DE2144583A1 - Pharmaceutical preparation and method for its use - Google Patents

Description

ARMOR KIARiHACEUTICAL COMPAET 111 East Wacker Drive Chicago, Illinois 60601

Pharmaceutical preparation and method for its use

The invention "relates to certain pharmaceutical preparations containing guanidine compounds and to methods of using them to make use of their recently found beneficial biological properties; in particular, it relates to preparations containing a class of guanidine compounds and their corresponding non-toxic acid addition salts which have vasoconstrictor properties , and therefore useful as vasoconstrictor agents when formulated into pharmaceutical preparations.

The class of compounds that can be used in the present invention has the following structural formula:

NH, - NlICWH.

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where mean:

R ^ hydrogen or alkyl with 1 to 4 carbon atoms,

R ~ hydrogen, hydroxy, chlorine, fluorine or bromine, or R ₁ and Rp together are a benzo group,

R ^ hydrogen, acetyl, chlorine, bromine, fluorine or hydroxy and

R ₇ , hydrogen, chlorine, bromine or fluorine with the proviso that when R ^ is chlorine, bromine or fluorine, Rp is the same radical and R ^ is not hydroxyl and the number of hydroxyl groups is never greater than one.

Examples of compounds which can be used according to the invention are: 3'-chloropnenylguanidine, phenylguanidine, 4'-chlorophenylguanidine, 4'-hydroxyphenylguanidine, 3'-hydroxyphenylguanidine, 1-naphthylguanidine, 4'-acetylphenylguanidine, 2'-methylphenylguanidine, 3 ¹ , 4'-methylphenylguanidine Dichlorophenylguanidine and 3 ' , 5'-dichlorophenylguanidine. Examples of salts which can be used according to the invention are: 3'-chlorophenylguanidine nitrate, pftenylguanidine nitrate, 4'-chlorophenylguanidine nitrate, 4-hydroxyphenylguanidine hydrochloride, 3'-hydroxyphenylguanidine hydrochloride, 1-naphthylguanidine nitrate, 4'-acetylchloride 2'-methylphenylguanidine nitrate, 3 ', 4 * -dichlorophenylguanidine hydrochloride and 3 ¹ ^' -dichlorophenylguanidine nitrate.

As used herein, "vasoconstrictor agent" is meant a means that can be used to improve the treatment of congestive conditions of the eye and nose and for the treatment of shock and other hypotensive conditions suitable. With the already known vasoconstrictor agents,

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which are on the market, it is z. B. to Methoxamine, ephedrine, epinephrine, oxymetazoline, phenylephrine, Levartenenol, naphazoline and tuaminoheptane. Although these compounds have proven to be a means of which have the desired vasoconstrictive effect, but they have also resulted in severe undesirable side effects, for example cardiac arrhythmias and excessive blood flow. In addition, these compounds, when used in topical formulations, are known to cause stinging, Burning sensation and a feeling of severe dryness.

The present invention is based on the biological activity of the guanidine compounds and their corresponding non-toxic acid addition salts of the formula given above, the a \ if the remarkable and surprising properties of these compounds and the specified salts decreases, after which a vasoconstrictor activity is achieved without any noticeable change in heart rate administered to the patient (human or animal) »to whom such a gown will occur. The preparations according to the invention can be used both on animals and on humans by oral, parent eral or topical V / ege with minimal effects on heart rate.

Accordingly, one of the main objects of the present invention is to provide new pharmaceutical preparations and methods of using them which are useful for vasoconstrictive therapy. A further aim of the invention is to provide new pharmaceutical preparations which contain aromatic guanidine compounds or their corresponding non-toxic acid addition salts, which can be used as vasolccn:. ■. ■:!] ■: - gate agents and freely have noticeable effects the heart rate of the patient, which are never administered. Another aim of the present.] ei ;, invention is finally to provide new pharmaceutical

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To raise preparations and procedures for their use, useful in the treatment of hypotensive conditions and as nasal and ocular decongestants.

These and other objects of the invention are achieved by the present Invention achieved in a remarkably unexpected manner, as from the following description and the examples of preferred embodiments of the invention.

The guanidine compounds used in the present invention can be prepared by any known method, e.g. B. be prepared by Addi-P tion of hydrogen cyanamide to an aromatic alaine or its mineral acid addition salt. The guanidines can be converted into their acid addition salts by the particular guanidine with a suitable mineral acid or organic acid, for example with hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, maleic acid, citric acid, acetic acid, tartaric acid, benzoic acid, propionic acid, carbonic acid or the like reacting., which are known to react therewith to form pharmaceutically acceptable salts, and need not be described in detail here to v / ground.

A suitable process for preparing the guanidines is that the appropriate aromatic amine mineral acid addition salt (or the aromatic amine with one molar equivalent of the appropriate mineral acid), a 50% aqueous solution Cyanamide solution and ethyl alcohol mix together and then the mixture was refluxed for 3 to 20 hours. To achieve an optimal yield, the Iol ratio is' from aromatic amine salt to cyanamide to ethyl alcohol 1.0: 1.5: 15 each. The products, i.e. H. the aromatic Guanidine mineral acid addition salts, are made from the Heäktionü-

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mixtures isolated and recrystallized from a suitable solvent, e.g. B. ¥ / ater or aliphatic Alcohols, purified. If the acid addition salt cannot be purified, add an alkali metal hydroxide to it converted to the free base and purified by recrystallization from a suitable solvent.

Another suitable method is "by having a Mixture of a suitable 1-aryl-2-methyl ~ 2-thiopseudourea hydroiodide, Manufactures ammonia and ethyl alcohol. The mixture is then refluxed for 20 hours. For optimum yield, the molar ratio of thiopseudourea to ammonia to ethyl alcohol should be 1: 3: 15 each. The products are made from their reaction mixtures isolated and converted into the hydrochloride salts for purification and identification.

One by one of the above methods or by one Another suitable method can be prepared guanidine compound by adding the appropriate acid to the guanidine compound in their acid addition salt, e.g. B. the hydrochloride are transferred. The guanidine compounds according to the invention can be used in the form of the free bases or in the form of their non-toxic, pharmaceutically acceptable salts. For example, the addition salts with organic and inorganic acids, e.g. B. the salts of hydrogen chloride acid, sulfuric acid, nitric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid, SuIfamic acid, succinic acid, fumaric acid, maleic acid, ethane disulphonic acid, Hydrobromic acid, benzoic acid and corresponding non-toxic acids can be used. The salts can be prepared by treating the guanidine base with an excess of the acid in a suitable solvent, for example ethanol, acetone, water or a mixture

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The mixture is heated to dissolve it and the salts crystallize during the process Cooling off.

The guanidines and their salts can be used in a suitable manner in therapeutically effective amounts both on animals can also be administered to humans. Through systemic Administration, for example, by the oral or parenteral routes, dosages of about 1 mg to about 5 mg per kg body weight of the patient (host) are administered. The compounds can be systemically applied to animals in Dosages of up to about 5 mg per kg of body weight are administered will. The dosage information mentioned above and below relate to the guanidine base content. The compounds used according to the invention have. excellent vasoconstrictor properties, low toxicity and relatively few side reactions established.

According to a preferred embodiment of the invention an aromatic guanidine or a salt thereof in the form of a pharmaceutical composition containing the guanidine compound and containing a pharmaceutical carrier. The carrier is a non-toxic one pharmaceutical substance that can be either solid or liquid. Examples of suitable solid carriers are lactose, Magnesium stearate, starch, sucrose, mannitol, sorbitol, cellulose powder, dicalcium phosphate, talc, stearic acid, Gelatin, agarpectin, acacia gum and the like. Examples of suitable liquid carriers are glycols, polyglycols, dimethyl sulfoxide, Peanut oil, olive oil, sesame oil, alcohols, water and the like. If desired, the carrier can also contain a retarding agent, such as B. glycerol monostearate or glycerol distearate, alone or mixed with a wax.

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The composition is preferably used for the sake of accuracy and convenience of administration formulated in a unit dosage form. When it is convenient Oral administration is effective and preferred and the dosage units suitable for oral administration are prepared. Examples of such dosage units in which solid carriers are used are tablets, filled capsules, packets and the like, and lozenges. The amount of solid carrier per unit dosage can be within one wide range varies and it preferably fluctuates from about 25 mg to 5%

The guanidines and their salts can with semi-solid and liquid carriers such. B. in solutions, suspensions, emulsions, ointments, suppositories and soft gelatin capsules. Such preparations can pancaval, ie through the natural and artificial openings in the body, for. To the mouth, anus, vagina, nostrils and stoma of colostomy patients, intravenously or intramuscularly using the appropriate preparation with an appropriate concentration of active ingredient depending on the mode of administration desired.

The above dosage forms are prepared according to conventional procedures produced by mixing, granulating, compressing, suspending and / or dissolving, as is used for production the desired dosage form is appropriate. The vasoconstriction a host animal and a host human that is in a condition that requires such treatment Required is easily achieved by giving the sick patient (host) an aromatic guanidine or a pharmaceutically acceptable acid addition salt of which administered in an amount sufficient to relieve the symptoms

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to mitigate me of the condition. The usual symptoms that requiring treatment are low blood pressure, ocular and nasal congestion, and the like Compound is preferably administered in the above-mentioned dosage amount and preferably in a pharmaceutical Carrier administered. The dosage level and the frequency of administration depend to a certain extent on it the degree of vasoconstriction or decongestion to be achieved, the history of the case, of the patient's reaction and the like.

The daily dosage can be administered in one or more parts and the administration can be pancaval or parenteral or topical. Administration to achieve systemic vasoconstriction is preferably oral and is most conveniently carried out with the aid of a tablet containing one of the active compounds and a pharmaceutical carrier. For local vasoconstriction, ie in the eyes, nose, etc., topical administration is preferred.

Particularly good vasoconstrictive results are obtained when the following aromatic preparations containing guanidines are administered to the animal organism: 3'-chlorophenylguanidine, phenylguanidine, 4 ¹ -chlorophenylguanidine, 4'-hydroxyphenylguanidine, ^ '- hydroxyphenylguanidine, * 1- Naphthylguanidine, 4'-acetylphenylguanidine, 2'-methylphenylguanidine, 3 ¹ , 4'-dichlorophenylguanidine and 3 ', 5'-dichlorophenylguanidine. Examples of salts which can be used in the preparations according to the invention are: 3'-chlorophenylguanidine nitrate, phenylguanidine nitrate, 4'-chlorophenylguanidine nitrate, 4'-hydroxyphenylguanidine hydrochloride, 3-hydroxyphenylguanidine hydrochloride, 1-naphthylguanidine. nitrate, ^ -'-Acetylphenylguanidine hydrochloride, 2'-Methy 1-phenylguanidine nitrate, 3 ', 4 · -diclilorphenylguanidine hydrochloride

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and 3 ', 5 ^I -dichlorophenylguanidine nitrate, the onset of activity after oral administration in the animal organism is rapid, with results being observed within half an hour and the activity continuing. This way the activity values will stay for 2 or more

Hours high and activity lasts for 24 hours. After topical or intravenous administration The onset of effects is quick and lasts for an hour or more.

The following examples are intended to illustrate the guanidine preparations according to the invention explain. The new pharmaceutical preparations embody the use of guanidine and its non-toxi- ■ see acid addition salts, the treatment of the animal organism according to the invention and those in this treatment occurring activities. Of course, the present invention is based on the examples or on the compounds Preparations, proportions, conditions and processes, which are given below by way of example, are not restricted. In all of the examples, the guanidines mentioned in each case were typical representatives of the entire class of the invention Compounds and preparations used.

example 1

3'-chlorophenylguanidine nitrate is made from a mixture of 12.8 g (0.1 mole) 3-chloroaniline, 9.0 g (equivalent to 0.1 Mol Hiro,) concentrated nitric acid, 12.6 g of a 50 show aqueous cyanamide solution (equivalent to 0.15 mol of cyanamide) and 100 ml of ethyl alcohol, which is heated under reflux for 20 hours, prepared. The reaction mixture is then Cooled to 0 G for 5 hours and the precipitated product is collected on a filter. The product is made by recrystallization Purified from ethyl alcohol. The purified,

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white, crystalline solid melts at 170 to 172 ° C with decomposition. The infrared spectrum agreed with the specified Structure.

Example 2

After an identical response process. as in both

In the game 1 was used, but where / instead of 3-chloroaniline is used, phenylguanidine nitrate is made. The product is based on the reaction mixture isolated in the manner indicated in Example 1. This material is purified by recrystallization from ethyl alcohol. The purified, white, crystalline product melts at 125 to 127 ° C. The infrared spectrum agrees with the assumed one Structure.

Example 3 -

Following the reaction procedure given in Example 1, at however, used 4-chloroaniline instead of 3-chloroaniline 4 -'-chlorophenylguanidine nitrate is produced. The product is isolated and purified in the manner indicated in Example 2. The purified, white, crystalline product Melts at 170 to 172 ° C. That . corresponds to the specified structure.

Example 4

duct melts at 170 to 172 ° C. The infrared spectrum is right

From a mixture of 10.9 g (0.1 mol) of 4-aminophenol, 10 g concentrated hydrochloric acid (equivalent to 0.1 mol HCl), 12.6 g of a 50% strength aqueous cyanamide solution (equivalent to 0.15 mol) and 100 ml of ethyl alcohol, which for 3 hours is heated under reflux, 4 '^ hydroxyphenylguanidine hydrochloride manufactured. The reaction mixture is then evaporated, leaving a viscous oil as a residue.

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This oil is dissolved in boiling isopropyl alcohol (120 ml) dissolved and an equal volume of ether is added. The precipitated solid is collected on a filter. The solid is recrystallized from ethyl alcohol Purified, white, crystalline solid melts at 198 to 200 ° G. The infrared spectrum agrees with the assumed one Structure.

Example 5

Following the procedure given in Example 4, but in which instead of 4- aminophenol 3 -Ami no phenol is used, J'-H ^ -droxyphenylguanidine hydrochloride is produced. That Product is made from the reaction mixture by evaporating the reaction solvent and triturating the residue isolated with acetone. The solid obtained after decanting is made from a mixture of isopropyl alcohol and acetone recrystallized in a ratio of 1: 2. The purified, white, crystalline solid melts at 155 to 157 ° C

The infrared spectrum Right , 37 N. with the ang eno; mme match. , 52 Analysis for C _n H ₁₀ ClIf ₃ calc .: C 44.81 H. 5 22nd , 40 Cl 18th , 90 found: 44.96 5 22nd 19th , 02 Example 6

Following the reaction procedure given in Example 1, but using 1-naphthylamine instead of 3-chloroaniline 1-naphthylguanidine nitrate is produced. The reaction mixture is evaporated to a solid residue. This residue is purified by recrystallization twice from aqueous ethyl alcohol. The infrared spectrum agrees with the assumed structure.

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Example 7

However, according to the reaction procedure of Example 4, in which the 4-aminophenol is replaced by 4-aminoacetophenone, is prepared 4'-Acetylpbenylguanidinh7y ^r hydrochloride. The product is isolated from the reaction mixture by removing the reaction solvent and triturating the residue with acetone. The solid obtained after trituration is purified by recrystallization from aqueous isopropyl alcohol. The white, crystalline product melts at 212 to 214 ° C. The Infra:
adopted structure.

Example 8

at 212 to 214 ° C. The infrared spectrum agrees with the

2'-Methylpheny! Guanidine is prepared by the reaction process given in Example 1, in which, however, 2-1.5ethylaniline is used instead of 3-chloroaniline. The reaction mixture is evaporated and the residue is triturated with ether. The ether is decanted off, leaving behind a crystalline plague. This material is purified by recrystallization from isopropyl alcohol. The white crystalline product melts at 128 Mr; 130 ⁰ C. The infrared spectrum agrees with the assumed structure.

Example 9

Using the reaction procedure given in Example 4, but this time using 3,4-dichloroaniline instead of 4-aninophenol and heating the reaction mixture under reflux for 20 hours, 3 "4" -Dichlorophenylguaiii ™ dine hydrochloride is prepared. The reaction mixture is evaporated and the residue is dissolved in a boiling, aqueous 2 η hydrochloric acid solution. This solution is filtered and ^{cooled to 0} ° C. for 18 hours. The precipitated solid is collected on a filter and dried.

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This solid is recrystallized from isopropyl alcohol. The white crystalline solid melts at 178 to 180 ° C. The infrared spectrum agrees with the assumed structure match.

Analysis for G _n HoCl _x W- ,:

Calcd .: C 3 ^, -96 H 3.35 Cl 44.22 W 17.47 found: 3 ^ -. 81 3.36 44.03 17.34-

Example 10

Ali a mixture of 16.2 g (0.1 mol) of 3,5-Dichloraniliii, 9.0 g of concentrated nitric acid (equivalent to 0.1 mol of HNO _7), 12.6 g of a ^ O / "aqueous cyanamide solution ( equivalent to 0.15 mol of cyanamide) and 100 ml of ethyl alcohol is prepared 3 ', 5 * -Dichlorophenylguanidine nitrate The mixture is refluxed for 20 hours and the reaction product is cooled to 0 ° C. for 5 hours Evaporation of the reaction solvent and trituration of the residue with acetone isolated. The crude product obtained after decanting off the acetone is purified by recrystallization from ethyl alcohol. The white crystalline solid melts at 199 to 201 ^° C. The infrared spectrum agrees with the assumed structure.
Analysis for C _n H _n Cl ₀ W ,, 0:

bor .: C 31.48 II 3.02 W 20.98
found: 31.69 3.12 20.79

Example 11

The following are examples of various dosage forms indicated which are useful for practicing the present invention when administered orally:

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Formulation A component Formulation B component component Formulation D component Parts Guanidine compound Guanidine compound Guanidine compound Guani din connection 60-300 Calcium carbonate Citric acid (anhydrous) Cornstarch Cornstarch 300 Citric acid (anhydrous) Sodium bicarbonate Lactose Lactose 290 Magnesium carbonate Monocalcium phosphate Magnesium stearate Talk 129 Formulation; C. Silicon dioxide (powdered) Parts 60-500 1000 2000 200 Parts 60-3OO 25-50 25-2000 1 - 5 Parts 60-300 25-50 25-200 10-50 0.1-2

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Formulation Ξ

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component

Gti ani din compound lactose Cellulose magnesium stearate

Parts
- 30 - 190 - 135 0.1 - 5

Formulation F component

Guanidine compound cellulose corn starch gelatin stearic acid

Parts 60 - JOO 15 - 200

10 - 50 5 - 35 15

Formulation G component

Guanidine compound tricalci tiraphosphate Corn starch acacia gum magnesium stearate

Parts 60-3OO 50-150

10 - 50

5-25 1—5

In any case, the ingredients are in the specified Proportions of a uniform powder with a Grind uniform grain size, mixed with the binder and compressed into tablets.

Example 12

By "compounding" the following Components in the specified proportions

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and heating the ingredients to about 15.6 ⁰ C (60 ⁰ I ¹ ) to dissolve them, suppositories are prepared that ^{melt at about 15.6 0} G (60 ⁰ F) and have the following composition. The solution is then poured into chilled molds and allowed to cool and solidify.

Ingredients quantity

Guanidine compound. 0.1 to 1.0 mg

Base made of lactose, polyethylene

glycol, polyethylene glycol 400,

Polyethylene glycol 4000, poly-

sorbate 80 and glycerin; 1g

Example 1g

Using 60 to 300 mg of a guanidine compound, which is introduced into a rapidly disintegrating base of starch, lactose, sodium saccharin and talc made a dragee for sublingual administration.

Example 14

The ingredients of the following compositions are mixed with one another mixed to form a solution suitable for intravenous administration. In any case, the Ingredients mixed and heated to about 50 to 60 C while stirring heated to effect dissolution »The solution is then sterile filtered, cooled to room temperature and made sterile Packaged vials.

Formuli augmentation H

Ingredients quantity

Guanidine compound 10-5OO mg

Sodium Chloride 89.0 mg

Water 99 g

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Formulation- I Ingredients Amount

10-500 mg

Glucose. !> g

water

example

The ingredients of the following compositions are mixed with one another mixed to produce a solution which is suitable for formulations for intramuscular and subcutaneous administration. In either case, the components mixed with one another while stirring and heated to 50 "to 60 C heated to effect dissolution «The solution is then sterile filtered, cooled to room temperature and put into sterile Packaged vials.

Formulation J Component quantity

Guanidine compound 10- "50 mg

16% aqueous gelatin

containing 0.5% phenol 100 g

Formulation K Component quantity

Guanidine compound 10 - ^ QO mg

sodium chloride 890 g

Water 99 g

Component quantity

10-5QO mg

water

Formulation M Component quantity

Guanidine compound 10 - ^ QQ mg

10-90% aqueous polyethylene

400 100 g

Example 16

The guanidine compound is used in a cream auxiliary from a water-miscible base made from stearic acid, Propylene glycol, sorbitol onostearate and monooleate * Polyoxyethylene sorbitan monostearate with citric acid and methyl and propyl parabans as protective substances, dispersed. The concentration of the guanidine compound is 0.1 to 50 mg per gram of excipient ► Alternatively, the guanidine compound also in corn oil, sesame oil, cottonseed oil, peanut oil or polyethylene glycols are dispersed with the addition of suitable protective substances.

Example 1?

The vasoconstrictor properties of various compounds according to the invention were determined pharmacologically using a recognized method. The change in heart rate in anesthetized dogs to which a guanidine compound had been administered intravenously is given below ea (Yifirtes) by means of an arterial Eauerkatlieters _s

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which was connected to a pressure transducer, controlled, the patient's heart rate was determined from the limb electrocardiogram determined and the cartoid arterial blood flow was measured with a flow probe around the artery around constantly monitored, the probe with a Na-electromagnetis see Flow meter was connected. It should be noted that in this way also three common vasoconstrictor agents, all commercial products, have been tested to camouflage have a reference base. The test connections are given in Table I below and the data are summarized in the tables below.

Table I ■ · .- ··

tested

link

(Abbreviation) ABCDEFGHIJ

chemical name

3 * -chlorophenylguanidine nitrate Phenylguanidine nitrate

4 * —Chlorph enylguanidine nitrate

4 * -Hydroxyphenylguanidine hydrochloride

5 * -hydroxyphenylguanidine hydrochloride 1-naphthylguanidine nitrate

4 * -acetylphenylguanidine hydrochloride

2 * - methylphenylguanidine nitrate

$ ', 4 * -Bichlorophenylguanidine hydrochloride

3 *, 5 ¹ -Dichlorophenylguanidine nitrate

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Table II anesthetic ied Dogs Changes in heart rate at dose (mg / kp; i.v.) 0.01 0.1 1.0 tested connection 0 ·. - - A. 0 0 0 B. 0 0 - C. 0 - 0 D. 0 - - E. O - - F. 0 0 O G O 0. - H - - - - - - I. 0 - - J - - - + Naphazoline - + + Phenylephrine 0 + - . - Phenylpropanolamih

Evaluation scale: - decrease in heart rate

0 no change in heart rate + increase in heart rate

Example 18

For each connection, additional data was determined by the Rise in mean arterial blood pressure measured after intravenous administration in an anesthetized dog became. The scale used to evaluate the results is given in Table III below and the test data are compiled in Table IV below, where the abbreviations given in Table I of Example 17 be used for the compounds tested.

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Tabel Tabel III Pressure increase in mm IV - 3 5 (mg / kg i.p. «Ρ? Evaluation of the activity Activity rating for 0 - - 10 0.1 Q 4 - - 25th 2 1 tested connection 11 - ■ 50 0 2 A. 26 - -75 3 3 B. 51 - 2 4th G 2 5 D '. the test connections 2 E. dose 1 ¥ 0.01 0 G 2 5 1.0 H 0 2 4th I. 2 4th 3 J 0 5 3 Naphazoline 0 3 5 Phenylephrine 0 5 Phenylpropanolamine 0 3 Example 19 0 3 4th 2 0 5 3 3 3 4th 0 .5 5

An aqueous solution was prepared containing 3 ', 4'-dichlorophenylguanidine hydrochloride and was suitable for use on the nose and eyes for decongestion

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the mucous membranes of these organs. The solution was stable, physiologically isotonic and had a pH value within the range from 6 to ■ ?. Me composition is given below. Put the sodium phosphate salts a buffer system, which is supposed to keep the pH at about 6.5, and the sodium bisulfite is used as an antioxidant. The sodium chloride gives the desired isotonicity and Thimerosol acts as a protective agent that the solution against protects bacterial contamination and mold contamination.

Formulation N component - 5 ¹ , 4 * -Dichlorophenylguanidine hydrochloride % By weight ' monobasic sodium phosphate 2, QO dibasic sodium phosphate 0.10 Sodium bisulfite 0.12 Sodium chloride 0.20 Sodium merthiolate (thimerosal) 0.15 0.01

Water 97, ^ 2

Compounds and salts which are particularly preferred for carrying out the invention are as follows: 3 * _t V-dichlorophenylguanidine - dine hydrochloride, 3'-hydroxyphenylguanidine hydrochloride, ^ 'Hydroxyphenylguanidine hydrochloride and ^' ^ chlorophenylguanidine nitrate and their corresponding bases.

From the above it can be seen that the present In accordance with the invention, all of the objectives set out above can be achieved in a remarkable and unexpected manner and that the fiction according to the compounds, pharmaceutical preparations and therapeutic methods to achieve suitable for vasoconstriction where such therapy is necessary is.

Patent claims:

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Claims (10)

21U583 Claims Λ . Pharmaceutical preparation, characterized in that it contains a pharmaceutically acceptable carrier and, as an essential active ingredient, a guanidine compound or a non-toxic acid addition salt thereof of the general formula _ KHCKH ₂ where mean: R ^ hydrogen or alkyl with 1 to 4 carbon atoms » Rp is hydrogen, hydroxy, chlorine, fluorine or bromine or R> j and Ro together represent a benzo group, R, hydrogen, acetyl, chlorine, bromine, fluorine or hydroxy and R ^, hydrogen, chlorine, bromine or fluorine, with the proviso that when R ^ is chlorine, bromine or fluorine, Rp is the same. Radical means and R, no hydroxy radical means, the number of hydroxy radicals never being greater than 1. 2. Preparation according to claim 1, characterized in that it contains 3 *, V-dichlorophenylguanidine as the guanidine compound. 3. Preparation according to claim 1, characterized in that it contains 3'-hydroxyphenylguanidine as guanidine compound. 4. Preparation according to claim 1, characterized in that it 209821/1056 21U583 contains as guanidine compound 4'-hydroxyphenylguanidine. 5 »Preparation according to claim 1, characterized in that» it contains 5'-chlorophenylguanidine as a guanidine compound. 6. A preparation according to claim 1, characterized in that it is used as an acid addition salt of a guanidine compound. 3 '»4 * - Contains dichlorophenylguanidine hydrochloride. 7 · Preparation according to claim 1 ", characterized in that it as an acid addition salt of a guanidine compound 3'-hydroxyphenylguanidine hydrochloride contains. 8. A preparation according to claim 1, characterized in that it as an acid addition salt of a guanidine compound, 4'-hydroxyphenylguanidine hydrochloride contains. 9. A preparation according to Claim 1, characterized in that it as an acid addition of a guanidine compound 3'-chlorophenylguanidine nitrate contains. 10. A pharmaceutical preparation according to claim 1, characterized in that it is in a dosage unit form in the form of tablets, filled capsules, packets, lozenges, coated tablets, sterile solutions, suspensions, emulsions, ointments, suppositories and soft gelatin capsules and a dose of about 1 supplies up to about 5 ^m S of guanidine per kg of body weight, 209821/1056