agent. 5ml the suspension obtained contain 50 mg of l- (2-bromo-4-methylphenyl) biguanide hydrochloride, 200 mg magnesium hydroxide and 200 mg aluminum hydroxide.

Example 25

50 g of l- (3-trifluoromethyl-H-chlorophenyl) biguanide acetate

and
5 g propyl p-hydroxybenzoate

are dissolved and diluted in water that has been distilled twice with 5000 ml, whereupon a modified Sorensen buffer solution is added in sufficient quantity to adjust the pH to 6.0. Sodium chloride is then dissolved in it in sufficient quantity to keep the resulting solution isotonic. The solution thus obtained is passed through a bacteriological filter and the Filträt in an autoclave at 120 ⁰ C for 15 minutes, treated to obtain a parenterally administrable solution containing 50 mg of l- (3-trifluoromethyl-4-chlorophenyl) -

30982 0/1051

contains biguanide acetate in 5 ml.

3 0 9820/1051

Claims (1)

where η denotes the numbers 1 to 3, Alk, Hal and R can be in any position in the ring, Alk denotes a straight-chain or branched lower alkyl or lower alkenyl radical with 1 to 7 carbon atoms, Hal denotes fluorine, chlorine, bromine or iodine and R represents hydrogen, fluorine, chlorine, bromine, iodine or a straight-chain or branched lower alkyl radical with 1 to 7 carbon atoms, with the proviso that Mk does not represent the 2-methyl radical if Hai chlorine odor ^J l-Drorn and at the same time] { Mean hydrogen or w ..> nn Hai and F dip 309820/1051 , BATH Represent 3,5-chloro substituents, and that Alk. Also denotes neither the 4-methyl nor the 4-butyl radical when Hal denotes the 3-chloro substituent and R denotes hydrogen, furthermore X, Y and Z being in any position of the ring where X and Y are each fluorine, chlorine, bromine or iodine and Z is hydrogen, fluorine, chlorine, bromine or iodine with the proviso that X or Y is not the 2-bromine substituent when the remaining Y or X denotes 4-chlorine or 4-bromine substituents, while Z represents the hydrogen atom, and that, provided that X and Y each represent chlorine and are in a position other than the 2- and 6-positions, Z does not represent a hydrogen atom, and that, if X, Y and Z are chlorine and X and Y are in the 3- and 4-positions, Z is in the 2-position, with X * also representing the 2-trifluoromethyl radical when Y * is halogen, nitro or trifluoromethyl means, X ¹ also represents the 3-trifluoromethyl radical, we nn Y 'represents halogen, nitro or trifluoromethyl, provided that Y' has a meaning other than the 4-halogen or 4-nitro substituent, X ¹ furthermore represents the'4-trifluoromethyl radical, provided that Y 'represents the nitro group or the trifluoromethyl radical, and finally X ^{1 represents} the hydrogen atom when Y ^{1 represents} the trifluoromethoxy, difluoroacetyl, trifluoroacetyl or trifluorosulfonyl radical, as well as the 309820/10 non-toxic acid addition salts thereof. 2) A compound according to claim 1, wherein X and Y are fluorine, chlorine or Drom and Z is hydrogen, Represents fluorine, chlorine or bromine. 3) A compound according to claim 1, wherein η the numbers 1 or 2 and Alk is a lower alkyl radical with 1 to 5 carbon atoms. 4) A compound according to claim 2, viorin η the Number 1 represents, alk methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl or tert-butyl means Hai, is
Fluorine, chlorine or bromine and R denotes hydrogen, fluorine, chlorine or bromine, as well as the non-toxic acid addition salts thereof. 5) A compound according to claim 1, wherein X ' represents the 2-trifluoromethyl radical. 6) A compound according to claim 1, wherein X ^{1 represents} the 3-trifluoromethyl radical. 7) A compound according to claim 1, wherein X * represents the 4-trifluoromethyl radical. 8) A connection according to claim 5> characterized in that that Y 'represents the fluorine, chlorine or bromine atom. 9) A connection according to claim 6, characterized in that that Y represents the fluorine, chlorine or bromine atom. 0 9 8/0/1051 10) M's new compounds 1- (2,6-diehlophenyl) -biguanide, 1- (2,3-dibromophenyl ') -biguanide, 1- (2,5-dibromophenyl) -biguan: d, 1- ( 2 , 6-dibromophenyl) -biguanide, 1- (3 » 4-dibromophenyl) -biguanide, 1- (3 > 5-dibromophenyl) -biguanide, 1- (2-chloro-3- ^: bromophenyl) -biguanide, 1- ( 2-chloro-5-bromophenyl) -biguanide, 1- (2-chloro-6-bromophenyl) -biguanide, 1- (3-chloro-4-bromophenyl) -biguanide, 1- (3-chloro-5-bromophenyl) -biguanide, l- (3-chloro-6-bromophenyl) -biguanide, l- (4-chloro-3-bromophenyl) -biguanide, 1- (2,4-difluorophenyl) -biguanide, l- (2,5- Difluorophenyl) -biguanide, 1- (2,6-difluorophenyl) -biguanide, .l- (2,4-diiodophenyl) -biguanide, 1- (2, ² l - dichloro-6-bromophenyl) -biguanide, 1- (2,6-dichloro-4-bromophenyl) -biguanide, 1- (2, ^ - dibromo-o-chlorophenyl) -biguanide, 1- (2,6-dibromo-4-chlorophenyl) -biguanide, 1- (2 , 6-dichloro-4-fluorophenyl) -biguanide, 1- (2,5-dichloro-4-fluorophenyl) -biguanide, 1- (2, o-dichloro- ¹ ! - iodophenyl) -biguanide, 309820/1051 1- (2-ChIOr- ^ I-brQm-6-fluorophenyl) -biguanide, 1- (2-bromo-4-fluoro-6-chlorophonyl) -biguanide, 1- (2-bromo- ^ l -chlor- 6-Π uorphenyl) -biguanide, 1- (2-iodine- ''! -Methylphenyl) -biguanide, 1- (2-methyl-1- ^J tj od phenyl) -biguanide, 1- (2-ethyl-4- iodophenyl) -biguanide, 1- (3-methy1-2, k, 6-trichlorophenyl) -biguanide, 1- (2-fluoro-4-methylphenyl) -biguanide, 1- (2-ChIOr- ^ - methylphenyl) -biguanide , 1- (2-Bromo-4-methylphenyl) biguanide, 1- (2-ethyl-4-chlorophenyl) biguanide, 1- (2-chloro- ⁱ l-ethylphenyl) biguanide, 1- (2-chloro) -4-propylphenyl) -biguanide, 1- (2-chloro-4-isopropylphenyl) -biguanld, l- (2-chloro-4-t-butylphenyl) -biguanide, l- (2, o-dichloro - ^ - methylphenyl ) -biguanide, l- (2,6-dichloro-4-ethylphenyl) -biguanide, l- (2,6-dichloro-4-propylphenyl) -biguanide, l- (2,6-dichloro-4-isopropylphenyl) - biguanid _f l- (2,6-dichloro-4-t-butylphenyl) -biguanide, l- (2-chloro - ^ - methyl-6-bromophenyl) -biguanide, l- (2-chloro - ^ - bromo-6 -methylphenyl) -biguanide, 1- (2-bromo-4-chloro-6-methylphenyl) -biguanide, 1- (2-Clilor-5-trifluorine thy lphenyl) -biguanide, 1- (4-bromo-2 -trifluoromctliy] phenyl) -biguanide, 309820/1051 l ~ (4-fluoro-2-trifluoromethylphenyl) -biguanide, l- (2-bromo-5-trifluoromethylphenyl) -biguanide, l- (2-fluoro-i3-trifluoromethylphenyl) -biguanide, 1- (2-trifluoromethyl-4-chlorophenyl) biguanide, l- (p-trifluoromethoxypheriy L) -biguanide, 1- (p-dimethylsulfamylphenyl) -biguanide and 1- [3,5-Di (trifluorinethyl) phenyl] biguanide. 11) Process for the preparation of blguanide compounds of the formulas: NH NH «I. NH-C-NH-C-NH ₂ NH NH I! II NH-C-NIt-C-NH, NH NH -NII-G-NH-C-NIL where η denotes the numbers 1. to ') ;, ALk, Hai and R can be in V) o dear Igor position in the ring, Alk a straight line C'dt>i' in front of /. branched lower ALkyi · or lower Λ Ikenyli'ost with 1 to 7 coal marbles means 30 9 8 2 0/1 0 δ 1 SAD ORIO (NAt. Hal is fluorine, chlorine, bromine or iodine and R is hydrogen, fluorine, chlorine, bromine, iodine or a straight-chain or branched lower alkyl radical with 1 to 7 carbon atoms, with the proviso that Alk does not represent the 2-methyl radical when Hal is chlorine or 4-bromine and R represent hydrogen at the same time or if Hal and R 3 »5-dichloro mean that Alk furthermore means a radical other than the ^ -methyl or 4-butyl radical, when Hal 3-chlorine and R mean hydrogen, in which furthermore, X, Y and Z can be in any position in the ring, χ and Y are fluorine, chlorine, bromine or iodine and Z is hydrogen, fluorine, chlorine, bromine or iodine with the proviso that X or Y is not 2- Bromine means bromine when the remaining Y or X is 4-chlorine or 4-bromine, while Z means hydrogen, and further that in those balls in which both X and Y represent chlorine atoms and are in a different than the 2- and 6-positions are, Z is not a hydrogen atom, and that in those cases in which X, Y and Z are all chlorine and X and Y are in the 3- and ^ -positions, Z is in the 2-position, wherein X ^{1 also represents} the 2-trifluoromethyl radical, if Y ^{1 represents} a halogen atom, the mitro group or the trifluoromethyl radical, X * also denotes the 3-trifluoromethyl radical, provided that Y * represents a halogen atom, the mitro group or the trifluoromethyl radical with 309820/1051 the condition that Y 'is not a ^ -halogen or 4-nitro, in which X' is also the 4-trifluoromethyl radical when Y ^{1 is} the nitro group or the trifluoromiethyl radical, and in which finally X ^{1 is} hydrogen when Y ^{1 is} trifluoromethoxy, difluoroacetyl , Trifluoroacetyl or trifluorosulfonyl, and non-toxic acid addition salts thereof, characterized in that an acid addition salt of an aniline of the formula .-NH, wherein n, Alk, Hal, R, X, Y, Z, X 'and Y' have the above meanings have, with cyanoguanidine in the presence of a weakly acidic, non-nucleophilic solvent at a 309820/1051 - 6ο - Brings temperature between 25 ⁰ C and 150 X in intimate contact and isolates the biguanide obtained. 12) Method according to claim 11, characterized in that one is considered a weakly acidic, non-nucleophile Solvent phenol, cresol or xylenol used. 13) Method according to claim 12, characterized in that one works at a temperature of 6θ to 100 ^C C. I ² O process for making a biguanide compound of the formulas: NH NH I! (I. NH-C-NH-C-NH- NH NH Il H NH-C-NH-C-NH, NH NH H H NH-C-NH-C-NH, where η denotes the numbers 1 to 3, Alk, Hai and R each other BAD ORiQtNAL 309820/1051 22512SÖ can be in any position in the ring, Alk is a straight-chain or branched lower alkyl or lower alkenyl radical having 1 to 7 carbon atoms, Hal is fluorine, chlorine, bromine or iodine and R is hydrogen ; Represents fluorine, chlorine, bromine, iodine or a straight-chain or branched lower alkyl rust having 1 to 7 carbon atoms, with the proviso that Alk represents a radical other than the 2-methyl radical when Hal is chlorine or 4-bromine and R is simultaneously hydrogen or if Hal and R 3 are> 5-dichloro, and Alk is a radical other than the 4-methyl or 4-butyl radical, provided that Hal is 3-chlorine and R is hydrogen, X, Y and Z are in any arbitrary position Ring, X and Y are fluorine, chlorine, bromine or iodine and Z is hydrogen, fluorine, chlorine, bromine or iodine, with the proviso that X or Y is a radical other than the 2-bromine radical, provided that the remaining Y or X is 4-chlorine or 4-bromine and Z is hydrogen, and that in those cases in which both X and Y are chlorine and are in positions other than the 2- and 6-positions, Z is not hydrogen, and in those cases in which X, Y and Z each represent chlorine and X and Y are in the 3 ~ ^and 3 4-positions, Z is in the 2-position, X ¹ denotes the 2-trifluoromethyl radical, if Y 'is a halogen atom, the nitrate group or the trifluoromethyl group 309820/1051 represents the rest, Χ 'represents the 3-tri'fluoromethyl radical,
when Y ¹ denotes a halogen atom, the nitro group or the trifluoromethyl group with the proviso that Y 'denotes a group other than the' + -halogen or 4-nitro group, X 'denotes the 4-trifluoromethyl group when Y' denotes the nitro group or the Trifluoromethyl radical, and X ¹ denotes hydrogen when Y ¹ denotes the trifluoromethoxy, difluoroacetyl, trifluoroacetyl or trifluorosulfonyl radical, as well as pharmaceutically acceptable acid addition salts thereof, characterized in that one cyanoguanidin and a substituted aniline of the formulas: where n, Alk, Hal, R, X, Y, Z, Χ * and Y 'have the above meanings, condensate in the presence of an acid »
slert. 15) Method according to claim l4, characterized in that that a mineral acid is used as the acid. 16) Method according to claim l4, characterized in that that the acid addition salt of the substituted aniline is condensed by heating with cyanoguanidine. 17) Method according to claim l6, characterized in that a salt is used as the acid addition salt Mineral acid used. 309820/1051 18) Method according to claim l4, characterized in that that the condensation is caused by heating to an elevated temperature. 19) The method according to claim 14, characterized in that by heating by the condensation temperature in a Dereiche of about 50 ⁰ C to about 150 ⁰ C. 20) Method of producing a biguanide compound of the formulas: NH NH f! (I. NH-C-NH-C-NH ' NH NH Il H NH-C-NH-C-NH, NH NH H H NH-C-NH-C-NH, where η denotes the numbers 1 to 3, Alk, Hai and R each other can be in any position in the ring, Alk 309820/1051 represents a straight-chain or branched lower alkyl or lower alkenyl radical with 1 to 7 carbon atoms, Hal, fluorine, chlorine, bromine or iodine and R denotes hydrogen, fluorine, chlorine, bromine, iodine or a straight-chain or branched lower alkyl radical 1 to 7 carbon atoms, with the proviso that Alk is a radical other than the 2 - methyl radical when Hal is chlorine or ^ -Bromo and R is simultaneously hydrogen or when Hal and R are 3,5-dichloro, and Alk is one is a radical other than the h -methyl or 4-butyl radical, provided that Hal is 3-chlorine and R is hydrogen, X, Y and Z can be in any position in the ring, and X and Y are fluorine, chlorine, bromine or iodine and Z denotes hydrogen, fluorine, chlorine, bromine or iodine, with the proviso that X or Y denotes a radical other than the 2-bromine radical, provided that the remaining Y or X denotes 4-chlorine or ^ -bromine and Z denotes hydrogen , and that in those cases where both X al s also Y mean chlorine and are in a position other than the 2- and 6-positions, Z does not mean hydrogen, and in those cases in which X, Y and Z each mean chlorine and X and Y are in the 3- and are 4-positions, Z is in the 2-position, X 'represents the 2-trifluoromethyl radical, if Y ^{1 represents} a halogen atom, the nitro group or the trifluoromethyl radical, X' represents the 3-trifluoromethyl radical, 309820 / 10B1 22.51 when Y ^{f is} a halogen atom., the nitro group or the trifluoromethyl radical, with the proviso that Y * is a radical other than the 4-halo or 4-nitro radical, X ^f denotes the 4-trifluoromethyl radical when Y 'is the nitro group or the Represents trifluoromethyl radical, and X ^! Hydrogen is when Y 'denotes the trifluoromethoxy, difluoroacetyl, trifluoroacetyl or trifluorosulfonyl radical, as well as pharmaceutically acceptable acid addition salts thereof. " characterized in that a substituent selected from the group consisting of halogen and the nitro group is introduced into a biguanide compound of the above form which has no halogen atom or no nitro group. 21) Process for the preparation of new substituted phenyl biguanide compounds, characterized in that that a connection is established which corresponds to one of the following formulas: NH NH ti Il NH-C-NH-C-NH ₂ NH NH Il H NH-C-MH-C-NH, 303 * ί # 5Jf -Ο / ' tan NK NH II II NH-C-NH-C-NH, where η denotes the numbers 1 to 3, Alk, Hal and R can be in any position in the ring, Alk denotes a straight-chain or branched lower alkyl or lower alkenyl radical having 1 to 7 carbon atoms, Hal is fluorine, chlorine, bromine or iodine and R represents hydrogen, fluorine, chlorine, bromine, iodine or a straight-chain or branched lower alkyl radical having 1 to 7 carbon atoms, with the proviso that Alk represents a radical other than the 2-methyl radical when Hal is chlorine or 4-bromine and R is simultaneously hydrogen or if Hal and R 3 are> 5-dichloro, and Alk is a radical other than the k -methyl or ^ -butyl radical, provided that Hal is 3-chlorine and R is hydrogen, X, Y and Z are in can be in any position in the ring, X and Y are fluorine, chlorine, bromine or iodine and Z is hydrogen, fluorine, chlorine, bromine or iodine, with the proviso that X or Y is a radical other than the 2-bromine radical, provided the lead Y or X denote 4-chlorine or 4-3rom and Z denote hydrogen, and that in those 309820/1051 . ■. 2251250 Cases in which both X as * s and Y are chlorine and are in a position other than the 2- and 6-position stages, Z is not hydrogen, and in those cases in which X, Y and Z are each chlorine and X and Y are in the 3- and / or 4-positions, Z is in the 2-position, X ^{1 is} the 2-trifluoromethyl radical, if Y 'is a halogen atom, the nitro group or the trifluoromethyl radical, X ^{1 is} the 3- Trifluoromethyl radical when Y ^f denotes a halogen atom, the nitro group or the trifluoromethyl radical with the proviso that Y 'represents a radical other than the 4-halogen or 4-nitro radical, X ¹ denotes the 4-trifluoromethyl ^{radical when Y 1 is} the nitro group or represents the trifluoromethyl radical, and X 'represents hydrogen when Y' represents the trifluoromethoxy, difluoroacetyl, trifluoroacetyl or trifluorosulfonyl radical, and of pharmaceutically acceptable acid addition salts thereof. 22) Process for the preparation of a biguanidver-. binding the formula: - R ₂ NH NH _{wherein Rg, R 1} , R ^, R 1 - and Rg, which can be the same or different. Hydrogen, lower alkyl, lower alkenyl, 309820/1051 225126Q Halogen, nitro, amino, di-lower alkylamino, halo-lower alkyl, Halo-lower alkoxy, halo-lower alkanoyl, hydroxyl, cyano, thiocyanato, carboxy-l, carbo-lower alkoxy, di-lower alkylsulfonamido, Lower alkylsulfonyl, halo-lower alkylsulfonyl, phenoxy, acyloxy, halophenoxy, phenyl or Halophenyl mean, as well as non-toxic acid addition salts thereof, characterized in that one Acid addition salt of an aniline of the formula: where R p, ^, R _r and have the above meanings, a weakly acidic with cyanoguanidine in the presence brings non-nucleophilic solvent at a temperature in the range between 25 ⁰ C and 150 ⁰ C intimately in contact and the obtained Phenyl! biguanide isolated. 309820/1051 23 · Use of the compound according to claim 1 in one gastrointestinal acid or stomach ulcer remedies. 24. Use of the compound of claim 1 in a gastrointestinal convulsive remedy 25. Use of the compound according to claim 1 in one hypertensive change remedies. 26. Use of a compound according to the formula NH NH Il II -NH- C- NH- C- NH ₂ wherein R ₂ , R 1, R, R, - and Rg, which can be the same or different, hydrogen, lower alkyl, lower alkenyl, halogen, nitro, amino, di-lower alkylamino, halo-lower alkyl, 1-halo-lower alkoxy, halo-lower alkanoyl, hydroxyl, cyano, thiocyanato , Carboxyl, carbo-lower alkoxy, di-lower alkylsulphonamides, lower alkylsulphonyl, halo-lower alkylsulphonyl, phenoxy, acyloxy, halophenoxy, -phenyl or! Halophenyl and their nontoxic acid addition salts in association with an acceptable carrier in a gastrointestinal hyperacid or peptic ulcer remedy. 27. Use of a compound according to the formula inspected 309820/1051 NH NH I! l ^f -NH-C-NH-C- NH, wherein R ₂ , R R ^, R, and ₂ , R ,, R ^, R, - and Rg, which can be the same or different, hydrogen, lower alkyl, lower alkenyl, halogen, nitro, amino, di-lower alkylamino, halogen leather alkyl, 1-halogen lower alkoxy, halogen lower alkanoyl, hydroxyl, cyano, thiocyanato, carboxyl , Carbo-lower alkoxy, di-lower alkylsulphonamides, lower alkylsulphonyl »halo-lower alkylsulphonyl, phenoxy, halophenoxy, phenyl or halophenyl and their non-toxic acid addition salts in association with an acceptable carrier in a gastrointestinal convulsive remedy, 28. Use of a compound according to the formula NH NH NH-C-KH-C-NH, where R ₀ , R- and ι ,, iv ^, ινπ «*» «. ... g that be the same or different can, hydrogen, lower alkyl, lower alkenyl, halogen, nitro, amino, di-lower alkylamino, halo-lower alkyl, 1-halo-lower alkoxy, halo-lower alkanoyl, hydroxyl, cyano, thiocyanato, carboxyl, carbo-lower alkoxy, di-lower alkyl sulfonamides, Lower alkylsulfonyl, halo-lower alkylsulfonyl, phenoxy, acyloxy, halophenoxy, phenyl or Halophenyl and their nontoxic acid a / iditol salts in association with an acceptable carrier in one hypertensive change remedies. ns- 309820/1051 OWGlNAL INSPECTED