DE2601158A1 - HEART STIMULANTIES - Google Patents

Description

Dr Ina, W '"- τ AHtZ
Dr. Haas-A. Browns

8 Müochaa 88, F.eüianaaontr. 28 ll |. January 1976

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MERCK & CO., INC. Rahway, New Jersey, V.St.A.

Cardiac stimulants

The trichloroetamidines used according to the invention are known per se and, according to DT-OS 2 121 401, are suitable for agricultural purposes. However, the cited reference does not say anything about the fact that any of the trichloroacetamidines described could have any pharmacological properties and especially cardiac effects. The suitability of the trichloroacetamidines mentioned as cardiac stimulants comes as a surprise and is in no way suggested by the prior art.

According to the invention, it has been found that certain compounds belonging to the class of substituted trichloroacetamidines display pronounced cardiac stimulating effects. They are therefore used as an active ingredient in pharmaceuticals

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ORIGINAL INSPECTED

used. The present invention would therefore "insist in it »known compounds defined a new area of application to tap into. In particular, the previously unknown heart-stimulating effect of certain substituted Trichloracetamidine can be detected. Furthermore, it is the object of the invention to make drugs available places which contain the compounds mentioned. The following explanations allow a further specification this task.

The substituted trichloroacetamidines used according to the invention, which have potent cardiotonic effects are best illustrated by the general formula below :

in which R _{1 is} a hydrogen atom or a lower alkyl radical,

Rp is a hydrogen atom or a lower alkyl radical and

R, a hydrogen atom, a cyano group, a lower alkyl, Lower-alkenyl, cycloalkyl or phenyl-lower-alkyl radical or one by a radical of the following general formula

-N-C-CCl

I If

in which R ₁ and R ₂ each have the meaning given above, is substituted lower alkylene radical, where R ₁ and R _{5 are} also with one another

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Inclusion of the amidine nitrogen atoms »to which they are bound, can be linked to form a 5- to 7-membered heterocyclic ring} also included are the pharmacologically acceptable salts of these compounds.

The term "Meder-alkyl radical" includes in the present description and in the claims straight-chain and branched-chain alkyl radicals having 1 to 5 carbon atoms, such as Methyl, ethyl, propyl, butyl, pentyl, isopropyl or tert-butyl group.

"Lower-alkenyl radicals" embraces straight and branched chain ones Alkenyl radicals with 2 to 5 carbon atoms and one or two unsaturated bonds, such as the vinyl »propenyl, Allyl »butenyl or 2,4-pentadienyl group.

The term “cycloalkyl radicals” includes cyeloalkyl radicals with 3 to 7 carbon atoms, such as the cyclopropyl, gyclobutyl, Cyclopentyl, cyclohexyl or cycloheptyl group.

"Halogen atoms" are to be understood as meaning fluorine, chlorine, bromine or iodine atoms.

The compounds according to the invention have valuable pharmacological ones Properties. First and foremost, they increase the contractility of the heart muscle. Because of this effect and the resulting increase in cardiac output or minute volume, the compounds provide a valuable means available for the treatment of heart failure.

Congestive heart failure occurs when the heart pumps less blood into the circulatory system than the metabolic requirement of the body requires. Therapy then consists in restoring the condition in which there is blood supply

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and needs are in balance. One can help this goal of the cardiotonics according to the invention which improve the myocardial contractility and the cardiac output in this way influence that it meets the requirements of the body functions.

The use of conventional heart stimulants is by theirs toxic effects to the heart or from harmful Side effects limited to the peripheral circulation. Although, for example, cardiac glycosides are used as cardiac muscle stimulants suitable, the doses sufficient to strengthen the failing heart are very close to those for symptoms of poisoning (like cardiac arrhythmia »dizziness or vomiting) leading threshold. Administration of adrenomimetics is in turn caused by the resulting arrhythmia »tachycardia, tachyphylaxis or altered peripheral resistance restricted·

The trichloroacetamidine derivatives of the invention have become proven to be pronounced heart muscle stimulants, which detract from the toxic side effects of conventional cardiac stimulants are essentially free. The cardiac stimulation is in warm-blooded animals by measuring the contractility (in vitro) on the isolated heart muscle and in vivo on anesthetized dogs provided with a cardiac voltmeter certainly.

The trichloroacetamidine derivatives according to the invention are administered to the patient suffering from heart failure in daily doses of about 0.1 to 50 mg / kg of body weight. It can be administered orally or parenterally. The compounds can be used alone or in a mixture with conventional medicament carriers. For example, tablets, dispersible powders , granules are suitable for oral administration! Capsules, syrups and elixirs »for parenteral purposes eg solutions, suspensions · dispersing

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sions and emulsions "like sterile" injectable aqueous Suspensions. To the orally administered preparations an appealing To give them appearance and taste, one or more conventional excipients »such as Sweeteners, flavoring and flavoring corrigents (flavoring agents), dyes or preservatives. Tablets can contain the active ingredient in a mixture with usual pharmacological compatible excipients, e.g. inert diluents such as calcium carbonate, sodium carbonate, Lactose or talc, granulating agents and disintegrants, such as starch or alginic acid, binders such as starch, gelatin or gum arabic, and lubricants, such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or conventional Methods are provided with a coating, which inhibits the disintegration and absorption in the gastrointestinal tract and thereby ensures a long-term delayed effect. Suspensions, syrups and elixirs can also contain the active ingredient in admixture with any conventional excipient used for such preparations, such as suspending agents (methyl cellulose, Tragacanth or sodium alginate), wetting agents (lecithin, polyoxyethylene stearate or polyoxyäthylensor- "bitamnonooleate) or preservatives (ethyl p-hydroxybenzoate). The Active ingredient alone or in a mixture with an inert, solid diluent such as calcium carbonate, calcium phosphate or kaolin. The injectables are formulated in the usual way and may contain suitable dispersing or wetting agents and suspending agents, for which the aforementioned and similar means are suitable. The proportion of that associated with the carrier or aid Active ingredient is up to about 90 56 in these medicinal products.

The cardiotonically effective dose of the for the therapy of

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The active ingredient used in congestive heart failure depends on the particular compound used and the severity of the disease. In general, however, a satisfactory healing effect is achieved at daily doses of about d 1 to about 50 mg / kg of body weight. The drugs are preferably administered two to four times a day in divided doses or in the form of sustained release preparations. I ^{1 For} most large warm-blooded animals that require such treatment, the total daily dose is about 0.7 to about 50 mg / kg, the administration preferably being carried out orally. The preparations suitable for internal administration contain from about 1 to about 25 mg / kg of active ingredient in thorough admixture with a solid or liquid pharmacologically acceptable carrier or diluent.

The preferred drugs from the point of view of preparation and ease of administration are solid preparations » in particular dry-filled capsules and tablets which contain about 1 to 25 mg of active ingredient per kg of body weight.

The following are the preferred embodiments of the present invention explained.

Preference according to the invention is given to those compounds of the above general formula in which R. and Ep are each, independently of one another, a hydrogen atom or a lower-alkyl radical and E is a hydrogen atom or a lower-alkyl or lower-alkenyl radical. Compounds which are particularly preferred according to the invention are: N-methyltrichloroacetamidine, Ν, Ν-dimethyltrichloroacetamidine, Ν, Ν, Ν ^1- trimethyltrichloroacetamidine, N-ethyltrichloroacetamidine, N-propyltrichloracetamidine, N-allyltrichloroacetamidine, N-allyltrichloroacetamidine and N'-allyltrichloroacetamidine and N'-allyltrichloroacetamidine.

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The compounds according to the invention are generally made from trichloroacetonitrile produced according to the following reaction scheme:

BH ClJBS + HHE ₉ E, > ClJC-CS-R ₀

Alkylation

Ii-S ₁

In the above reaction scheme, E. denotes a hydrogen atom or a lower alkyl radical, E «a hydrogen atom or a lower alkyl radical and E- is a hydrogen atom, a Cyano group or a lower-alkyl-, lower-alkenyl-, cycloalkyl- or phenyl-lower-alkyl radical (including the niently toxic, pharmacologically acceptable salts of these Links).

According to the above reaction scheme, erichloroacetonitrile is reacted with the appropriate primary or secondary amine to give the H-substituted or N _t N-disubstituted trichloroacetonitrile. The reaction is preferably carried out in the presence of a solvent, although such a solvent is not absolutely necessary. If you use a solvent «preferably nan organic substances» such as aliphatic or aromatic hydrocarbons. Specific examples of suitable solvents are hexane, benzene, toluene and petroleum ether. Other solvents that can be used are ethers, such as diethyl ether or tetrahydrofuran, "halogen-containing solvents" such as chloroform,

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Carbon tetrachloride or chlorobenzene, as well as dimethyl sulfoxide and N, fl-dimethylf οηπβτηΐ d. The reaction is carried out at temperatures of 0 Ms TOO ⁰ C (or Ms to the reflux temperature of the reaction medium, if this is below 100 ⁰ C). The reaction is generally complete after 1 to 48 hours. The reaction is preferably allowed to proceed for 4 to 24 hours at about tree temperature. The reaction product is isolated by conventional methods.

If you use salts from primary or secondary mines » one has to add a base to the reaction mixture which desired ümin releases. Examples of suitable bases are tertiary amines such as trialkylamines, pyridine or ΪΓ, Ν — di— methylaniline, inorganic bases such as alkali and alkaline earth hydroxides, carbonates and bicarbonates, as well as organometallic bases, such as .ftlkalialko3d.de.

The second stage of the reaction sequence consists in the alkylation of the ίϊ-substituted or ίΤ, Ιί-disubstituted üPrichloracetamidins to Kj ^ '- disubstituted or E, 2f, Έ * -trisubstituted en trichloroetamidine. Bie reaction is with auxiliary e of any iierkömmlichenAlkylierungsmittels as a Kieder-alkylfluorsulfonats or üTieder-alkyl halide performed · The reaction is carried out for 1 to 48 hrs., At temperatures from 0 to 100 ⁰ C Coder to Eückflußtemperatur of Eeaktionsgemiseh.es, if this is less than 100 ° G) and, if necessary, in the presence of a Ιιδ-solvent, as has been explained above. The reaction is preferably carried out for 4 to 24 hours at about tree temperature. The reaction product is isolated in the customary manner.

The cyclic amidines can also be made from 3irichloroacetonitrile and a Jmin. In this case, however, a diamine is used, for example a JÜLkyldi—

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amine. The diamine is - if appropriate in the presence of a solvent - combined with trichloroacetonitrile ^{at temperatures from 0 to 10O 0 C.} The batch is kept in the temperature range mentioned for 1 hour to 5 days. The reaction is preferably carried out for 8 hours to 2 days with stirring at about room temperature. The reaction proceeds much more smoothly if, in view of the one mole of ammonia released in the cyclic amidine ring closure, one mole of a base acceptor (such as p-toluenesulfonic acid or hydrochloric acid) is added. The base acceptor reacts with the ammonia to form an easily separable salt, which makes product isolation easier.

If R ~ is a mederalkylene radical, which by a remainder of the following general formula

-K-C- CCl,

I Il J

R ₂ NR ₁

in which R ₁ and Rp each have the meaning given above, is substituted, the reaction starts from trichloroacetonitrile and a diamine. To synthesize the desired bis-compound, however, 2 moles of trichloroacetonitrile are used per mole of diamine. The reaction takes place under the same conditions as in the synthesis of the other substituted amidines; the bis-compound obtained is isolated by conventional methods.

The following examples are intended to explain the compounds used according to the invention and the methods of the invention in more detail; however, they are not intended to limit the invention in any way.

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example 1

Trichloroacetamidine

30 g of trichloroacetonitrile are introduced into 300 ml of liquid ammonia within 10 minutes. The mixture is then stirred for 7 hours under a dry ice condenser under reflux conditions. The dry ice condenser is then removed and the ammonia is allowed to evaporate within 15 to 20 hours. 100 ml of benzene are added to the residue, the mixture is filtered through diatomaceous earth and the filtrate is evaporated at 35 ° C./15 to 20 mm Hg to give an oil (30 g). The oil is stirred with 200 ml of hot hexane. The mixture is filtered, the filtrate is cooled to 5 ⁰ C, the solid constituents are filtered off and dried for 2 hours the! Filter residue. At 25 ° C / 5O mm Hg. This gives 17.5 g Trichloracetamidin base of Ep. 41 * 5 ⁰ to 43.5 C

example Trichloroacetamidine hydrochloride

2 ml of 7.6N anhydrous ethanolic hydrochloric acid are added to a solution of 2 g of trichloroetamidine base in 15 ml of ethyl acetate. After cooling to 5 ⁰ C, the white Peststoff formed (Trichloracetamidin hydrochloride) is filtered off and dried at 25 ° C mm / 0.2.

example U-methyltrichloroacetamidine hydrochloride

8 ml of trichloroacetonitrile are introduced into a mixture of 10 ml of 40% aqueous methylamine and 5 ml of water at 5 to 15 ^° C. over a period of 10 minutes with thorough stirring. After stirring for 2 hours, the lower layer is separated and placed in

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50 ml of ethanol dissolved. The solution is dried over anhydrous magnesium sulfate and filtered. The residue obtained upon solvent evaporation at 30 ⁰ C and a reduced pressure is dissolved in 50 ml Ithylacetat. Is added to the solution with an excess of anhydrous ethanolic hydrochloric acid, the mixture is cooled and filtered, the N-Methyltrichloracetamidin hydrochloride (Pp 221 ⁰ C under dark coloring;. 234-235 ⁰ C with decomposition) from.

example

gyH-Dimethyltrichloroacetamidine hydrochloride

In analogy to Example 3, but using 15% aqueous dimethylamine instead of the aqueous methylamine, Njlf-dimethyltrie-moracetamidine hydrochloride from ϊρ is obtained. 191 to 194 ⁰ C (decomposition).

example N- (n-propyl) -trichloroacetami.dine hydrochloride

A solution of 2.95 g of n-propylamine in 30 ml of benzene is introduced into a solution of 5% of trichloroacetonitrile in 30 ml of benzene at 10 to 15 ° C. within 30 minutes. Inschließend the solution is stirred for 3 days at 20 to 25 ° C and then evaporated at 35 to 4O ⁰ C under reduced pressure. The residue is dissolved in a mixture of equal parts by volume of ethanol and ethyl acetate and excess anhydrous ethanolic hydrochloric acid is added. The hydrochloride is then precipitated by adding ethyl acetate. After crystallization from ethanol / ethyl acetate, 8.65 g of H- (n-propyl) -trichloroaceteamide hydrochloride with a melting point of 201.5 to 208.5 ° are obtained.

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example N-benzyl trichloroacetamidine

A solution of 10.8 g (0.1 mol) of benzylamine in 60 ml of benzene is introduced into a solution of 10 ml of trichloroacetonitrile in 60 ml of benzene at 10 to 15 ^° C. over the course of 20 minutes while stirring. The solution is then stirred for 18 hours at 20 to 25 ^° C. and then evaporated at 50 ^° C. under reduced pressure. After two-fold recrystallization of the residue from 100 ml of hexane 81.5 are obtained 18.9 g of N-Benzyltrichloracetamidin mp. 84.0 to ⁰ C.

example N-Benzyltrichloroacetamidine hydrochloride

15 g of N-benzyltrichloroacetamidine are dissolved in ethyl acetate, the solution is acidified with an excess of anhydrous ethanolic HCl and the batch is cooled. Thereafter, the precipitated N-Benzyltrichloracetamidin hydrochloride (12.5 g), mp. 198.5 Ms 206.5 ⁰ C (decomposition) was filtered off.

Example 8

1,2-bis (trichloroacetamidino) ethane

A solution of 2.4 g (0.040 mole) of ethylenediamine in 100 ml of benzene is added within 20 min. Under stirring at 10 ⁰ C with a solution of 11.56 g (0.08 mole) of trichloroacetonitrile in 12 ml of benzene. The solution is then stirred for 15 minutes at 5 to 10 ^° C., allowed to ^{warm to 20 °} C. and stirred for 2 hours at this temperature. The residue remaining after the solvent has been separated off at 30 ^° C. and reduced pressure is recrystallized from a benzene / hexane mixture.

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Two further recrystallizations from benzene give 1,2-bis (trichloroacetamidino) ethane of p. 108 to 116 ⁰ C,

At s ρ i e 1

2-trichloromethyl-2-imidazoline

A solution of 3 g (0.05 mol) of ethylenediamine and 9 "5 g (0.05 mol) of p-toluenesulfonic acid hydrate in 50 ml of methanol is stirred for 30 min. At 25 ⁰ G and then with 7" 22 g (0 , 05 mol) of trichloroacetonitrile were added. The batch is stirred for a further 20 hours at 20 to 25 ^° C., filtered and the filtrate is evaporated under reduced pressure. The residue is washed with water and dissolved in benzene. Then it is washed again with water and saturated sodium chloride solution. The benzene extract is then dried over anhydrous sodium sulfate and filtered. The residue remaining on evaporation of the piltrate is applied to a silica gel column which is eluted with a solvent mixture of 25% methanol and 75% chloroform. Those fractions which, on the basis of thin-layer chromatographic determination, contain 2-trichloromethyl-2-imidazoline are combined and evaporated. This gives 1.2 g of 2-trichloromethyl-2-imidazoline of boiling point 85 ^° C. (decomposition).

Example 10

1,3-bis (trichloroacetamidino) propane dihydrochloride hydrate

In a solution of 14 "4 g (0.1 mole) of trichloroacetonitrile in 60 ml of benzene is within 20 min. Under stirring at 10 ⁰ C a solution of 3.7 g (0.05 mole) of 1,3-diaminopropane in 50 ml of benzene entered. The solution is then stirred for 15 minutes.

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at 5 "to 1ο ° Ό, it leaves at 20 ⁰ C to warm and stir them" 20 hours ". at this temperature. The after solvent evaporation at 30 ⁰ C and reduced pressure and the residue is dissolved in ethyl acetate and the solution with an excess of 221 is an anhydrous ethanolic hydrochloric acid and filtered. by drying the residue at 25 ⁰ C and reduced pressure receives 17 "4 g of 1,3-bis (trichloracetamidinoj-propane dihydrochloride in the form of the hydrate of Pp. to 225 ⁰ C.

Example 11 N-allyl trichloroacetamidine hydrochloride

A solution of 8.55 g (0.15 mol) of allylamine in 75 ml of benzene is introduced into a solution of 15 ml of trichloroacetonitrile in 100 ml of benzene at 10 to 15 ^° C. over the course of 20 minutes. Inschließend the solution is stirred for 18 hrs. At 20 to 25 ° C and then evaporated at 45 ⁰ C and reduced pressure. The residue is dissolved in a mixture of 50 ml of ethanol and 50 ml of ethyl acetate and excess anhydrous ethanolic hydrochloric acid is added to the solution. By addition of 4OO ml ethyl acetate 30.2 g of N-Allyltrichloracetonitril hydrochloride (m.p. 171 ⁰ C under dark coloring;. 177 to 181 ⁰ C with decomposition) precipitated. Recrystallization from ethanol / ethyl acetate provides the analysis sample with the same melting point values.

Example 1_2

N-cyclobutyltrichloroacetamidine

A mixture of 5.08 g (0.047 mole) cyclobutylamine hydrochloride, 4t76 g (0.047 mol) of triethylamine and 10.25 g

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(0.071 mol) of trichloroacetonitrile in 20 ml of benzene and 10 ml of dimethyl sulfoxide is ^{stirred for 18 hours at 20 "to 25 °} C. Then 30 ml of benzene and 2 ml of saturated sodium bicarbonate solution are added and the mixture is poured into 100 ml of saturated sodium chloride solution The benzene layer is separated and washed twice with 100 ml of water each time, twice with 20 ml of 3N hydrochloric acid each time and finally again with 20 ml of water. The acid extracts and the last water extract are combined, washed with 50 ml of benzene and then made alkaline with saturated sodium bicarbonate solution the crude product is extracted in three 100 ml portions of benzene. The benzene extracts are combined, washed with water and dried over anhydrous magnesium sulfate. Then, it is filtered, the filtrate is evaporated under reduced pressure and the residue is recrystallized from hexane , 73 g N-Cyclobutyltrichloracetamidin Pp from 65 "5 to 69.5 ⁰ C Three other Umkristall isations from hexane provide the analysis sample from pp. 68 to 70 ⁰ C.

Example 1_3

N-Allyl-N ¹ -methyl trichloroacetamidine hydrochloride

A mixture of 1.5 g (7.5 mmol) of N-Allyltrichloracetamidin and 0.86 g (7.5 mmol) of methyl fluorosulfonate in 30 ml benzene is stirred at 20 to 25 ⁰ C for 18 hrs., Then decanted to the benzene solution of insoluble oil, which is then washed with more benzene. The insoluble oil is then partitioned between benzene and saturated sodium bicarbonate solution. The benzene extract is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The piltrate is mixed with excess ethanolic hydrochloric acid and filtered

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again. By drying of the residue 0 »9 g 83 receives N-allyl-IT ¹ -methyltrichloracetamidin hydrochloride from Pp. To 87 ⁰ C (decomposition).

Example 14 N-Cyclopropyltrichloroacetamidine

A solution of 3 g (0.53 mole) of cyclopropylamine and 11.55 g (0,080MoI) of trichloroacetonitrile in 20 ml of benzene is stirred for 20 h at 25 ⁰ C. It is then extracted with 20 ml of 3N hydrochloric acid, the aqueous extract is mixed with 25 ml of water and extracted with 50 ml of benzene. The aqueous extract is then made alkaline with saturated sodium bicarbonate solution and extracted three times with 50 ml of benzene each time. The combined benzene extracts are washed with water, dried over anhydrous magnesium sulfate and filtered. The piltrate is evaporated under reduced pressure and the residue is recrystallized from hexane; This gives 3 "33 g N-Cyclopropyltrichloracetamidin from Pp. 48.5 to 50.5 ⁰ C. Two more recrystallizations from hexane give the analytical sample of Pp. 50.0 to 50.5 ⁰ C.

Example 15 NyN ^ '- trimethyltrichloroacetamidine fluorosulfonate

A solution of 1.7 g (0.015 mole) of methyl fluorosulfonate in 10 ml of benzene is gradually added in 15 ml of benzene with vigorous stirring at 25 ⁰ C in a solution of 3.24 g (0.017 mol) of NJN-Dimethyltrichloracetamidin. . Thereafter, the mixture is stirred 23 hours the batch at 25 ⁰ C. Subsequently, the [, !!, filtered FF 'Trimethyltrichloracetamidin fluorosulfonate and at 25 ° C / 0.2 mm dried!; 3.8 g of the compound of Pp 103 to 107 ⁰ C are obtained,

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Example 1_6

N-cyantrichloroacetamidine "

A solution of 3.6 g (0.025 mole) of trichloroacetonitrile in 50 ml of methanol. Stirred for 20 hours at 20 to 25 ⁰ G, then mixed with 1.05 g (0.025 mole) of cyanamide and then an additional 24 hr. At 20 to 25 ⁰ C stirred. The residue remaining when the solution is evaporated under reduced pressure is recrystallized from acetonitrile; there are obtained 166.7 N-Cyantrichloracetamidin from Ep. to 167.2 ⁰ C.

Example 17

Tablets suitable for oral administration can be prepared using conventional tableting methods, which contain the components listed below. Doses of are suitable for the therapy of heart failure one or two such tablet (s) when administered two to four times per day.

Components Proportions, mg N-methyltrichloroacetamidine 10 Tragacanth 10 Lactose 237.5 Cornstarch 25th Talk 15th Magne s iums t e ar at 2.5

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Example 18 Dry-filled capsules

It is conventionally prepared for oral administration suitable capsules containing the ingredients listed below. Such capsules can be in a dose of one or two capsules when administered two to four times per day as a cardiac stimulant will.

Ingredients Proportions, mg

NiH-dimethyltrichloroacetamidine 20

inert, solid diluent

(Starch, milk sugar, kaolin, etc.) 280

Example Ij)

Sterile suspension for injection purposes and Plüssigsuspension for oral use

The following drugs are prepared according to conventional methods using the specified amount of active ingredient formulated. The injectable suspension and the liquid suspension for oral use are suitable preparations as unit doses which can be used for the therapy of heart failure. The injectable suspension is suitable for a single daily administration, while the oral liquid suspension is advantageous for the same purpose given two to four times a day.

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15708Y * 3 260 1158 .P. q.s. Liquid sweetness
pension for
oral purposes Components Proportions, mg .P. qsauf
1 ml 10 N-ethyltrichloroacetamidine injectable
suspension .P. Sodium carboxymethyl cellulose, U.S.P. 50 Methyl cellulose 1.25 Polyvinyl pyrrolidone 0.4 Lecithin 5 Benzyl alcohol 3 47.5 Magnesium aluminum silicate 0.01 q.s. Corrections of taste or taste
(flavor) q.s. dye 4.5 Methyl paraben
(methyl p-hydroxybenzoate), TJ.S 1.0 Propyl paraben
(propyl p-hydroxybenzoate) »US 1.5 Polysorbates 80
(Polyoxyethylene sorbitan monooleate), US 2500 70 # Sorbitol Solution, U.S.P. q.s. PH adjustment buffer qsauf
5 ml water

Example 20

Tablets and capsules suitable for oral administration

Using conventional methods,! Tablets and capsules, which contain the ingredients listed below. They can be in doses of one or two Tablets or capsules can be used as cardiac stimulants when administered one to four times per day.

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Components

260 1158 Shares, mg Tablets Capsules 25th 100 20th 212.5 200 25th 15th 2.5

N-allyl trichloroacetamidine Tragacanth lactose corn starch talc

Magnesium stearate

total 300.0 300.0

It is "known that N-substituted amidines in the tautomeric Equilibrium exist. When in the present application of a substituted amidine is mentioned, which one Has certain substituents on one of the amidine nitrogen atoms, what is actually meant is the tautomeric mixture. However, the tautomerism is abolished when a single amidine nitrogen atom is disubstituted, as well as im Case of the ΪΤ, Ιϊ, ΙΤ'-trisubstituted amidines.

Many of the aforementioned compounds also have optical activity, i.e. they are normally found as racemic mixtures of the respective d- and 1-optical isomers before. If a particular compound thus has a center of asymmetry and is therefore considered to be a mixture of the optical d- and 1-isomers occurs, both the individual isomers fall as well as the racemic mixture under the invention.

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Claims (11)

& CO., INC. ^lk - January 1976 157O8Y PATENT CLAIMS (V) Medicaments for the treatment of heart failure comprising an inert carrier and at least one compound the general formula below Cl ₃ CCNR ₂ in which R ^ is a hydrogen atom or a lower alkyl radical means, R _{2 is} a hydrogen atom or a lower alkyl radical and R, a hydrogen atom, a cyano group, a Lower alkyl, lower alkenyl, cycloalkyl or phenyl-lower-alkyl radical or one of the following general radicals formula -N-C- CCl I Il R ₂ in which R ₁ and R ₂ each have the meaning given above, substituted Nie- - 21 - 609830/0801 denotes the -alkylene radical, where R ₁ and IL, also with one another, including the amidine nitrogen atoms to which they are bonded, to form one
heterocyclic ring can be linked, and / or the non-toxic, pharmacologically acceptable Salts of these compounds. 2. Medicament according to claim 1, characterized in that it contains 1 to 90 wt .- $ of the active compound (s). 3. Medicament according to claim 1, characterized in that the active compound has the general formula given, where R _{1 is} a hydrogen atom or a _{lower alkyl radical, R 2 is} a hydrogen atom or a lower alkyl radical and R-, a hydrogen atom or a lower alkyl
or Meder-alkenyl radical. 4. Medicament according to claim 3 »characterized in that the active compound is N-methyl-trichloroacetamidine. 5. Medicament according to claim 3, characterized in that the active compound is ΙΓ, ΙΓ-dimethyltrichloroacetamidine. 6. Medicament according to claim 3 »characterized in that the active compound NjlJjlT-irimethyltrichloroacetamidine
is. 7. Medicament according to claim 3, characterized in that the active compound is N-ethyltrichloroacetamidine. 8. Medicament according to claim 3, characterized in that the active compound is ΪΓ-propyltrichloroacetamidine. - 22 - 609830/0801 157O8Y J 9. Medicines after. Claim 31 characterized in that the active compound is N-allyltrichloroacetamidine. 10. Medicament according to claim 3 »characterized in that the active compound is if ¹ -methyl-N-allyltrichloroacetamidine . 11. Medicament according to claim 3 »characterized in that the active compound is N-cyantrichloroacetamidine. - 23 - 609830/0801