DE2601137A1 - SUBSTITUTED PERHALOGENALKYLAMIDINES AND HEART STIMULANTIES - Google Patents

Description

y patent attorneys;

Dr. ? ng. W. '^ r Abltl
Dr. Dicier F, Morf
Dr. Hans-Α. Browns

& Mäaeüsa 68, Pieuzaaauentr. 28 Hi JANUARY 1976

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

Substituted perhaloalkylamidines and cardiac stimulants

DT-OS 2 121 401 describes certain trichloroacetamidines intended for agricultural purposes. An indication that the trichloroacetamidines in question are generally used as pharmaceuticals and specifically as cardiac agents could be suitable, but is missing in the cited reference.

According to the invention were now certain new, to the class of Compounds belonging to substituted perhaloalkylamidines have been found which have pronounced cardiac stimulating effects unfold and are therefore used as an active ingredient component of drugs.

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The object of the invention is therefore to develop new compounds, in particular new substituted perhaloalkylamidines, Methods for preparing these new substituted perhaloalkylamidines and the new compounds mentioned to provide medicinal products containing them possible.

The invention thus relates to new substituted perhaloalkylamidines, which can be represented by the general formula below

N-It ₁
it '

RCNR ₉

ι * ■

^R 3

in which R is a perhalogenated alkyl radical having 1 to 5 carbon atoms means,

R _{1 represents} a hydrogen atom, a phenylcarbamoyl group or a lower-alkyl, lower-alkanoyl or lower-alkoxalyl radical,

R2 is a hydrogen atom or a lower alkyl or lower alkanoyl radical and

R-z is a lower alkyl, phenyl lower alkyl, lower alkenyl, Lower alkynyl, cycloalkyl or cycloalkenyl radical, which radicals one or more hydroxyl, hydroxy-lower-alkyl, lower-alkoxy, Lower alkylthio, lower alkanoyloxy, lower alkanoylamino, Phenyl, hydroxyphenyl, lower alkoxyphenyl, phenoxy, phenylsulfinyl, naphthylsulfinyl, Cycloalkyl, lower alkylphenyl, lower alkenylphenyl, Have phenylcycloalkyl and / or halogen substituents,

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a perhalogenalkylamidino-lower-th alkylsubstituier- phenyl-lower-alkyl radical or an alkyl-low with the amidine sticks toff atom linked via an optionally lower alkyl-, lower alkoxy- or benzoyl-substituted 5- to 7-membered heterocyclic radical containing one or two heteroatoms in the form of oxygen and / or nitrogen atoms or benzoheterocyclic radical whose benzene ring is fused to a 5- to 7-membered heterocyclic ring with one or two heteroatoms in the form of oxygen and / or nitrogen atoms, where Rp and R , or Rj and R, including the two amidine S ticks toff atoms can be linked to form a 5- to 7-membered heterocyclic ring, which is hydroxyl, lower alkoxy, phenyl or halogen or to a lower alkyl or lower alkoxy substituted benzene ring is condensed,

as well as the non-toxic, pharmacologically acceptable salts of these compounds, "where if a particular compound has a labile proton (as in an amino or hydroxyl group), this proton can also be replaced by a glycoside residue (such as a glucoside residue)

The term "lower-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 alkenyl radicals having 2 to 5 carbon atoms with a linear or branched configuration and one or two unsaturated bonds, such as the vinyl, propenyl, allyl, butenyl or 2,4-pentadienyl group.

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"Lower alkynyl radicals" embraces straight or branched-chain alkyl radicals having 2 to 5 carbon atoms and a triple bond, "such as the ethynyl, 1-propynyl, propargyl or pentynyl group.

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

"Cycloalkenyl" embraces 4-7 cycloalkenyl groups Carbon atoms and one or two unsaturated bonds, such as the cyclobutenyl, cyclohexenyl, cycloheptenyl or cyclohexadienyl group.

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

"Heterocyclic radicals" embraces 5- to 7-membered heterocycles with one or two oxygen or nitrogen atoms (or one oxygen and one nitrogen atom) as heteroatoms. Specific examples of these heterocyclic radicals are the furyl, tetrahydrofuryl, pyrrollyl, pyrrolidinyl, Morpholinyl, piperidinyl, pyridyl, pyranyl, pyrimidinyl, Piperazinyl, pyrazinyl, oxapinyl and azepinyl groups. Analogously, the term "benzoheterocyclic radicals" includes those Residues whose benzene ring is fused to one of the aforementioned heterocyclic radicals, the indolyl group is preferred.

It is known that N-substituted amidines are in tautomeric equilibrium. \ Lenn. In the present application, when a substituted amidine is mentioned which has a certain substituent on one of the amidine nitrogen atoms, in reality the tautomeric mixture is always meant. However, the tautomerism is canceled if

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a single amidine nitrogen atom is disubstituted, as well as in the case of N, N, N ^f -trisubstituted amidines.

Many of the above compounds also possess optical activity, ie, they are normally referred to as racemic mixtures of the optical specific d- and 1-isomers in question before. If a particular compound thus has a center of asymmetry and therefore occurs as a mixture of the d- and 1-optical isomers, both the individual isomers and the racemic mixture are within the scope of the invention.

The compounds according to the invention have valuable pharmacological 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 form valuable agents for the treatment of heart failure.

The heart becomes congestive when it pumps less blood into the circulatory system than the body's metabolic needs require. Therapy then consists in restoring the condition in which blood supply and demand are in balance. You can achieve this goal with the help of the fiction, contemporary cardiotonics, which improve the cardiac muscle contractility and increase the cardiac output so much that it meets the requirements of the body functions.

The use of conventional heart stimulants is due to their toxic effects on the heart or by harmful side effects limited to the peripheral circulation. For example, although the cardiac glycosides are Suitable cardiac muscle stimulants, the doses sufficient to strengthen the failing heart are very close to that of Symptoms of intoxication (such as cardiac arrhythmia, dizziness or

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Vomiting) leading threshold. Administration of adrenomimetics is in turn due to the occurring arrhythmia, tachycardia, tachyphylaxis or changed peripheral Resilience limited.

The perhaloalkylamidine derivatives of the invention have proved to be pronounced heart muscle stimulants "which are essentially free from the toxic side effects of conventional cardiac stimulants. The heart stimulation is carried out on warm-blooded animals by measuring the contractility on the isolated heart muscle and in vivo using a cardiac tension meter provided anesthetized dogs.

The fiction, contemporary Perhalogenalkylamidinderivate are the patient suffering from heart failure in daily Doses of about 0.1 to 50 mg / kg body weight are administered. The administration can take place orally or parenterally »here the compounds can be used alone or in admixture with conventional excipients. For oral For example, tablets, dispersible powders, granules, capsules, syrups and elixirs are suitable for administration, for parenteral purposes e.g. solutions, suspensions, dispersions and emulsions such as sterile, injectable aqueous Suspensions. In order to give the orally administrable preparations an attractive appearance and taste, can you give them one or more conventional excipients, such as Incorporate sweeteners, flavoring agents, colorings or preservatives. Tablets can contain the active ingredient in a mixture with common pharmacologically acceptable excipients, e.g. inert diluents, v / ie calcium carbonate, sodium carbonate, milk sugar or talc, granulation auxiliaries and disintegrants such as starch or alginic acid, binders such as starch, gelatin or gum arabic, as well as lubricants such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or by conventional methods

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be provided with a coating, which inhibits the disintegration and absorption in the gastrointestinal tract and thus ensures a long-term delayed effect. Suspensions, syrups and elixirs can also be mixed with any conventional excipients used for such preparations, such as suspending agents (methyl cellulose, tragacanth or sodium alginate), wetting agents (lecithin, polyoxyethylene stearate or polyoxyethylene sorbitan monooleate) or preservatives (p-hydroxybenzoic acid ether) , contain. The active ingredient can be contained in capsules alone or in admixture with an inert, solid diluent such as calcium carbonate, calcium phosphate or kaolin. The injection preparations are formulated in the usual way and can contain suitable dispersing or wetting agents and suspending agents, for which the aforementioned and similar agents are suitable. The proportion of the active ingredient combined with the carrier or auxiliary agent is up to about 90 % in these medicinal preparations.

The cardiotonically effective dose for heart failure therapy The active ingredient used depends on the particular compound used and the severity of the disease. In general however, at daily doses of about 0.1 to about 50 mg / kg of body weight, it becomes a satisfactory healing effect achieved. The drugs are preferably administered two to four times daily in divided doses or in the form of Delayed-release preparations administered. For most large warm-blooded animals requiring treatment require, the total daily dose is about 0.7 to about 50 mg / kg, the administration preferably being oral Ways takes place. The preparations suitable for oral purposes contain about 1 to about 500 mg of active ingredient in a thorough mixture with a solid or liquid, pharmacologically acceptable carrier or diluent *

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The drugs preferred from the viewpoint of preparation and ease of administration are solid preparations, in particular dry-filled capsules and tablets, which have an active ingredient content of about 10 to 250 mg.

The following are the preferred embodiments according to the invention explained.

Those compounds of the above are preferred according to the invention general formula where

R is a trichloromethyl group,

R _{1 is} a hydrogen atom or a lower alkyl radical, Rp is a water to ff atom or a lower alkyl radical and

R, a lower alkyl, phenyl lower alkyl, lower alkenyl or lower alkynyl radical, which radicals one or more hydroxyl, hydroxy-lower alkyl, lower alkoxy, Lower alkylthio, lower alkanoyloxy, phenyl, hydroxyphenyl, lower alkoxyphenyl, phenoxy, Cycloalkyl, phenylcycloalkyl and / or halogen substituents exhibit,

mean.

In turn, these preferred compounds become those compounds with the above general formula particularly preferred in which

a hydrogen atom or a lower alkyl radical, a hydrogen atom or a lower alkyl radical and

R, a lower-alkyl or phenyl-lower-alkyl radical, which radicals one or more hydroxyl, lower alkanoyloxy, phenyl, lower alkoxyphenyl and / or Have phenoxy substituents,

mean.

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Most preferred among the aforementioned compounds are those compounds with the above general formula in which PLj and R ₂ are each independently a hydrogen atom or a lower-alkyl radical and PU is a phenyl-substituted hydroxy-lower-alkyl radical or a substituted lower-alkyl radical with a or represent several hydroxyphenyl, lower alkoxyphenyl, phenoxy and / or hydroxyl substituents. Particularly preferred connections are:

N- (p-hydroxyphenethyl) -trichloroacetamidine, N- (o-hydroxybenzyl) -trichloroacetamidine, N- (2-Hydroxy-3-phenoxypropyl) -trichloroacetamidine, N- (ß-Hydroxyphenäthyl) -trichloroacetamidine and N- (p-methoxybenzyl) trichloroacetamidine.

Further compounds preferred according to the invention are those Compounds with the above general formula in which

R is a trichloromethyl group,

R-I denotes a hydrogen atom or a lower alkyl radical,

R _{2 is} a hydrogen atom or a lower alkyl radical and

R, denotes a lower alkyl radical, which is replaced by a heterocyclic or benzoheterocyclic radical is substituted, which is from indole, pyrimidine, piperidine, Furan, tetrahydrofuran, pyridine or piperazine and optionally lower-alkyl, lower-alkoxy or benzoyl substituted.

Particularly preferred of these compounds are those in which R, R 1 and R ₂ each have the aforementioned meaning and R 1 represents a lower alkyl radical which is optionally substituted by methyl, methoxy or benzoyl

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Rest of indole, pyrimidine, piperidine or furan substituted is.

Of these compounds, even more preferred are those in which R ₁ and R ₂ each have the meaning given above and R- represents a methyl or ethyl group which is substituted by an indolyl group which may be methyl- or methoxy-substituted.

In the case of the most preferred compounds, the aforementioned indolyl group is unsubstituted.

Particularly preferred compounds are: N- (3-indolylmethyl) -trichloroacetamidine, N- [2- (5-methyl-3-indolyl) ethyl] trichloroacetamidine, N- (1-methyl-3-indolylmethyl) -trichloroacetamidine, N- (5-methoxy-3-indolylmethyl) trichloroacetamidine and N- (1-Benzoyl-3-indolylmethyl) trichloroacetamidine.

Due to the complicated structure of the invention Connections, it is often the case that a particular connection has several appropriate names. the each designation depends on which part of the molecule serves as a starting point for the nomenclature. It is often quite permissible to choose different parts of the molecule, each of which is a suitable starting point for the notation.

A specific example of different names for one and the same compound is N- [2- (5-methyl-3-indolyl) ethyl] trichloroacetamidine or 5-methyl-3- (2-trichloroacetamidino ethyl) indole.

The compounds of the invention can according to the following Reaction scheme made from perhaloalkyl nitriles will:

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NH RC = N + NHR ₂ R ₃ > RC-NR ₂

«3

Alkylation or J

> RCNR ₂

Acylation '

^R 3

In the above reaction scheme:
R is a perhalogenated alkyl radical,

Rj is a phenylcarbamoyl group or a lower alkyl, Lower alkanoyl or lower alkoxalyl radical,

R _{2 is} a hydrogen atom or a lower alkyl radical and

Rz is a lower-alkyl, phenyl-lower-alkyl, lower-alkenyl, Never the alkynyl, cycloalkyl or cyclo ■ alkenyl radical, -which radicals one or more hydroxyl, hydroxy-lower-alkyl-, lower-alkoxy-, lower-alkylthio-, Lower alkanoyloxy, lower alkanoylamino, Phenyl, hydroxyphenyl, lower alkoxyphenyl, phenoxy, phenylsulfinyl, naphthylsulfinyl, cycloalkyl, lower alkylphenyl, Lower alkenylphenyl, phenylcycloalkyl, Have lower alkanoyl and / or halogen substituents, or

one via a lower alkyl radical with the amidine nitrogen atom linked, optionally lower-alkyl-, lower-alkoxy- or benzoyl-substituted 5- to 7-membered heterocyclic radical with one or two heteroatoms in the form of oxygen and / or nitrogen atoms or benzoheterocyclic radical whose benzene ring is attached to a 5- to 7-membered heterocyclic Ring with one or two heteroatoms in

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Form of oxygen and / or nitrogen atoms is condensed, mean.

This also includes the non-toxic, pharmacologically acceptable salts of the compounds in question; if a particular compound has a labile proton (as in an amino or hydroxyl group), it can be replaced by a glycoside residue.

According to the above reaction scheme, the perhaloalkyl nitrile is reacted with the appropriate primary or secondary amine to give the N-substituted or Ν, Ν-disubstituted perhaloalkylamidine. The reaction is preferably carried out in the presence of a solvent, although it is not absolutely necessary. When using a solvent, preference is given to 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, carbon tetrachloride or chlorobenzene, so / ie dimethyl sulfoxide, Ν, Ν-dimethylformamide and hexame thy lphosphoramide. The reaction is at temperatures of O to 1OO ° C or to the reflux temperature of the reaction medium, if this is below 100 ⁰ C, carried out, the reaction is generally complete after 1 to 48 hours.. The reaction is preferably allowed to proceed for 4 to 24 hours at room temperature. The reaction product is isolated by conventional methods.

If salts of primary or secondary amines are used, a base must be added to the reaction mixture which liberates the desired amine. Examples of suitable bases are tertiary amines such as trialkylamines, pyridine or N ₁ N-dimethylaniline, inorganic bases such as alkali and alkaline earth hydroxides, carbonates and bicarbonates, and organometallic bases such as alkali alkoxides,

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The second stage of the reaction sequence consists in the alkylation of the N-substituted or Ν, Ν-disubstituted perhalo-lower-alkylamidine to the Ν, Ν'-disubstituted or N, N, N'-tr! -Substituted perhalo-lower-alkylamidine. The reaction is carried out with the aid of a conventional alkylating agent such as a lower alkyl fluorosulfonate or lower alkyl halide. The reaction is carried out for 1 to 48 hrs., At temperatures from O to 10O ⁰ C or to the reflux temperature of the reaction mixture (if this is less than 10O ⁰ C) and optionally in the presence of a solvent, as discussed above. The reaction is preferably carried out for 4 to 24 hours at about room temperature. The reaction product is isolated in the customary manner.

An alternative to carrying out the second process stage consists in the acylation of the amidine nitrogen atom, this being provided with a lower alkanoyl, phenylcarbamoyl or lower alkoxalyl substituent. The acylation is carried out with the aid of any conventional acylating agent which is suitable for introducing the desired radicals R ^. If R _{1 represents} a phenylcarbamoyl group or a lower alkanoyl or lower alkoxalyl radical, suitable acylating agents are especially acid halides or anhydrides of the general formula below

0
η

R ₄ -CX

in which R 1 represents a lower alkyl or lower alkoxycarbonyl radical and X represents a halogen atom or an anhydride radical of the general formula

It

-C-R ^ - 13 -

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means, or isocyanates of the general formula below

R ₅ -N = C = O
in which R _{5 is} a phenyl group.

The reaction is preferably carried out in the presence of an inert aprotic solvent such as a hydrocarbon (Benzene, toluene, alkanes) or a halogenated hydrocarbon (chloroform, methylene dichloride, carbon tetrachloride, chlorobenzene). The reaction is carried out at temperatures from room temperature to the reflux temperature of the reaction mixture carried out and is completed after 30 minutes to 6 hours. The reaction product is isolated according to conventional methods Methods.

When X represents a halogen atom, 1 mole of hydrohalic acid is liberated during the reaction. It is appropriate the reaction mixture for binding this acid per mole of 1 mole of a tertiary amine (such as pyridine or triethylamine) to add.

The cyclic amidines can also be prepared from a perhalo-lower alkyl nitrile and an amine. In this case, however, a diamine is used, for example an alkyl diamine which is optionally hydroxyl, lower alkoxy, phenyl or halogen or is substituted by a condensed benzene radical with optionally lower alkyl or lower alkoxy substituted benzene ring. The diamine is - if appropriate in the presence of a solvent - combined with a perhalo-lower alkyl nitrile ^{at temperatures from 0 to 100 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 room temperature. The reaction

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runs -much smoother when you look at that released in the ring closure leading to the cyclic amidine one mole of ammonia each one mole of a base acceptor (such as p-toluenesulfonic acid or hydrochloric acid) clogs. The base acceptor reacts with the ammonia to form an easily separable salt, thereby isolating the product is facilitated.

The examples below are intended to illustrate the invention Explain connections and methods in more detail; however, they are not intended to limit the invention in any way.

example N- (2-hydroxyethyl) trichloroacetamidine

A solution of 18.3 g (0.3 mol) of ethanolamine and 57.6 g (0.4 mol) of trichloroacetonitrile in 600 ml of benzene is ^{stirred for 4 hours at 20 to 25 °} C. and then evaporated under reduced pressure. The residue is recrystallized twice from benzene / hexane and once from ethyl acetate / hexane "This gives 31.8 g of N- (2-hydroxyethyl) -trichloracetamidin, mp. 74 to 76 ⁰ C.

example N- (4-Methoxybenzyl) -trichloraceous tamidine-hydrο chloride

A solution of 11.05 g (0.077 mol) of trichloroacetonitrile in 10 ml of benzene is introduced into a solution of 10 g (0.073 mol) of p-methoxybenzylamine in 50 ml of benzene at 25 ° C. with stirring. The solution obtained is stirred for 20 hr. At 20 to 25 ⁰ C and then evaporated at 30 to 4O ⁰ C under reduced pressure. The residue is dissolved in chloroform and the solution is passed through a column containing 100 g of silica gel

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walk through. It is then eluted with chloroform, with several Fractions are obtained. Those fractions which, on the basis of the thin-layer chromatographic analysis N- (4- "methoxybenzyl) -trichloroacetamidine united. The residue obtained on evaporation of the mixture is dissolved in ethanol. The solution is added at O C with an excess of anhydrous ethanolic Hydrochloric acid and the hydrochloride precipitates with diethyl ether. After recrystallization from ethanol / diethyl ether one obtains 17.5 g of N- (4-methoxybenzyl) -trichloroacetamidine hydrochloride with a melting point of 226 to 228 ° C.

example

5-methoxy-5- (2-trichloroacetamidinoethyl) indole

A mixture of 3.0 g (0.0132 mol) of 5-methoxytryptamine hydrochloride, 1.34 g (0.0132 mol) of triethylamine and 2.89 g (0.020 mol) of trichloroaeetonitrile in 5 ml of benzene and 10 ml of dimethyl sulfoxide is 21 Stirred at 20 to 25 ^° C. for hours and then diluted with 50 ml of saturated sodium chloride solution. Then the benzene layer is separated, washed twice with 50 ml of water each time and dried over anhydrous magnesium sulfate. It is filtered, the filtrate is evaporated under reduced pressure and the residue is recrystallized four times from benzene / hexane. To 152.5 thereby obtained 0.58 g 5-methoxy-3- (2-trichloracetamidinoäthyl) indole mp. 153.5 to ⁰ C.

In a corresponding manner, but using 3- [2-aminoethyl] -5-methylindole hydrochloride instead of S-methoxytryptamine hydrochloride, 3- [2-trichloroacetamidinoethyl] -5-methylindole of melting point 102 to 103.5 is obtained ⁰ C.

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Example 4

N- (314-Dihydroxyphenäthyl) -trichlor ace tamidine hydrochloride

A mixture of 4.75 g (0.025 mol) of dopamine hydrochloride, 2.75 g (0.027 mol) of triethylamine and 7.20 g (0.050 mol) of trichloroacetonitrile in 5 ml of dimethylformamide is stirred for 20 hours at 25 ° C. and then filtered . The filtrate is evaporated at 70 ° C./0.5 mm Hg, the residue is dissolved in ethyl acetate, the solution is washed with 5% strength sodium carbonate solution, water and saturated sodium chloride solution, the ethyl acetate extract is dried over anhydrous magnesium sulfate, filtered, and the piltrate is mixed with a Excess of anhydrous ethanolic hydrochloric acid, evaporated under reduced pressure, the residue was washed twice with 50 ml of ethyl acetate each time, dissolved in methanol and the solution evaporated at 25 ° C / 0.5 mm. This gives 7.0 g of N- (3,4-dihydroxyphenethyl) trichloraceous tamidine hydrochloride hemihydrate.

Example 5

2-trichloromethyl-3,4,5,6-tetrahydropyrimidine

A solution of 3.7 g (0.05 mol) of 1,3-diaminopropane and 9.5 g (0.05 mol) of p-toluenesulfonic acid hydrate in 50 ml of methanol is ^{stirred for 10 minutes at 25 °} C. and then with 7.22 g (0.05 mol) of trichloroacetonitrile were added. The reaction mixture is then stirred for 5 days at 25 ^° C., filtered and the filtrate is evaporated under reduced pressure. The residue is washed with water and then recrystallized from cyclohexane. 6.0 g of 2-trichloromethyl-3,4,5,6-tetrahydropyrimidine of melting point 113 to 116 ^° C. are obtained.

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Example 6

N-propargyl trichloroacetamidine hydrochloride

A mixture of 1.82 g (0.02 mol) of propargylamine hydrochloride, 4.5 g (0.031 mol) of trichloroacetonitrile and 2.1 g (0.02 mol) of triethylamine in 5 ml of dimethylformamide is used for 16 hours at 20-25 ° C stirred. The reaction mixture is then diluted with water and then extracted with benzene. The benzene extract is washed four times with water, dried over anhydrous magnesium sulfate, filtered, the filtrate is evaporated under reduced pressure, the residue is dissolved in benzene and the solution is treated with an excess of anhydrous ethanolic hydrochloric acid. The solvent is evaporated off under reduced pressure The residue obtained is washed with diethyl ether and then recrystallized from ethanol / diethyl ether, giving 2.8 g of N-propargyltrichloroacetamidine hydrochloride with a melting point of 180 ^° C. (decomposition).

example N- (4-methoxycinnamyl) trichloroacetamidine

A mixture of 3.0 g (0.015 mol) of 4-methoxycinnamylamine hydrochloride, 1.5 g (0.015 mol) of triethylamine and 3.2 g (0.022 mol) of trichloroacetonitrile in 15 ml of dimethylformamide is stirred at 20 to 25 ° C. for 2 hours. The reaction mixture is then diluted with water and extracted with benzene. The extract is washed four times with water, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure and the residue is recrystallized from benzene / hexane. 77 is thereby obtained 2.11 g of N- (4-methoxycinnamyl) -trichloracetamidin mp. 79.5 to ⁰ C. After two recrystallizations from benzene / hexane gives the analytical sample, mp. 79 to

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In a corresponding manner, but using 2,3-dimethyl-4-hydroxybenzylamine hydrochloride instead of 4-methoxycinnamylamine hydrochloride, N- (2,3-dimethyl-4-hydroxyphenyl) trichloroacetamidine of melting point 145.5 is obtained to 148.5 ⁰ C

Example 8 N- (2-Cyclohexenyl) trichloroacetamidine

A mixture of 2.6 g (0.019 mol) of 2-cyclohexenylamine hydrochloride, 1.9 g (0.019 mol) of triethylamine and 4.5 g (0.031 mol) of trichloroacetonitrile in 10 ml of dimethylformamide is heated at 20 to 25 ^° C. for 18 hours stirred and then ^{evaporated at 50 0} C / 0.2 mm. The residue is dissolved in benzene and the solution is washed three times with 50 ml of water and 50 ml of saturated sodium chloride solution each time. Then the benzene extract is dried over anhydrous magnesium sulfate and filtered. The residue from evaporation of the filtrate gives, after recrystallization from hexane 1 g N- (2-cyclohexenyl) -trichloracetamidin, mp. 61 to 63 ⁰ C.

In the same way, but using 3- (4-acetamidophenoxy) -2-hydroxypropylamine hydrochloride instead of 2-cyclohexenylamine hydrochloride, one obtains N- [3- (4-acetamidophenoxy) -2-hydroxypropyl] -trichloroacetamidine, melting point 124.5 to 131.5 ° C (decomposition).

example N- (2-hydroxybenzyl) trichloroacetamidine

A solution of 3.26 g (0.023 mol) of trichloroacetonitrile and 2.53 g (0.021 mol) of 2-hydroxybenzylamine in 25 ml of dimethyl sulfoxide is ^{stirred for 20 hours at 20 to 25 °} C. and then poured into 200 ml of cold water. Then extracted

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the crude product with the help of two 150 ml portions of benzene, The combined benzene extract is washed with water and saturated sodium chloride solution over anhydrous sodium sulfate dried and filtered. The filtrate is evaporated, the residue is dissolved in chloroform and the solution is passed through run a silica gel column. Several fractions are obtained on elution with chloroform. Those factions which due to Thin-layer chromatographic determination containing the product are combined and evaporated. The residue is recrystallized from cyclohexane. 2.6 g of N- (2-hydroxybenzyl) trichloroacetamidine are obtained from m.p. 112 to 115 ° C.

Example 10 N- (4-hydroxyphenethyl) trichloroacetamidine

A mixture of 10.41 g (0.060 mol) of tyramine hydrochloride and 60 ml of dimethylformamide is mixed with 6.06 g (0.06 mol) of triethylamine and then with 12 g (0.083 mol) of trichloroacetonitrile at 0 to 5 ° C. while stirring . Then the mixture is stirred for 1 hr. At 0 to 5 ° C and then for 3 hrs. At 20 to 25 ⁰ C and pouring it thereto in 600 ml of water. The crude product is extracted with benzene, the extract is washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in ethyl acetate and the solution is saturated with hydrogen chloride gas. The supernatant is decanted from the gummy precipitate formed, washed with ethyl acetate and dissolved in water. The solution is mixed with excess saturated sodium carbonate solution and the product is extracted into benzene. The extract is washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure and the residue is recrystallized from benzene / hexane. This gives 8.5 g

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N- (4-hydroxyphenethyl) -trichloroacetamidine from mp. 94 to

Example 11

trans-N- (2-phenylcyclopropylmethyl) trichloroacetamidine

A solution of 7142 g (0.0404 mol) of trans-2-phenylcyclopropylmethylamine hydrochloride, 4.09 g (0.0404 mol) of triethylamine and 8.81 g (0.061 mol) of trichloroacetonitrile in 20 ml of dimethyl sulfoxide and 15 ml of benzene is 17 Stirred at 20 to 25 ^° C. for hours and then mixed with 50 ml of benzene. The reaction mixture is then poured into 100 ml of saturated sodium chloride solution, into which 5 ml of saturated sodium bicarbonate solution have been incorporated. The benzene layer is then separated off, washed twice with 100 ml of water each time and extracted twice with 20 ml of 3N hydrochloric acid each time. The acid extract is diluted with 25 ml of water, made alkaline with saturated sodium bicarbonate solution and extracted three times with 100 ml of benzene each time. The combined benzene extracts are washed with water, dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate gives 8.98 g of trans-N- (2-phenylcyclopropylmethyl) -trichloroacetamidine.

In a corresponding manner, but using 2-aminoethylphenylsulfoxide hydrochloride or 2-aminoethyl-2-naphthylsulfoxide hydrochloride instead of trans-2-phenylcyclopropylmethylamine hydrochloride, 2-trichloroacetamidinoethylphenylsulfoxide hydrochloride with a melting point of 184 to 186 ^° C. is obtained ( Decomposition) or 2-trichloroacetamidinoethyl-2-naphthylsulfoxide hydrochloride with a melting point of 194 to 195 ^° C.

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Example 12

Ν- (2,3-dichloro-4-hydroxybenzyl) trichloroacetamidine

A) 2,3-dichloro-4-hydroxybenzaldehyde oxime

A solution of 10 g (0.052 moles) of 2,3-dichloro-4-hydroxybenzaldehyde and 10.84 g (0.15 mol) of hydroxylamine hydrochloride in 75 ml of ethanol and 75 ml of pyridine are refluxed for 5.5 hours boiled and then evaporated under reduced pressure. The residue is recrystallized twice from hot water, 7 »44 g of the oxime are obtained.

B) 2,3-dichloro-4-hydroxybenzylamine hydrochloride

A mixture of 4.0 g (0.0194 mol) of 2,3-dichloro-4-hydroxybenzaldehyde oxime and 0.5 g of a 5 % rhodium-containing activated carbon catalyst in 100 ml of ethanol and 8 ml of 8N anhydrous ethanolic hydrochloric acid is at an initial pressure of 2.11 kg / cm (30 psi) and 25 ° C hydrogenated until uptake of two equivalents of hydrogen and then filtered. The piltrate is evaporated under reduced pressure and the residue is recrystallized from ethanol / diethyl ether. 3.37 g of 2,3-dichloro-4-hydroxybenzylamine hydrochloride are obtained.

C) N- (2,3-dichloro-4-hydroxybenzyl) trichloroacetamidine

A mixture of 1.5 g (6.6 mol) of 2,3-dichloro-4-hydroxybenzylamine hydrochloride, 0.99 g (6.9 mmol) of trichloroacetonitrile and 0.70 g of triethylamine in 14 ml of dimethyl sulfoxide is used for 20 hours. stirred at 20 to 25 ° C and then evaporated within 15 min. under reduced pressure at 40 ⁰ C. The residue is poured into 150 ml of water, the yellow-brown precipitate formed is filtered off, dried and recrystallized from cyclohexane. This gives 1.03 g

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(46.4%} N- (2,3-dichloro-4-hydroxybenz7l) -trichloracetamidin of mp. 165-168 ⁰ C.

Following the procedure according to C), but using 3-aminomethyl-i-benzoylindole hydrochloride instead of 2,3-dichloro-4-hydroxybenzylamine hydrochloride, N- (1-benzoyl-3-indolylmethyl) trichloroacetamidine is obtained from mp. 113.5 to 115.5 ⁰ C

Example 13

5-phenyl-2-trichloromethyl-3,4,5,6-tetrahydropyrimidine

A solution of 100 mg (0.67 mmol) of 2-phenyl-1,3-diaminopropane, 113 mg of p-toluenesulfonic acid hydrate and 100 mg of trichloroacetonitrile in 5 ml of methanol is stirred for 3 days at 20 to 25 ° C and then at 25 ° C ⁰ C evaporated under reduced pressure. The residue is dissolved in chloroform and the solution is run through a silica gel column. Several fractions are obtained on elution with chloroform. Those fractions which contain the product on the basis of thin-layer chromatographic determination are evaporated under reduced pressure after being combined. The residue is dissolved in ethanol, the solution is treated with an excess of anhydrous ethanolic hydrochloric acid and diluted with diethyl ether. 24 mg of 5-phenyl-2-trichloromethyl-3,4,5,6-tetrahydropyrimidine hydrochloride of melting point 265 to 270 ^° C. (decomposition) are obtained.

Example 14 N-Allyl-N-methyltr ichlorace tamidine-hydro genmale inat

A solution of 3.6 g (0.0506 mol) of N-methylallylamine in 30 ml Benzene is stirred into a solution within 20 minutes

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of 6 ml of trichloroacetonitrile in 30 ml of benzene at 10 to 15 ⁰ C entered. After the addition is complete, the solution is ^{stirred at 20 to 25 °} C. for ^{20 hours and then evaporated at 50 °} C. under reduced pressure. When the residue is distilled, 6.2 g of N-allyl-N-methyltrichloroacetamidine with a boiling point of 66 ° to 70 ° C./0.2 mm are obtained. An ethanol solution of 5 g of the N-allyl-N-methyltrichloroacetamidine base is mixed with 2.5 g of maleic acid, ethyl acetate is added and the batch is cooled. 4.9 g of N-Al13yl-N-methyl trichloroacetamidine hydrogen maleate with a melting point of 101 ° to 107 ° C. are obtained. The pure compound with a melting point of 101 to 106 ° C. is obtained by recrystallization from ethanol / ethyl acetate.

Example 15

N- (2-Hydroxy-5-phenoxypropyl) trichloroacetamidine

A mixture of 10.6 g (0.0635 mol) of 2-hydroxy-3-phenoxypropylamine and 11.0 g (0.0762 mol) of trichloroacetonitrile in 250 ml of benzene and 150 ml of ethyl acetate is heated at 20 to 25 ° C. for 23 hours stirred and then filtered. The residue obtained when the solvent is evaporated off under reduced pressure is recrystallized from benzene / hexane. This gives 15.4 g of N- (2-hydroxy-3-phenoxypropyl) -trichloracetamidin of mp. 86-87 ⁰ C.

Example 16

N- (2-acetoxy-3-phenoxypropyl) trichloroacetamidine hydrochloride

A) 2-acetoxy-3-phenoxypropylamine hydrochloride

A solution of 6.09 g (0.030 mole) of 2-hydroxy-3-phenoxypropylamine in 100 ml of glacial acetic acid with hydrogen chloride gas

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saturated. 2.6 g (0.033 mol) of acetyl chloride are added and stir the solution for three days at 20 to 25 ° C. Then steams the batch is introduced under reduced pressure, benzene is added and the mixture is again evaporated under reduced pressure a. This process is repeated again with benzene, twice with toluene and twice with petroleum ether. You get finally 7.68 g of crude 2-acetoxy-3-phenoxypΓopylamine hydrochloride, which is used in the next process stage without further purification.

B) N- (2-acetoxy-3-phenoxypropyl) -trichloracetamidin hydrochloride

A total of 0.5 g (5 mmol) (CpHc) · $ are added in small portions over a period of 10 minutes. with thorough stirring at 20 to 25 ° C into a mixture. of 1.23 g (5 mmol) of 2-acetoxy-3-phenoxypropylamine hydrochloride and 1.44 g (10 mmol) of trichloroacetonitrile in 5 ml of dimethylformamide. The batch is then stirred for 90 minutes, diluted with water and extracted with benzene. The combined extracts are washed five times with water, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated, the residue is dissolved in benzene and an excess of anhydrous ethanolic hydrochloric acid is added to the solution. It is then evaporated again under reduced pressure and the residue obtained is dried for 20 hours at 56 ° C./0.2 mm over phosphorus pentoxide. 0.97 g of N- (2-acetoxy-3-phenoxypropyl) -trichloroacetamidine hydrochloride with a melting point of 70 ° to 77 ° C. (decomposition) are obtained.

Following the procedure according to B), but using 3,4-dipivaloyloxyphenethylamine hydrochloride or 4-ß-diacetoxyphenethylamine hydrochloride instead of 2-acetoxy-3-phenoxypropylamine hydrochloride, N- (3,4-Dipivaloyloxyphenäthylj- trichloracetamidin hydrochloride, mp. 115-121 ⁰ C (dec.) and N- (4, ß-Diacetoxyphenäthyl) -trichloracetamidin hydrochloride, mp. 200.5 to 204.5 ° C

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Example 17 N- (2-methylthioethyl) trichloroacetamidine hydrochloride

A solution of 500 mg (5.5 mmol) of 2-Methylthioäthylamin and 1.5 g (10.4 micromoles) of trichloroacetonitrile in 10 ml of benzene is 20 hrs. And stirred at 20 to 25 ⁰ C then evaporated under reduced pressure. The residue obtained is dissolved in diethyl ether, the solution is treated with an excess of anhydrous ethanolic hydrochloric acid and the insoluble components are filtered off. After drying for 20 hours at 25 ° C./0.2 mm over phosphorus pentoxide, 1.1 g of N- (2-methylthioethyl) trichloroacetamidine hydrochloride are obtained.

In a corresponding manner, but using 4-methoxybenzylamine instead of 2-Methylthioäthylamin well as Bromdichloracetonitril in place of trichloroacetonitrile, one obtains 209.5 N- (4-methoxybenzyl) -bromdichloracetamidin hydrochloride, mp. To 210 ⁰ C (dec.) .

Example 18

3-Hydroxy-N-trichloroacetimidopiperidine hydrochloride

A mixture of 2.02 g (0.02 mol) of 3-hydroxypiperidine and 5.0 g (0.035 mol) of trichloroacetonitrile in 100 ml of benzene is stirred at 20 to 25 ° C. for 20 hours. Then you treat the reaction mixture with decolorizing activated charcoal, filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in diethyl ether and the solution is added with an excess of anhydrous ethanolic hydrochloric acid. The salt that precipitates out is isolated and removed Recrystallized methanol / ethyl acetate. 2.65 g of J-hydroxy-N-trichloroacetimidopiperidine hydrochloride are obtained M.p. 151-156 ° C (dec.).

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Example 19

N-tetrahydrofurfuryl trichloroacetamidine

A solution of 5.05 g (0.05 mol) of tetrahydrofurfurylamine and 9.5 g (0.066 mol ") of trichloroacetonitrile in 50 ml of benzene is ^{stirred for 20 hours at 20 to 25 °} C. and then evaporated under reduced pressure. The residue is evaporated Recrystallized twice from benzene / hexane, 8.3 g of N-tetrahydrofurfuryltrichloroacetamidine of melting point 75 ° to 78 ° C. being obtained.

In a corresponding manner, but using 3-aminomethyl-1-methylindole instead of tetrahydrofurfurylamine, one obtains 90 N- (1-methyl-3-indolylmethyl) -trichloracetamidin mp. 91.5 to ⁰ C.

Example 20

N- (2-hydroxymethylbenzyl) trichloroacetamidine

A solution of 3.0 g (0.022 mol) of 2-aminomethybenzyl alcohol and 3.32 g (0.024 mol) of trichloroacetonitrile in 12 ml of benzene is ^{stirred for 3 days at 20 to 25 °} C., evaporated under reduced pressure, with 100 ml Chloroform added% nd filtered. The filtrate is passed through a column containing 200 g of silica gel, several fractions being collected. Those fractions which, on the basis of thin-layer chromatographic determination, contain N- (2-hydroxymethylbenzyl) trichloroacetamidine are evaporated after combining. The residue is recrystallized twice from cyclohexane. This gives 2 g of N- (2-hydroxymethylbenzyl) trichloroacetamidine with a melting point of 110 to 112 ° C.

In the same way, but using 4-methylbenzylamine or 1,3-bisaminomethylbenzene instead of

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2-aminomethylbenzyl alcohol, N- (4-methylbenzyl) trichloroacetamidine is obtained of melting point 78 to 81 ° C or 1,3-bis (trichloroacetamidinomethyl) benzene of melting point 91 to 94 ° C.

example 2A_ N- (3-indolylmethyl) trichloroacetamidine

A solution of 4.76 g (0.033 mol) of trichloroacetonitrile in 15 ml of benzene is converted into a solution of 3.18 g (0.022 mol) of 3-aminomethylindole in 25 ml of anhydrous dimethyl sulfoxide ^{within 15 minutes at 20 to 25 ° C. while stirring} registered. After stirring for 20 hours at 20 to 25 ° C., the mixture is evaporated under reduced pressure. "The oily viscous residue obtained is extracted twice with 100 ml each time and once with 50 ml warm chloroform. The combined extracts are filtered and then twice with 100 ml The aqueous acid extracts are combined and extracted twice with 100 ml of chloroform each time, the extract is filtered, the clear, aqueous filtrate is made alkaline with saturated aqueous sodium bicarbonate solution and the product is extracted with three 200 ml portions The combined extracts are washed with water, dried over magnesium sulfate and filtered. Evaporation of the filtrate gives N- (3-indolylmethyl) trichloroacetamidine. The analytical sample of mp 135 is obtained by three recrystallization from a benzene / hexane mixture , from 5 to 138.5 ⁰ C

In a corresponding manner, but using 3-aminomethyl-5-methoxyindole instead of 3-Aminomethylindol, one obtains 131.5 N- (5-methoxy-3-indolylmethyl) -trichloracetamidin mp. 132.5 to ⁰ C.

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Example 22

N- (ρ-methoxybenzyl) trifluoroacetamidine

About 9.5 g (0.01 mol) of trifluoroacetonitrile, cooled with the aid of a dry ice / acetone bath, are admixed with 6.85 g (0.05 mol) of p-methoxybenzylamine over the course of 15 minutes. The mixture is stirred and allowed to warm to 25 ° C. within 20 to 22 hours. After two-fold recrystallization from hexane 83.5 86.5 obtained 5.08 g of N- (p-methoxybenzyl) -trifluoracetamidin mp. 86.5 to ⁰ C. A further recrystallization from hexane affords the analytical sample, mp. To 87, 5 ⁰ C.

Example 23

N- (p-methoxybenzyl) pentachloropropionamidine

A mixture of 8.3 g (0.036 mol) of pentachloropropionitrile, 3.29 g (0.024 mol) of p-methoxybenzylamine and 35 ml of benzene is ^{stirred for 3 days at 20 to 25 °} C. and then filtered. The filtrate is evaporated under reduced pressure to a gummy, solid residue which is dissolved in 60 ml of chloroform. It is then extracted three times with 25 ml of 3N hydrochloric acid each time and then twice with 25 ml of water each time. The aqueous extracts are combined, made alkaline with saturated sodium bicarbonate solution and extracted three times with 100 ml of chloroform each time. The combined extracts are washed three times with water, dried over anhydrous magnesium sulfate and filtered, and the filtrate is evaporated under reduced pressure. After two-fold recrystallization from hexane 104 105 obtained 0.53 g of N- (p-methoxybenzyl) -pentachlorpropionamidin mp. To 105 ⁰ C. A further recrystallisation gives the analytical sample, mp. To 1o6 ° C.

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Example 24

N-acetyltrichloroacetamidine

^ »9 g (0.062 mol) of acetyl chloride are stirred at 0 ° C in a solution of 10 g (0.062 mol) of trichloroacetamidine and 6.3 g (0.062 mol) of triethylamine in anhydrous tetrahydrofuran dripped in. The batch is then stirred for a further 30 minutes at 25 ° C. and the triethylamine hydrochloride is filtered off off and washed with tetrahydrofuran. The solid residue obtained on evaporation of the filtrate becomes clear Recrystallized methylene dichloride diethyl ether; this gives N-acetyltrichloroacetamidine with a melting point of 125.5 to 126.5 ° C

Example 25

N- [3- (2-AlIy! Phenoxy) -2-hydroxypropyl] -trichloroacetamidine

A) 3- (2-Allylphenoxy) -2-hydroxypropylamine hydrochloride

A solution of 19.0 g (0.10 mol) 3- (2-allylphenoxy) -1,2-epoxypropane and 10.0 g (0.10 mole) succinic acid imide in 100 ml of absolute ethanol and 1 ml of pyridine is added with stirring Boiled under reflux for 24 hours. The solution is then evaporated to dryness under reduced pressure and the residue crystallizes once from a benzene / hexane mixture and once from an isopropanol / hexane mixture around; this gives N- [3- (2-allylphenoxy) -2-hydroxypropyl] succinimide from m.p. 66 to 68 ° C.

A solution of 15.0 g (0.052 mol) of N- [3- (2-AlIy! Phenoxy) -2-hydroxypropyl] succinimide in 200 ml of absolute ethanol and 100 ml of 9N anhydrous ethanolic hydrochloric acid is 14 hours. refluxed. The solution is then evaporated to dryness under reduced pressure and crystallized the residue from an ethanol / benzene / hexane mixture

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around. In this case, 103 to give 3- (2-allylphenoxy) -2-hydroxypropylamine hydrochloride, mp. 111.5 to ⁰ C.

B) N- [3- (2-Allylphenoxy) -2-hydroxypropyl] -trichloroacetamidine

The neutralization of 1.22 g (5 mmol) 3- (2-AlIyI-phenoxy) -2-hydroxypropylamine hydrochloride The free base obtained with potassium carbonate and extraction with benzene is dissolved in 30 ml of benzene. 1 g is added to the solution (6.93 mmol) of trichloroacetonitrile and leaves the resulting mixture Stand for 20 hours at 20 to 25 ° C. The mixture is then evaporated under reduced pressure and the residue is dissolved in Chloroform and causes a solid substance to precipitate by adding hexane. The solid is filtered off and evaporated the filtrate; N- [3- (2-allylphenoxy) -2-hydroxypropylJ-trichloroacetamidine is obtained in the form of an oil.

Example 26

N- (4-methoxybenzyl) -N ^! -phenylcarbamoyltrichloroacetamidine

0.30 g (2.5 mmol) of phenyl isocyanate are added in 25 ml of benzene with stirring at 20 to 25 ⁰ C in a solution of 0.7 g (2.5 mmol) of N- (4-methoxybenzyl) -trichloracetamidin. The solution obtained in this way is stirred for 20 hours at 20 to 25 ° C. and then evaporated under reduced pressure. By recrystallization from a benzene / hexane mixture, N- (4-methoxybenzyl) -N ¹ -phenylcarbamoyl trichloroacetamidine with a melting point of 126 ° to 127 ° C. is obtained from the residue.

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Example 27

N- (2-acetoxy-3-phenoxypropyl) -N'-ethyloxalyltrichloroacetamidine

A mixture of 0.98 g (2.5 mmol) of N- (2-acetoxy-3-phenoxypropyl) -trichloroacetamidine hydrochloride, 0.50 g (3.9 mmol) of oxalyl chloride and 40 ml of carbon tetrachloride is stirred for 5 hours. (or until completely dissolved) boiled under reflux. The residue remaining on evaporation under reduced pressure is stirred with 25 ml of absolute ethanol for 3 hours. It is then evaporated again to dryness and the residue is chromatographed on two 2000 / U thick silica gel plates with 5 % methanol / 95 % chloroform. 49 is thereby obtained N- (2-acetoxy-3-phenoxypropyl) -N'-äthyloxalyltrichloracetamidin mp. To 53 ⁰ C.

Example 28

N-Ethyloxalyl-N'-methyltrichloroacetamidine

N-Methyltrichloracetamidin is reacted analogously to Example 27 with oxalyl chloride and ethanol to N-Äthyloxalyl-N'-me thyltrichlorace tamidin, mp. 130 to 133 ⁰ C.

Example 29

7-methyl-3-trichloromethyl-4,5-dihydro-1H-2,4-benzodiazepine

A) 1,2-bis (aminomethyl) -4-methylbenzene dihydrochloride

A mixture of 7.94 g (0.042 mol) 1,2-bis (chloromethyl) -4-methylbenzene, 16.7 g (0.09 mol) of potassium phthalimide and 125 ml of dimethylformamide are refluxed for 2 hours and after cooling, poured into 800 ml of water. The emerging

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Precipitate is filtered off, washed with water and dried. This gives the bis-phthalimidomethyl intermediate from m.p. 241 to 244 ° C (shrinkage or sintering at 236 ° C).

A solution of 14.5 g (0.035 mol) of 1,2-bis (phthalimidomethyl) -4-methylbenzene and 2.7 g (0.08 mol) of 95 tiger hydrazine in 250 ml of methanol is refluxed for 22 hours and then cooled with the help of an ice bath. After acidification with 15 ml of concentrated hydrochloric acid, the mixture is refluxed for 30 minutes and filtered after cooling. The filtrate is strongly concentrated under reduced pressure. The crude product which separates out is filtered off and recrystallized twice from 95% ethanol. This gives 1,2-bis- (aminomethyl) -4-methylbenzene dihydrochloride, mp. 277 ⁰ C (dec.).

B) 7-methyl-3-trichloromethyl-4,5-dihydro-1 H-2,4-benzodiazepine

A solution of 1.67 g (7.48 mmol) of 1,2-bis (aminomethyl) -4-methylbenzene-dihydrochloride in 30 ml of warm methanol is mixed with 0.81 g (15 mmol) of sodium methylate while stirring. After 30 min. Is added 1.43 g (75 mmol) of p-toluenesulfonic acid hydrate and 1.08 g (75 mmol) of trichloroacetonitrile are added and the mixture is stirred for 18 hrs. At 20 to 25 ⁰ C. Then the solvent is concentrated by evaporation under reduced pressure, the residue is extracted with warm benzene, the extract is treated with decolorizing activated charcoal (charcoal), filtered through magnesium sulfate and the filtrate is evaporated. In this case, from 110.5 to 112.5 ⁰ C (Schrumpfungbzw. Sintering at 1O5 ° C) to obtain 7-methyl-3-trichloromethyl-4,5-dihydro-iH-2,4-benzodiazepine, mp..

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Example 30 . ., ■

N ~ (2-ß-I> -Glucosyloxybenzyl) -trichloroacetamidine

A) 2,3,4,6-tetraacetyl-1ß- (2-azidomethylphenyl) -D-glucopyranoside

2.0 g (31 mmoles) of sodium azide v / earths in a solution of 8.0 g (16 mmoles) of 2,3,4,6-tetraacetyl-1β- (2-bromimethylphenyl) -D-glucopyranoside in 100 ml of anhydrous dimethylformamide "Recorded at 25 ⁰ C. Then mixture is stirred for the reaction for 2 h., it is poured into 300 ml of water and extracted twice with jeveils 150 ml of diethyl ether. the extract is washed twice with 100 ml of water, dried over anhydrous sodium sulfate and concentrated under The azide having a melting point of 143 ° to 149 ° C. is obtained from the solid residue by recrystallization from a chloroform / diethyl ether mixture

B) N- (2-ß-D-glucosyloxybenzyl) -trichloroacetamidine

0.58 g of 2,3,4,6-tetraacetyl-1ß- (2-azidomethylphenyl) -D-glucopyranoside are hydrogenated in 25 ml of ethyl acetate for 22 hours at atmospheric pressure over 0.1 g of palladium-activated carbon containing 10% Pd as a catalyst . The catalyst is then filtered off and the filtrate is evaporated under reduced pressure to give an oil which is crude 2,3,4,6-tetraacetyl-1ß- (2-aminomethylphenyl) -D-glucopyranoside. The crude product is dissolved in 5 ml of anhydrous methanol and about three drops of 0.1N methanolic sodium methylate solution are added to the solution. After boiling under reflux for 20 minutes (exclusion of water), the solvent is evaporated off under reduced pressure, giving crude 1β- (2-aminomethylphenyl) -D-glucopyranoside. This crude product is dissolved in 1.4 ml of anhydrous dimethylformamide, the solution treated with 0.4 g (2.8 mmol) of trichloroacetonitrile, the mixture is stirred 2 hrs. At 25 ⁰ C, adding 40 ml ether

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added, whereby a gummy solid substance precipitates. This • is separated into its components by preparative thin layer chromatography (silica gel; 20 % methanol / chloroform); the product (R “0.55) is eluted with methanol. When the methanol evaporates, a glassy substance remains, which is crushed and slurried with ether. The slurry is filtered and the residue is dried, ie, the desired compound, mp. 85 ° C (dec.).

Example 31

N- (2-methoxybenzyl) bromodichloroacetamidine hydrochloride

A solution of 3.29 g (0.024 mol) of o-methoxybenzylamine and 5.17 g (0.027 mol) of bromodichloroacetonitrile in 20 ml of benzene is stirred for 18 hours at 20 to 25 ^° C. and then filtered. The filtrate is evaporated under reduced pressure, the residue is dissolved in 20 ml of absolute ethanol and the solution is acidified with an excess of anhydrous ethanolic hydrochloric acid. The crystallization of N- (2-Me thoxybenzyl) -br omdichlorace tamidine hydrochloride is stimulated by adding diethyl ether.

Example 32

Tablets suitable for oral administration and containing the ingredients listed below can be prepared by conventional tabletting methods. For the therapy of heart failure, doses of one or two such tablet (s) are suitable when administered two to four times per day.

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Ü 9 B 3 Q / 0 y 2 9

15564 Y,

Components

N- (p-hydroxyphenethyl) trichloroacetamidine

Tragacanth

Lactose

Cornstarch

Talk

Magnesium stearate

5 2601137 Proportions, mg 10 5 10 237, 25th 15th 2,

Example 55 Dry-filled capsules

Capsules suitable for oral administration are conventionally prepared containing the ingredients set out below contain. Such capsules can be administered in a dose of one or two capsules two to four times used as cardiac stimulants per day.

Ingredients Proportions, mg

N- (2-hydroxybenzyl) trichloroacetamidine 20th

inert, solid diluent (starch, milk sugar, kaolin, etc.) 280

Example 34

Sterile suspension for injection and liquid suspension for oral use

The following medicinal products are formulated according to conventional methods using the specified amount of active ingredient.

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B09830 / 0929

15564 Y

mulates. The injectable suspension and the oral liquid suspension 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 advantageously used two to four times for the same purpose
administered daily.

Components

N- (2-Hydroxy-3-phenoxypropyl) -trichloroacetamidine "

Sodium carboxymethyl cellulose, U.S.P.

Methyl cellulose

Polyvinyl pyrrolidone

Lecithin

Benzyl alcohol

Magnesium aluminum silicate Flavor or smell corrections (flavor)

dye

Methyl paraben (methyl p-hydroxybenzoate), U.S.P.

Propyl paraben (propyl p-hydroxybenzoate), U.S.P.

Polysorbate 80 (polyoxyethylene sorbitan monooleate), U.S.P.

70% Sorbital Solution, U.S.P. PH adjustment buffer Viasse r

Shares, mg Sus
pension Sus
pension 50 10 1.25 0.4 VJI 3 0.01 47.5 q.s. q.s. 4.5 1.0 1.5 2500 q.s. q.s. qs on
1 ml qs on
5 ml

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example

35

Tablets and capsules suitable for oral administration _ ^

Using conventional methods, tablets and capsules containing the ingredients listed below can be getting produced. They can be in doses of one or two tablets or capsules with one to four times administration used as cardiac stimulants per day.

Components

N- (ß-hydroxyphenethyl) trichloroacetamidine

Tragacanth lactose corn starch talc

Magne s iums te arat

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

total 300.0

300.0

The synthesis examples below illustrate the preparation of some of the starting compounds used in the aforementioned examples described.

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Synthesis example 1

Intermediates for the synthesis of N- (2,3-dimethyl-4-hydroxybenzyl) -trichloroacetamidine

A) 2,3-Dimethyl-4-hydroxybenzaldehyde oxime

A solution of 3.75 g (0.075 mol) of 2,3-dimethyl-4-hydroxybenzaldehyde and 5.21 g (0.075 mol) of hydroxylamine hydrochloride in 30 ml of ethanol and 30 ml of pyridine is refluxed for 5.5 hours and then evaporated under reduced pressure. 172.5 is obtained from the residue by recrystallization from an ethanol / water mixture, the oxime, mp. 174.5 to ⁰ C

B) 2,3-dimethyl-4-hydroxybenzylamine hydrochloride

A mixture of 3.3 g (0.02 mol) of 2,3-dimethyl-4-hydroxybenzaldehyde oxime and 0.3 g of a palladium-activated carbon catalyst containing 10% Pd in 100 ml of ethanol and 50 ml of 9.6N anhydrous ethanolic hydrochloric acid is hydrogenated for 20 hours at an initial pressure of 2.11 kg / cm (30 psi) and 20 to 25 ^° C. and then filtered. The filtrate is evaporated under reduced pressure and the residue is recrystallized from an ethanol / diethyl ether mixture. This gives 2,3-dimethyl-4-hydroxybenzylamine hydrochloride with a melting point of 252 to 255 ° C.

Synthesis example 2

Intermediates for the synthesis of N- (1-Benzoyl-3-indolylmethyl) -trichloroacetamidine

A) N- (3-indoly / methyl) tert-butyl carbamate

A mixture of 3.75 g (0.026 mole) 3-aminomethylindole, 7.62 g

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(0.026 mol) tert-butyl ^ j ^^ - trichlorophenyl carbonate, 3.2 g (0.032 mol) triethylamine and 150 ml chloroform are refluxed with stirring for 17 hours. The cooled solution is washed twice with 50 ml of 1N sodium hydroxide solution each time, twice with 30 ml of 1N hydrochloric acid each time, twice with 50 ml of 1N sodium hydroxide solution each time and three times with 50 ml of water each time. The chloroform extract is then dried over magnesium sulfate, filtered and the filtrate is evaporated. 102 is obtained from the residue by recrystallization from a diethyl ether / petroleum ether mixture N- (3-indolylmethyl) -t-butyl carbamate, mp. To 103 ⁰ C.

B) 3-aminomethyl-i-benzoylindole hydrochloride

3.7 g (0.015 mol) of N- (3-indolylmethyl) -tert-butylcarbamate are washed into a mixture of 0.15 mol of sodium hydride (0.72 g of a 50% mineral oil dispersion of NaH, mineral oil-free with petroleum ether) and with stirring 30 ml of dimethylformamide are added. The mixture is stirred 20 min. At 5O ⁰ C. and after cooling it to 20 to 25 ° C with 2.1 g (0.015 mol) of benzoyl chloride. The reaction mixture is then stirred for 2 hours at 20 to 25 ° C. and then diluted with water and diethyl ether. The ether layer is separated off, washed with water, dried over anhydrous magnesium sulfate and filtered. The residue obtained on evaporation of the filtrate under reduced pressure is chromatographed over 250 g of silica gel, eluting with benzene, 50% chloroform / benzene and chloroform N- (1-Benzoyl-3-indolylmethyl) -tert, -butylcarbamate-containing fractions are combined and evaporated.

Into an ice bath-cooled solution of 2.1 g (6 mmol) of N- (1-benzoyl-3-indolylmethyl) -tert-butyl carbamate anhydrous hydrogen chloride is added to anhydrous hydrogen chloride in 50 ml of ethyl acetate for 10 minutes

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initiated. After the excess hydrogen chloride was removed by purging with nitrogen, "brings to the 3-aminomethyl-i-benzoylindole hydrochloride (mp. 247-253 ⁰ C) by the addition of Diäthylather to precipitate.

Synthesis example 3

Intermediate product for the synthesis of N- (4, ß-diacetoxyphenethyl) trichloroacetamidine hydrochloride

4, ß-diacetoxyphenethylamine hydrochloride

A mixture of 4.75 g (0.025 mol) djl-octopamine hydrochloride, 50 ml of acetyl chloride and 50 ml of glacial acetic acid. Boiled under stirring for 2 hours under reflux and maintained then for 2 days, "at 20 to 25 ⁰ C. Then the mixture is evaporated The mixture is evaporated to dryness under reduced pressure, benzene is added to the residue, the mixture is evaporated again, petroleum ether is added to the residue obtained and the mixture is filtered, giving 4, β-diacetoxyphenylamine hydrochloride.

Synthesis example 4

Intermediates for the synthesis of N- [3- (4-acetamidophenoxy) -2-hydroxypropyl] -trichloroacetamidine

A) N- [3- (4-acetamidophenoxy) -2-hydroxypropyl] benzylamine hydrochloride

A solution of 10.4 g (0.0502 mol) 1- (4-acetamidophenoxy) -2,3-epoxypropane and 5.40 g (0.0504 mol) benzylamine in 20 ml dimethylformamide is 11/4 hours to 100 ⁰ C heated and then cooled. 400 ml of hexane are then added to the reaction mixture. The insoluble solid which precipitates out on trituration is filtered off and converted from ethyl acetate

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0 9 8 3 0/0929

crystallized; this gives 12.4 g of N- [3- (4-acetamidophenoxy) -2-hydroxypropyl] benzylamine (Base) from m.p. 117.5 to 123.5 ° C. The hydrochloride is made free by acidifying a methanol solution of the base with an excess of anhydrous Ethanolic hydrochloric acid and evaporated under reduced pressure.

B) 3- (4-acetamidophenoxy) -2-hydroxypropylamine hydrochloride

A solution of 5.5 g (0.0157 mol) of N- [3- (4-acetamidophenoxy) -2-hydroxypropyl] benzylamine hydrochloride in 100 ml of ethanol and 50 ml of water is heated at 40 to 53 ° C. for 2 hours and an initial pressure of 2.64 kg / cm (37 $ 5 psi) over 1 g of a 10 % Pd-containing palladium-activated carbon catalyst and then filtered. The residue obtained on evaporation under reduced pressure is recrystallized from absolute ethanol. 3.26 g of 3- (4-acetamidophenoxy) -2-hydroxypropylamine hydrochloride with a melting point of 194 to 197 ^° C. are obtained

Synthesis example 5

Intermediates for the synthesis of 2-trichloroacetamidinoethyl-2-naphthylsulfoxide hydrochloride ^

A) N- [2- (2-naphthylthioethyl) -! - phthalimide

A solution of 4.60 g (0.20 gram atom) of sodium in 150 ml of methanol is added under nitrogen with 32 g (0.20 mol) 2-naphthylthiol added. After 10 minutes, 50.8 g are added (0.2 mol) of 2-bromoethylphthalimide is added and the mixture is stirred 2 hours at 20 to 25 ° C and then boiled for 2 hours with stirring and reflux. Then you narrow down the approach reduced pressure at 40 ° C to about half of its output

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input volume and adds water. The solid which precipitates out is filtered off and recrystallized from 300 ml of acetone. 52.1 g of N- [2- (2-naphthylthioethyl) -] phthalimide of melting point 73 ° to 79 ° C. are obtained. A further 5 g of a product with a melting point of 75 ° to 80 ° C. are precipitated by adding water to the mother liquors. Further recrystallizations from acetone / water and ethyl acetate / hexane to provide the analytical sample, mp. 80 to 81.5 ⁰ C.

B) 2- (2-Aminoethylthio) naphthalene hydrochloride

A mixture of 57.6 g (0.173 mol) of N- [2- (2-naphthylthioethyl) -] - phthalimide, 5.77 ml of 95% hydrazine, 300 ml of ethanol, 100 ml of methanol and 12 ml of water is taken for 2 hours Boiled under reflux, mixed with 25 ml of concentrated hydrochloric acid, refluxed for a further 90 min. And hot filtered. After cooling to room temperature, it is filtered again and the filtrate is concentrated at 40 ° C. under reduced pressure Pressure to about 250 ml and filtered a third time after cooling. This gives 27.6 g of 2- (2-aminoethylthio) naphthalene hydrochloride from m.p. 167.7 to 174.7 ° C.

C) 2-Aminoäthyl- * 2-naphthyl sulfoxide-hydro chloride

A total of 2.3 ml are added to a solution of 5.44 g (0.0227 mol) of 2- (2-aminoethylthio) naphthalene hydrochloride in 50 ml of water and 50 ml of methanol within 5 minutes at 20 to 25 ^{° C.} 30 % ± total hydrogen peroxide entered. The batch is refluxed for 8 hours while stirring, 100 mg of potassium sulfite are added and the mixture is left to stand at 20 to 25 ° C. for 3 days. The mixture is then filtered and the filtrate is evaporated to dryness on a steam bath under reduced pressure. The residue is mixed with 10 ml of ethanol and again evaporated under reduced pressure. After two more

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times in this way, the residue is washed with isopropanol and ethanol. After drying, 4.72 g of 2-aminoethyl-2-naphthylsulfoxide hydrochloride with a melting point of 136 ° to 142 ° C. (decomp.) Are obtained. By ümkristallisation from methanol / ethyl acetate to 145 is the analytical sample, mp. To 153.7 ⁰ C (dec.).

Synthesis example 6

Intermediate for the synthesis of N- (5-methoxy-3-indolylmethyl) -trichloroacetamidine

3-aminomethyl-5-methoxyindole

0.95 g (0.019 mol) of hydrazine hydrate are added with stirring to a suspension of 5.13 g (0.017 mol) of N- (5-methoxy-3-indolylmethyl) phthalimide in 60 ml of anhydrous methanol. The batch is stirred for 18 hours at 20 to 25 ^° C. and then 60 ml of anhydrous methanol and 40 ml of 3N hydrochloric acid are added. The mixture is then stirred for a further 2 hours at 20 to 25 ° C. and then filtered. The filtrate is evaporated under reduced pressure, heated on the steam bath after the addition of 50 ml of water and filtered. The filtrate is made alkaline with 5N potassium hydride and the product is extracted with chloroform. The extract is dried over magnesium sulfate and filtered. When the chloroform is evaporated off under reduced pressure, 3-aminomethyl-5-methoxyindole with a melting point of 98 to 100.5 ° C. is obtained.

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09830/0 929

Claims (22)

ν 260ri3 claims 1. A process for preparing the compounds of general formula standing demand ^ NH ^E 3 in which R is a perhalogenated lower alkyl radical, preferably a trichloromethyl group, _f R «is a hydrogen atom or a lower alkyl or represents lower alkanoyl radical and R, a lower-alkyl, phenyl-lower-alkyl, Lower alkenyl, lower alkynyl, cycloalkyl or cycloalkenyl radical, which radicals one or more hydroxyl, hydroxy-lower-alkyl, lower-alkoxy, Lower alkylthio, lower alkanoyloxy, lower alkanoylamino, phenyl, hydroxyphenyl, Lower alkoxyphenyl, phenoxy, phenylsulfinyl, naphthylsulfinyl, cycloalkyl, lower alkylphenyl, Have lower alkenylphenyl, phenylcycloalkyl and / or halogen substituents, a perhaloalkylamidino-lower-alkyl-substituted one Phenyl-lower-alkyl radical or a lower-alkyl radical with the amidine -Nitrogen atom linked, optionally lower-alkyl, lower-alkoxy or benzoyl-substituted 5- to 7-membered heterocyclic radical with one or two heteroatoms in the form of Oxygen and / or nitrogen atoms or benzoheterocyclic radical whose benzene ring is attached to a - 45 - ß09830 / 0929 5- to 7-membered heterocyclic ring with condensed one or two heteroatoms in the form of oxygen and / or nitrogen atoms is, means each amino or hydroxyl group with a labile proton optionally in its place has a glycoside residue, as well as the non-toxic, pharmacologically acceptable Salts of these compounds, characterized in that a ρerhalogenosed Lower alkyl nitrile (preferably trichloroacetonitrile) with an amine of the general formula below -NR ₂ R ₃ in the Rp and R-. each have the meaning given above,
brings to implementation. 2. Process for the preparation of the compounds of the general formula below NR ₁
RCNR ₅ , in which R is a perhalogenated lower alkyl radical, preferably a trichloromethyl group, R _{1 represents} a phenylcarbamoyl group or a lower-alkyl, lower-alkanoyl or lower-alkoxalyl radical, R _{2 is} a hydrogen atom or a lower-alkyl or lower-alkanoyl radical and R, a lower-alkyl, phenyl-lower-alkyl, Lower-alkenyl, lower-alkynyl, cyeloalkyl or cycloalkenyl radicals, which radicals have an or several hydroxyl-, hydroxy-lower-alkyl-, Nie- - 46 - ß09830 / 0929 der-alkoxy-, lower-alkylthio-, lower-alkanoyloxy-, Lower alkanoylamino, phenyl, hydroxyphenyl, lower alkoxyphenyl, phenoxy, phenylsulfinyl, Naphthylsulfinyl, cycloalkyl, Ni. der-alkylphenyl-, lower-alkenylphenyl-, phenylcycloalkyl- and / or have halogen substituents, a perhaloalkylamidino-lower-alkyl-substituted one Phenyl-lower-alkyl radical or a lower-alkyl radical with the amidine -Nitrogen atom linked, optionally lower-alkyl, lower alkoxy or benzoyl substituted 5- to 7-membered heterocyclic radical with one or two heteroatoms in the form of oxygen and / or nitrogen atoms or benzoheterocyclic Radical whose benzene ring is attached to a 5- to 7-membered heterocyclic ring with one or two heteroatoms in the form of oxygen and / or nitrogen atoms is condensed, means each amino or hydroxyl group with a labile proton optionally in its place has a glycoside residue, and the non-toxic, pharmacologically acceptable salts of these compounds, characterized in that one a compound of the general formula below NH
RCN-Rp ^E 3 in which R, R "and R" are each as indicated above Have meaning with an alkylating or acylating agent for reaction brings. - 47 - B09830 / 0929 3. Process for the preparation of the compounds of the general formula below NR ₁ RCNR «
t ^ ^B 3 in which R is a ρ erhalo generated lower alkyl radical, preferably a trichloromethyl group, Rg denotes a hydrogen atom or a lower alkyl radical is and R ₁ and R, are linked to one another, including the two amidine nitrogen atoms, to form a 5- to 7-membered heterocyclic ring which is optionally hydroxyl, lower alkoxy, phenyl or halogen, or to an optionally lower alkyl or lower -alkoxy-substituted benzene ring is condensed, as well as the non-toxic, pharmacologically acceptable Salts of these compounds, characterized in that a perhalo-lower alkyl nitrile with an optionally hydroxyl-, lower-alkoxy-, phenyl- or halogen-substituted or to an optionally lower-alkyl- or lower- -alkoxy substituted benzene ring condensed alkyl diamine brings to implementation (whereby one preferably trichloroacetonitrile as perhalo-lower-alkylnitrile as well as a lower-alkyldiamine is used, which is optionally hydroxyl-, lower-alkoxy- or phenyl-substituted or at an optionally lower alkoxy-substituted benzene ring is condensed) and the cyclic amidine obtained optionally reacted with an alkylating or acylating agent. 4. Compounds of the general formula below - 48 - 609830/0929 NR ₁
RCNR ₉ ^R 3 in which R represents a perhalogenated alkyl radical with 1 to 5 carbon atoms, R- is a hydrogen atom, a phenylcarbamoyl group or a lower alkyl, lower alkanoyl or Represents lower alkoxalyl radical, R «is a hydrogen atom or a lower alkyl or lower alkanoyl radical and R, a lower-alkyl, phenyl-lower-alkyl, Lower-alkenyl, lower-alkynyl, cycloalkyl or cycloalkenyl radical, which radicals one or several hydroxyl, hydroxy-lower-alkyl-, lower-alkoxy-, Lower alkylthio, lower alkanoyloxy, lower alkanoylamino, phenyl, hydroxyphenyl, Lower alkoxyphenyl, phenoxy, phenylsulfinyl, naphthylsulfinyl, cycloalkyl, lower alkylphenyl, Lower alkenylphenyl, phenylcycloalkyl, lower alkanoyl and / or halogen substituents exhibit, a perhaloalkylamidino-lower-alkyl-substituted phenyl-lower-alkyl radical or one via a lower alkyl radical with the amidine nitrogen atom linked, optionally lower-alkyl-, lower-alkoxy- or benzoyl-substituted 5- to 7-membered heterocyclic radical with one or two heteroatoms in the form of oxygen and / or nitrogen atoms or benzoheterocyclic radical whose benzene ring is attached to a 5- to 7-membered heterocyclic ring with one or two heteroatoms in the form of oxygen and / or Nitrogen atoms is condensed, means, where Rg and R-, or R-j and R ^ also with each other - 49 - 609830/0929 including the two amidine nitrogen atoms can be linked to a 5- to 7-membered heterocyclic ring, which hydroxyl, lower-alkoxy-, phenyl- or halogen-sub-. substituted or to a lower alkyl or lower alkoxy substituted Benzene ring is condensed, each amino or hydroxyl group with a labile proton optionally having a glycoside residue in its place, as well as the non-toxic, pharmacologically acceptable Salts of these compounds. 5. Compounds according to claim 4, characterized in that R is a trichloromethyl group, R- is a hydrogen atom or a lower-alkyl radical, Rp is a hydrogen atom or a lower alkyl radical and R ^ a lower alkyl, phenyl lower alkyl, lower alkenyl or lower alkynyl radical, which radicals have a or more hydroxyl, hydroxy-lower-alkyl, lower alkoxy, Lower alkylthio, lower alkanoyloxy, phenyl, hydroxyphenyl, lower alkoxyphenyl, phenoxy, Cycloalkyl, phenylcycloalkyl and / or halogen substituents exhibit, mean. 6. Compounds according to claim 5, characterized in that R is a trichloromethyl group, R «is a hydrogen atom or a lower alkyl radical, Rp is a hydrogen atom or a lower alkyl radical and R, a lower-alkyl or phenyl-lower-alkyl radical, which radicals one or more hydroxyl, lower alkanoyloxy, phenyl, lower alkoxyphenyl and / or Have phenoxy substituents, mean. - 50 - 09830/0929 7 · Compounds according to claim 5 _f, characterized in that R is a trichloromethyl group, R- is a hydrogen atom or a lower alkyl radical, Rp is a hydrogen atom or a lower alkyl radical and R, a substituted lower-alkyl radical, the substituents of which are one or more hydroxyl, phenyl, Represent lower alkoxyphenyl and / or phenoxy group (s), mean. 8. N- (p-hydroxyphenethyl) trichloroacetamidine, a compound according to claim 4. 9 · N- (2-hydroxybenzyl) trichloroacetamidine, a compound according to claim 4. 10. N- (2-Hydroxy-3-phenoxypropyl) -trichloroacetamidine, a Connection according to claim 4. ■ 11 · N- (ß-Hydroxyphenäthyl) -trichloracetaraidin, a compound according to claim 4. 12. N-Cp-methoxybenzylI-trichloroacetamidine, a compound according to claim 4. 13. Compounds according to claim 1, characterized in that R is a trichloromethyl group, R.J a hydrogen atom or a lower alkyl radical, Rg is a hydrogen atom or a lower alkyl radical and R, a lower alkyl radical, which is replaced by a heterocyclic or substituted benzoheterocyclic radical which is different from indole, pyrimidine, piperidine, - 51 - 609830/0 929 564Y ^ 260113 Furan, tetrahydrofuran, pyridine or piperazine derived and optionally lower alkyl, lower alkoxy or is benzoyl-substituted, "mean. 14. Compounds according to claim 13 _f, characterized in that R is a trichloromethyl group, R.J a hydrogen atom or a lower alkyl radical, Rp is a hydrogen atom or a lower alkyl radical and R-3 is a lower alkyl radical, which is optionally replaced by a methyl, methoxy or benzoyl-substituted radical of indole, pyrimidine, piperidine or Furan is substituted, mean. 15. Compounds according to claim 14, characterized in that R-i a by an optionally methyl or methoxy . substituted indole radical represents substituted methyl or ethyl group. 16. Compounds according to claim 15, characterized in that the indole radical is unsubstituted. 17. N- (3-indolylmethyl) trichloroacetamidine, a compound according to claim 16. 18. N- (5-methyl-3-indolylethyl) trichloroacetaraidine, a compound according to claim 15. 19 «N- (1-methyl-3-indolylmethyl) -trichloroacetamidine, a A connection according to claim 15. 20. N- (5-Methoxy-3-indolylmethyl) trichloroacetamidine, a A connection according to claim 15. - 52 - 6 09630/0929 15 564Y 260VPw 21. N- (1-Benzcryl-3-indolylmethyl) -trichloroacetainidine, a Connection according to claim 14 22. Cardiac stimulants of an inert carrier and at least a compound of the general formula below NR ₁
RCNR ₉ ^E 3 in which R is a perhalogenated lower alkyl radical, RJ represents a hydrogen atom, a phenylcarbamoyl group or a lower alkyl, “lower alkanoyl or lower alkoxalyl radical, Rg is a hydrogen atom or a lower alkyl or lower alkanoyl radical and
R, a lower-alkyl, phenyl-lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl or cycloalkenyl radical, which radicals one or more hydroxyl, hydroxy-lower-alkyl, lower-alkoxy , Lower alkylthio, lower alkanoyloxy, lower alkanoylamino, phenyl, hydroxyphenyl, lower alkoxyphenyl, phenoxy, phenylsulfinyl, naphthylsulfinyl, cycloalkyl, lower alkylphenyl, lower alkenylphenyl, phenylcycloalkyl - and / or halogen substituents, a perhaloalkylamidino-lower-alkyl-substituted phenyl-lower-alkyl radical or an optionally lower-alkyl-, lower-alkoxy- or benzoyl-substituted 5- to 7-membered heterocyclic radical linked to the amidine nitrogen atom via a lower-alkyl radical with one or two heteroatoms in the form of oxygen and / or nitrogen atoms or benzoheterocyclic radical, the benzene ring of which is attached to a 5- to 7-membered heterocyclic ring with one or two - 53 - 609830/0929 Heteroatoms in the form of oxygen and / or nitrogen atoms is condensed, where R ₂ and IU or R ^ and R, including the two amidine nitrogen atoms, can be linked to form a 5- to 7-membered heterocyclic ring, which is hydroxyl-, lower-alkoxy-, phenyl- or halogen-substituted or fused to a lower-alkyl- or lower-alkoxy-substituted benzene ring, each amino or hydroxyl group with a labile proton optionally in its place has a glycoside residue, as well as the non-toxic, pharmacologically acceptable Salts of these compounds. 23 · Heart stimulants according to claim 22, characterized in that that in the general formula R is a T ri chlorine thylgruppe and the radicals R-j and R ^ including the two amidine nitrogen atoms to form a 5- to 7-membered one heterocyclic ring are linked, which is optionally hydroxyl-, lower-alkoxy- or phenyl-substituted or on an optionally lower alkoxy substituted benzene ring is condensed. - 54 - 609830/0929