BE837569A - NEW PERHALOGENOALCOYLAMIDINES SUBSTITUTED AS HEART STIMULANTS - Google Patents

Description

       

   <EMI ID = 1.1>

  
technique, being described for applications in agriculture {. See German patent application (Offenlegungschrift)

  
2,121,401]. There is no indication, however, that the disclosed trichloroacetamidines possess any pharmacological properties and there is specifically no reference to any cardiac effects.

  
Some new compounds have been discovered included in

  
 <EMI ID = 2.1>

  
which exhibit marked cardiac stimulating effects and are used in compositions for the administration of these compounds. Thus, the object of the present invention is to describe new compounds. More particularly, it relates to novel substituted perhaloalkylamidines. It also relates to the preparation of these new substituted perhaloalkylamidines. Still another object are compositions and methods of treatment using these novel compounds. Other objects and advantages of the invention will further emerge from the following description.

  
The new substituted perhaloalkylamidines

  
of the present invention can be represented by the following structural formula:

  

 <EMI ID = 3.1>


  
in which

  
R is a perhalogenated alkyl group having 1 to 5 carbon atoms

  
carbon;

  
 <EMI ID = 4.1>

  
lower nucleus, and

  
R3 is lower alkyl, lower phenylalkyl,

  
lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, which groups are substituted with one or more <EMI ID = 5.1>
(lower alkanoyl) amino, phenyl, hydroxyphenyl, (lower alkoxy) phenyl, phenoxy, phenylsulfinyl, naphthylsulfinyl, cycloalkyl, (lower alkyl) phenyl, (alkoxy)

  
 <EMI ID = 6.1>

  
R3 is also a lower phenylalkyl group substituted with

  
a perhaloalkylamidino lower alkyl group;

  
 <EMI ID = 7.1>

  
chain links connected to the nitrogen atom of the anidine group through a lower alkyl group. The heterocyclic group contains one or two hetero atoms chosen from oxygen and nitrogen

  
 <EMI ID = 8.1>

  
by a lower alkyl, lower alkoxy or benzoyl group, in which the benzo portion is condensed with a 5 to 7 membered heterocyclic ring comprising one or two hetero atoms chosen from oxygen and nitrogen; and

  
 <EMI ID = 9.1>

  
5- to 7-membered heterocyclic comprising both nitrogen atoms of the amidine group; this heterocyclic ring being substituted by hydroxy, lower alkoxy, phenyl, halo, (lower alkyl) benzo or (lower alkoxy) benzo groups; and their pharmaceutically acceptable non-toxic salts; when a particular compound contains a labile proton, such as an amino or hydroxy group, that proton can be transformed into a glycoside such as a glucoside, etc.

  
In the present description and the appended claims, the term "lower alkyl" should be understood as including alkyl groups containing from 1 to 5 carbon atoms both straight chain and branched chain, such as methyl, ethyl, propyl, etc. butyl, pentyl, isopropyl, tert-butyl, etc.

  
The term "lower alkenyl" embraces straight or branched chain alkenyl groups containing from 2 to 5 carbon atoms in a straight or branched configuration and 1 or

  
2 unsaturations such as vinyl, propenyl, allyl, butenyl, 2,4 - pentadienyl, etc.

  
The term "lower alkynyl" embraces alkyl groups of 2 to 5 carbon atoms in a straight or branched configuration containing a triple bond such as ethynyl, 1-propynyl, propargyl, pentynyl, etc.

  
The term "cycloalkyl" should be understood to include cycloalkyl groups containing from 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

  
The term "cycloalkenyl" is to be understood as englo-

  
 <EMI ID = 10.1>

  
which contain 1 or 2 unsaturations such as cyclobutenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, etc.

  
The term "halo" or "halogen" embraces the halogen atoms of fluorine, chlorine, bromine and iodine.

  
The term "heterocyclic group" embraces 5 to 7 membered heterocycles with one or two oxygen or nitrogen atoms as hetero atoms. Included are furyl, tetrahydrofuryl, pyrrolyl, pyrrolidinyl, morpholi-

  
 <EMI ID = 11.1>

  
nyl, pyrazinyl, cxapinyl, azepinyl, etc. Similarly, benzoheterocyclic groups include groups in which a benzo moiety is condensed with one of the above heterocyclic groups, with indolyl being preferred.

  
It is well known to those skilled in the art that N-substituted amidines exist in tautomeric equilibrium. Thus, in the present description and the appended claims, whenever a substituted amidine which comprises a subs-

  
 <EMI ID = 12.1>

  
is actually considering the tautomeric mixture. Tautomerism is destroyed, however, when a single nitrogen atom of the amidine is

  
 <EMI ID = 13.1>

  
In addition, many of the foregoing compounds are optically active. That is, they normally exist under the force of racemic mixtures of d and 1 optical isomers. Thus, when a particular compound has an asymmetric center and exists

  
 <EMI ID = 14.1>

  
Individual isomers as well as the racemic mixture are contemplated as included within the general scope of the present invention.

  
The compounds according to the invention exhibit interesting pharmacological properties. They act mainly on the force of contraction of the heart muscle. By increasing the force of contraction of the heart muscle resulting in increased cardiac output, these compounds provide an interesting means for treating heart failure.

  
Congestive cardiac decompensation results from the heart pumping less blood than is required by the body's metabolic demands. The aim of treatment is to restore the balance between demand and supply of blood. This can be achieved by use of the present cardiotonic agents which improve the contractility of the myocardium and act on cardiac output so as to meet the demands of the body.

  
The use of common agents to stimulate the failing heart is limited by their toxic effects on the heart or by their harmful side effects on the peripheral circulation. For example, although cardiac glycosides are myocardial stimulants and can restore the failed heart, they do so in doses very close to those which produce toxic symptoms of cardiac arrhythmia, nausea and vomiting. The use of sympathomimetic agents is limited by the associated phenomena of arrhythmia, tachycardia, tachyphylaxis or impaired peripheral resistance.

  
The present perhaloalkylamidine derivatives have been found to be active myocardial stimulants which substantially avoid the toxic manifestations of prior art cardiac stimulants. We observe this stimulus

  
 <EMI ID = 15.1>

  
in isolated cardiac muscle and in vivo in anesthetized dogs wearing a cardiac strain gauge. Drifts

  
of perhaloalkylamidines according to the invention are administered to the patient suffering from heart failure in doses of approximately 0.1 to 50 mg per kg of body weight and per day.

  
For such use, the compounds according to the invention can be administered orally or parenterally alone or in admixture with conventional pharmaceutical vehicles. They can be administered orally in forms such as tablets, dispersible powders, granules, capsules, syrups and elixirs, and parenterally in the form of solutions, suspensions, dispersions, emulsions, etc. , for example a sterile injectable aqueous suspension. Compositions for oral use may contain one or more conventional adjuvants, such as sweeteners, flavorings, colorants and preservatives, so that an elegant and palatable preparation is obtained.

   Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, eg inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, eg. starch and alginic acid, binders, for example starch, gelatin and acacia, and lubricants, for example magnesium stearate, stearic acid and talc. Tablets can be uncoated or coated by conventional techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period of time.

   Similarly, suspensions, syrups and elixirs can contain the active ingredient in admixture with any of the conventional excipients used for the preparation of such compositions, for example suspending agents (methylcellulose, tragacanth and gum. 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, for example calcium carbonate, calcium phosphate or kaolin.

   The injectable compositions are composed as known in the art and may contain suitable dispersing or wetting agents and suspending agents identical or similar to those mentioned above. These pharmaceutical preparations can

  
 <EMI ID = 16.1>

  
nation with the vehicle or adjuvant.

  
Effective cardiotonic doses of the active ingredient used for the treatment of heart failure may vary depending on the particular compound used and the severity of the condition being treated. In general, however, satisfactory results are obtained when the compounds are administered.

  
in daily doses of between 0.1 and 50 mg approximately per kg of body weight of the animal, preferably in divided doses two to four times a day, or in a sustained release form. For most large mammals in need of such treatment, the total daily dose is between about 0.7 and 50 mg per kg, preferably administered orally. Dosage forms suitable for oral use contain from about 1 to 500 mg of the active compound in intimate admixture with a pharmaceutically acceptable solid or liquid carrier or diluent.

  
The preferred pharmaceutical compositions of the point

  
In view of preparation and ease of administration are solid compositions, in particular dry-filled capsules and tablets containing from 10 to 250 mg of active ingredient.

  
Preferred embodiments of the invention

  
One aspect of preferred embodiments of the present invention relates to compounds of the preceding structural formula wherein

  
R is a trichloromethyl group;

  
 <EMI ID = 17.1>

  
R2 is hydrogen or a lower alkyl group; and

  
 <EMI ID = 18.1>

  
lower, lower alkenyl or lower alkynyl, these groups being substituted by one or more hydroxy, lower hydroxyalkyl, lower alkoxy, (lower alkyl) thio groups,

  
 <EMI ID = 19.1>

  
laughing) phenyl, phenoxy, cycloalkyl, phenylcycloalkyl or halo.

  
 <EMI ID = 20.1>

  
A particularly preferred group of compounds included in this aspect of the preferred embodiments are those compounds of the foregoing structural formula wherein

  
 <EMI ID = 21.1>

  
and

  
 <EMI ID = 22.1>

  
lower, these groups being substituted by one or more hydroxy, (lower alkanoyl) pxy, phenyl, (lower alkoxy) phenyl or phenoxy groups.

  
Particularly preferred compounds of this aspect of the preferred embodiments are the compounds of the formula.

  
 <EMI ID = 23.1>

  
while hydrogen or a lower alkyl group and

  
 <EMI ID = 24.1>

  
wherein the substituents are one or more hydroxyphenyl, (lower alkoxy) phenyl, phenoxy or hydroxy groups. Particular preferred compounds are as follows:

  
 <EMI ID = 25.1>

  
Another aspect of the preferred embodiments of the present invention relates to the compounds of the preceding structural formula in which:

  
R is a trichloromethyl group;

  
 <EMI ID = 26.1>

  
and

  
R3 is a lower alkyl group substituted with a heterocyclic or benzoheterocyclic group chosen from indole, pyrimidine, piperidine, furan, tetrahydrofuran, pyridine and piperazine, these groups being optionally substituted by lower alkyl, lower alkoxy or benzoyl groups.

  
 <EMI ID = 27.1>

  
Another group of compounds according to this aspect of the preferred embodiments are the compounds in

  
 <EMI ID = 28.1>

  
lower alkyl substituted with an indole, pyrimidine, piperidine or furan group which is optionally substituted with a methyl, methoxy or benzoyl group.

  
Particularly preferred compounds of this aspect of preferred embodiments of the present invention are

  
 <EMI ID = 29.1>

  
indole optionally substituted with a methyl or methoxy group.

  
Particularly preferred compounds are obtained when the indole is unsubstituted.

  
Particular preferred compounds are as follows:

  
 <EMI ID = 30.1>

  
Due to the complexity of the present compounds, it is often possible to refer to a particular compound in several ways. The particular name will depend on what part of the molecule is chosen as the root of the name, and often it is quite possible to choose parts of a molecule each of which could appropriately serve as the root of the name.

  
As an example, there may be mentioned N- [2- (5-methyl-3-

  
 <EMI ID = 31.1>

  
chloroacetamidinoethyl) indole, both names denoting the same compound.

  
The compounds according to the invention can be prepared from a perhaloalkylnitrile as shown in the following reaction scheme:

  

 <EMI ID = 32.1>


  
or

  
R is a perhalogenated alkyl group,

  
 <EMI ID = 33.1>

  
laughing, phenylcarbamoyl or lower alkoxalyl;

  
 <EMI ID = 34.1>

  
and

  
 <EMI ID = 35.1>

  
or cycloalkenyl, these groups being substituted by one or more hydroxy, lower hydroxyalkyl, lower alkoxy, (lower alkyl) thio, (lower alkanoyl) oxy, (alka-

  
 <EMI ID = 36.1>

  
common) phenyl, phenoxy, phenylsulfinyl, naphthylsulfinyl, cycloalkyl, (lower alkyl) phenyl, (lower alkenyl) phenyl, phenylcycloalkyl, lower alkanoyl or halo;

  
 <EMI ID = 37.1>

  
chain links, linked to the nitrogen atom of the amidine by a lower alkyl radical, containing one or two hetero atoms chosen from oxygen and nitrogen or a benzoheterocyclic group optionally substituted by a lower alkyl or lower alkoxy group or benzoyl, where the benzo portion is condensed with a 5 to 7 membered heterocyclic ring having one or two hetero atoms selected from oxygen and nitrogen, and their pharmaceutically acceptable non-toxic salts and when a particular compound contains a proton labile such as an amino or hydroxy group, this proton can be replaced by a glycoside.

  
In the reaction scheme above, we react *

  
 <EMI ID = 38.1>

  
in a solvent; however, such a solvent is not necessary. When using a solvent, organic solvents such as aliphatic or aromatic hydrocarbons are preferred. Examples are hexane, benzene, toluene, petroleum ether, etc. Other solvents that can be used :: 100 of

  
ethers such as ethyl ether, tetrahydrofuran and the like; halogenated solvents such as chloroform, carbon tetrachloride, chlorobenzene, etc; dimethyl-

  
 <EMI ID = 39.1>

  
etc. The reaction is carried out between 0 [deg.] C and 100 [deg.] C or the reflux temperature of the reaction medium if it is below
100 [deg.] C. The reaction is generally complete within 1 to 48 hours. It is preferred to run the reaction at substantially room temperature for 4-24 hours. The product is isolated by techniques known to those skilled in the art.

  
When the salts of primary or secondary amines are used as the reactant, it is necessary to add to the reaction mixture a base which will liberate the desired free amine. Suitable bases are tertiary amines such as

  
 <EMI ID = 40.1>

  
inorganic bases such as alkali metal and alkaline earth metal hydroxides, carbonates and bicarbonates and organic metal bases such as alkali metal alcoholates.

  
The second step in the reaction sequence involves alkylation of perhalo (lower alkyl) amidine

  
 <EMI ID = 41.1>

  
titled. The alkylation reaction uses any normal alkylating agent such as lower alkyl fluorosulfonates, lower alkyl halides, etc. The reaction is optionally carried out in a solvent as indicated below.

  
 <EMI ID = 42.1>

  
reflux of the reaction mixture if the latter is below 100 [deg.] C, for 1 to 48 hours. It is preferred to run the reaction at substantially room temperature for 4-24 hours. The product is isolated by techniques known to those skilled in the art.

  
Alternatively, a second step of the present process involves acylating the amidine nitrogen so that it is substituted with a lower alkanoyl, phenylcarbamoyl or lower alkoxalyl group. The acylation is performed with any normal acylating agent which will produce the

  
 <EMI ID = 43.1>

  
lower, phenyl, carbamoyl or lower alkoxalyl, typical acylation groups are acid halides, anhydrides or isocyanates having the formula:

  

 <EMI ID = 44.1>


  
where R4 is lower alkyl or (lower alkoxy) car-

  
 <EMI ID = 45.1>

  
the anhydride:

  

 <EMI ID = 46.1>


  
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), etc. The reaction is carried out between room temperature and the reflux temperature of the reaction mixture and is complete in 1/2 hour to 6 hours, the product being isolated by techniques known to those skilled in the art.

  
When X is a halide, one mole of a hydrohalic acid is released during the course of the reaction. he

  
It is advantageous to add one molar equivalent of a tertiary amine, such as pyridine or triethylamine, to the reaction mixture for reaction with the acid liberated.

  
Cyclic amidines can also be prepared from

  
 <EMI ID = 47.1>

  
In this case, however, a diamine such as an alkyl amine is used which may optionally be substituted by hydroxy, lower alkoxy, phenyl, halo groups or by a condensed benzo ring, this benzo ring being optionally substituted by a lower alkyl group or lower alkoxy. The diamine is combined with a perhalo (lower alkyl) -

  
 <EMI ID = 48.1>

  
before and it is kept at this temperature for 1 hour to 5 days. Preferably, the reaction mixture is stirred at substantially room temperature for a period of

  
8 hours to 2 days. The reaction is greatly facilitated by the addition of a molar equivalent of a base acceptor such as p-toluenesulphonic acid, hydrochloric acid, etc. This is useful in the reaction because during cyclization to form the cyclic amidine, one mole of ammonia is released. The base acceptor reacts with ammonia forming a salt which is easily removed and aids in the isolation of the product.

  
The following non-limiting examples illustrate the compounds and methods of the present invention.

Example 1

  
 <EMI ID = 49.1>

  
benzene is stirred at 20-25 [deg.] C for 4 hours. After concentration under reduced pressure, the residue is recrystallized twice from benzene-hexane and once from acetate.

  
 <EMI ID = 50.1>

  
trichloroacetamidine, melting point 74-76 [deg.] C.

Example 2

  
 <EMI ID = 51.1>

  
A solution of 11.05 g (0.077 mole) of trichloroacetonitrile in 10 cc of benzene is added to a stirred solution of 10.0 g (0.073 mole) of p-methoxybenzylamine in

  
 <EMI ID = 52.1>

  
through a column containing 100 g of silica gel. Elution with chloroform gives a series of fractions. The <EMI ID = 53.1>

  
dine as determined by thin layer chromatography are combined and concentrated. The residue is dissolved in ethanol, treated with excess ethanolic solution of a-

  
 <EMI ID = 54.1>

  
precipitated with ethyl ether. Recrystallization from ethanol-ethyl ether gives 17.5 g of hydrochloride.

  
 <EMI ID = 55.1>

  
A mixture of 3.0 g (0.0132 mole) of 5-methoxytryptamine hydrochloride, 1.34 g (0.0132 mole) of triethylamine

  
 <EMI ID = 56.1>

  
 <EMI ID = 57.1>

  
for 21 hours. The reaction mixture is then diluted with 50 carbs of saturated sodium chloride solution. The benzene layer is separated, washed with two portions of

  
 <EMI ID = 58.1>

  
After filtration and concentration under reduced pressure, the residue is recrystallized four times from benzene-hexane to give 0.58 g of 5-methoxy-3- (2-trichloroacetamidino-

  
 <EMI ID = 59.1>

  
A mixture of 4.75 g (0.025 mole) of dopamine hydrochloride, 2.75 g (0.027 mole) of triethylamine and 7.20 g

  
 <EMI ID = 60.1>

  
dissolved in ethyl acetate and washed with a solution

  
with 5% sodium carbonate, with water and with a saturated solution of sodium chloride. After drying the extract with ethyl acetate over anhydrous magnesium sulfate and filtration, the filtrate is treated with an excess of ethanolic solution of anhydrous hydrochloric acid and concentrated under pressure.

  
 <EMI ID = 61.1>

  
te of N- (3,4-dihydroxyphenethyl) -trichloroacetamidine. Example ^

  
 <EMI ID = 62.1>

  
A solution of 3.7 g (0.050 mole) of 1,3-diaminopropane and 9.5 g (0.050 mole) of p-toluene acid hydrate

  
 <EMI ID = 63.1>

  
10 minutes and then 7.22 g (0.050 mol) of trichloroacetonitrile are added. After stirring at 25 [deg.] C for five days, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is washed with water and recrystallized from cyclohexane to give 6.0 g of 2-tri-

  
 <EMI ID = 64.1>

  
A mixture of 1.82 g (0.020 mole) of propargylamine hydrochloride, 4.5 g (0.031 mole) of trichloroacetonitrile

  
 <EMI ID = 65.1>

  
reaction is diluted with water and processed by extraction

  
with benzene. After washing the benzene extract with water four times, drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure, the residue is dissolved in benzene and treated with excess anhydrous ethanolic hydrochloric acid. The solvents are removed under reduced pressure and the residue is washed with ethyl ether and recrystallized from ethanol-ethyl ether to give 2.8 g of N-propargyltrichloroacetamidine hydrochloride, point

  
 <EMI ID = 66.1> <EMI ID = 67.1>

  
of dimethylfoxmamide is stirred at 20-25 [deg.] C for 2 hours. The reaction mixture is diluted with water and worked up by extraction with benzene. After washing the benzene extract with water four times, the benzene extract is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is recrystallized from benzene-hexane to give 2.11 g of N- (4 - métbLoxycianamyl) -t; richloroacétamicline,

  
 <EMI ID = 68.1>

  
lizations from benzene-hexane.

  
According to the previous procedure, using

  
 <EMI ID = 69.1>

  
sub in benzene and washed with three 50 cc portions of water and 50 cc of saturated sodium chloride solution. The benzene extract is dried over anhydrous magnesium sulfate, filtered and concentrated. Recrystallization of the residue

  
 <EMI ID = 70.1>

  
acetamidine, melting point 61-63 [deg.] C.

  
According to the previous procedure, using

  
 <EMI ID = 71.1> <EMI ID = 72.1>

  
zene. The benzene extracts are combined, washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue is dissolved in chloroform and passed through a gel column.

  
 <EMI ID = 73.1>

  
fractions. Fractions containing product as determined by thin layer chromatography are combined and concentrated. The residue is recrystallized from cyclohexans

  
 <EMI ID = 74.1>

  
To a stirred mixture of 10.41 g (0.060 mole) of tyramine hydrochloride and 60 carbons of dimethylformamide at 0-5 [deg.] C, 6.06 g (0.060 mole) of triethylamine and then 12 g are added.
(0.083 mole) of trichloroacetonitrile. After stirring at 0-5 [deg.] C for 1 hour, the reaction mixture is stirred at 20-25 [deg.] C

  
 <EMI ID = 75.1>

  
of water. The crude product is extracted with benzene, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in ethyl acetate and saturated with gaseous hydrochloric acid. The gummy precipitate is separated by decantation, washed with ethyl acetate and dissolved in water. After addition of an excess of saturated sodium carbonate solution, the product is extracted into benzene. The benzene extract is washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Recrystallization from benzene-hexane gives 8.5 g of N- (4-hydroxyphenethyl) trichloroacetamidine, point of

  
 <EMI ID = 76.1>

  
A solution of 7.42 g (0.0404 mole) of trans 2-phenylcyclopropylmethylamine hydrochloride, 4.09 g (0.0404 mole) of triethylamine and 8.81 g (0.061 mole) of trichloro- <EMI ID = 77.1>

  
hydrochloric acid 3N. The acid extract is diluted with 25 cm <3> of water, made basic with a saturated solution of sodium bicarbonate.

  
 <EMI ID = 78.1>

  
of benzene. The benzene extracts are combined, washed with water, dried over anhydrous magnesium sulfate, filtered and

  
 <EMI ID = 79.1>

  
methyl) trichloroacetamidine.

  
According to the previous procedure, using 2-aminoethylphenylsulfoxide hydrochloride or 2-aminoethyl-2-naphthylsulfoxide hydrochloride in place of the hydrochloride

  
 <EMI ID = 80.1>

  
is refluxed for 5.5 hours and then concentrated under reduced pressure. The residue is recrystallized twice

  
from hot water to give 7.44 g of oxime.

  
 <EMI ID = 81.1> until fixation of two equivalents of hydrogen. After filtra-. tion, the filtrate is concentrated under reduced pressure. The residue

  
 <EMI ID = 82.1>

  
15 minutes, the residue is poured into 150 or <3> water. The tan-colored precipitate is filtered off, dried and recreated.

  
 <EMI ID = 83.1>

  
indole instead of 2,3-dichloro-4-hydroxybenzylamine hydrochloride, N- (1-benzoyl-3-indolylmethyl) -tri- is obtained.

  
 <EMI ID = 84.1>

  
diaminopropane, 113 mg of p-toluenesulfonic acid hydrate

  
 <EMI ID = 85.1>

  
stirred at 20-25 [deg.] 0 for 3 days. After concentration under reduced pressure at 25 [deg.] C, the residue is dissolved in chloroform and passed through a column of silica gel. Elution with chloroform gives a series of fractions. Fractions containing product, as determined by thin layer chromatography, are combined and concentrated under reduced pressure. The residue is dissolved in ethanol, treated with excess ethanolic solution of anhydrous hydrochloric acid and diluted with ethyl ether to give 24 mg of hydrochloride.

  
 <EMI ID = 86.1>

  
melting point 265-2? 0 [deg.] C, dec.

Example 14

  
 <EMI ID = 87.1>

  
A solution of 3.6 g (0.0506 mol) of N-methyl-

  
 <EMI ID = 88.1>

  
 <EMI ID = 89.1>

  
residue gives 6.2 g of N-allyl-N-methyltrichloroacetamidine, boiling point 66-70 [deg.] C under 0.2 mm. 2.5 g of maleic acid are added to a solution of 5 g of N-allyl-N-methyl-trichloroacetamidine base in ethanol. Addition of ethyl acetate and cooling gives 4.9 g of hydrogen maleate.

  
of N-allyl-N-methyltrichloroacetamidine, melting point
101-107 [deg.] C. Recrystallization from ethanol-ethyl acetate gives a pure sample, mp 101-106 [deg.] C.

Example 15

  
 <EMI ID = 90.1>

  
A mixture of 10.6 g (0.0635 mole) of 2-hydroxy-3phenoxypropylamine and 11.0 g (0.0762 mole) of trichloro-

  
 <EMI ID = 91.1>

  
ethyl is stirred at 20-25 [deg.] C for 23 hours. After filtration, the solvents are removed under reduced pressure. The residue is recrystallized from benzene-hexane to give

  
 <EMI ID = 92.1>

  
melting point 86-7 [deg.] C.

Example 16

  
 <EMI ID = 93.1>

  
saturated with gaseous hydrochloric acid. Acetyl chloride, 2.6 g (0.033 mol) is added and the solution is stirred at
20-25 [deg.] C for 3 days. After concentration under reduced pressure, benzene is added and the mixture is again concentrated under reduced pressure. This process is repeated once more with benzene, twice with toluene and twice with petroleum ether to obtain 7.68 g of chlorine.

  
 <EMI ID = 94.1>

  
midine

  
A total of 0.50 g (5.0 mmol) of triethylamine is added in small portions over 10 minutes to a well stirred mixture.

  
 <EMI ID = 95.1>

  
tation for 1.5 hours, the reaction mixture is diluted with water and treated by extraction with benzene. The benzene extract is washed five times with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is dissolved in benzene and treated with an excess of anhydrous ethanolic hydrochloric acid. After concentration under reduced pressure, the residue is dried over phosphorus pentoxide at

  
 <EMI ID = 96.1>

  
N- (2-Acetoxy-3-phenoxy-propyl) -trichloroacetamidine hydrochloride, mp 70-77 [deg.] C, dec.

  
In accordance with part B of the previous operating mode

  
 <EMI ID = 97.1>

  
N- (3,4-dipivaloyloxyphenethyl) trichloroaceous &#65533; amidine hydrochloride, mp 115-121 [deg.] C (dec) and N- (4, (3-diacetoxyphenethyl) -trichloroacetamidine hydrochloride are obtained. , mp 200.5-204.5 [deg.] C, respectively.

Example 17

  
 <EMI ID = 98.1>

  
A solution of 500 mg (5.5 mmol) of 2-methylthioethylamine and 1.50 g (10.4 mmol) of trichloroacetonitrile

  
 <EMI ID = 99.1>

  
and then concentrated under reduced pressure. The residue is dissolved in ethyl ether and treated with an excess of ethanolic solution of anhydrous hydrochloric acid. Matter

  
 <EMI ID = 100.1>

  
Phosphoric acid at 25 [deg.] C and at a pressure of 0.2 mm for 20 hours to give 1.1 g of N- (2-methylthioethyl) trichloroacetamidine hydrochloride.

  
According to the previous procedure, using

  
4-methoxybenzylamine instead of 2-methylthioethylamine and bromodichloroacetonitrile instead of trichloroacetonitrile, N- (4-methoxybenzyl) hydrochloride is obtained -

  
 <EMI ID = 101.1>

  
A mixture of 2.02 g (0.020 mole) of 3-hydroxypiperidine and 5.0 g (0.035 mole) of trichloroacetonitrile in

  
 <EMI ID = 102.1>

  
addition of decolorizing charcoal and filtration, the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl ether and treated with an excess of hydrochloric acid solution in anhydrous ethanol. The precipitated salt is collected and recrystallized from methanol-ethyl acetate to give 2.65 g of 3-hydroxy-N-trichloro-hydrochloride.

  
 <EMI ID = 103.1>

  
furylamine and 9.5 g (0.066 mol) of trichloroacetonitrile

  
 <EMI ID = 104.1>

  
and then concentrated under reduced pressure. The residue is recrictallized twice from benzene-hexane to give 8.3 g of N-tetrahydrofurfuryltrichloroacetamidine, melting point 75-78 [deg.] C.

  
According to the previous procedure, using 3-aminoethyl-1-methylindole in place of tetrahydrofurfurylamine, N- (1-methyl-3-indolylmethyl) -trichloroacetamidine, melting point 90.0-91, is obtained. 5 [deg.] C.

Example 20

  
 <EMI ID = 105.1>

  
A solution of 3.0 g (0.022 mole) of 2-aminomethylbenzyl alcohol and 3.32 g (0.024 mole) of trichloroaceto

  
 <EMI ID = 106.1>

  
3 days. After concentration under reduced pressure, 100 car of chloroform is added and the mixture is filtered. Fractions

  
 <EMI ID = 107.1>

  
as determined by thin layer chromatography, are combined and concentrated. The residue is recrystallized twice from cyclohexane to give 2.0 g of N- (2-hydroxymethyl-

  
 <EMI ID = 108.1>

  
under reduced pressure to a viscous oil. The residue is treated by extraction with two portions of 100 cm <3> and a por-

  
 <EMI ID = 109.1>

  
Combined chloroform strokes are washed first with two 100 cm portions of water and then with three portions of dilute hydrochloric acid. aqueous acidic extracts are combined, processed by extraction with two 100 cm portions

  
of chloroform and filtered. The clear aqueous filtrate is made basic with a saturated aqueous solution of sodium bicarbonate and the product is extracted into three 200 cc portions of chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered and

  
 <EMI ID = 110.1>

  
shooting of a benzene-hexane mixture.

  
According to the previous procedure, using 3-aminomethyl-5-methoxy-indole in place of 3-aminomethyl-

  
 <EMI ID = 111.1> <EMI ID = 112.1>

  
of dimethylformamide is stirred at 20-25 [deg.] C for 2 hours. The reaction mixture is diluted with water and worked up by extraction with benzene. After washing the benzene extract with water four times, the benzene extract is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is recrystallized from benzene-hexane

  
 <EMI ID = 113.1>

  
lizations from benzene-hexane.

  
According to the previous procedure, using

  
 <EMI ID = 114.1>

  
A mixture of 2.6 g (0.019 mole) of 2-cyclohexenylamine hydrochloride, 1.9 g (0.019 mole) of triethylamine and 4.5 g (0.031 mole) of trichloroacetonitrile in 10 cm <3> of dimethylformamide is stirred at 20-25 [deg.] C for 18 hours.

  
 <EMI ID = 115.1>

  
The benzene extract is dried over anhydrous magnesium sulfate, filtered and concentrated. Recrystallization of the residue

  
 <EMI ID = 116.1>

  
acetamidine, melting point 61-63 [deg.] C.

  
According to the previous procedure, using

  
 <EMI ID = 117.1>

  
A solution of 3.26 g (0.023 mole) of trichloroacetonitrile and 2.53 g (0.021 mole) of 2-hydroxybenzylamine <EMI ID = 118.1>

  
zene. The benzene extracts are combined, washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. the residue is dissolved in chloroform and passed through a column of silica gel. Elution with chloroform gives a series of fractions. Fractions containing product as determined by thin layer chromatography are combined and concentrated. The residue is recrystallized from cyclohexans to give 2.6 g of N- (2-hydroxybenzyl) -trichloroacetamidine, melting point 112-115 [deg.] C.

Example 10

  
 <EMI ID = 119.1>

  
6.06 g (0.060 mol) of triethylamine are added and then 12 g
(0.083 mole) of trichloroacetonitrile. After stirring at 0-5 [deg.] C for 1 hour, the reaction mixture was stirred at 20-25 [deg.] C for a further 3 hours and then poured into 600 cc of water. The crude product is extracted with benzene, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in ethyl acetate and saturated with gaseous hydrochloric acid. The gummy precipitate is separated by decantation, washed with ethyl acetate and dissolved in water. After addition of an excess of saturated sodium carbonate solution, the product is extracted into benzene. The benzene extract is washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.

   Recrystallization from benzene-hexane gives

  
 <EMI ID = 120.1>

  
fusion 94-5 [deg.] C.

Example 11

  
 <EMI ID = 121.1>

  
of trans 2-phenylcyclopropylmethylamine, 4.09 g (0.0404 mole) of triethylamine and 8.81 g (0.061 mole) of trichloro- <EMI ID = 122.1>

  
100 cm <3> of saturated sodium chloride solution, containing 5 cm <3> of saturated sodium bicarbonate solution, the benzene layer is separated. After washing! * Benzene extract

  
 <EMI ID = 123.1>

  
made basic with saturated sodium bicarbonate solution

  
 <EMI ID = 124.1>

  
of benzene. The benzene extracts are combined, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to give 8.98 g of trans N- (2-phenylcyclopropyl-

  
 <EMI ID = 125.1>

  
According to the previous procedure, using 2-aminoethylphenylsulfoxide hydrochloride or 2-aminoethyl-2-naphthylsulfoxide hydrochloride instead of trans-2-phenylcyclopropylmethylamine hydrochloride, 2-trichloroacetamidinoethylphenylsulfoxide hydrochloride is obtained, point mp 184-186 [deg.] C (dec) and 2-trichloroacetamidinoethyl-2-naphthylsulfoxide hydrochloride, mp 194.0-

  
 <EMI ID = 126.1>

  
A solution of 10 g (0.052 mol) of 2,3-dichloro-4-

  
 <EMI ID = 127.1>

  
 <EMI ID = 128.1>

  
is refluxed for 5.5 hours and then concentrated under reduced pressure. The residue is recrystallized twice

  
from hot water to give 7.44 g of oxime.

  
 <EMI ID = 129.1>

  
of rhodium on carbon in 100 cm <3> of ethanol and 8 cm <3> of an 8.0 N ethanolic solution of anhydrous hydrochloric acid is

  
 <EMI ID = 130.1> <EMI ID = 131.1>

  
tion, the filtrate is concentrated under reduced pressure. The residue

  
 <EMI ID = 132.1>

  
 <EMI ID = 133.1>

  
 <EMI ID = 134.1>

  
of dimethylsulfoxide is stirred at 20-25 [deg.] C for 20 hours. After concentration under reduced pressure at 40 [deg.] C for

  
 <EMI ID = 135.1>

  
tan color is filtered off, dried and recreated.

  
 <EMI ID = 136.1>

  
and 100 mg of trichloroacetonitrile in 5 cc of methanol is stirred at 20-25 [deg.] C for 3 days. After concentration under pressure

  
 <EMI ID = 137.1>

  
and passed through a column of silica gel. Elution with chloroform gives a series of fractions. Fractions containing product, as determined by thin layer chromatography, are combined and concentrated under reduced pressure. The residue is dissolved in ethanol, treated with an excess of ethanolic solution of anhydrous hydrochloric acid and diluted with ethyl ether to give 24 mg of 5-phenyl-2-trichloromethyl-3,4 hydrochloride. , 5,6-Tetrahydropyrimidine, mp 265-2? 0 [deg.] C, dec.

Example 14

  
 <EMI ID = 138.1>

  
A solution of 3.6 g (0.0506 mol) of N-methylallylamine in 30 cm5 of benzene is added over 20 minutes to a stirred solution of 6 cm of trichloroacetonitrile in

  
 <EMI ID = 139.1>

  
The solution was stirred at 20-25 "C for 20 hours and then concentrated at 50 [deg.] C under reduced pressure. Distillation of the residue gave 6.2 g of N-allyl-N-methyltrichloroacetamidine, boiling point 66- 700C under 0.2 mm. Has a solution of 5 g

  
 <EMI ID = 140.1>

  
2.5 g of maleic acid are added. Addition of ethyl acetate and cooling gives 4.9 g of N-allyl-N-methyltrichloroacetamidine hydrogen maleate, melting point.
101-107 [deg.] C. Recrystallization from ethanol-acetate

  
 <EMI ID = 141.1>

  
A mixture of 10.6 g (0.0635 mole) of 2-hydroxy-3phenoxypropylamine and 11.0 g (0.0762 mole) of trichloro-

  
 <EMI ID = 142.1>

  
tion, the solvents are removed under reduced pressure. The residue is recrystallized from benzene-hexane to give

  
 <EMI ID = 143.1>

  
A solution of 6.09 g (0.030 mole) of 2-bydroxy-3-

  
 <EMI ID = 144.1>

  
saturated with gaseous hydrochloric acid. Acetyl chloride, 2.6 g (0.033 mol) is added and the solution is stirred at
20-25 [deg.] C for 3 days. After concentration under reduced pressure, benzene is added and the mixture is again concentrated under reduced pressure. This process is repeated once more with benzene, twice with toluene and two <EMI ID = 145.1>

  
crude 2-acetoxy-3-phenoxypropylamiae hydrate which is used without further purification in the next step.

  
 <EMI ID = 146.1>

  
midine

  
A total of 0.50 g (5.0 mmol) of triethylamine is added in small portions over 10 minutes to a well stirred mixture.

  
 <EMI ID = 147.1>

  
phenoxypropylamine and 1.44 g (10 mmol) of trichloroaceto

  
 <EMI ID = 148.1>

  
tation for 1.5 hours, the reaction mixture is diluted with water and treated by extraction with benzene. The benzene extract is washed five times with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is dissolved in benzene and treated with an excess of anhydrous ethanolic hydrochloric acid. After concentration under reduced pressure, the residue is dried over phosphorus pentoxide at

  
 <EMI ID = 149.1>

  
N- (3,4-dipivaloyloxyphenethyl) trichloroaceous amidine hydrochloride, mp 115-121 [deg.] C (dec), and

  
 <EMI ID = 150.1>

  
melting point 200.5-204.5 [deg.] C, respectively.

Example 17

  
 <EMI ID = 151.1>

  
A solution of 500 mg (5.5 mmol) of 2-methylthioethylamine and 1.50 g (10.4 mmol) of trichloroacetonitrile

  
 <EMI ID = 152.1>

  
and then concentrated under reduced pressure. The residue is dissolved in ethyl ether and treated with an excess of ethanolic solution of anhydrous hydrochloric acid. The insoluble material is separated by filtration and dried over phosphorus pentoxide at 25 [deg.] C and under 0.2 mm pressure for 20 hours to give 1.1 g of N- (2-methylthioethyl) hydrochloride. trichloroacetamidine.

  
According to the previous procedure, using

  
4-methoxybenzylamine instead of 2-methylthioethylamine and bromodichloroacetonitrile instead of trichloroacetonitrile, N- (4-methoxybenzyl) bromodichloroacetamidine hydrochloride is obtained, melting point 209.5-210.0 [deg.] C (Dec).

Example 18

  
 <EMI ID = 153.1>

  
A mixture of 2.02 g (0.020 mole) of 3-hydroxypiperidine and 5.0 g (0.035 mole) of trichloroacetonitrile in

  
 <EMI ID = 154.1>

  
addition of decolorizing charcoal and filtration, the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl ether and treated with an excess of hydrochloric acid solution in anhydrous ethanol. The precipitated salt is collected and recrystallized from methanol-ethyl acetate

  
 <EMI ID = 155.1>

  
acetimidopiperidine, mp 151-156 [deg.] C, dec.

Example 19

  
 <EMI ID = 156.1>

  
A solution of 5.05 g (0.050 mol) of tetrahydrofurfurylamine and 9.5 g (0.066 mol) of trichloroacetonitrile in 50 cm 3 of benzene is stirred at 20-25 [deg.] C for 20 hours and then concentrated. under reduced pressure. The residue is recrictallized twice from benzene-hexane to give

  
 <EMI ID = 157.1>

  
fusion 75-78 "0.

  
According to the previous procedure, using 3-aminoethyl-1-methylindole in place of tetrahydrofurfurylamine, N- (1-methyl-3-indolylmethyl) -trichloro- is obtained.

  
 <EMI ID = 158.1>

  
3 days. After concentration under reduced pressure, <EMI ID = 159.1> is added

  
as determined by thin layer chromatography, are combined and concentrated. The residue is recrystallized twice from cyclohexane to give 2.0 g of N- (2-hydroxymethyl-

  
 <EMI ID = 160.1>

  
According to the previous procedure, by using 4-methylbenzylamine or 1, 3-bisaminomethyl benzene instead of 2-aminomethylbenzyl alcohol, N- (4methylbenzyl) -trichloroacetamidine, melting point? 8, is obtained. 0-81.0 [deg.] C

  
 <EMI ID = 161.1>

  
A solution of 4.76 g (0.033 mol) of trichloroaceto

  
 <EMI ID = 162.1>

  
stirred solution of 3.18 g (0.022 mole) of 3-aminomethyl-indole in 25 cm 3 of anhydrous climethylsulfoxide at 20-25 [deg.] 0 ... After stirring at 20-25 [deg.] C for 20 hours , the mixture is concentrated under reduced pressure to a viscous oil. The residue is treated by extraction with two portions of 100 cm <3> and a por-

  
 <EMI ID = 163.1>

  
Combined chloroform strokes are washed first with two 100 cm 3 portions of water and then with three portions of dilute hydrochloric acid. The aqueous acid extracts are combined, processed by extraction with two 100 cm portions

  
of chloroform and filtered. The clear aqueous filtrate is made basic with a saturated aqueous solution of sodium bicarbonate.

  
 <EMI ID = 164.1>

  
of chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered and concentrated to give N- (3-indolylmethyl) -trichloroacetamidine. A pure sample for analysis, melting point

  
 <EMI ID = 165.1>

  
shooting of a benzene-hexane mixture.

  
According to the previous procedure, using

  
 <EMI ID = 166.1>

  
indole, we get N- (5-methoxy-3-indolylmethyl) -tri- <EMI ID = 167.1>

  
cooled with a dry ice-acetone bath, 6.85 g (0.050 mol) of p-methoxybenzylamine are added over 15 minutes. The mixture is stirred and allowed to warm to 20-25 ° C over 20-22 hours.

  
Two recrystallizations from hexane give 5.08 g of

  
 <EMI ID = 168.1>

  
8?, 5 [deg.] C, is obtained after further recrystallization from hexane.

Example 23

  
 <EMI ID = 169.1>

  
After filtration, the filtrate is concentrated to a solid material

  
 <EMI ID = 170.1>

  
tions of 25. cm <3> of 3N hydrochloric acid and then with two

  
 <EMI ID = 171.1>

  
made basic with saturated sodium bicarbonate solution and extracted with three 100 cc portions of chloroform. The combined aqueous chloroform extracts are washed three times with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Two recrystallizations from hexane give 280.53 g of

  
 <EMI ID = 172.1>

Example 24

  
N-acetyltrichloroacetamidine

  
Acetyl chloride (4.9 g, 0.062 mol) is added dropwise to a stirred solution of trichloroacetamidine
(10.0 g, 0.062 mole) and triethylamine (6.3 g, 0.062 mole)

  
 <EMI ID = 173.1> triethylamine is separated by filtration and washed with tetrahydrofuran. Evaporation of the filtrate gives a solid residue which is recrystallized from methylene chloride-eoxide.

  
 <EMI ID = 174.1>

  
fusion 125.5-126.5 [deg.] C.

  
 <EMI ID = 175.1>

  
 <EMI ID = 176.1>

  
A solution of 19.0 g (0.10 mole) of 3- (2-allylphenoxy) -1,2-epoxypropane and 10.0 g (0.10 mole) of succinimide in 100 cm <3> of ethanol absolute and 1 cm <3> of pyridine is stirred at reflux for 24 hours. After concentration to dryness under reduced pressure, the residue is recrystallized once from

  
 <EMI ID = 177.1>

  
A solution of 15.0 g (0.052 mol) of N- [3- (2-allylphenoxy) -2-hydroxypropyl] succinimide in 200 cm <3> of absolute ethanol and 100 in 'of 9N ethanolic solution of hydrochloric acid anhydrous is heated at reflux for 14 hours.

  
After concentration to dryness under reduced pressure, the residue is recrystallized from an ethanol-benzene-hexane mixture to give 3- (2-allylphenoxy) -2-hydroxypropyl- hydrochloride.

  
 <EMI ID = 178.1>

  
The free base obtained by neutralizing 1.22 g (5.0 mmol) of 3- (2-allylphenoxy) -2-hydroxypropylamine hydrochloride with potassium carbonate and extraction with benzene is dissolved in this benzene. Add trichloro-

  
 <EMI ID = 179.1>

  
20-25 [deg.] C for 20 hours. After concentration 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 material is concentrated to give N- [3,2- (allylphenoxy) -2-hydroxypropyl] trichloroacetamidine as an oil.

Example 26

  
 <EMI ID = 180.1>

  
mmol) to a stirred solution of 0.70 g (2.5 mmol) of N- (4methoxybenzyl) -trichloroacetamidine in 25 cm <3> of benzene at
20-25 [deg.] C and the resulting solution is stirred at 20-25 [deg.] C for
20 hours. After concentration under reduced pressure, the residue is recrystallized from a benzene-hexane mixture for

  
 <EMI ID = 181.1>

  
Carbon dioxide is stirred at reflux for 5 hours until dissolution is complete. After concentration under

  
 <EMI ID = 182.1>

  
absolute for 3 hours and then reconcentrated to dryness. The residue

  
 <EMI ID = 183.1>

  
 <EMI ID = 184.1>

  
 <EMI ID = 185.1>

  
The reaction of N-methyltrichloroacetamidine with oxalyl chloride and ethanol according to the procedure

  
 <EMI ID = 186.1>

  
A mixture of 7.94 g (0.042 mole) of 1,2-bis (chloromethyl) -4-methylbenzene, 16.70 g (0.090 mole) of phthalimide

  
 <EMI ID = 187.1>

  
at reflux for 2 hours. After pouring in the reaction mixture

  
 <EMI ID = 188.1>

  
with water and dried to give the bis phthalimidomethyl intermediate, melting point 241-2WC, contracting at
236 [deg.] C.

  
 <EMI ID = 189.1>

  
dant 22 hours then cooled in an ice bath. After

  
 <EMI ID = 190.1>

  
mixture is heated at reflux for 30 minutes, cooled and filtered. The filtrate is concentrated under reduced pressure to a small volume. the crude product is filtered off and recrystallized twice from 95% ethanol to give

  
 <EMI ID = 191.1>

  
hot thanol, 0.81 g (15 mmol) of sodium methoxide is added with stirring. After 30 minutes, 1.43 g (75 mmol) of p-toluenesulfonic acid hydrate and 1.08 g are added.

  
(75 mmoles) of trichloroacetonitrile and the mixture is stirred

  
at 20-25 [deg.] C for 18 hours. The solvents are removed under reduced pressure and the residue is treated by extraction with hot benzene. The benzene extract is treated with bleaching charcoal, filtered through magnesium sulfate and concentrated to give 7-methyl-3-trichloromethyl-4,5-

  
 <EMI ID = 192.1>

  
contracting at 105 [deg.] C.

Example 30

  
 <EMI ID = 193.1>

  
side

  
Sodium azide, 2.0 g, 31 mmol, is added to

  
 <EMI ID = 194.1>

  
the reaction mixture is poured into 300 cm <3> of water and treated by extraction with two portions of 150 cm <3> of ethyl ether.

  
 <EMI ID = 195.1> <EMI ID = 196.1> of water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solid residue is recrystallized from a mixture of chl orof elm-ethyl ether to give

  
 <EMI ID = 197.1>

  
ethyl at atmospheric pressure for 22 hours on 0.1 g of 10% palladium on carbon as a catalyst. After separation of the catalyst by filtration, the filtrate is concentrated under reduced pressure to an oil. 2,3,4,6-Tetraacetyl-

  
 <EMI ID = 198.1>

  
of 0.1N methanolic solution of sodium methoxide. After heating under reflux for 20 minutes under anhydrous conditions, the solvent is removed under reduced pressure to

  
 <EMI ID = 199.1>

  
solid gummy. By chromatography on thin layers of preparation (silica gel, 20% methanol-chloroform), the constituents are separated and the product, Rf 0.55, is removed with methanol. Evaporation of the methanol gives a glass which is crushed, slurried with ether, separated by filtration and

  
 <EMI ID = 200.1>

  
A solution of 3.29 g (0.024 mole) of o-methoxybenzylamine and 5.17 g (0.027 mole) of bromodichloroacetonitrile

  
 <EMI ID = 201.1>

  
After filtration and concentration of the filtrate under reduced pressure, the residue is dissolved in 20 cm 3 of absolute ethanol and acidified with an excess of ethanolic solution of anhydrous hydrochloric acid. Addition of ethyl ether causes crystallization of N- (2-methoxybenzyl) -bromodi- hydrochloride.

  
 <EMI ID = 202.1>

Example 32

  
Tablets suitable for oral administration which contain the following ingredients can be prepared by conventional tableting techniques. These tablets are useful for treating heart failure at a dose of 1 or 2 tablets two to four times a day.

  

 <EMI ID = 203.1>


  
 <EMI ID = 204.1>

  
Dry filled capsules

  
Capsules suitable for oral administration which contain the following ingredients are prepared in a conventional manner. These capsules are useful as cardiac stimulants at a dose of 1 or 2 capsules two to four times a day.

  

 <EMI ID = 205.1>

Example 34

  
Sterile suspension for injection and liquid suspension for oral administration

  
The following pharmaceutical compositions are prepared with the indicated amount of active ingredient using standard techniques. The suspension for injection and the liquid suspension for oral administration represent compositions useful in unit doses and can be administered in the treatment of heart failure. The suspension for injection is suitable for once daily administration while the liquid oral suspension is conveniently administered 2-4 times a day for this purpose.

  

 <EMI ID = 206.1>

Example 35

  
Tablets and capsules usable for oral administration

  
Tablets and capsules containing the ingredients listed below can be prepared by conventional techniques and are useful as cardiac stimulants at a dose of 1 or 2 tablets or capsules one to four times a day.

  

 <EMI ID = 207.1>


  
Starting materials for some of the preceding Examples are described in the following Preparations.

  
Preparation 1

  
 <EMI ID = 208.1>

  
A solution of 3.75 g (0.075 mole) of 2,3-dimethyl-4hydroxybenzaldehyde and 5.21 g (0.075 mole) of hydrochloride

  
 <EMI ID = 209.1>

  
is heated at reflux for 5.5 hours and then concentrated under reduced pressure. The residue is recrystallized from an ethanol-water mixture to give the oxime, melting point

  
 <EMI ID = 210.1>

  
A mixture of 3.3 g (0.020 mol) of 2,3-dimethyl-4.-

  
 <EMI ID = 211.1>

  
for 20 hours. After filtration, the filtrate is concentrated under reduced pressure. The residue is r &#65533; crystallized from an ethanol-ethyl ether mixture to give the hydrochloride.

  
 <EMI ID = 212.1>

  
17 hours. The cooled solution is washed with two portions

  
 <EMI ID = 213.1>

  
of magnesium, filtered and concentrated. The residue is recrystallized from an ethyl ether-petroleum ether mixture to give

  
 <EMI ID = 214.1>

  
 <EMI ID = 215.1>

  
anhydrous magnesium, filtered and concentrated under reduced pressure. The residue is chromatographed on 250 g of silica gel and eluted with benzene, a 50:50 chloroform-benzene mixture and chloroform. fractions containing N- (1-benzoyl-3-

  
 <EMI ID = 216.1>

  
very.

  
A solution of 2.1 g (6.0 mmol) of N- (1-benzoyl-3-

  
 <EMI ID = 217.1>

  
is cooled in an ice bath while anhydrous hydrochloric acid is passed through the solution for 10 minutes. After removing excess hydrochloric acid gas by purging with nitrogen, ethyl ether is added to pre-

  
 <EMI ID = 218.1>

  
of fusion 24? -253 [deg.] C.

  
Preparation 3

  
Intermediate product for the synthesis of N- hydrochloride

  
 <EMI ID = 219.1>

  
of glacial acetic acid is stirred at reflux for 2 hours and then at 20-25 [deg.] C for 2 days. After concentration to dryness under reduced pressure, benzene is added to the residue and it is then reconcentrated. Petroleum ether is added to the re-

  
 <EMI ID = 220.1>

  
Preparation 4

  
 <EMI ID = 221.1>

  
amine in 20 cm <3> of dimethylformamide is heated at 100 [deg.] C for hour, then cooled. Add hexane,

  
 <EMI ID = 222.1>

  
insoluble solid is filtered off and recrystallized from ethyl acetate to give '12.4 g of N- [3- (4-

  
 <EMI ID = 223.1>

  
hydrate by acidifying a solution of the base in methanol with an excess of ethanolic solution of anhydrous hydrochloric acid and concentrating under reduced pressure.

  
 <EMI ID = 224.1>

  
10% palladium on carbon catalyst at 40-53 [deg.] C and an initial pressure of about 3.0 kg / cm for 2 hours. After filtration and concentration under reduced pressure, the residue is recrystallized from absolute ethanol to give

  
 <EMI ID = 225.1>

  
propylamine, melting point 194-197 [deg.] C.

  
Preparation $

  
Intermediate products for the synthesis of hydrochloride

  
 <EMI ID = 226.1>

  
To a solution of 4.60 g (0.20 gram atom) of sodium in 150 cc of ethanol under nitrogen is added 32.0 g (0.20 mol)

  
 <EMI ID = 227.1>

  
After concentration to about half of the initial volume under reduced pressure at 24-40 [deg.] C, water is added. The precipitated solid matter is separated by filtration and recrystallized.

  
 <EMI ID = 228.1>

  
Further starting from acetone-water and from ethyl acetate-hexane a pure sample is obtained for analysis, mp 80.0-81.5 [deg.] C.

  
 <EMI ID = 229.1>

  
is heated at reflux for 2 hours. Concentrated hydrochloric acid, 25 cm, is added and after heating under reflux for 1 1/2 hours hot filtration is carried out. After cooling to room temperature and filtering again, the filtrate is concentrated under reduced pressure at 40 [deg.] C

  
 <EMI ID = 230.1>

  
in 5 minutes to a solution of 5.44 g (0.0227 mol) of 2- (2-aminoethylthio) -naphthalene hydrochloride in 50 car of water

  
and 50 cm <3> of methanol at 20-25 [deg.] C. After stirring at reflux for 8 hours, 100 mg of potassium sulfite are added and the reaction mixture is left at 20-25 [deg.] C for 3 days. The mixture is filtered and concentrated to dryness under reduced pressure at

  
 <EMI ID = 231.1>

  
it is then reconcentrated under reduced pressure. After repeating this process two more times, the residue is washed with isopropanol and ethanol to give 4.72 g of hydrochloride.

  
 <EMI ID = 232.1>

  
Dec. A pure sample for analysis, melting point 145-
153.0 OC is obtained by recrystallization from ethyl methanolacetate.

  
Preparation 6

  
 <EMI ID = 233.1>

  
3-aminomethyl-5-methoxyindole

  
Hydrazine hydrate, 0.95 g (0.019 mole), is

  
 <EMI ID = 234.1>

  
anhydrous and stirred at 20-25 [deg.] C for 18 hours. After addition

  
 <EMI ID = 235.1>

  
Anhydrous dric, the mixture is stirred at 20-25 [deg.] C for a further two hours and then filtered. The filtrate is concentrated under

  
 <EMI ID = 236.1>

  
boiling and filtered. This filtrate is made basic with 5N potassium hydride and the product is extracted into chloroform. After drying the chloroform extract over magnesium sulfate and filtration, the chloroform is removed under reduced pressure to give 3-aminomethyl-5-methoxy-indole,

  
 <EMI ID = 237.1>


    

Claims (1)

<EMI ID = 238.1> - CLAIMS - 1 - A compound having the formula: <EMI ID = 239.1> wherein R is a perhalogenated alkyl group having 1 to 5 carbon atoms; <EMI ID = 240.1> <EMI ID = 241.1> <EMI ID = 242.1> lower alkanoyl; and <EMI ID = 243.1> lower, lower alkenyl, lower alkynyl, cycloalkyl or cycloalkenyl, these groups being substituted by one or more hydroxy, lower hydroxyalkyl, lower alkoxy, (lower alkyl) thio, (lower alkanoyl) oxy, (lower alkanoyl) amino, phenyl, hydroxyphenyl , (lower alkoxy; phenyl, phenoxy, phenylsulfinyl, naphthylsulfinyl, cycloalkyl, (lower alkyl) phenyl, (lower alkenyl) phenyl, phenylcycloalkl, lower alkanoyl or halo; <EMI ID = 244.1> killed by a perhaloalkyl amidino lower alkyl group; <EMI ID = 245.1> linked to the nitrogen of the amidine, through a lower alkyl group, which contains one or two hetero atoms selected from oxygen and nitrogen or a benzoheterocyclic group optionally substituted by a lower alkyl, lower alkoxy or benzoyl group in wherein the benzo portion is condensed with a 5 to 7 membered heterocyclic ring having one or two heteroatoms selected from oxygen and nitrogen; and <EMI ID = 246.1> substituted by hydroxy, lower alkoxy, phenyl, halo or by a lower alkyl or lower alkoxy substituted benzo group; and each amino hydroxy group with a labile proton is optionally converted into a glycoside; and their pharmaceutically acceptable non-toxic salts. 2 - A compound according to claim 1, characterized in that R is a tricbloromethyl group; <EMI ID = 247.1> <EMI ID = 248.1> and <EMI ID = 249.1> lower, lower alkenyl or lower alkynyl, these groups being substituted by one or more hydroxy, hydroxy lower alkyl, lower alkoxy, (lower alkyl) thio, lower alkanoyl) oxy, phenyl, hydroxyphenyl, (lower alkoxy) <EMI ID = 250.1> halo. 3 - A compound according to claim 2, characterized in that R is a trichloromethyl group; <EMI ID = 251.1> R2 is hydrogen or a lower alkyl group; and R3 is lower alkyl or phenyl lower alkyl, these groups being substituted by one or more hydroxy, (lower alkanoyl) oxy, phenyl, (lower alkoxy) phenyl or phenoxy groups. 4 - A compound according to claim 2, characterized in that: R is a trichloromethyl group; <EMI ID = 252.1> <EMI ID = 253.1> <EMI ID = 254.1> which the substituents are one or more hydroxy, phenyl, (lower alkoxy) phenyl, phenoxy or hydroxy groups. 5 - A compound according to claim 4, characterized in that it is chosen from the following :. <EMI ID = 255.1> <EMI ID = 256.1> 6 - A compound according to claim 1, characterized in that: R is a trichloromethyl group; <EMI ID = 257.1> <EMI ID = 258.1> and R3 is a lower alkyl group substituted with a heterocyclic or benzoheterocyclic group selected from indole, pyrimidine, piperidine, furan, tetra.hydrofuran, pyridine and piperazine groups, these groups being optionally substituted by lower alkyl, lower alkoxy or benzoyl groups. 7 - A compound according to claim 6, characterized in that: R is a trichloromethyl group; <EMI ID = 259.1> and R2 is hydrogen or a lower alkyl group; <EMI ID = 260.1> indole, pyrimidine, piperidine, furan group which is optionally substituted by a methyl, methoxy or benzoyl group. <EMI ID = 261.1> in that R3 is a methyl or ethyl group substituted by an indole group optionally substituted by a methyl or methoxy group. 9 - A compound according to claim 8, characterized in that the indole group is not substituted. <EMI ID = 262.1> in that it is chosen from among the following: <EMI ID = 263.1> N- (1-Benzoyl-3-indolylmethyl) -trichloroacetamidine. 11 - A process for the preparation of a compound having the formula: <EMI ID = 264.1> in which R is a perhalogenated alkyl group; R2 is hydrogen, lower alkyl or lower alkanoyl; R3 is lower alkyl, phenyl lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl or cycloalkenyl, these groups being substituted by one or more hydroxy, hydroxy (lower alkyl), lower alkoxy, (lower alkyl) thio, (lower alkanoyl) oxy, (lower alkanoyl) amino, phenyl, hydroxyphenyl, (lower alkoxy) phenyl, phenoxy, phenylsulfinyl, naphthylsulfinyl, cycloalkyl, (lower alkyl) phenyl, (lower alkenyl) <EMI ID = 265.1> R, is also a lower phenylalkyl group substituted with a perhaloalkylamidino lower alkyl group; <EMI ID = 266.1> chain links linked to the nitrogen atom of the amidine group through a lower alkyl group and containing one or two hetero atoms selected from oxygen and nitrogen or a benzoheterocyclic group <EMI ID = 267.1> lower xy or benzoyl, where the benzo portion is condensed with a 5 to 7 membered heterocyclic ring comprising one or two hetero atoms chosen from oxygen and nitrogen; and wherein each amino or hydroxy group with a labile proton is optionally transformed into a glycoside; and their pharmaceutically acceptable non-toxic salts, according to which a perhalogenated (lower alkyl) nitrile is reacted with an amine having the formula: <EMI ID = 268.1> in which R2 and R3 are as defined above. <EMI ID = 269.1> the formula : <EMI ID = 270.1> in which R is a perhalogenated lower alkyl group; <EMI ID = 271.1> phenylcarbamoyl or lower alkoxalyl; <EMI ID = 272.1> lower alkanoyl; <EMI ID = 273.1> laughing, lower alkenyl, lower alkynyl, cycloalkyl or cycloalkenyl, these groups being substituted by one or more hydroxy, hydroxy lower alkyl, lower alkoxy groups. <EMI ID = 274.1> cycloalkyl, phenylcycloalkyl, (lower alkyl) phenyl, (lower alkenyl) phenyl or halo; R3 is also a lower phenylalkyl group substituted with a perhaloalkyl amidino lower alkyl group; R3 is also a 5 to 7 membered heterocyclic group, linked to the nitrogen atom of the amidine group by a lower alkyl group, containing one or two hetero atoms chosen from oxygen and nitrogen or a benzoheterocyclic group optionally substituted with a lower alkyl, lower alkoxy or benzoyl group in which the benzo portion is condensed with a 5 to 7 membered heterocyclic ring comprising one or two heteroatoms selected from oxygen and nitrogen; and wherein each amino or hydroxy group with a labile proton is optionally transformed into a glycoside; and their pharmaceutically acceptable non-toxic salts, according to which a compound having the formula: <EMI ID = 275.1> <EMI ID = 276.1> <EMI ID = 277.1> 13 - A process for the preparation of a compound having the formula: <EMI ID = 278.1> in which R is a perhalogenated lower alkyl group; R2 is hydrogen or a lower alkyl group; and <EMI ID = 279.1> 5- to 7-membered heterocyclic comprising the two amidine nitrogen atoms, this heterocyclic ring being optionally substituted by hydroxy, lower alkoxy, phenyl, halo groups or by a condensed benzo ring, this benzo ring being optionally substituted by a group lower alkyl or lower alkoxy; and their pharmaceutically acceptable non-toxic salts, according to which a perhalogeno- (lower alkyl) nitrile with an alkyl diamine optionally substituted with hydroxy, lower alkoxy, phenyl, halo or with a condensed benzo ring, this benzo ring being optionally substituted by a lower alkyl or lower alkoxy group and the amidine is optionally treated resulting cyclic with an alkylating agent or an acylating agent. 14 - A method for the treatment of heart failure, according to which an effective amount of a compound according to one of claims 1 to 10 is administered. 15 - As a new drug, a compound according to one of claims 1 to 10. 16. The invention in its various aspects, in substance, as described above.