RU2193555C2 - Methylisopropyl-[(3-n-propoxyphenoxy)ethyl]amine or its pharmaceutically acceptable salt, methods of its synthesis (variants), pharmaceutical composition, method of topical anesthesia - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, pharmacy. SUBSTANCE: invention relates to novel methylisopropyl-[(3-n-propoxyphenoxy)-ethyl]amine of the formula (I)

where R¹ means n-propyl group; R² means methyl group; R³ means isopropyl group, or its pharmaceutically acceptable salt that show properties of topical anesthetics and can be used for preparing medicinal agent used for topical anesthesia. Methods of synthesis compound of the formula (I) involve interaction of a) compound of the formula (II)

with compound of the formula (III) HN(R²)R³ (III) or its acid-additive salt either of b) compound of the formula (IV)

with compound of the formula (V) R²(R³)NCH₂CH₂Hal (V) or its acid-additive salt. In indicated compounds (II) (V) R¹-R³ have the above indicated values; Hal means Cl, Br or J. Pharmaceutical composition comprises compound of the formula (I) or its pharmaceutically acceptable salt in mixture with pharmaceutically acceptable adjuvant, diluting agent or carrier. Method of topical anesthesia involves application of compound of the formula (I) or its pharmaceutically acceptable salt taken in therapeutically effective dose on skin of patient suffering with pain or sensitive to pain. EFFECT: improved method of synthesis, valuable analgetic properties. 9 cl, 2 tbl, 3 dwg, 16 ex

Description

 This invention relates to pharmaceutically useful compounds, in particular to derivatives of [(3-alkoxy-phenoxy) -ethyl] -dialkylamine, their use as medicines, in particular anesthetics (e.g., local anesthetics), pharmaceutical compositions containing them, and methods for their synthesis.

 Some [(4-methoxy-phenoxy) -alkyl] -diethylamine derivatives are described as herbicides in European Application 0103252. Their use as pharmaceuticals is not proposed.

 Certain [(3- and [(4-alkoxy-phenoxy) -alkyl] -alkyl-propargyl- and -cyclopropylamine derivatives, as is known from US Pat. No. 3,221,054, are useful for treating psychiatric diseases; and [(2,6-dimethoxy- phenoxy) ethyl] dimethylamine is described as an antidepressant in US Pat. No. 3,205,136. The use of these compounds as anesthetics is not proposed.

 [(4-alkoxy-phenoxy) ethyl] -morpholine and piperidine derivatives are known as local anesthetics from French Patent 1,173,136. In addition, some 3-substituted phenoxyethylamine derivatives, including (3-alkoxy-phenoxy) ethyl] dimethylamine derivatives are described as local anesthetics in US Pat. No. 3,105,854 and French Special Medicament Patent 302 M.

 However, the need for more effective anesthetic compounds remains. Moreover, there is a need, especially for effective local anesthetics, which can be applied in a separate place, for example, on the skin.

 We have found that some compounds not specifically described, but included in the scope of the description of the invention of US patent 3105854, exhibit unexpectedly good properties of anesthetics and are especially useful as local anesthetics.

где R¹ представляет н-пропил,
R² - метил,
R³ - изопропил,
или его фармацевтически приемлемой соли (далее в описании они называются "соединениями данного изобретения").The invention relates to a compound of formula I

where R ¹ represents n-propyl,
R ² is methyl,
R ³ - isopropyl,
or a pharmaceutically acceptable salt thereof (hereinafter referred to as “the compounds of this invention”).

 Pharmaceutically acceptable salts include non-toxic organic or inorganic acid addition salts, for example, hydrochlorides, hydrobromides, sulfates, hydrosulfates, nitrates, lactates, acetates, citrates, benzoates, succinates, tartrates, trifluoroacetates and the like. Preferred acid addition salts include hydrochlorides.

 The compounds of this invention may also contain one or more asymmetric carbon atoms and, therefore, may exhibit optical isomerism and / or diastereoisomerism. All diastereoisomers can be separated using well-known methods, for example, chromatography or fractional crystallization. Various optical isomers can be isolated by resolution of a racemic or other mixture of compounds using well-known methods, for example, fractional crystallization or HPLC. On the other hand, the desired optical isomers can be obtained by reacting suitable optically active starting materials under conditions that will not cause racemization, or by derivatization, for example homochiral acid, followed by separation of the diastereomeric derivatives by well-known methods (e.g., HPLC, silica gel chromatography). All stereoisomers are included within the scope of this invention.

Alkyl groups R ¹ , R ² and R ³ may be linear or branched. Typical alkyl groups that may be mentioned are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and isopentyl; preferred alkyl groups are those in which R ² and R are not ethyl at the same time.

Preferred compounds of the invention are compounds in which R ¹ is n-propyl, n-butyl or n-pentyl, R ² is methyl, ethyl or isopropyl, and R ³ is isopropyl.

More preferred compounds of this invention are compounds in which R ¹ is n-propyl or n-butyl, R ² is methyl, ethyl or isopropyl, and R ³ is isopropyl.

Even more preferred compounds of this invention are compounds in which R ¹ is n-propyl or n-butyl, R ² is methyl or ethyl, and R ³ is isopropyl.

Particularly preferred compounds of the invention are compounds in which R ¹ is n-propyl, R ² is methyl or ethyl, and R ³ is isopropyl.

The most preferred compounds of this invention are compounds in which R ¹ represents n-propyl, R ² represents methyl, and R ³ represents isopropyl.

где R¹ принимает значения, определенные выше, с соединением формулы III
HN(R²)R³ III
где R² и R³ принимают значения, определенные выше, например, при повышенной температуре (например, при кипячении с обратным холодильником) в присутствии подходящего органического растворителя (например, толуола); или
(b) взаимодействие соединения формулы IV

где R¹ принимает значения, определенные выше, с соединением формулы V,
R²(R³)NCH₂CH₂Hal V
где Hal представляет собой Сl, Вr или I, и R² и R³ принимают значения, определенные выше, или с его кислотно-аддитивной солью, например, при повышенной температуре (например, при кипячении с обратным холодильником) в присутствии подходящего основания (например, этоксида натрия) и подходящего органического растворителя (например, этанола).In accordance with this invention, a method for producing compounds of formula I, which includes the following stages:
(a) the interaction of the compounds of formula II

where R ¹ takes the values defined above, with the compound of formula III
HN (R ² ) R ³ III
where R ² and R ³ take the values defined above, for example, at elevated temperature (for example, when boiling under reflux) in the presence of a suitable organic solvent (for example, toluene); or
(b) the interaction of the compounds of formula IV

where R ¹ takes the values defined above, with a compound of formula V,
R ² (R ³ ) NCH ₂ CH ₂ Hal V
where Hal is Cl, Br or I, and R ² and R ³ are as defined above, or with its acid addition salt, for example, at elevated temperature (for example, by refluxing) in the presence of a suitable base (for example , sodium ethoxide) and a suitable organic solvent (e.g. ethanol).

Compounds of formula II may be prepared by a method analogous to that described in US Pat. No. 3,105,854, for example, by reacting a compound of formula IV above with a compound of formula VI
NalCH ₂ CH ₂ Nal, (VI)
where Hal is as defined above. Compounds of formula II can be prepared in this way, for example, at room temperature in the presence of a two-phase solvent system and a suitable ion pair extraction agent. Suitable organic solvents for the two-phase system are alkyl dihalides of formula VI, taken in excess, and hydroxytetrabutylammonium is a suitable ion pair extraction agent.

The compounds of formula IV are commercially available and can easily be obtained by well-known methods. For example, compounds of formula IV can be prepared by reacting resorcinol with a compound of formula VII
R ¹ Hal, VII
wherein Hal and R ¹ are as defined above, for example, at elevated temperature (for example, by refluxing) in the presence of a suitable base (eg sodium ethoxide) and a suitable organic solvent (eg ethanol).

 Compounds of formula III, V, VI and VII are either commercially available or can easily be prepared using known methods.

 The compounds of this invention can be isolated from reaction mixtures using well-known methods.

 The compounds of this invention are useful compounds since they have pharmacological activity. Thus, they are indicated for use as pharmaceuticals.

 Thus, in accordance with a further aspect of the present invention, there is provided a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

 In particular, the compounds of this invention possess anesthetic properties, for example, as shown in the experiment described below. Thus, they are useful as anesthetics, in particular local anesthetics, and especially topically applied local anesthetics.

 Thus, the compounds of this invention are indicated for the treatment of pain, including localized pain.

 The compounds of this invention will typically be administered parenterally, in particular topically in the form of pharmaceutical compositions comprising the active ingredient in a pharmaceutically acceptable dosage form.

 We prefer the administration to be local to the skin.

 Types of compositions of this invention for topical administration to the skin that may be mentioned include emulsions, creams, lotions, ointments, and skin plaques. Compositions comprising the compounds of the invention for topical administration may include other ingredients commonly used for parenteral administration of pharmaceutically active compounds.

 Thus, in accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

 Compositions comprising the compounds of this invention can be prepared by methods that are themselves known. Typically, the active substance will be from 0.5 to 15 wt.% The drug, more precisely from 5 to 10 wt.%.

 In accordance with a further aspect of the present invention, there is provided a method of treating pain, which comprises administering a therapeutically effective amount of a compound of formula I, as defined above, or a pharmaceutically acceptable salt thereof to a subject suffering from pain or is sensitive to pain.

 The compounds of this invention have the advantage that they can be applied topically to intact skin, and also have a faster effect and longer duration than compounds of the prior art.

Biological tests
Experience A
Local anesthesia in a guinea pig experiment
Local anesthesia and analgesia during occlusion of intact guinea pig skin are studied by applying a lipid composition of local anesthetics in accordance with a method similar to that described in J. Pharmacol. Exp. Ther. 85, 78 (1945), which is described in detail below.

On the back of a male guinea pig (Dunkin-Hartley line; weight in the range of 300 to 400 g), hair is removed using a depilator (Opilca ^® ; Hans Schwarzkopf GmbH, Hamburg, Germany). The smooth skin on which the hair was removed is washed with soap and water, and before the next experiment, the animal is kept in a cage under a flat lamp for two hours.

The response in the form of a cramp is obtained by injecting a skin on the back of an animal cannula (22G; Kifa, without a tip) or Frey filament (4.74% Semmes-Weinstein pressure aesthesiometer). A round piece of gauze (1-8 layers) is saturated with the test composition in a thin plastic cup (4.5 cm ² ) and applied in the middle of the back of the animal. Then, the cup is covered samoadgezivom ^{(Fixomull ®; BDF Beirsdorf AG,} Hamburg, Germany) and the occlusion eventually protect the elastic bandage. Groups of two, three, and six animals are used for each test composition.

 The surface is treated for a period of time up to 15 minutes before removing the kit. The treated area is then wiped with a cloth and then checked for local sensitivity. The skin that was in contact with the composition is punctured with a cannula or Frey filament under constant pressure six times in various places and the presence or absence of a response in the form of a seizure is noted. This procedure is repeated at regular intervals of five minutes.

 The number of injections that do not cause a response indicates the degree of anesthesia or analgesia of sensitivity. The percentage of anesthesia / analgesia after the time of effective contact expresses the total number of injections that do not cause a response, and their percentage of the total number of injections.

Examples
Source materials
Example A
3- (n-propoxy) phenol
A sodium ethoxide solution is prepared by adding sodium (11.5 g; 0.5 mol) to ethanol (500 ml). Resorcinol (55 g; 0.5 mol) is added to the resulting solution with stirring, and then, after half an hour, n-propyl bromide (67.5 g; 0.55 mol). The reaction mixture is then heated to boiling point and refluxed for 3 hours. After cooling, the resulting salt was removed by filtration, and the solvent was evaporated. The residue was partitioned between a dilute aqueous sodium hydroxide solution and ether. The ether phase is extracted with a dilute sodium hydroxide solution and the combined aqueous phases are neutralized using a dilute aqueous hydrochloric acid solution. The precipitated product is extracted with ether, washed with water and dried over magnesium sulfate. After evaporation, the residue is chromatographed on silica gel using toluene: diisopropyl ether (2: 1) as an eluent to give 27.4 g (36% yield) of the title product as an oil (93% pure). The title compound is further purified by distillation.

T.kip. 118-120 ^o C (6 mm Hg).

 MB = 152 (GC-MS).

Example B
3- (n-butoxy) phenol
By the method described in Example A above, from resorcinol (55 g; 0.5 mol) and n-butyl bromide (75.4 g; 0.55 mol), the title product is obtained in 32.4 g (39%) yield in as an oil (92% purity).

T.kip. 148 ^o C (12 mm Hg).

 MB = 166 (GC-MS).

Example C
3- (n-pentoxy) phenol
By the method described in Example A above, from resorcinol (55 g; 0.5 mol) and n-pentyl bromide (83.1 g; 0.55 mol), the title product is obtained in 36.0 g (40%) yield in as an oil (92% purity).

T.kip. 128-131 ^o C (5 mm Hg).

 MB = 180 (GC-MS).

Example D
1- (2-bromoethoxy) -3-n-propoxybenzene
A solution of 3- (n-propoxy) phenol (15.2 g; 0.1 mol; from Example A described above) in 1,2-dibromoethane (100 ml; 1.16 mol) is added to a solution of tetrabutylammonium hydrosulfate (34 g ; 0.1 mol) and a solution of sodium hydroxide (8.0 g; 0.2 mol) in water (100 ml). The mixture is vigorously stirred, during which a 50% solution of sodium hydroxide in water (33 ml) is added dropwise over half an hour. After this, stirring is continued for one hour. The organic phase is separated, washed with water and dried over magnesium sulfate. The solvent was evaporated and the residue was taken up in diethyl ether (150 ml). The precipitated salt was removed by filtration and the diethyl ether was evaporated. The residue was distilled to give the title compound (14.0 g; 54%) as an oil (97% pure).

T.kip. 112-115 ^o C (0.05 mm Hg).

 MB = 259 (GC-MS).

Example E
1- (2-bromoethoxy) -3-n-butoxybenzene
Obtained by a method similar to the method described above in Example D, from 3- (n-butoxy) phenol (16.6 g; 0.1 mol; from Example B above) and 1,2-dibromoethane (100 ml; 1.16 praying). The residue was chromatographed on silica gel using diisopropyl ether as eluent. The resulting oil was distilled off to give 23.1 (85%) of the title compound as an oil, which then crystallized (98% pure).

T.kip. 105-108 ^o C (0.01 mm Hg).

Mp 32-34 ^o C.

 MB = 273 (GC-MS).

Example F
1- (2-bromoethoxy) -3-n-pentoxybenzene
Obtained in accordance with the method described in Example E above, from 3- (n-pentoxy) phenol (18.0 g; 0.1 mol; from Example C described above) and 1,2-dibromethane (100 ml; 1 , 16 moles). The resulting residue was chromatographed on silica gel using diisopropyl ether as eluent to give 26.1 g (91% yield) of the title compound as an oil, which then crystallized (96% pure).

 MB = 287 (GC-MS).

General methods for preparing compounds of formula I
Method A
Aminoethylation of 3-alkoxyphenols
A sodium ethoxide solution is prepared by adding sodium (2.3 g; 0.1 mol) to ethanol (100 ml; 1.63 mol). To the resulting solution was added the corresponding 3-alkoxyphenol (0.05 mol; from Examples A-C described above), the mixture was stirred for half an hour and the corresponding 2-dialkylaminoethyl chloride hydrochloride (0.05 mol) was added, the resulting mixture was heated to boiling point and refluxed for 1 to 10 hours. After cooling, the resulting salt was removed by filtration and the solvent was evaporated. The residue was dissolved in excess dilute hydrochloric acid and the acid solution was extracted with diethyl ether. The solution was made basic with dilute sodium hydroxide, the product was extracted with diethyl ether and the extracts dried over potassium carbonate. The product is purified by vacuum distillation.

Method B
Amination of 1- (2-bromoethoxy) -alkoxybenzenes
A mixture of 1- (2-bromoethoxy) alkoxybenzene (0.04 mol; from Examples DF described above) and the corresponding amine (0.12 mol) in toluene (80 ml) is heated under reflux for 50 to 1000 hours or incubated at 100 ^o C in an autoclave for 7 hours. After cooling, the resulting salt was removed by filtration and the solvent was evaporated. The residue was dissolved in excess dilute hydrochloric acid and the acid solution was extracted with diethyl ether. The solution was made basic with dilute sodium hydroxide, the product was extracted with diethyl ether and the extracts dried over potassium carbonate. The product is purified by vacuum distillation.

Examples 1-9
Compounds of Formula I
The following compounds of formula I are prepared in accordance with the general methods described above:
isopropyl methyl [2- (3-n-propoxy-phenoxy) ethyl] -amine (Example 1);
ethyl isopropyl- [2- (3-n-propoxy-phenoxy) ethyl] -amine (Example 2);
diisopropyl- [2- (3-n-propoxy-phenoxy) ethyl] -amine (Example 3);
diethyl- [2- (3-n-propoxy-phenoxy) ethyl] -amine (Example 4);
isopropyl methyl- [2- (3-n-butoxy-phenoxy) ethyl] -amine (Example 5);
ethyl isopropyl- [2- (3-n-butoxy-phenoxy) ethyl] -amine (Example 6);
diisopropyl- [2- (3-n-butoxy-phenoxy) ethyl] -amine (Example 7);
ethyl isopropyl- [2- (3-n-pentoxy-phenoxy) ethyl] -amine (Example 8) and
diisopropyl- [2- (3-n-pentoxy-phenoxy) ethyl] -amine (Example 9).

 An accurate description of the methods, reaction times, yields and characteristic data are given in table. 1.

Example 10
The compounds of Examples 1 to 9 were tested in accordance with the procedure of Test A described above, and it was found that they all exhibit 100% anesthetic / analgesic properties using a contact time of 15 minutes.

1. Inventive step
To evaluate the inventive step of the claimed compounds, the applicant makes a comprehensive comparison with the compounds disclosed in US Pat. No. 3,105,854 (hereinafter D1). The pharmaceutical activity of the compounds of example 1 of the present invention (compound A) is compared with the activity of the compounds of examples 17 and 7 from D1 (compounds 1 and 2, respectively).

 The present invention relates to pharmaceutically active compounds and their use as local anesthetics for topical use on intact and intact skin of humans or animals.

 An unexpected property of the compounds of the present invention is their function as a topical local anesthetic. Additionally, the compounds of the present invention are characterized by a rapid onset of action, i.e., a property of great importance for local anesthesia.

 To demonstrate that these properties are unexpected from the point of view of the closest prior art, the applicants conducted two series of experiments. The first is an in vitro skin penetration study, and the second is the in vivo determination of local anesthesia in guinea pigs. Both experiments are most suitable for demonstrating the real properties of topical local anesthetics on intact and intact skin of humans or animals.

2.1. In vitro skin penetration study
For in vitro penetration experiments, modified Franz stationary diffusion cells were used, on which the flow of compounds A, 1 and 2 was determined, i.e. the rate at which compounds penetrate intact and intact skin. To achieve the same thermodynamic activity, all three compounds were saturated in a Monash V solution (40% isopropyl alcohol, 25% glycerol, and 35% water). The skin of the abdominal wall of guinea pigs was used as a membrane. First, the guinea pigs were shaved from the back and the hair removed. After slaughter, the skin was completely separated from the abdominal wall and stored at -80 ^° C until use. After thawing, thin sections of skin with a thickness of about 0.4 mm were excised. Excised thin sections were cut into small pieces and placed in diffusion cells. The receiving compartment contained phosphate buffered saline (pH 7.4), and the temperature was maintained at 32 ^° C. Saturated solutions were applied to the stratum corneum. Samples from the receiving compartment were analyzed by spectrophotometry, respectively. The flow was determined by the slope of the curve of the cumulative amounts of compounds A, 1 and 2 in the receiving compartment versus time.

2.1.1. In Vitro Skin Penetration - Results
The average in vitro skin fluxes for all three compounds over a 2-hour period are shown in FIG. 1 and tab. 1.

 The stationary flows of all three compounds were different. The penetration rate (flow) of compound A is 56% higher than for compound 2. This is an undeniable indicator that compound A has advantageous properties over the most relevant prior art, i.e. compound 2 (see table. 2).

2.2. In vivo cutaneous application in guinea pigs
Methods: Three saturated compositions of compounds A, 1 and 2 in a Monash V solution were tested after cutaneous application on intact skin during fixation in guinea pigs. Before testing, animals were shaved and their back hair removed. Round gauze pieces saturated with the experimental composition in a thin plastic cap (4.5 cm ² ) were applied to the middle of the back and fixed on the animal. Each composition was tested in groups of 3 animals using two different fixation times, 5 and 10 minutes. Anesthesia was evaluated by pinning a skin area with a 22-G needle without a tip, starting 5 minutes after removal of the test composition, and then at regular time intervals. Anesthesia was assessed by the absence of responsive skin twitches.

2.2.1. results
Only the composition containing compound A gave complete anesthesia after 5- and 10-minute fixation. A contact time of 5 and 10 minutes is considered as a very short contact time in the area of local anesthesia. The duration of action was more than one hour (Fig. 2 and 3). This is an undeniable indicator that compound A of the present invention has advantageous properties over compounds of the prior art. Compound A has (i) a faster onset of action, (ii) a longer duration of action, and (iii) complete anesthesia compared to compound 2, which is considered to be the most relevant prior art.

от которого соединение в примере 1 по настоящей заявке (выше относится к соединению А) отличается в отношении числа атомов углерода в радикале алкокси и заместителях в аминогруппе.2.3. Problem Solving Approach
D1 refers to meta-substituted phenoxyalkylamines and the general formula includes all compounds of formula I of the present application. Example 7 in D1 discloses a compound of the formula

from which the compound in example 1 of the present application (above refers to compound A) differs in terms of the number of carbon atoms in the alkoxy radical and substituents in the amino group.

 The target problem to be solved by specialists in this field can be seen in the provision of additional local anesthetics for topical use on the intact skin of humans or animals.

 The target problem is solved in that the number of carbon atoms in the alkoxy radical and substituents in the amino group is different. The data in the table. 1 and in FIG. 1-3 serve as a comparative example showing that compound A of the present invention has advantageous properties over the most relevant prior art. Neither D1 nor any other document gives a hint of increased penetration through the skin, faster onset of action, longer duration of action, or increased analgesic efficacy when the number of carbon atoms in the alkoxy radical and / or substituents in the amino group changes. In addition, there is no experimental data in D1 allowing the reader to extrapolate and thus predict that the compounds of the present invention will show increased skin penetration rate, faster onset of action, longer duration of action, and improved efficacy when applied topically to intact skin human or animal.

 None of the unexpected and advantageous properties that distinguish the compounds of the present invention are not disclosed or even not anticipated in D1. A specialist who is faced with the objective problem of providing additional local anesthetics for topical use on the intact skin of humans or animals will not find guidance in D1 in this way.

 Thus, the present invention has an inventive step with respect to D1. The following are the structures of compounds A, 1 and 2.

вStructure

in

Claims (9)

1. The compound of formula I

where R ¹ represents n-propyl;
R ² represents methyl;
R ³ represents isopropyl;
or a pharmaceutically acceptable salt thereof.  2. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof for use in local anesthesia.  3. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient in the preparation of an anesthetic.  4. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient in the preparation of a local local anesthetic.  5. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the manufacture of a medicament for local anesthesia.  6. A pharmaceutical composition for local anesthesia containing a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.  7. A method of local anesthesia, which comprises applying to the skin a therapeutically effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof to a patient suffering from pain or is sensitive to pain. 8. A method of obtaining compounds of formula I, which includes the interaction of the compounds of formula II

where R ¹ has the meanings indicated in paragraph 1,
with a compound of formula III
HN (R ² ) R ³
where R ² and R ³ have the meanings indicated in paragraph 1,
or with its acid addition salt. 9. A method for producing compounds of formula I, which comprises reacting a compound of formula IV

where R ¹ has the meanings indicated in paragraph 1,
with a compound of formula V
R ² (R ³ ) NCH ₂ CH ₂ Hal
where Hal represents Cl, Br or I, and R ² and R ³ have the meanings indicated in paragraph 1,
or with its acid addition salt.

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