NO754426L - - Google Patents

Description

Process for the production of substituted perhaloalkylamidines.

The present invention relates to a method for the production of new substituted perhaloalkylamidines which have a high degree of activity as cardiac stimulants.

Certain trichloroacetamidines are previously known and discussed for agricultural purposes, see DT Publication No. 2,121,401.

However, there is no indication that the trichloroacetamides listed there have any pharmacological properties, and in particular there is no reference to any cardiac effect.

Certain high compounds falling in the group of substituted perhaloalkylamidines have been discovered, which compounds exhibit marked cardiac stimulating effects, and can be used in preparations for administration of the compounds. It is thus an aim of the invention to provide a method for the production of new substituted perhaloalkylamidines.

The new substituted perhaloalkylamidines that are produced according to the invention can be specified by the following general formula:

where R is perhalogenated alkyl of 1-5 carbon atoms;

R 1 is hydrogen, lower alkyl, lower alkanoyl, phenylcarbamoy1

or lower cocoxalyl;

R 2 is hydrogen, lower alkyl or lower alkanoyl; and

RQ is lower alkyl, phenyl-lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkeny 1, which groups are substituted, with one or more of the substituents hydroxy, hydroxy-lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyloxy, lower alkanoylamino , phenyl, hydroxyphenyl, lower alkoxyphenyl, phenoxy, .phenylsulfinyl, naphthylsulfinyl, cycloalkyl, lower alkylphenyl, lower alkenylphenyl, phenylcycloalky1 or halogen;

R is also phenyl-lower alkyl substituted by perhaloalkylamidino-lower alkyl;

R^ can also be a heterocyclic group with 5-7 members connected to the amidine nitrogen via a lower alkyl group. The heterocyclic group contains 1 or 2 heteroatoms selected from oxygen and nitrogen, or a benzoheterocyclic group optionally substituted with lower alkyl, lower alkoxy or benzoyl, where the benzo group is condensed with a 5-7 membered heterocyclic ring with one or two heteroatoms selected from oxygen and nitrogen; and

R_ and R or R and R may be united to form a

3 in o

heterocyclic ring with a ring size of 5-7 members including the two amidine nitrogen atoms; which heterocyclic ring is substituted with hydroxy, lower alkoxy, phenyl, halogen or a lower alkyl or lower alkoxy substituted benzo group; and non-toxic, pharmaceutically acceptable salts thereof; when a particular compound contains a labile proton, such as an amino or hydroxy group, such a proton can be transferred to a glycoside such as glucoside and the like.

The term "lower alkyl" is intended here to include alkyl groups with 1-5 carbon atoms with both straight and branched chain, such as methyl, ethyl, propyl, butyl, pentyl, isopropyl, t-butyl and the like.

The term "lower alkenyl" includes those straight or branched chain alkenyl groups containing 2-5 carbon atoms in either a straight or branched configuration and 1 or 2 unsaturations such as vinyl, propenyl, allyl, butenyl, 2,Zf-pentadienyl and the like.

The term "lower alkynyl" includes alkyl groups of 2-5 carbon atoms in either a straight or branched configuration containing a triple bond such as ethynyl, 1-propynyl, propargyl, pentyny1 and the like.

The term "cycloalkyl" is intended to include those cycloalkyl groups containing 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "cycloalkenyl" is intended to include the cycloalkyl groups of 4-7 carbon atoms containing 1 or 2 unsaturations such as cyclobutenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.

The term "halogen" includes the halogen atoms fluorine, chlorine,

bromine and iodine.

The "heterocyclic" groups include the heterocyclic groups with 5-7 members with one or two oxygen and/or nitrogen atoms. This group includes furyl, tetrahydrofuryl, pyrrolyl, pyrrolidinyl, morpholinyl, piperidinyl, pyridyl, pyranyl, pyrimidinyl, piperazinyl, pyrazinyl, oxapinyl, azepinyl and the like.

In a similar way, the benzoheterocyclic groups include those groups where a benzo unit is condensed with one of the above-mentioned heterocyclic groups, the indolyl group being preferred.

It is well known to those skilled in the art that N-substituted amidines exist in tautomeric equilibrium. When a substituted amidine is described here which indicates a particular substituent on one of the amidine nitrogen atoms, the tautomeric mixture is thus meant. However, the tautomerism is destroyed when a single amidine nitrogen atom is disubstituted and in N,N,N'-trisubstituted amidines.

Moreover, many of the foregoing compounds are optically active. That is to say, they usually exist as racemic mixtures of d- and 1-optical isomers. Thus, when a particular compound has a center of asymmetry and thus exists as a mixture of d- and 1-optical isomers, the individual isomers as well as the racemic mixture are considered to be covered by the present invention.

The process compounds exhibit valuable pharmacological properties. They primarily affect the contractile force of the heart muscle. By increasing the contractile force of the heart muscle with the consequent increase in cardiac output, these compounds provide a valuable means of treating heart failure.

Congestive heart failure occurs when the heart pumps less

blood than is required by the body's metabolic needs. The aim of therapy is to restore the balance between supply and demand for blood. This can be achieved by the use of present cardiotonic agents which improve rayocardial contractility and influence cardiac output to meet the body's demands.

The use of the present agents to stimulate the failing heart is limited by their toxic effects on the heart or by adverse side effects on the peripheral circulation. E.g. although the cardiac glycosides are myocardial stimulants and can restore the failing heart, they do so at doses very close to those producing toxic symptoms of irregular heart activity, nausea and vomiting. The use of sympathomimetic agents is limited by associated arrhythmia, tachycardia, tachyphylaxis or altered peripheral resistance.

Present perhaloalkylamidine derivatives which are produced according to the invention have been shown to be significant myocardial stimulants which essentially avoid the toxic manifestations of the previously known cardiac stimulants. This cardiac stimulation is observed in animals by measuring the contractile effect on isolated cardiac muscle and in vivo in anesthetized dogs that have a cardiac strain gauge. The perhaloalkylamidine derivatives produced according to the invention are administered to the patient with heart failure in amounts of from approx. 0.1 to 50 mg/kg body weight per day.

For such use, the method compounds may be administered orally or parenterally as such or mixed with conventional pharmaceutical carriers. They can be administered orally in such forms as tablets, dispersible powders, grains, capsules, syrups and elixirs, and parenterally as solutions, suspensions, dispersions, emulsions and the like, e.g. a sterile injectable aqueous suspension. The preparations for oral use may contain one or more conventional excipients such as sweeteners, flavoring agents, coloring agents and preservatives, in order to obtain an elegant and tasty preparation. Tablets may contain the active ingredient in admixture with the conventional pharmaceutically acceptable excipients, e.g. inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and breaking agents, e.g. starch and alginic acid, binding agents, e.g. starch, gelatin and acacia, and lubricants, e.g. magnesium stearate, stearic acid and talc. The tablets can be uncoated or coated using known methods to delay the breakdown and absorption in the digestive tract and thereby provide a sustained effect over a longer period of time. similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any conventional excipients used in the preparation of such preparations, e.g. suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preservatives (ethyl-p-hydroxybenzoate). Capsules can contain the active ingredient alone or in admixture with an inert solid diluent, e.g. calcium carbonate, calcium phosphate and kaolin. The injectable preparations are composed in a known manner and may contain suitable dispersing and wetting agents and suspending agents which are identical or similar to those mentioned above. These pharmaceutical preparations can contain up to approx. 90% of the active ingredient in combination with the carrier or excipient.

The cardiotechnically effective dose of active ingredient used in the treatment of heart failure may depend on the particular compound used and the degree of disorder being treated. However, satisfactory results are generally obtained when the compounds are administered in a daily dose of from about. 0.1 mg to approx. 50 mg/kg body weight, preferably given in divided doses two to four times daily, or in prolonged release form. For most large mammals that need the aforementioned treatment,

is the total daily dose from approx. 0.7 to approx. 50 mg/kg, preferably administered orally. Dosage forms suitable for oral use contain from approx. 1 to approx. 500 mg of active ingredient in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

The preferred pharmaceutical preparations from a manufacturing point of view and due to ease of administration are solid preparations, especially dry-filled capsules and tablets containing approx. 10 - 250 mg active ingredient.

One side of the preferred embodiments of the present invention is fulfilled in the above structural formula. when:

R is trichloromethyl,

R^ is hydrogen or lower alkyl,

R 2 is hydrogen or lower alkyl, and

R^ is lower alkyl, phenyl-lower alkyl, lower alkenyl or lower alkynyl which groups are substituted with one or more substituents which are hydroxy, hydroxy-lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyloxy, phenyl, hydroxyphenyl, lower alkoxyphenyl , phenoxy, cycloalkyl, phenylcycloalkyl or halogen.

A more organized group of method compounds within this aspect of the preferred embodiments is obtained when in the above structural formula:

R^ is hydrogen or lower alkyl,

R 2 is hydrogen or lower alkyl, and

R3„ is lower alkyl or phenyl-lower alkyl, which groups are substituted with one or more of the substituents hydroxy, lower alkanoyloxy, phenyl, lower alkoxyphenyl or phenoxy.

The most preferred embodiments of this aspect of the preferred embodiments are realized in the preceding structural formula where R^ and R^ independently of each other are hydrogen or lower alkyl, and R^ is hydroxy-lower alkyl, substituted with phenyl > or R^ is substituted lower alkyl where the substituents are one or more of hydroxyphenyl, lower alkoxyphenyl, phenoxy or hydroxy. Particular preferred compounds are: N-(p-hydroxyphenethyl)-trichloroacetamidine

N-(o-hydroxybenzyl)-trichloroacetamide

N-(2-hydroxy-3-phenoxypropyl)-trichloroacetamide

N-(P-hydroxyphenethyl)-trichloroacetamide

N-(p-methoxybenzyl)-trichloroacetamide

Another aspect of the preferred compounds that are produced, according to the invention, is realized in the preceding structural formula where:

R is trichloromethyl1,

R^ is hydrogen or lower alkyl,

R 2 is hydrogen or lower alkyl, and

R^ is a lower alkyl group substituted with a heterocyclic or benzoheterocyclic group selected from indole, pyrimidine, piperidine, furan, tetrahydrofuran, pyridine and piperazine, which groups are optionally substituted with lower alkyl, lower alkoxy or benzoyl.

A further group of compounds of this aspect of preferred embodiments is realized when R, R 1 and R 2 are as above, and R 2 is lower alkyl substituted with indole, pyrimidine, piperidine or furan optionally substituted with methyl, methoxy or benzoyl.

The most preferred group of compounds of this aspect of the preferred embodiments of the invention is where and R 2 are as indicated above, and R 1 is methyl or ethyl substituted with indole optionally substituted with methyl or methoxy.

The most preferred compounds are obtained when the mentioned indole

is unsubstituted.

Specific preferred compounds are: N-(3-indolyImethyl)-trichloroacetamide N-[2-(5-methyl-3-indolyl)-ethyl]-trichloroacetamide N-(1-methyl-3~indolyImethy1)-trichloroacetamide N-(5 -methoxy-3-indolylmethyl)-trichloroacetamide N-(1-benzoyl-3-indolylmethyl)-trichloroacetamide

Due to the complexity of the process connections

it is often possible to name a particular compound correctly in more than one way. The particular name will depend on which part of the molecule is chosen as the core of the name, and often it is quite possible to choose parts of a molecule where several of them can suitably serve as the core of the name.

An example would be N-[2-(5-methyl-3-indoly1)-ethyl]-trichloroacetamidine and 5-methy1-3-(2-trichloroacetamidinoethyl)-indole, both of which represent the same compound.

The process compounds can be prepared from a perhalo-

o

genalkylnitrile as shown in the following reaction scheme:

where R is perhalogenated alkyl;

R 1 is lower alkyl, lower alkanoyl, phenylcarbamoyl or

lower alkoxyalyl;

R 2 is hydrogen or lower alkyl; and

R^ is lower alkyl, phenyl-lower alkyl, lower alkenyl,

lower alkynyl, cycloalkyl or cycloalkenyl, which groups are substituted by one or more of hydroxy, hydroxy-lower alkyl,

Lower Alkoxy, Lower Alkylthio, Lower Alkanoyloxy, Lower Alkanoylamino, Phenyl, Hydroxypheny 1, Lower Alkoxyphenyl, Phenoxy, Phenylsulfinyl, Naphthylsulfinyl, Cycloalkyl, Lower Alkylphenyl, Lower Alkenylphenyl,

phenylcycloalkyl, lower alkanoyl or halogen;

wherein R^ can also be a heterocyclic group with 5-7 members containing one or two heteroatoms which are oxygen and/or nitrogen, or a benzoheterocyclic group which is optionally substituted with lower alkyl, lower alkoxy or benzoyl, where the benzo unit is condensed with a 5-7 membered heterocyclic ring with one or two heteroatoms which are oxygen and/or nitrogen, and the non-toxic pharmaceutically acceptable salts thereof, and when a particular compound contains a labile proton which

an araino or hydroxy group, such a proton may be replaced by a glycoside.

In the above reaction scheme, the perhaloalkylnitrile is reacted with the appropriate primary or secondary amine to form the N-substituted or N,N-disubstituted perhaloalkylamidine. The reaction is preferably carried out in a solvent, but such a solvent is not necessary. When a solvent is used, organic solvents such as aliphatic or aromatic hydrocarbons are preferred. Examples are hexane, benzene, toluene, petroleum ether and the like. Other solvents that can be used are ethers such as diethylether, tetrahydrofuran and the like, halogenated solvents such as chloroform, carbon tetrachloride, chlorobenzene and the like, dimethylsulfoxyd, N,N-dimethylformamide, hexamethyl-phosphoramide and the like. The reaction is carried out at from 0° to 100°C, or at the reflux temperature of the reaction medium if this is below 100°C. The reaction is generally complete in from 1 to 48 hours. It is preferred to carry out the reaction substantially at room temperature for from 4 to 24 hours. The product is isolated by methods known per se.

When primary or secondary amine salts are used as the reactants, it is necessary to add a base to the reaction mixture which will release the desired free amine. Suitable bases are tertiary amines such as trialkylamines, pyridine, N,N-dimethylaniline and the like, inorganic bases such as alkali metal and alkaline earth metal hydroxides,

-carbonates and -bicarbonates, and organometallic bases such as alkali met allalkoxides. o

The second step in the reaction sequence comprises an alkylation of the N-substituted or N,N-disubstituted perhalogen-lower alkylamidine to form the N,N'-disubstituted or N,N,N•-tris-substituted perhalogen-lower alkylamidine. In the alkylation reaction, any standard alkylating agent such as lower alkyl fluorosulfonates, lower alkyl halides and the like is used. The reaction is optionally carried out in a solvent as mentioned above, and is carried out at from 0°C to 100°C or at the reflux temperature of the reaction mixture if this is below 100°C for from 1 to 48 hours. It is preferred to carry out the reaction substantially at room temperature for from 4 to 24 hours. The product is isolated in a manner known per se.

An alternative second step in this method comprises the acylation of the amidine nitrogen so that it is substituted with a lower alkanoyl, phenylcarbamoyl or lower alkoxyalyl group. The acylation is carried out with any common acylating agent which will give the desired groups for R 1 . When R^ is lower alkanoyl, phenylcarbamoyl or lower alkoxyalyl, typical acylating agents are acid halides, anhydrides or isocyanates of the formula: where R^ is lower alkyl or lower alkoxycarbonyl, R^ is phenyl and X is a halide or anhydride :

The reaction is preferably carried out in an inert aprotic solvent such as a hydrocarbon solvent (benzene, toluene, alkanes), halogenated hydrocarbons (chloroform, methylene chloride, carbon tetrachloride, chlorobenzene) and the like. The reaction is carried out at from room temperature to the reflux temperature of the reaction mixture and is complete within 1/2 to 6 hours, and the product is isolated by methods known per se.

When X is a halide, 1 mol is released. of a hydrohalide acid during the reaction. It is advantageous to add 1 molar equivalent of a tertiary amine, such as pyridine or triethylamine, to the reaction mixture to react with the liberated acid.

The cyclic amidines can also be prepared from a perhalogen-lower alkylnitrile and an amine. In this case, however, a diamine is used such as an alkyldiamine, which may optionally be substituted with hydroxy, lower alkoxy, phenyl, halogen, or a condensed benzo ring, which benzo ring is optionally substituted with lower alkyl or lower alkoxy. The diamine is combined with a perhalogen-lower alkylnitrile at from 0° to 100°C, optionally in the presence of a solvent, and is kept at this temperature for from 1 hour to 5 days. Preferably, the reaction mixture is stirred substantially at room temperature for from 8 hours to 2 days. The reaction is greatly facilitated by the addition of 1 molar equivalent of a base acceptor such as p-toluenesulfonic acid, hydrogen chloride or the like. This is helpful in the reaction, because during the ring closure to form the cyclic amidine, 1 mole of ammonia is released. The base acceptor reacts with the ammonia to form a salt which is easily removed and facilitates the isolation of the product.

The following examples are given to illustrate the method according to the invention.

Example 1

N-(2-hydroxyethyl)-trichloroacetamide

A solution of 18.39 g (0.30 mol) of ethanolamine and 57.6 g (0.40 mol) of trichloroacetonitrile in 600 ml of benzene is stirred at 20 - 25°C for 4 hours. After evaporation under reduced pressure, the residue is recrystallized twice from benzene-hexane and once from ethylacetate-hexane which gives 31.89N-(2-hydroxyethyl)-trichloroacetamidine with melting point 74 - 76°C.

Example 2

N- (4-Methoxybenzyl)-trichloroacetamide hydrochloride

A solution of 11.05 g (0.077 mol) of trichloroacetonitrile i

10 ml of benzene is added to a stirred solution of 10.0 g

(0.073 mole) of p-methoxybenzylamine in 50 ml of benzene at 25°C. After stirring at 20 - 25°C for 20 hours, the solution is evaporated under reduced pressure at 30 - 4o°C. The residue is dissolved in chloroform<p>g is passed through a column containing 100 g of silica gel. Elution with chloroform gives a series of fractions. The fractions containing N-(4-methoxybenzyl)-trichloroacetamide as determined by thin layer chromatography are combined and evaporated. The residue is dissolved in ethanol, treated with an excess of ethanolic anhydrous hydrogen chloride solution at 0 C, and the hydrochloride salt is combined with ethyl ether. Recrystallization from ethanol-ethyl ether gives 17.5 g of N-(4-methoxybenzyl)-trichloroacetamidine hydrochloride with melting point 226 - 228°C

Example 3

5- methoxy- 3- f 2- trichloroacetamidinoethyl)- indole

A mixture of 3.0 g (0.0132 mol) of 5-methoxy-tryptamine hydrochloride, 1.349 g (0.0132 mol) of triethylamine and 2.89 g (0.020 mol) of trichloroacetonitrile in 5 ml of benzene and 10 ml of dimethylsulfoxyd om- stirred at 20 - 25°C for 21 hours. The reaction mixture is then diluted with 50 ml of saturated sodium chloride solution. The benzene layer is separated, washed with 2 x 50 ml water and dried over anhydrous magnesium sulphate. After filtration and evaporation under reduced pressure, the residue is recrystallized four times from benzene-hexane, whereby 0.5895-methoxy-3-(2-trichloroacetamidinoethyl)-indole with melting point 152.5 is obtained. - 153.5°C.

By following the above procedure using 3-[2-aminoethyl]-5-methylindole hydrochloride instead of 5-methoxy-tryptamine hydrochloride, 3-[2-trichloroacetamidinoethyl]-5-methylindole with melting point 102 - 103.5°C is obtained

Example 4

N-(3,4-dihydroxyphenethyl)-trichloroacetamidine hydrochloride

A mixture of 4.75 g (0.025 mol) dopamine hydrochloride,

2.75 g (0.027 mol) of triethylamine and 7.20 g (0.050 mol) of trichloroacetonitrile in 5 ml of dimethylformamide are stirred at 25°C for 20 hours. After filtration, the filtrate is evaporated at 70°C (0.5 mm Hg).' The residue is dissolved in ethyl acetate and washed with 5% sodium carbonate solution, water and a saturated sodium chloride solution. After drying the ethyl acetate extract rectified. over anhydrous magnesium sulfate and filtration, the filtrate is treated with an excess of ethanolic anhydrous hydrogen chloride solution and evaporated under reduced

Print. The residue is washed with 2 x 50 ml of ethyl acetate, dissolved in methanol and evaporated at 0.5 mm and 25°C, whereby 7.0 g of N-(3,4-dihydroxyphenethyl)-trichloroacetamidine hydrochloride hemihydrate is obtained. Example 5

2^i^rjnetj2yl- 3, 4, 5, 6- tetrahydropyrimidine

A solution of 3.7 g (0.050 mol) of 1,3-diaminopropane and 9.5 g (0.050 mol) of p-toluenesulfonic acid e-hydrate in 50 ml of methanol is stirred at l\Cl for 10 minutes followed by the addition of 7.22 g (0.050 mol) trichloroacetonitrile. After stirring at 25°C for 5 days, the reaction mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is washed with water and recrystallized from cyclohexane, thereby obtaining 6.0 g of 2-trichloromethyl-3,4,5,6-tetrahydropyrimidine with a melting point of 113 - 116°C.

Example 6

N-propa rgyl ricloracet amidine hydrochloride

A mixture of 1.82 g (0.020 mol) propargylamine hydrochloride, 4>5 g (0.031 mol) trichloroacetonitrile and 2.1 g (0.020 mol) triethylamine in 5 ml dimethylformamide is stirred at 20 - 25°C for 16 hours. The reaction mixture is diluted with water and extracted with benzene. After washing the benzene extract with water four times, drying over anhydrous magnesium sulphate, filtration and evaporation under reduced pressure, the residue is dissolved in benzene and treated with an excess of ethanolic anhydrous hydrogen chloride. Resolution-. the agents are removed under reduced pressure, and the residue is washed with ethyl ether and recrystallized from ethanol-ethyl ether, thereby obtaining 2.8 g of N-propargyltrichloroacetamidine hydrochloride with a melting point of 180°C (decomposition).

Example 7

N-((4-methoxycinnamyl)-trichloroacetamidine).

A mixture of 3.0 g (0.015 mol) 4-raethoxycinnamylamine hydrochloride, 1.5 g (0.015 mol) triethylamine and 3.2 g (0.022 mol) trichloroacetonitrile in 15 ml dimethylformamide is stirred at 20 - 25°C for 2 hours. The reaction mixture is diluted with water and extracted with benzene. The benzene extract is washed four times with water, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue is recrystallized from benzene-hexane, which gives 2.11 g of N-(4-methoxycinnamyl)-trichloroacetamide with a melting point of 77 - 79.5°C. An analytical sample with a melting point of 79 - 80°C was obtained after two further recrystallizations from benzene-hexane.

By following the above procedure using 2,3-dimethyl-4-hydroxybenzylamine hydrochloride instead of 4-methoxy-cinnamylamine hydrochloride, N-(2,3-dimethyl-4-hydroxyphenyl)-trichloroacetamide with a melting point of 145.5- l48.5°C.

Example 8

N-(2-cyclohexenyl)-trichloroacetamide

One. mixture of 2.6 g (0.019 mol) of 2-cyclohexenylamine hydrochloride, 1.99 g (0.019 mol) of triethylamine and 4.5 g (0.031 mol). trichloroacetonitrile in 10 ml of dimethylformamide is stirred at 20 - 25°C for 18 hours. After evaporation at 0.2 mm and 50°C, the residue is dissolved in benzene and washed with 3 x 50 ral of water and 50 ml of saturated sodium chloride solution. The benzene extract is dried over anhydrous magnesium sulphate, filtered and evaporated. Recrystallization of the residue from hexane yields 1.0 g of N-(2-cyclohexenyl)-trichloroacetamidine with melting point 61 - 63°C.

By following the above procedure using 3-(4-acetamidophenoxy)-2-hydroxypropylamine hydrochloride instead of 2-cyclohexenylamine hydrochloride, N-[3~(4-acetamidophenoxy)-2-hydroxypropyl]-trichloroacetamide with melting point 124 is obtained .5 - 131.5°C (decomposition).

Example 9

N-(2-Hydroxybenzyl)-triloracetamidine

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 dimethylsulfoxide is stirred at 20 - 25°C for 20 hours. The solution is poured into 200 ml of cold water, and the crude product is extracted into 2 x 150 ml of benzene. The benzene extracts are combined, washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated. The residue is dissolved in chloroform and passed through a silica gel column. Elution with chloroform gives a series of fractions. The fractions containing the product determined by thin-layer chromatography are combined and evaporated. The residue is recrystallized from cyclohexane, whereby 2.6 g of N-(2-hydroxybenzy1)-trichloroacetamide with a melting point of 112 - 115°C are obtained.

Example lp

N-(4-hydroxyphenethyl)-trichloroacetamide

To a stirred mixture of 10.41 g (0.060 mol) of tyramine hydrochloride and 60 ml of dimethylformamide at 0 - 5°C is added 6.06 g (0.060 mol) of triethylamine followed by 12 g (0.083 mol) of trichloroacetonitrile. After stirring at 0 - 5°C for 1 hour, the reaction mixture is stirred at 20 - 25°C for a further 3 hours and then poured into 600 ml of water. The crude product is extracted with benzene, washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is dissolved in ethyl acetate and saturated with hydrogen chloride gas. The gummy precipitate that separates by decantation is washed with ethyl acetate and dissolved in water. After adding an excess of saturated sodium carbonate solution, the product is extracted in benzene. The benzene extract is washed with water, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. Recrystallization from benzene-hexane yields 8.5 g of N-(4-hydroxyphenethyl)-trichloroacetamide with a melting point of 94 - 95°C.

Example 11

Trans-N-(2-phenylcyclopropylmethyl)-trichloroacetamidine

A solution of 7.42 g (0.0404 mol) trans-2-phenylcyclopropylmethylamine hydrochloride, 4.099 (0.0404 mol) triethylamine and 8.81 g (0.061 mol) trichloroacetonitrile in 20 ml of dimethylsulfoxide and 15 ml of benzene is stirred at 20 - 25°C for 17 hours. 50 ml of benzene is added, and after the reaction mixture is completely in 100 ml of saturated sodium chloride solution containing 5 ml of saturated sodium bicarbonate solution, the benzene layer is separated. After washing the benzene layer with 2 x 100 ml of water, the organic extract is extracted with 2 x 20 ml of 3 N hydrochloric acid. The acid extract is diluted with 25 ml of water, made alkaline with saturated sodium bicarbonate solution and extracted with 3 x 100 ml of benzene. The benzene extracts are combined, washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated, whereby 8.989trans-N-(2-phenylcyclopropyl-methyl)-trichloroacetamidine is obtained.

By following the above procedure using 2-aminoethylphenylsulfoxide hydrochloride or 2-aminoethyl-2-naphthylsulfoxide hydrochloride instead of trans-2-phenylcyclopropylmethylamine hydrochloride, 2-trichloroacetamidinoethylphenylsulfoxide hydrochloride is obtained with a melting point of 184 - 186°C (decomposition ) and 2-trichloro-acetamidinoethy1-2-naphthylsulfoxyd hydrochloride with melting point 194.0 - 195.0°C.

Example 12

N-(2,3-dichloro-4-hydroxy.benzyl)-trichloroacetamidine

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

A solution of 10 g (0.052 mol) of 2,3-dichloro-4-hydroxybenzaldehyde and 10.84 g (0.15 mol) of hydroxylamine hydrochloride in 75 ml of pyridine is treated under reflux for 5.5 hours and then evaporated under reduced pressure . The residue is recrystallized twice from hot water, whereby 7.449 oxime is obtained.

B. 2, 3- dik. lo r- 4- hydroxybehzy lamin- hy dro chloride

A mixture of 4.0 g (0.0194 mol) 2,3-dichloro-4-hydroxybenzaldehyde oxime and 0.5 g 5% rhodium-on-carbon catalyst in 100 ml ethanol and 8 ml 8.0 N ethanolic anhydrous hydrogen chloride solution hydrogenated at an initial pressure of 2.1 kg/cm^ and 25°C until two equivalents of hydrogen are taken up. After filtration, the filtrate is evaporated under reduced pressure. The residue is recrystallized from ethanol-ethyl ether, whereby 3.37 g of 2,3-dichloro-4-hydroxybenzylamine hydrochloride is obtained.

C. N-(2,3-dichloro-4-hydroxybenzyl)-trichloroacetamide

A mixture of 1.5 g (6.6 mmol) of 2,3-dichloro-4-hydroxybenzy1-amine hydrochloride, 0.99 g (6.9 mmol) of trichloroacetonitrile and 0.70 g of triethylamine in 14 ml of dimethylsulfoxide is stirred at 20 - 25°C for 20 hours. After evaporation under reduced pressure at 40°C i

After 15 minutes, the residue is poured into 150 ml of water. The. leathery yellow sediments

is removed by filtration, dried and recrystallized from cyclohexane whereby 1.03 g (46.4%) of N-(2,3-dichloro-4-hydroxybenzyl)-trichloroacetamide with melting point l65 - l68°C is obtained.

By following part C of the above procedure using 3-aminomethyl-1-benzoylindole hydrochloride instead of 2,3-dichloro-4-hydroxybenzylamine hydrochloride, N-(1-benzoyl-3-indolylmethyl)-trichloroacetamide with melting point 113 .5 - 115.5°C.

Example 13

5- phenyl- 2- trichlorohy1- 3, 4, 5, 6- tetrahydropyrimidine

A solution of 100 mg (0.67 mmol) 2-phenyl-1,3-diaminopropane, 113 mg p-toluenesulfonic acid hydrate and 100 mg trichloroacetonitrile in 5 ml methanol is stirred at 20 - 25°C for 3 days. After evaporation under reduced pressure at 25°C, the residue is dissolved in chloroform and passed through a silica gel column. Elution with chloroform gives a series of fractions. The fractions containing the product, determined by thin-layer chromatography, are combined and evaporated under reduced pressure. The residue is dissolved in ethanol, treated with an excess of ethanolic anhydrous hydrogen chloride solution and diluted with ethyl ether, thereby obtaining 24 mg of 5-phenyl-2-trichloromethyl-3,4,5,6-tetrahydropyrimidine hydrochloride with a melting point of 265 - 270°C ( cleavage).

Example 14

N- allyl - N- meth ylt r iclo race t amidin- hy droge runa lea t

A solution of 3.6 g (0.0506 mol) of N-methylallylamine i

30 ml of benzene is added over 20 minutes to a stirred solution of 6 ml of trichloroacetonitrile in 30 ml of benzene at 10 - 15°C. After the addition is finished, the solution is stirred at 20 - 25°C for 20 hours and then evaporated at 50°C under reduced pressure. Distillation of the residue gives 6.2 g of N-allyl-N-methyltrichloroacetamidine with boiling point 66 - 70°C at 0.2 mm. To a resolution of

2.5 g of maleic acid are added to 5 g of N-allyl-N-methyltrichloroacetamidine base in ethanol. Addition of ethyl acetate and cooling gives 4.9 g of N-allyl-N-methyltrichloroacetamidine hydrogen maleate with melting point 101 - 107°C. Recrystallization from ethanol-ethyl acetate gives a pure sample with a melting point of 101 - 106°C.

Example 15

N-(2-hydroxy-3-phenoxypropyl)-trichloroacetamidine

A mixture of 10.6 g (0.635 mol) 2-hydroxy-3-phenoxypropylamine and 11.0 g (0.0762 mol) trichloroacetonitrile in 250 ml benzene and 150 ml ethyl acetate is stirred at 20 - 25°C for 23 hours. After filtration, the solvents are removed under reduced pressure. The residue is recrystallized from benzene-hexane whereby 15,49N-(2-hydroxy-3-phenoxypropyl)-trichloroacetamidine with melting point 86 - 87°C is obtained.

Example 16

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

A. 2-acetoxy-3-phenoxypropylamine hydrochloride

A solution of 6.09 g (0.030 mol) of 2-hydroxy-3-phenoxypropylamine in 100 ml of glacial acetic acid is saturated with hydrogen chloride gas. 2.6 g (0.033 mol) of acetyl chloride are added, and the solution is stirred at 20 - 25 Ci for 3 days. After evaporation under reduced pressure, benzene is added, and the mixture is evaporated again under reduced pressure. This process is repeated once more with benzene, twice with toluene and twice with petroleum ether, thereby obtaining 7.68 g of crude 2-acetoxy-3-phenoxypropylamine hydrochloride, which is used without further purification in the next step.

B. N- ( 2.- acet oxy- 3- phenoxypropyl- trichloracet amidine- hy dr ochlor id

A total of 0.50 g (5.0 mmol) of triethylamine is added in small portions over 10 minutes to a well-stirred mixture of 1.23 g (5.0 mmol) of 2-acetoxy-3-phenoxypropylamine hydrochloride and 1.449(10 mmol) of trichloroacetonitrile in 5 ml of dimethylformamide at 20 - 25°C. After stirring for 1.5 hours, the reaction mixture is diluted with water and extracted with benzene. The benzene extract is washed five times with water, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue is dissolved in benzene and treated with an excess of ethanolic anhydrous hydrogen chloride. After evaporation under reduced pressure, the residue is dried over phosphorus pentoxide at 56°C and 0.2 mm for 20 hours, whereby 0.979N-(2-acetoxy-3-phenoxypropyl)-trichloroacetamidine hydrochloride with melting point 70 - 77°C (decomposition) is obtained.

By following part B of the above procedure using 3,4-dipivaloyloxyphenethylamine hydrochloride or 4,(3-diacetoxy-phenethylamine hydrochloride instead of 2-acetoxy-3-phenoxypropylamine hydrochloride, N-(3,4~ dipivaloyloxyphenethyl)-trichloroacetamidine hydrochloride with melting point 115 - 121°C (decomposition), respectively N-(4,(3-diacetoxyphenethyl)-trichloroacetamidine hydrochloride with melting point 2O0.5 - 204.5°C.

Example 17

N-(2-methylthioethyl)-trichloroacetamide hydrochloride

A solution of 500 mg (5.5 mmol) 2-methylthioethylamine and 1.50 g (10.4 mmol) trichloroacetonitrile in 10 ml benzene is stirred at 20 - 25°C for 20 hours and then evaporated under reduced pressure. The residue is dissolved in ethyl ether and treated with an excess of ethanolic anhydrous hydrogen chloride solution. The insoluble material is removed by filtration and dried over phosphorus pentoxide at 25°C and 0.2 mm pressure for 20 hours, whereby 1.1 g of N-(2-methylthio-ethyl)-trichloroacetamidine hydrochloride is obtained.

By following the above procedure using 4-methoxybenzylamine instead of 2-methylthioethylamine and bromodichloroacetonitrile instead of trichloroacetonitrile, N-(4-methoxybenzyl)-bromodichloroacetamidine hydrochloride with melting point 209.5 210.0°C (decomposition) is obtained.

Example 18

3- hydroxy- N- tricloracet imidopiperidine hydrochloride

A mixture of 2.02 g (0.020 mol) of 3-hydroxypiperidine and

5.0 g (0.035 mol) of trichloroacetonitrile in 100 ml of benzene are stirred at 20 - 25°C for 20 hours. After adding decolorizing charcoal and filtering, the filtrate is evaporated under reduced pressure. The residue is dissolved in ethyl ether and treated with an excess of ethanolic anhydrous hydrogen chloride solution. The precipitated salt is collected and recrystallized from methanol-ethyl acetate, whereby 2.65 g of 3-hydroxy-N-trichloroacetimidopiperidine hydrochloride with melting point 151 - 156°C (decomposition) is obtained.

Example 1 19

N-tet rahydrofurfuryl ricloracetamidine

A solution of 5.05 g (0.050 mol) tetrahydrofurfurylamine and. 9.5 g (0.066 mol) of trichloroacetonitrile in 50 ml of benzene are stirred at 20 - 25°C for 20 hours and then evaporated under reduced pressure. The residue is recrystallized twice from benzene-hexane, which gives 8.3 g of N-tetrahydrofurfuryltrichloroacetamide with a melting point of 75 - 78°c.

By following the above procedure using 3-aminomethyl-1-methylindole instead of tetrahydrofurfurylamine, N-(1-methyl-3-indolylmethyl)-trichloroacetamidine is obtained with a melting point of 90.0 - 91.5°C.

Example 20

N-(2-Hydroxymethylbenzyl)-trichloroacetamide

A solution of 3.0 g (0.022 mol) of 2-aminomethylbenzyl alcohol and 3.32 g (0.024 mol) of trichloroacetonitrile in 12 ml of benzene is stirred at 20 - 25°C for 3 days. After evaporation under reduced pressure, 100 ml of chloroform is added, and the mixture is filtered. The chloroform filtrate is passed through a column containing 200 g of silica gel, and a series of fractions are collected. The fractions containing N-(2-hydroxymethylbenzyl)-trichloroacetamide, determined by thin-layer chromatography, are combined and evaporated. The residue is recrystallized twice from cyclohexane, whereby 2.0 g of N-(2-hydroxymethylbenzyl)-trichloroacetamidine with a melting point of 110.0 - 112.0°C is obtained.

By following the above procedure using 4-methylbenzylamine or 1,3-bis-aminomethylbenzene instead of 2-aminomethylbenzyl alcohol, N-(4-methylbenzyl)-trichloracet-amidine with melting point 78.0-81.0 is obtained °C, respectively 1,3-bis-(trichloroacetamidinomethyl)-benzene with melting point 91 - 94°C.

Example 21

N-(3-indolylmethyl)-X ricloracetamidine

A solution of 4.76 g (0.033 mol) of trichloroacetonitrile i

15 ml of benzene are added over 15 minutes to a stirred solution of 3.18 g (0.022 mol) of 3-aminomethylindole in 25 ml of dry dimethylsulfoxide at 20 - 25°C. After stirring at 20-25°C for 20 hours, the mixture is evaporated under reduced pressure to a viscous oil. The residue is extracted with 2 x 100 ml and 1 x 50 ml of hot chloroform. After filtration, the combined chloroform extracts are first washed with 2 x 100 ml of water followed by three portions of dilute hydrochloric acid. The aqueous acid extracts are combined, extracted with 2 x 100 ml chloroform and filtered. The clear, aqueous filtrate is made alkaline with a saturated aqueous solution of sodium bicarbonate, and the product is extracted into 3 x 200 ml of chloroform.

The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered and evaporated, whereby N-(3-indolylmethyl)-trichloroacetamidine is obtained. An analytical sample with a melting point of 135.5 - 138.5°C is obtained after three recrystallizations from a benzene-hexane mixture.

By following the above procedure using 3-aminomethyl-5-methoxy-indole instead of 3-aminomethyl-indole, N-(5-methoxy-3-indolylmethyl)-trichloroacetamide with melting point 131.5 - 132.5°C is obtained

Example 22

N-(p-Methoxybenzyl)-trifluoroacet amidine

To approx. 9.50 g (0.010 mol) trifluorocetonitrile cooled with a dry ice-acetone bath are added in the course of 15 minutes to 6.85 g (0.050 mol) p-methoxybenzylamine. The mixture is stirred and allowed to warm to 20 - 25°C over 20 - 22 hours. Two recrystallizations from hexane yield 5.08 g of N-(p-methoxybenzyl)-trifluoroacetamidine with melting point 83.5 - 8.6.5°C. An analytical sample melting at 86.5-87.5°C is obtained by further recrystallization from hexane.

Example 23

N-(p-Methoxybenzyl)-pent achloropropionamidine

A mixture of 8.30 g (0.036 mol) pentachloropropionitrile,

3.29 g (0.024 mol) of p-methoxybenzylamine and 35 ml of benzene are stirred at 20 - 25°C for 3 days. After filtration, the filtrate is evaporated to a rubbery, solid substance under reduced pressure. The residue is dissolved in 60 ml of chloroform and extracted with 3 x 25 ml of 3 N hydrochloric acid followed by 2 x 25 ml of water. The aqueous extracts are combined, made alkaline with saturated sodium bicarbonate solution and extracted with 3 x 100 ml chloroform. The combined chloroform extracts are washed three times with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Two recrystallizations from hexane give 0.53 g of N-(p-methoxybenzyl)-pentachloropropionamidine with melting point 104.0 - 105.0°C. Further recrystallization yields an analytical sample with a melting point of 105.0 - 106.0°C.

Example 24

N-acetyl ricloracetamide

4.9 g (0.062 mol) of acetyl chloride is added dropwise to a stirred solution of 10.0 g (0.062 mol) of trichloroacetamidine and 6.3 g (0.062 mol) of triethylamine in 100 ml of dry tetrahydrofuran at 0°C. After stirring for a further 30 minutes at 25°C, the triethylamine hydrochloride is filtered off and washed with tetrahydrofuran. Evaporation of the filtrate gives a solid residue which is recrystallized from methylene chloride-diethyl ether, whereby N-acetyltrichloroacetamidine is obtained with a melting point of 125.5 - 126.5°C.

Example 25

N-[3~(2-α-11ylphenoxy)-2-hydroxypropyl]-trichloroacetamide

A'3-C2-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 mol) succinimide in 100 ml absolute ethanol and 1 ml pyridine is stirred under reflux for 24 hours.

After evaporation to dryness under reduced pressure, the residue is recrystallized once from a benzene-hexane mixture and once from an isopropanol-hexane mixture, thereby obtaining N-[3-(2-allylphenoxy)-2-hydroxypropyl]-succinimide with melting point 66 - 68°C.

A solution of 15.0 g (0.052 mol) of N-[3-(2-allylphenoxy)-2-hydroxypropyl]-succinimide in 200 ml of absolute ethanol and 100 ml of 9 N ethanolic anhydrous hydrogen chloride solution is heated under reflux for 14 hours. After evaporation to dryness under reduced pressure, the residue is recrystallized from an ethanol-benzene-hexane mixture, whereby 3-(2-allylphenoxy)-2-hydroxypropylamine hydrochloride with a melting point of 103 - 111.5 C is obtained.

B. N-[3-(2-allylphenoxy)-2-hydroxypropyl]-trichloroacetamide

The free base obtained by neutralization. of 1.22 g

(5.0 mmol) of 3-(2-allylphenoxy)-2-hydroxypropylamine hydrochloride with potassium carbonate and extraction with benzene is dissolved in 30 ml of benzene. 1.0 g (6.93 mmol) of trichloroacetonitrile is added, and the mixture is allowed to stand at 20 - 25°C for 20 hours. After evaporation under reduced pressure, the residue is dissolved in chloroform, and a solid is precipitated by the addition of hexane. The filtrate remaining after filtering off the solid is evaporated, whereby N-[3-(2-allyl-phenoxy)-2-hydroxypropyl]-trichloroacetamide is obtained as an oil.

Example 26

N-(4-Methoxybenzyl)-N'-phenylcarbamoyl ricloracetamidine

0.30 g (2.5 mmol) of phenyl isocyanate is added to a stirred solution of 0.70 g (2.5 mmol) of N-(4-methoxybenzyl)-trichloroacetamide in 25 ml of benzene at 20 - 25°C, and the the resulting solution is stirred at 20 - 25°C for 20 hours. After evaporation under reduced pressure, the residue is recrystallized from a benzene-hexane mixture whereby N-(4-methoxybenzyl)-N'-phenylearbamoyl-trichloroacetamide with a melting point of 126 - 127°C is obtained.

Example 27

N-(2-acetoxy-3-phenoxy propy 1). - N ' - ethyloxa lyl ricloracetamidine

A mixture of 0.989 (2.5 mmol) N-(2-acetoxy-3-phenoxy-propyl)-trichloroacetamidine hydrochloride, 0.50 g (3.9 mmol) oxalyl chloride and 40 ml. carbonated chloride is stirred under reflux for 5 hours until dissolution is complete. After evaporation under reduced pressure, the residue is stirred with 25 ml of absolute ethanol

3 hours and then evaporated again to dryness. The residue is chromatographed on two 2000 µm thick silica gel plates with 5% methanol-95%

chloroform whereby N-(2-acetoxy-3-phenoxypropyl)-N<*->ethyloxalyltrichloroacetamidine with melting point 49 - 53°C is obtained.

Example 28

N-ethyloxalyl-N'-methyltrichloroacetamidine

Reaction of N-methyltrichloroacetamide with oxalyl chloride and ethanol by the method according to the previous example gives N-ethyloxalyl-N'-methyltrichloroacetamide with a melting point of 130 - 133°C.

Example 29

7- methyl - 3- trichloromethyl - 4 , 5- dihydro- ll-f- 2 , 4- benzodiazepine A. 0 1, 2- bis -( aminomethyl)- 4- methylbenzene- dihydrochloride

A mixture of 7.94 g (0.042 mol) of 1,2-bis-(chloromethyl)-4-methylbenzene, 16.70 g (0.090 mol) of potassium phthalimide and 125 ml of dimethylformamide is heated under reflux for 2 hours. The cooled reaction mixture is poured into 800 ml of water, the precipitate is filtered off, washed with water and dried, whereby a bis-phthaimidomethyl intermediate is obtained with a melting point of 24l - 244°C, shrinking at 236°C.

A solution of 14.5 g (0.035 mol) of 1,2-bis-(phthalimido-methyl)-4-methylbenzene and 2.70 g (0.080 mol) of 95% hydrazine in 250 ml of methanol is stirred under reflux for 22 hours and then cool in an ice bath. After acidification with 15 ml of concentrated hydrochloric acid, the mixture is heated under reflux for 30 minutes, cooled and filtered. The filtrate is evaporated under reduced pressure to a small volume. The crude product is removed by filtration and recrystallized twice from 95% ethanol, whereby 1,2-bis-(aminomethyl)-4-methylbenzene dihydrochloride with melting point 277°C (decomposition) is obtained.

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

To a solution of 1.67 g (7.48 mmol) of 1,2-bis-(aminomethyl)-4-methylbenzene dihydrochloride in 30 ml of hot methanol, 0.81 g (15 mmol) of sodium methoxy is added while stirring. After 30 minutes, 1.43 g (75 mmol) p-toluenesulfonic acid hydrate is added

and 1.08 g (75 mmol) of trichloroacetonitrile, and the mixture is stirred at

20 - 25°C for 18 hours. The solvents are removed under reduction

pressure, and the residue extracted with hot benzene. The benzene extract is treated with decolorizing charcoal, filtered through magnesium sulfate and evaporated to obtain 7-methyl-3-trichloromethyl-4,5-dihydro-1H-2,4-benzodiazepine with melting point 110.5 - 112.5°C under shrinkage at 105°C..

Example 30

■ N-(2-P-D-glucosyloxybenzyl)-trichloroacetamide

A. 2, 3, 4, 6- tetraacetyl- 10-( 2- azidomethylphenyl)- D- glucopyranoside

2.0 g (31 mmol) of sodium azide are added to a solution of 8.0 g (16 mmol) of 2,3,4,6-tetraacetyl-10-(2-bromomethylphenyl)-D-glucopyranoside in 100 ral of dry dimethylformamide at 25°C. After stirring for 2 hours, the reaction mixture is poured into 300 ml of water and extracted with 2 x 150 ml of ethyl ether. The organic phase is washed with 2 x 100 ml of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The solid residue is recrystallized from a chloroform-ethyl ether mixture, whereby the azide is obtained at 143 - 149°c.

B. N-(2-B-D-glucosyloxybenzyl)-trichloroacetamide

0.5892,3,4,6-tetraacetyl-10-(2-azidomethylphenyl)-D-glucopyranoside is hydrogenated in 25 ml of ethyl acetate at atmospheric pressure for 22 hours over 0.1 g of 10% palladium-on-carbon as catalyst.

After filtering off the catalyst, the filtrate is evaporated under reduced pressure to an oil. The crude 2,3,4,6-tetraacetyl-10-(2-aminomethylphenyl)-D-glucopyranoside is dissolved in 5 ml of anhydrous methanol and treated with approx. 3 drops of 0.1 N methanolic sodium methoxide solution. After boiling under reflux for 20 minutes under anhydrous conditions, the solvent is removed under reduced pressure to give crude 1 R-(2-aminomethylphenyl)-D-glucopyranoside. This material is dissolved in 1.4 ml of dry dimethylformamide and treated with 0.40 g (2.8 mmol) of trichloroacetonitrile. After stirring for 2 hours at 25°C, 40 ml of ether is added, which causes precipitation of a rubbery, solid substance. Preparative layer chromatography

(silica gel, 20% methanol-chloroform) separates the components and the product, Rf 0.55, is removed with methanol. Evaporation of the methanol gives a glass which is crushed, slurried with ether, filtered and dried, thereby obtaining the desired product with a melting point of 85°C (decomposition).

Example 31

N-(2-methoxybenzy1)-bromodichloroacetamide 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 at 20 - 25 C for 18 hours. After filtration and evaporation of the filtrate under reduced pressure, the residue is dissolved in 20 ml of absolute ethanol and acidified with an excess of ethanolic anhydrous hydrogen chloride solution. Addition of ethyl ether causes crystallization of N-(2-methoxybenzyl)-bromodichloroacetamidine hydrochloride.

Example 32

Tablets suitable for oral administration containing the following ingredients can be prepared by conventional tableting methods. Such tablets are useful in the treatment of heart failure at a dose of 1 or 2 tablets 2 to 4 times a day.

Example 33

Dry filled capsules

Capsules suitable for oral administration containing the following ingredients are prepared in a conventional manner. Such capsules are useful as cardiac stimulants at a dose of 1 or 2 capsules 2 to 4 times daily.

Example 34

Sterile suspension for injection and oral liquid suspension

The following pharmaceutical preparations are prepared with the specified amount of active ingredient using conventional methods. The injectable suspension and the oral liquid suspension represent preparations which are useful as unit doses and can be administered in the treatment of heart failure. The injectable suspension is suitable for administration once daily, while the oral liquid suspension is suitably administered 2 to k times daily for this purpose.

Example 35

Tablets and capsules suitable for oral administration

Tablets and capsules containing the ingredients indicated below can be prepared by conventional methods and are useful as cardiac stimulants at a dose of 1 or 2 tablets or capsules 1 to 4 times daily';

Starting materials for some of the preceding examples are. described in the following methods.

Method 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 heated under reflux in

5.5 hours and then evaporated under reduced pressure. The residue is recrystallized from an ethanol-water mixture to obtain the oxime with a melting point of 172.5 - 174.5°C.

B. '2,3-dimethyl-4-hydroxybenzylamine hydrochloride

A mixture of 3.3 g (0.020 mol) 2,3-dimethyl-4-hydroxybenzaldehyde oxime and 0.30 g 10% palladium-on-carbon catalyst in 100 ml ethanol and 50 ml 9.6 N ethanolic anhydrous hydrogen -chloride solution is hydrogenated at an initial pressure of o 2.1 kg/cm<2> and 20 - 25°C for 20 hours. After filtration, the concentrate is evaporated under reduced pressure. The residue is recrystallized from an ethanol-ethyl ether mixture, whereby 2,3-dimethyl-4-hydroxybénzyl-amine hydrochloride with a melting point is obtained. 252 - 255°C.

Method 2

Starting materials for the synthesis of N-(1-benzoyl-3-indolylmethyl)-tricloracetamidine

A. N-(3-indolylmethyl)-t-butylcarbarnate

A mixture of 3.759(0.026 mol) 3-aminomethylindole,

7.62 g (0.026 mol) t-butyl-2,4,5-trichlorophenylcarbonate, 3.2 g (0.032 mol) triethylamine and 150 ml chloroform are stirred under reflux for 16 hours. The cooled solution is washed with 2 x 50 ml

. 1 N sodium hydroxide solution, 2 x 30 ml 1 N hydrochloric acid, 2 x 50 ml

1 N sodium hydroxide solution and 3 x 50 ml water. The chloroform extract is dried over magnesium sulphate, filtered and evaporated. The residue is recrystallized from an ethyl ether-petroleum ether mixture whereby N-(3-indolylmethyl)-t-butyl arbamate with a melting point of 102 - 103°C is obtained.

B. 3-aminomethyl-1-benzoylindole hydrochloride

3.70 g (0.015 mol) of N-(3-indolylmethyl)-t-butyl carbonate is added to a stirred mixture of sodium hydride, 0.72 g (0.015 mol)

of a 50% sodium hydride mineral oil dispersion washed free of mineral oil with petroleum ether, in 30 ml of dimethylformamide. After stirring at 50°C for 20 minutes and cooling to 20 - 25°C, 2.1 g (0.015 mol) of benzoyl chloride are added. The reaction mixture is stirred at 20 - 25°C for 2 hours and then diluted with water and ethyl ether. The ether layer is separated, washed with water, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue is chromatographed over 250 g of silica gel and eluted with benzene, 50% chloroform-benzene and chloroform. The fractions containing pure N-(1-benzoyl-3-indolylmethyl)-t-butylcarbamate are combined and evaporated

A solution of 2.1 g (6.0 mmol) of N-(1-benzoyl-3-indolyl-methyl)-t-butyl carbamate in 50 ml of ethyl acetate is cooled in an ice bath while anhydrous hydrogen chloride is passed through the solution for 10 minutes. After removing excess hydrogen chloride gas by flushing with nitrogen, ethyl ether is added to precipitate 3-aminomethyl-1-benzoylindole hydrochloride with melting point 247 - 253°C.

Method 3

Starting material for synthesis of. N-(4,S-diacetoxyphenethy 1)-trichloroacetamidine hydrochloride

4, P-diacetoxyphenethylamine hydrochloride

A mixture of 4.75 g (0.025 mol) d,1-oetopamine hydrochloride, 50 ml of acetyl chloride and 50 ml of glacial acetic acid is stirred under reflux in

2 hours and then at 20 - 25°C for 2 days. After evaporation to

dryness under reduced pressure, benzene is added to the residue and evaporated again. Petroleum ether is added to the residue. Filtration gives 4,B-diacetoxyphenethylamine hydrochloride.

Method 4

Starting materials for the synthesis of N-[3-(4-acetamidophenoxy)-2-hydroxy-propyl [- 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) of benzylamine in 20 ml of dimethylformamide are heated at 100°C for 1.25 hours, and then cooled. 400 ml of hexane are added to the reaction mixture. After trituration, the insoluble solid is filtered off and recrystallized from ethyl acetate, which gives 12,49N-[3-(4-acetamidophenoxy)'-2-hydroxypropyl]-benzylamine as the base with melting point 117.5 - 123.5°C . The hydrochloride is obtained by acidifying a solution of the base in methanol with an excess of ethanolic anhydrous hydrogen chloride solution and evaporation under reduced pressure.

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

A solution of 5.5 g (0.0157 mol) N-[3-(4-acetamido-phenoxy)-2-hydroxypropyl]-benzylamine hydrochloride in 100 ml of ethanol and 50 ml of water is hydrogenated over 1 g of 10% palladium-on-carbon catalyst at 40 - 53 C and an initial pressure of 372.63 kg/cm for 2 hours. After filtration and evaporation under reduced pressure, the residue is recrystallized from absolute ethanol, which gives 3.26 g of 3-(4-acetamidophenoxy)-2-hydroxypropylamine hydrochloride with a melting point of 194 - 197°C.

Method 5

Starting materials for the synthesis of 2-trichloroacetamidinoethyl-2-naphthyl sulfoxide hydrochloride

A. N-1" 2-(2-naphthylthio)-ethyl]-ft ha lim id

To a solution of 4.60 g (0.20 g atom) of sodium in 150 ml of methanol under nitrogen is added 32.0 g (0.20 mol) of 2-naphthyl-thiol. After 10 minutes, 50.8 g (0.20 mol) of 2-bromoethylphthalimide is added, and the mixture is stirred at 20 - 25°C for 2 hours, and then it is stirred under reflux for 2 hours. After evaporation to approx. water is added to half the original volume under reduced pressure at 40°C. The precipitated solid is removed by filtration and recrystallized from it. 300 ml of acetone, which gives 52.1 g of N-[2-(2-naphthylthio)-ethyl]-phthalimide with a melting point of 73.0 - 79.0 C. Addition of water to the mother liquor precipitates a further 5 g of product with a melting point of 75, 0 - 80.0°C. Further recrystallization from acetone-water and ethyl acetate-hexane yields an analytical sample with a melting point of 80.0 - 81.5°C.

B • 2-(2-aminoethylthio)-naphthaene hydrochloride

A mixture of 57.6 g (0.173 mol) N-[2-(2-naphthylthio)-ethyl]-phthalimide, 5.77 ml of 95% hydrazine, 300 ml of ethanol, 100 ml of methanol and 12 ml of water is heated under reflux for 2 hours.

25 ml of concentrated hydrochloric acid is added, and after heating under reflux for 1.5 hours, it is filtered while hot. After cooling to room temperature, filter again, the filtrate is evaporated under reduced pressure at 40°C to approx. 250 ml and cool. Filtration yields 27.6 g of 2-(2-aminoethylthio)-naphthalene hydrochloride with melting point 167.7~174.79C

C. 2- aminoethyl- 2- naphthyl sulfoxide hydrochloride

A total of 2.3 ml of 30% hydrogen peroxide is added over the course of 5 minutes to a solution of 5.449 (0.0227 mol) 2-(2-amino-ethylthio)-naphthalene hydrochloride in 50 ml of water and 50 ml of methanol at 20 - 25°C. After stirring under reflux. for 8 hours is added

100 mg of potassium sulphite, and the reaction mixture is allowed to stand at 20 - 25°C for 3 days. The mixture is filtered and evaporated to dryness under reduced pressure on a steam bath. 10 ml of ethanol is added to the residue, and then evaporated again under reduced pressure. After repeating this treatment two more times, the residue is washed with isopropanol and ethanol and dried, thereby obtaining 4.72 g of 2-aminoethyl-2-naphthylsulfoxide hydrochloride with a melting point of 136 - 142°C (decomposition). An analytical sample with a melting point of 145 - 153.7°C (decomposition) is obtained by recrystallization from methanol-ethyl acetate.

Method 6

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

3- aminomethyl- 5- methoxyindole

0.95 g (0.019 mol) hydrazine hydrate is added to a stirred suspension of 5.139 (0.017 mol) N-(5-methoxy-3-indolylmethyl)-phthalimide in 60 ml dry methanol and stirred at 20 - 25°C for 18 hours. After adding 60 ml of dry methanol and 40 ml of 3 N

hydrochloric acid, the mixture is stirred at 20-25°C for a further 2 hours and then filtered. The filtrate is evaporated under reduced pressure, heated with 50 ml of water on a steam bath and filtered. The filtrate is made alkaline with 5 N potassium hydride, and the product is extracted into chloroform. After drying the chloroform extract over magnesium sulfate and filtering, the chloroform is removed under reduced pressure, whereby 3-aminomethyl-5-methoxyindole with a melting point of 98.0 - 100.5°C is obtained.

Claims (2)

1. Procedure for the preparation of a compound with the formula: wherein R is perhalogenated lower alkyl; R 2 is hydrogen, lower alkyl or lower alkanoyl; R 1 is lower alkyl, phenyl-lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl or cycloalkenyl, which groups are substituted by one or more of hydroxy, hydroxy-lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyloxy, lower alkanoylamino, phenyl, hydroxyphenyl, lower alkoxyphenyl, phenoxy, phenylsulfinyl, naphthylsulfinyl , cycloalkyl, lower alkylphenyl, lower alkenylphenyl, phenylcycloalkyl or halogen; R 3„ is also phenyl-lower alkyl substituted with perhalo-alkylamidino-lower alkyl; R^ can also be a heterocyclic group with 5-7 members bound to the amidine nitrogen by a lower alkyl group and containing 1 or 2 heteroatoms which are oxygen and/or nitrogen, or a benzoheterocyclic group optionally substituted with lower alkyl, lower alkoxy or benzoyl where the benzo group is condensed with a 5-7 membered heterocyclic ring with 1 or 2 heteroatoms which are oxygen and/or nitrogen; and where.each amino or hydroxy group with a labile proton optionally is-transferred to a glycoside; and the non-toxic, pharmaceutically acceptable salts thereof, characterized in that a perhalogenated lower alkylnitrile is reacted with an amine of the formula: where R^ and R^ are as indicated above. 2. Procedure for the preparation of a compound with the formula: wherein R is perhalogenated lower alkyl; R 1 is lower alkyl, lower alkanoyl, phenylcarbamoyl or lower alkoxyalyl; R 2 is hydrogen, lower alkyl or lower alkanoyl; R3„ is lower alkyl, phenyl-lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl or cycloalkenyl, which groups are substituted with one or more of hydroxy, hydroxy-lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyloxy, lower alkanoylamino, phenyl, hydroxyphenyl, lower alkoxyphenyl, phenoxy, phenylsulfinyl, naphthylsulfinyl, cycloalkyl, phenylcycloalkyl, lower alkylphenyl, lower alkenylphenyl or halogen; R.3 „ is also phenyl-lower alkyl substituted with perhalo-alkylamidino-lower alkyl; R3„ is also a heterocyclic group with 5-7 members attached to the amidine nitrogen by a lower alkyl group and contains 1 or 2 heteroatoms which are oxygen and/or nitrogen, or a benzoheterocyclic group optionally substituted with lower alkyl, lower alkoxy or benzoyl , where the benzo group is condensed with a 5-7 membered heterocyclic ring with 1 or 2 heteroatoms which are oxygen and/or nitrogen; and where each amino or hydroxy group with a labile proton is optionally transferred to a glycoside; and non-toxic, pharmaceutically acceptable salts thereof, characterized in that a compound of the formula: where R, R 2 and R 1 are as indicated above, is treated with an alkylating agent or an acylating agent. 3- Procedure for the preparation of a compound with the formula: wherein R is perhalogenated lower alkyl; R is hydrogen or lower alkyl; and R^ and R^<:> are united to form a heterocyclic ring with 5-7 members including 2 amidine nitrogen atoms, which heterocyclic ring is optionally substituted with hydroxy, lower alkoxy, phenyl, halogen or a condensed benzo ring which is optionally substituted with lower alkyl or lower alkoxy; and non-toxic, pharmaceutically acceptable salts thereof, characterized in that trichloroacetonitrile is reacted with a lower alkyldiamine which is optionally substituted with hydroxy, lower alkoxy, phenyl or a condensed benzo ring which is optionally substituted with lower alkoxy, which comprises bringing perhalogen-lower-alkylnitrile into contact with an alkyldiamine which is optionally substituted with hydroxy, lower alkoxy, phenyl, halogen or a fused benzo ring, which benzo ring is optionally substituted with lower alkyl or lower alkoxy, and optionally treating the cyclic amidine formed with an alkylating agent or an acylating agent.