KR950002830B1 - Amino alcohols - Google Patents

Abstract

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Description

Amino Alcohols and Pharmaceutical Compositions Containing the Same

The present invention relates to novel aminoalcohols derived from 2- (3,4-dichlorobenzyl) -2-aminoethanol and methods for their preparation and their therapeutic applications.

The present invention relates to aminoalcohol of general formula (I) and acid addition salts thereof

Wherein R ₁ is lower alkyl, R ₂ is H or lower alkyl, R ₃ is H, lower alkyl, lower alkenyl, lower phenylalkyl or lower cyclo alkyl alkyl having 3-6 carbon atoms in the ring, or R _{When divalent} H, lower alkanoyl, lower phenylalkanoyl or cycloalkyl carbonyl having 3-6 carbon atoms in the ring, R ₂ and R ₃ are heterocycles saturated with 5-7 chains with their bound nitrogen atoms Wherein the heterocycle may comprise an oxygen, sulfur or nitrogen atom as a second hetero atom not directly connected to the nitrogen atom, the latter nitrogen hetero atom being C _1-4 It may have an alkyl substituent of.

The lower alkanoyl and alkyl radicals are linear or branched and contain 1-5 carbon atoms, and the alkenyl radicals preferably contain 2-5 especially 3 carbon atoms, whereas the cycloalkyl radicals contain 3-6 carbon atoms. It is good to do.

Acetic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid in therapeutically acceptable acids forming acid addition salts with the compounds according to the invention And inorganic acids or organic acids such as pamophosphoric acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfuric acid and tartaric acid.

The present invention relates to racemic and optically active forms of the following general formula (I) compounds.

The compounds of the present invention act on the central nervous system (SNC) and have analgesics that were not expected in aminoalcohols. Accordingly, an object of the present invention is to use compound (I) as a drug and an analgesic agent acting on the central nervous system.

Preferred among the compounds of the present invention are those in which R ₁ is methyl, R ₂ is hydrogen or methyl, and R ₃ is hydrogen or methyl.

The present invention also provides a compound of formula (Ia) of Table A wherein R ₂ and R ₃ are hydrogen by reducing the acid of formula (II) with boron or aluminum hydride,

In order to obtain a compound of formula (Ib) in which NR ₂ R ₃ forms a hetero cycle, the compound of formula (1a) is reacted with a reagent of the formula

X- (CH ₂ ) _m -R _5- (CH ₂ ) _n -X '

Wherein X and X 'are the same or different halogen, R ₅ is a monovalent bond, m and n are integers of 1 to 3, m + n is 4 or more and 6 or less, or R ₅ is oxygen, sulfur or As NR ₆ R ₆ is H or C ₁ -C ₄ alkyl and m and n are integers from 1 to 3 and m + n is 3 or more and 5 or less) R ₃ is alkanoyl, phenylalkanoyl or cycloalkyl car To prepare a compound of formula (Ic) which is carbonyl, a compound of formula (Ia) is converted to an acylating agent of formula (R ₄ -COX) (X is halogen, R ₄ is a homologue linked directly below R ₃ ). Acylated and an alkylating agent of formula (R ₃ -X) (X is halogen) to prepare a compound of formula (Id) wherein R ₂ is H, R ₃ is alkyl, alkenyl, phenyl alkyl or cycloalkyl Alkylating the compound of formula (Ia), reducing the compound of formula (Ic) with boron or aluminum hydride, or reducing the compound of formula (IV) Sikimyeo reduced to titanium hydride

R ₂ is alkyl and R ₃ is reacted with an aldehyde of general formula (R ₄ HO) in the presence of formic acid to produce a compound of general formula (Ie) such as R ₂ , To prepare a compound of formula (Ie) wherein _divalent alkyl and R ₃ is alkyl, alkenyl, phenylalkyl or cycloalkylalkyl, the compound of formula (Id) is substituted in the presence of formic acid (R ₄ CHO) To react with phosphorus aldehyde and to prepare an acid addition salt, the present invention relates to a process for preparing the compound of the present invention, including the process of reacting the compound of formula (I) with an acid.

The method for preparing the compound of the present invention is summarized in Table 1 below, and the dichlorobenzyl radical is not shown in the general formula of the compounds of Table 1 below.

TABLE 1

Starting products in the preparation of the compounds of the invention are optically active as racemic amino acids of the general formulas (II) and (IV):

Wherein R ₁ is a lower alkyl radical, a phenyl-lower alkyl radical or cycloalkyl radical, R ₄ as defined in formula (I) is a cognate water attached to the R ₃ just below _{(R 3 = -CH 2 R 4} ).

Compounds of formulas (II) and (IV) may be prepared by a variety of methods, including those described in Examples 1 and 2 of French Patent Specification No. 7702360. First, as in Example 1 of the specification, , 4-dichlorobenzylchloride or bromide can be condensed with isocyano-ester of the general formula (III) to obtain the racemic amino acid of the general formula (II),

Wherein R ₁ is lower alkyl radical as described above, A is low molecular weight alkyl radical.

The compound of formula (II) which is optically active as well as the product of racemic and optically active form of formula (IV), as applied to the compounds of formulas (II) and (IV). Amino acids of) can also be obtained.

As shown in Table 1, compounds (Ia), (Ib), (Ic), (Id), and (Ie), wherein R ₁ is lower alkyl radicals as defined above, are represented by the general formula (I) According to the compound and prepared from compounds (II) and (IV) by the following reaction.

The compound of formula (Ia) is obtained by reducing the carboxyl group of the compound of formula (II) under the action of a reducing agent such as boron or aluminum hydride according to reaction (a), and the compound of formula (Ib) Accordingly obtained by cyclizing the amino group of the compound of formula (Ia) with a compound of the following formula,

X- (CH ₂ ) _m -R _5- (CH ₂ ) _n -X '

(That wherein, X and X 'are the same or different, a halogen atom such as iodine, bromine or chlorine, R ₅ is a member self-bond or oxygen, sulfur or a NR ₆ R ₆ is H or C ₁ -C ₄ In which m and n are 1, 2 or 3)

The compound of formula (Ib) forms a heterocycle in which the radicals R ₂ and R ₃ of formula (I) consist of 5-7 atoms with the nitrogen atom to which they are attached, wherein the second hetero atom is nitrogen, oxygen or sulfur Characterized in that the compound of formula (Ic) is prepared by N-acylating the compound of formula (Ia) with an alkanoyl halide of the following general formula according to reaction (c),

R ₄ -COX

Wherein X is a halogen atom such as chlorine or bromine, R ₄ is lower alkyl radical or lower phenylalkyl, R ₄ is a radical linked directly below R ₃ (R ₃ = CH ₂ R ₄ ), or R ₄ is cyclo Alkyl and a compound of formula (Id) are prepared from compounds of formula (la), (lc), (iv) according to the following reaction:

(d) Alkenyl halides of formula (R ₃ -X), wherein X is a halogen atom such as bromine and R ₃ is alkenyl, such as allyl radical, are reacted with a compound of formula (Ia) ) Reactions to generate derivatives.

(d ') the N-alcoyl functional group of compound (Ic) as defined above is reduced with a reducing agent as in reaction (a) so that R ₃ is a lower alkyl radical, a lower phenylalkyl radical or a cycloalkyl alkyl radical Reaction to obtain a compound.

(d '') a reaction in which both the carboxyl and N-alkoyl functional groups of compound (IV) as defined above are reduced with the above-mentioned reducing agent to give the same compound (Id) as obtained in reaction (d ').

Compounds of formula (Ie) are prepared based on compounds (Ia) and (Id) according to the following reaction:

(e) R ₂ and R ₃ are the same by reducing dialkylation of aminoalcohols of formula (Ia) under the action of aldehydes of general formula (R ₄ -CHO), wherein R ₄ is hydrogen or lower alkyl radicals; Reaction using formic acid to obtain a compound of formula (I) which is lower alkyl radicals, in particular methyl radicals.

(e ') The compound of formula (Id) is reacted with a reductive monoalkylation reaction, as described in reaction (e), wherein R ₂ is a lower alkyl radical, in particular methyl and R ₃ is reactions (d), (d') and A reaction for obtaining a compound (Ie) which is a radical corresponding to the compound (Id) obtained by (d '').

As described above, the compounds of the present invention are obtained by the following reactions:

Reduction reaction (a), (d '), (d ")

Monoalkylated or dialkylated (b), (d), (e) and (e '), acylated (c).

The reduction reaction consists in reducing the carbonyl groups of the carboxyl and / or amide functional groups to obtain primary alcohol and / or secondary amine functionalities, respectively.

The reaction uses known methods and reagents and is summarized in the table described in "Advaced Organic Chemistry", page 1118 (J. March, Second French edition, 1977-McGraw Hill). It is stated that reducing agents such as boron and aluminum hydride derivatives are effective in carrying out the reaction. More particularly preferred as reagents for this reaction are lithium-aluminum hydride and borane dimethyl sulfide complexes (hereinafter referred to as BSM).

The reduction reaction is preferably carried out in a non-dissociative aprotic medium in a solvent such as diethyl ether, diisopropyl ether, 1, 2-dimethoxyethane or tetrahydrofuran (THF).

To obtain the complete reaction, stoichiometric excess of BMS complex is used relative to the product to be reduced. This excess depends on the characteristic functional groups of the structural formulas used and on the number of carbonyl groups to be reduced and the presence of other groups or functional groups in the structural formula that react with the BMS. Thus, for functional groups in special cases, 2-8 moles of BMS are used for 1 mole of product to be treated, 2.5-3.5 moles of BMS for 1 mole of compound ((Ic) (reaction d "), For 1 mole of compounds (II and IV) (reactions a and d ''), 4-6 moles of BMS are preferably used.

In the reduction reaction, 1 to 10 parts by weight of the above product is added to 100 parts by weight of THF under a nitrogen atmosphere having been dehumidified, with 3 to 7 parts being particularly preferred for 100 parts. After addition of the amount of BMS described above, the mixture is refluxed for 30 minutes to 10 hours to allow the total reaction to occur. But 3-5 hours is most preferred. Then methanol is added to the mixture followed by the addition of sodium hydroxide, whereby the aminoalcohol is separated from the mixture with a reducing agent and finally the aminoalcohol is separated according to the known method described in the Examples.

Monoalkylation and dialkylation reactions are carried out by the action of alkyl halides or by the action of aldehydes and formic acid, also referred to as reductive alkylation reactions.

In the first case of a reductive alkylation reaction (reactions b and d), the solvent used is inert to the alkyl halides, for example toluene and acetonitrile. Generally, when one mole of product is to be obtained by alkylation, 0.5-1.5 mole of halides dissolved in 2 to 3 liters of the solvent selected above are used. A ratio of 0.85-1.20 moles of alkyl bromide or iodine to 1 mole of reacted product is preferred. A base is optionally added to assist the reaction, which may be an inorganic material such as anhydrous sodium carbonate, or an organic material such as triethylamine may be used. Conditions of time with the reaction temperature are applied depending on the characteristics of the solvent and the reactivity of the product and are usually between 20 and 110 ° C for 1-24 hours. Suitable temperature and time is 40-110 ° C. for 2-5 hours. The alkyl product is then separated and purified by the conventional method described in the Examples.

In the second case of reductive alkylation reactions (reactions e and e '), this reaction first alkylates the above-mentioned aldehyde (R ₄ -CHO) with the product. The undissolved intermediate is then reduced to pure formic acid, the first reaction being carried out at a temperature in the range of 20-50 ° C. and the next reaction for 1 to 5 hours in the range of 60-100 ° C.

In the general case, 1.2-3.5 moles of pure aldehyde or 30-40% by weight aqueous formaldehyde solution and 2-5 moles of pure formic acid are required for 1 mole of alkylated product in monoalkylation and dealkylation by the above-mentioned method. The reduction of formic acid is obtained by heating the mixture at 90-100 ° C. for 1-2 hours.

The acylation reaction (c) described above is carried out in a single phase medium such as toluene in the presence of an organic base such as trimethylamine or in an ideal medium such as a water-1,2-dichloroethane mixture in the presence of sodium hydroxide. In both cases, the acid chloride is used in stoichiometric proportions or in smaller amounts than the aminoalcohol used.

Generally, in one molecule of aminoalcohol in 2-10 liters of solvent, cold inorganic or organic base is added followed by addition of the acid chloride at a rate of 0.5-1 mole. The reaction is carried out by stirring the mixture at 0 ° C-30 ° C for 1-5 hours, preferably at 10-20 ° C for 1-2 hours, and then separating the product in the same manner as above.

British Patent No. 1 434 826, pages 2, lines 37-42, describes the general formula of alcohols comprising the compounds according to the invention. However, no detailed manufacturing method or exact example is given. Therefore, these are novel compounds that have never been produced and the general formulas presented in this document are only conjectures.

The invention is illustrated in the following examples without limitation, and the methods used are known. However, some limitations are required.

During the extraction step, the organic phase containing the desired product is extracted with water or saturated sodium chloride solution and washed until the wash solution is neutral. Residual water is removed by standing on a dehydrating agent such as anhydrous sodium sulfate for several hours before evaporating the solvent. The solvent is evaporated in vacuo and in a water bath, and the temperature is adjusted to the boiling point of the solvent to be removed. When the product is purified by crystallization, the solvent used for this purpose is given the boiling point value of the product given or obtained in the literature. The separated product in solid, crystalline or amorphous form can be heated under vacuum to remove residual solvent to give a product of constant weight. Hydrochloride of the product is prepared systematically according to the method described in Example 1.

The purity, homogeneity and physical characteristics of the product according to the invention are also measured according to the method outlined below.

The melting point was based on the capillary method using a "Mettler FPI" device, but no correction was made.

Purity was measured by thin layer chromatography.

Support: Silica gel 60F 254 (Merck)

Sediment: about 100mcg

Elution: 10 cm rise in the mixture

A-butanol: acetic acid: water 8: 2: 2 (v / v / v)

B-methylene chloride: methanol 9: 1 (v / v)

C-methylene chloride: methanol 9.2: 0.5 (v / v)

D-methylene chloride: acetone 8: 2 (v / v)

Expression: Plates were observed under UV light at a wavelength of 254 nm and then sprayed with Dragendorff reagent.

This example presents the RF values measured with the mobile solvent used. Beneficiation is measured on a 2 dm long tube.

The obtained product having the structure shown above is confirmed by NMR spectrum ( ¹ H NMR) for both at 60 MHz. The product is used either alone in deuterated chloroform (CDCl ₃ ) or in deuterated chloroform mixed with sulfoxide (D-6).

The nature of the signal, the chemical shift of the signals in p.p.m compared to the tetramethyl silane used as reference, and the number of protons each signal has in each spectrum. It is also used to compare "exchangeable" quantum by the addition of deuterium oxide.

THF herein is tetrahydrofuran and BMS is borane-dimethylsulfide.

Example 1

1A- (±) 2-methyl-2-amino-3- (3, 4-dichlorophenyl) -propanol (JO 1275)

General formula (I) = R ₁ = CH ₃ ; R ₂ = R ₃ = H

Into a reactor protected from moisture and under nitrogen atmosphere, 625 ml of tetrahydrofuran (THF) and 24.8 g (0.1 mol) of (±) 2- (2,3-dichlorobenzyl) -alanine were added sequentially.

38.0 g (0.5 mole) of borane-dimethylsulfide (BMS) complex was added dropwise to the suspension obtained at 20 ° C for at least 30 minutes. Stirring was continued at room temperature for 15 minutes. The mixture was then refluxed for 4 _1/2 hours. After cooling to 5 [deg.] C., 75 ml of methanol was slowly added not to exceed 20 [deg.] C. and then 75 ml of N sodium hydroxide solution was added in the same manner. The suspension obtained is left overnight to filter off insoluble matter. The filtrate is evaporated in vacuo and in a water bath and the resulting white residue is dissolved in 500 ml of water. The mixture is acidified to pH 1 by addition of concentrated acid (d = 1.18).

The resulting solution is extracted twice with 150 ml of ether. The ether phase is removed and the acidic layer is alkalined to pH 12 by addition of concentrated sodium hydroxide solution (d = 1.38) under cold conditions, followed by addition of saturated sodium chloride solution.

The alkaline mixture is extracted three times with 200 ml of ether, and the mixed ether phase is washed with saturated sodium chloride solution and then dried. After evaporation of the ether, an aminoalcohol was obtained as a white amorphous solid residue.

Weight: 21.5g Yield: 91.8%

Melting Point = 96 ℃ TLC: A-0.7

¹ H-NMR (CDCl ₃ ): 0.95 (s, 3H), 2.25 (s, 3H exchangeable), 2.65 (s, 2H), 3.30 (s, 2H), 6.90-7.40 (m, 3H).

Hydrochloride: 21 g (0.09 mol) of aminoalcohol is dissolved in 220 ml of methylene chloride. At the same time as stirring, 90 ml of 3N hydrochloric acid ether is added so as not to exceed 10 ° C. After 15 minutes the solvent was evaporated and the resulting residue was retreated in the same manner as above with 220 ml of methylene chloride and 60 ml of 3N hydrochloric acid. The crude product obtained after evaporation was recrystallized in a mixture of 150 ml ethanol and 300 ml ether. The purified crystalline product was filtered off and dried under vacuum at 40 ° C.

Weight: 19.6g Yield: 80.5%

Melting Point: 171 ℃

Elemental Analysis for C ₁₀ H ₁₄ Cl ₃ NO:

Theoretical value (%): C; 44.39, H; 5.22, Cl; 39.31, N; 5.18, O; 5.19

Found (%): C; 44.44, H; 5.15, Cl; 39.20, N: 5.16, O; 6.05

1B-(+) 2-Methyl-2-amino-3- (3,4-dichlorophenyl) -propanol (JO 1307)

General formula (I): R ₁ = CH ₃ ; R ₂ = R ₃ = H.

According to the reduction method described above, 23.0 g (92 mmol) of (+) 2- (3,4-dichlorobenzyl) alanine was reduced to obtain the corresponding d-rotating aminoalcohol.

Weight: 20.0g Yield: 92.8%

Melting point: 86 ° C. TLC: A; 0.7

=+1.6°(C=5%, 메탄올).

= + 1.6 ° (C = 5%, methanol).

¹ H-NMR (CDCl ₃ ) Same as the product of Example (1A).

Hydrochloride: yield = 92.2%, melting point 144 DEG C (acetone).

Elemental Analysis for C ₁₀ H ₁₄ Cl ₃ NO:

Theoretical value (%): C; 44.39, H; 5.22, Cl; 39.31, N; 5.18, O; 5.91

Found (%): C; 44.33, H; 5.24, Cl; 39.20, N; 5.10, O; 5.75

1C-(-) 2-methyl-2-amino-3- (3,4-dichlorophenyl) -propanol

General formula (I): R ₁ = CH ₂ ; R ₂ = R ₃ = H.

Using the same method as in the above-described example, 60.0 g (242 mmol) of (-) 2- (3,4-dichlorobenzyl) -alanine was reduced to obtain l-rotating aminoalcohols. This crude product was purified by crystallization in ether-hexane mixtures.

Weight: 55.6g Yield: 98.1%

Melting point: 85 ° C. TLC: A; 0.7

=1.8°(C=5%, 메탄올).

= 1.8 ° (C = 5%, methanol).

Same as ¹ H-NMR (CDCl ₃ ) (1A) and (1B).

Example 2

(±) 2-isopropyl-2-amino-3 (3,4-dichlorophenyl) -propanol (JO 1579)

General formula (I) -R ₁ = CH (CH ₃ ) ₂ ; R ₂ = R ₃ = H.

The product was prepared according to the method of Example (1A) using 67.2 g (0.243 mol) of (±) 2-isopropyl-2- (3,4-dichlorobenzyl) -glycine.

After evaporation of the extraction solvent, a product was obtained which was an amorphous white solid.

Weight: 39.0g Yield: 61.2%

Melting Point = 85 ° C. TLC: A: 0.7

¹ H-NMR (CDCl ₃ ): 0.85 (d, 3H), 1.00 (d, 3H), 1.35-2.00 (m, 4H, 3H exchangeable), 2.65 (s, 2H), 6.90-7.45 (m, 3H ).

Hydrochloride: Yield 83.5%, Melting point 176.5 ° C (ethyl acetate)

Elemental Analysis for C ₁₂ H ₁₈ Cl ₃ NO, 0.75 H ₂ O:

Theoretical value (%): C; 46.17, H; 6.25, Cl; 34.08, N; 4,48, O; 0.96

Found (%): C; 46.16, H; 6.15, Cl; 34.34, N; 4.43, 0; 8.84

Example 3

(±) 2-pentyl-2-amino-3 (3, 4-dichlorophenyl) -propanol (JO1562)

General formula (I) -R ₁ = (CH ₂ ) ₄ -CH ₃ ; R ₂ = R ₃ = H.

The product was prepared according to the method of Example (1A) using 60.0 g (0.197 mol) of (±) 2-pentyl-2- (3, 4-dichlorobenzyl) -glycine.

Weight: 43.0g 75.2%

Melting point = 36 ° C. (hexanes) TLC: A; 0.85.

: H-NMR (CDCl ₃ ): 0.95 (t, 3H), 1.35 (s, 8H), 2.90 (m, 3H exchangeable), 2.75 (s, 2H), 3.35 (s, 2H), 7.00-7.50 ( m, 3H).

Hydrochloride: Yield 82.1%, melting point 155 ° C (acetone)

Elemental Analysis for C ₁₄ H ₂₂ Cl ₃ NO:

Theoretical value (%): C; 51.47, H; 6.79, Cl; 32.56, N; 4.28, 0; 4.90

Found (%): C; 51.33, H; 6.73, Cl; 32.42, N; 4.20, O; 4.89

Example 4

4A-Step 1: (±) N-formyl-2- (3, 4-dichlorobenzyl) -alanine

Intermediate (IV) R ₁ = CH ₃ ; R ₄ = H.

49.6 g (0.2 moles) of (±) 2- (3,4-dichlorobenzyl) -alanine was dissolved in 80.0 ml of pure formic acid (d = 1.22) in a device completely shielded from moisture. While stirring, the mixture was heated to 60 ° C. and the resulting solution was maintained at this temperature for 15 minutes and 63.0 ml of pure acetic anhydride was added for 40 minutes while maintaining a temperature of 58-62 ° C.

After 15 minutes, 13.0 ml of water was added slowly and the solution gradually cooled. Crystallization started at about 40 ° C. and complete crystallization by stirring at 5 ° C. for 2 hours.

The product is filtered, washed with ice water until the wash water is neutral and dried under vacuum at 80 ° C. until constant weight.

Weight: 32.6g Yield: 59.0%

¹ H-NMR (DMSO-CDCl ₃ ): 1.45 (s, 3H), 3.25 (s, 2H), 6.95-7.50 (m, 3H), 7.90 (s, 1H exchangeable), 8.00 (d, 1H), 10.65 (s, wide, 1H interchangeable).

Step 2: (±) 2-methyl-2-methylamino-3- (3, 4-dichlorophenyl) -propanol (JO 1276)

General formula (I): R ₁ = R ₂ = CH ₃ ; R ₃ = H.

Under nitrogen atmosphere and under damp conditions, 21.3 g (77.1 mmol) of the product obtained in step 1 were dissolved in 400 ml of THF.

29.2 g (385 mmol) of BMS complex was added at 20 ° C. for 30 minutes. This mixture was then refluxed for 4 _1/2 hours and then cooled to 5 ° C.

65.0 ml of methanol is added dropwise successively, followed by addition of 65 moles of sodium hydroxide solution not to exceed 20 ° C. The insolubles were filtered off and the residue obtained by concentration of the filtrate was dissolved in 350 ml of N hydrochloric acid.

The solution is extracted three times with 125 ml of ether and alkalinized to pH 12 using a saturated sodium chloride concentrated soda solution.

The alkaline mixture is extracted three times with 200 ml of methylene chloride. This mixed organic phase was treated by known methods and evaporated to yield an amorphous white solid product.

Weight: 13.4g Yield: 70.1%

Melting point = 123 ° C. TLC: A; 0.5.

¹ H-NMR (DMSO-CDCl ₃ ): 0.95 (s, 3H), 2.35 (s, 1H exchangeable in 4H), 2.65 (s, 1H interchangeable in 3H), 3.25 (s, 2H), 6.95-7.50 (m, 3 H).

Hydrochloride: Yield 73.0%, melting point 226 ° C (ethanol)

Elemental Analysis for C ₁₁ H ₁₆ Cl ₃ NO:

Theoretical value (%): C; 46.42, H; 5.67, Cl; 37.37, N; 4.92, 0; 5.62

Found (%): C; 46.58, H; 5.67, Cl; 37.30, N; 4.85, O; 5.79

4B-Step 1: (+) N-formyl-2- (3,4-dichlorobenzyl) -alanine

Intermediate (IV) R ₁ = CH ₃ ; R ₄ = H.

The product was obtained in 70.6% yield following the method of Example 4A-step 1 using (+) 2- (3,4-dichlorobenzyl) -alanine.

¹ H-NMR (DMSO-CDCl ₃ ): 1.45 (s, 3H), 3.30 (9, 2H), 7.05-7.65 (m, 1H interchangeable in 4H), 8.10 (d, 1H), 10.35 (s wide, 1H exchangeability).

Step 2: (+) 2-methyl-2-methylamino-3- (3, 4-dichlorophenyl) -propanol (JO 1308)

Formula (I): R ₁ = R ₂ = CH ₃ , R ₃ = H.

19.0 g (69 mmol) of the product obtained from the above-mentioned step were reduced using the BMS complex according to the method of step 2 of Example 4-A. The crude product obtained was purified by crystallization in methylene chloride.

Weight: 10.7g Yield: 62.5%

Melting point: 113 ° C. TLC: A; 0.5

=+1.8°(C=5%, 메탄올).

= + 1.8 ° (C = 5%, methanol).

¹ H-NMR (DMSO-CDCl ₃ ) Same as the racemate product of Example 4A.

Example 5

Step 1: (±) N-formyl-2-pentyl-2- (3, 4-dichlorobenzyl) -glycine

Intermediate (IV) R ₁ = (CH ₂ ) ₄ CH ₃ : R ₄ = H.

The product was obtained according to the method of Example 4-Step 1 using 50.0 g (0.164 mol) of (±) 2-pentyl-2- (3, 4-dichlorobenzyl) -glycine.

Weight: 47.8g Yield: 87.7%

TLC: A; 0.4

Step 2: (±) 2-pentyl-2-methylamino-3- (3,4-dichlorophenyl) -propanol (JO 1563)

General formula (I): —R ₁ = (CH ₂ ) ₄ —CH ₃ ; R ₂ = CH ₃ ; R ₃ -H.

Example 4- According to the method of step 2, 47.4 g (0.143 mol) of the derivative obtained in the previous step 1 were reduced to obtain the product.

Weight: 33.0g Yield: 75.8%

TLC: A; 0.75

¹ H-NMR (CDCl ₃ ): 0.95 (t, 3H), 1.30 (s, 8H), 1.85 (s2H, exchangeable), 2.35 (s, 3H), 2.65 (s, 2H), 3.25 (5s, 2H ), 6.95-7.50 (m, 3 H).

Hydrochloride: yield = 53.2%, melting point 151 캜 (ethyl acetate).

Elemental Analysis for C ₁₅ H ₂₄ Cl ₃ NO:

Theoretical value (%): C; 52.87, H; 7.10, Cl; 31.22, N; 4.11, O; 4.70

Found (%): C; 52.81, H; 7.14, Cl: 31.06, N: 4.08, O; 4.61

Example 6

Examples 6A, 6B by reducing (±), (+) and (-) N-acetyl-2- (3,4-dichlorobenzyl) -alanine to the BMS complex according to the method of step 2 of Examples 4A and B And 6C of corresponding aminoalcohols.

6A- (±) 2-methyl-2-ethylamino-3- (3,4-dichlorophenyl) -propanol (JO 1277)

General formula (I): R ₁ = CH ₃ ; R ₂ = H; R ₃ = C ₂ H ₅ .

Yield: 71.7% TLC: A; 0.6

Melting Point = 110 ° C (methylene chloride)

¹ H-NMR (DMSO-CDCl ₃ ): 0.85-l.20 (m, 6H), 2.40-2.85 (m, 4H), 2.90-3.15 (m, 2H, exchangeable), 3.25 (s, 2H), 6.90-7.40 (m, 3 H).

Hydrochloride: Yield = 74.9%, Melting Point: 245 ° C (ethanol)

Elemental Analysis for C ₁₂ H ₁₈ Cl ₃ NO:

Theoretical value (%): C; 48.26, H; 6.08, Cl; 35.62, N; 4.69, O; 5.36

Found (%): C; 48.32, H; 6.01, Cl; 35.63, N; 4.58, 0; 5.45

6B-(+) 2-Methyl-2-ethylamino-3- (3,4-dichlorophenyl) -propanol (JO 1295)

General formula (I): R ₁ = CH ₃ ; R ₂ = H; R ₃ = C ₂ H ₅

Yield: 55.6% TLC: A; 0.6

Melting Point = 105 ° C (ether)

¹ H-NMR (DMSO-CDCl ₃ ) Same as the product of Example 6A.

Hydrochloride: yield = 82.2%, melting point 268 DEG C (methanol).

=+4.2°(C=1%, 물).

= + 4.2 ° (C = 1%, water).

Elemental Analysis for C ₁₂ H ₁₈ C ₁₃ NO:

Theoretical value (%): C; 48.26, H; 6.08, Cl; 35.62, N; 4.69, O; 5.36

Found (%): C; 48.22, H; 6.02, Cl; 35.58, N; 4.63, O; 5.19

6C-(-) 2-methyl-2-ethylamino-3- (3,4-dichlorophenyl) -propanol (JO 1296)

General formula (I) = R ₁ = CH ₃ ; R ₂ = H: R ₃ = C ₂ H ₅ .

Yield: 67.9% TLC: A; 0.6

Melting point = 107 ° C (ether)

¹ H-NMR (DMSO-CDCl ₃ ) Same as the product of Example 6A.

Hydrochloride: yield = 75.6%, jungjung 269 ℃ (methanol-ether).

=-5°(C=1%, 물).

= -5 ° (C = 1%, water).

Elemental Analysis for C ₁₂ H ₁₈ Cl ₃ NO:

Theoretical value (%): C; 48.26, H: 6.08, Cl; 35.62, N; 4.69, O; 5.36

Found (%): C; 48.16, H; 6.13, Cl; 35.75, N; 4.53, 0; 5.31

Example 7

(±) 2-methyl-2-allylamino-3- (3,4-dichlorophenyl) -propanol (JP 1453)

General formula (I): R ₁ = CH ₃ ; R ₂ = H; R ₃ = CH ₂ -CH = CH ₂

30.0 g (128 mmol) of (±) 2-methyl-2-amino-3- (3,4-dichlorophenyl) -propanol (JO 1275-Example 1A) and 14.0 g (116 mmol) of brominated brothyl allyl in a moisture proof reactor Stirred suspension in 300 ml of acetonitrile. The mixture was left at room temperature for 1 hour and then heated to 30-50 ° C. for 2 hours.

After cooling, the insolubles obtained are filtered and suspended in 2 L of demineralized water, alkaneated with caustic soda solution and the resulting mixture is extracted three times with 750 ml of ether. This mixed ether phase is treated by known methods. After evaporation of the ether, 13.8 g of residue is crystallized in 1 L of hexane. This product is filtered off and dried under vacuum.

Weight: 11.2 g Yield: 31.9%

Melting point: 106 ° C. TLC: B; 0.4

¹ H-NMR (CDCl ₃ ): 1.00 (s, 3H), 1.90 (s, wide, 2H, exchangeable), 2.65 (s, 2H), 3.10-3.35 (m, 4H), 5.15 (t, 2H) , 5.60-6.25 (m, 1 H), 6.90-7.45 (m, 3 H).

Hydrochloride: yield = 94.7%, melting point 230 DEG C (ethanol-ether).

Elemental Analysis for C ₁₃ H ₁₈ Cl ₃ NO:

Theoretical value (%): C; 50.26, H; 5.84, Cl; 34.24, N; 4.51, 0; 5.15

Found (%): C; 50.22, H; 5.75, Cl; 34.33, N; 4.44, O; 5.00

Example 8

8A- (±) N-cyclopropanecarboxy-2-methyl-2-amino-3- (3, 4-dichlorophenyl) -propanol

General formula (I): R ₁ = CH ₃ ; R ₂ = H;

0.57 g (14.2 mmol) sodium hydroxide solution in pellet form dissolved in 25 ml of water, 5.0 g (21.3 mmol) of aminoalcohol in 100 ml of 1, 2-dichloroethane according to the method of Example 1A (JO 1275) To the solution.

After the mixture was vigorously stirred and cooled to 5 ° C., 1.48 g (14.2 mmol) of cyclopropane carboxylic acid chloride were added dropwise for 30 minutes at a temperature of 10 ° C. or less. Stirring was continued at 5-10 ° C. for 1 hour, then the organic phase was separated and extracted with 20 ml of N hydrochloric acid and treated in the usual manner.

After the solvent was separated, a yellow viscous oil product was obtained.

Weight: 4.3g Yield: 66.6%

TLC: B; 0.65-0.75

¹ H-NMR (CDCl ₃ ): 0.55-1.65m, 7H), 3.05 (q, 2H), 3.55-3.85 (m, 3H), 5.10 (q, 1H exchangeable), 5.55 (s, wide, 14) , 6.90-7.45 (m, 3 H).

8- (±) 2-methyl-2-cyclopropanemethylamino-3- (3, 4-dichlorophenyl) -propanol (JO 1454)

General formula (I): R ₁ = CH ₃ ; R ₂ = H;

4.2 g (13.9 mmol) of aminoalcohol of Example 8A were dissolved in 60 ml of THF in a moisture proof reactor. Under nitrogen atmosphere, 3.16 g (41.7 mmol) of BMS was added to the solution in a known manner, and the mixture was refluxed for 4 1/2 hours. After cooling, 6.0 ml of methanol was added sequentially followed by 6.0 ml of N sodium chloride solution.

After filtering the insolubles, the obtained filtrate was concentrated to dissolve the residue obtained in 100 ml of 2N hydrochloric acid. The diacid-suspension was extracted twice with 50 ml of ether, alkalized to pH 12 with caustic soda solution and then extracted again with ether. This ether phase was mixed and treated by known methods. After evaporation, inoalgohol in the form of a viscous oil was obtained.

Weight: 2.9g Yield: 72.4%

TLC: B; 0.25-0.4

¹ H-NMR (CDCl ₃ ): 0.05-1.25 (m, 7H), 2.05 (s, wide; 2H exchangeable), 2.45 (d, 2H), 2.65 (s, 2H), 3.20 (s, 2H), 6.90-7.45 (m, 3 H).

Hydrochloride: Yield = 86.3% Melting point = 237 ° C. (ethanol-ether)

Elemental Analysis for C ₁₄ H ₂₀ Cl ₃ NO:

Theoretical value (%): C; 51.79, H; 6.21, Cl; 32.76, N; 4.31, 0; 4.93

Found (%): C; 51.87, H; 6.10, Cl; 32.69, N; 4.27, O; 4.83

Example 9

9A- (±) N-pivalyl-2-methyl-2-amino-3- (3,4-dichlorophenyl) -propanol

General formula (I): R ₁ = CH ₃ ; R ₂ = H;

R ₃ = -CO-C (CH ₂ ) ₃

3.7 g (36 mmol) triethylamine was added to a 5.0 g (21.3 mmol) aminoalcohol suspension of Example 1A (JO 1275) in 30.0 ml of toluene.

While stirring the suspension at 4 ° C., a 2.53 g (21 mmol) pivaloyl chloride solution in 30.0 ml of toluene was added for 1 hour. After the addition, stirring was continued for 1 hour, and the solution was extracted twice with 25 ml of N hydrochloric acid. The toluene phase was extracted twice with 25 ml of saturated sodium bicarbonate solution and then treated in the usual manner. After removal of the toluene, a product in the form of a pale yellow viscous oil was obtained.

Weight: 6.0g Yield: 89.7%

TLC: B; 0.6-0.7

¹ H-NMR (CDCl ₃ ): 0.90-1.25 (m, 12H), 2.95 (q, 2H), 3.60 (d, 2H), 4.90 (t, 1H, exchangeable), 5.40 (s, wide, 1H) , 6.85-7.40 (m, 3 H).

9B- (±) 2-methyl-2- (2, 2-dimethyl) propylamino-3- (3,4-dichlorophenyl) -propanol (JO 1455)

General formula (I): R ₁ = CH ₃ ; R ₂ = H;

R ₃ = -CH ₂ -C (CH ₃ ) ₃

According to the method of Example 8B, 5.4 g (17 mmol) of the amide obtained above were reduced to 2.6 g (34 mmol) of BMS complex.

Weight: 4.5g Yield: 87.0%

Melting point: 91 ° C. (hexane) TLC: B; 0.45-0.55

¹ H-NMR (CDCl ₃ ): 0.95 (s, 12H), 1.30-2.05 (m, wide, 2H exchangeable), 2.25 (s, 2H), 2.65 (s, 2H), 3.25 (s, 2H), 6.90-7.45 (m, 3 H).

Hydrochloride: Yield = 71.5% Melting Point = 235 ° C. (Methanol-Ether)

Elemental Analysis for C ₁₅ H ₂₄ Cl ₃ NO:

Theoretical value (%): C; 52.87, H; 7.10, Cl: 31.22, N; 4.11, O; 4.69

Found (%): C; 53.02, H; 6.98, Cl; 31.15, N; 4.09, O; 4.57

Example 10

10A- (±) N-phenylacetyl-2-methyl-2-amino-3- (3, 4-dichlorophenyl) -propanol

General formula (I): R ₁ = CH ₃ ; R ₂ = H;

R ₃ = CO -CH ₂ -C ₆ H ₅

The product was obtained according to the method of Example 8A using 5.0 g (21.3 mmol of aminoalcohol and 2.2 g (14.2 mmol) of phenyl acetate chloride obtained in Example 1A (JO I275).

Weight: 4.9 g Yield: 65.3%

TLC: C; 0.80

¹ H-NMR (CDCl ₃ ): 1.05 (s, 3H), 2.90 (q, 2H), 3.55 (d, 2H), 4.70 (s, 2H), 4.90 (s, wide, 1H, exchangeable), 5.45 (s wide, 1H), 6.70-7.50 (m, 8H).

10B- (±) 2-methyl-2- (2-phenyl) -ethylamino-3- (3, 4-dichlorophenyl) -propanol (JO 1456)

General formula (I): R ₁ = CH ₃ ; R ₂ = H;

R ₃ = -CH ₂ -CH ₂ -C ₆ H ₅

The product was obtained according to the method of Example 8B by reducing 4.8 g (13.6 mmol) of the aminoalcohol described above to 3.1 g (40.8 mmol) of BMS complex.

Weight: 2.9g Yield: 63.0%

Melting point: 113 ° C. (hexane) TLC: B; 0.6-0.7

¹ H-NMR (CDCl ₃ ): 0.90 (s, 3H), 1.3-3.2 (m wide, 2H exchangeable), 3.55 (s, 2H), 3.75 (s, 4H), 3.15 (s, 2H), 6.75 -7.35 (m, 8H)

Hydrochloride: Yield = 84.0% Melting Point = 235 ° C (ethyl acetate)

Elemental Analysis for C ₁₈ H ₂₂ Cl ₃ NO:

Theoretical value (%): C; 57.29, H; 5.92, Cl; 28.38, N; 3.74, 0; 4.27

Found (%): C; 57.65, H; 5.84, Cl; 28.30, N; 3.68, 0; 4.22

Example 11

(±) 2-methyl-2- (N-methyl, N-ethyl) -amino-3- (3,4-dichlorophenyl) -propanol (JO 1291)

General formula (I): R ₁ = CH ₃ ; R ₂ = CH ₃ ; R ₃ = C ₂ H ₅

On a water bath at about 50 ° C., 20.0 g (76.3 mmol) of the aminoalcohol of Example 6A (JO 1277) were thoroughly mixed with 17.6 ml of a 30% formaldehyde solution (wt / v). By cooling the obtained paste to 15 ° C. and slowly adding 12.9 ml of pure formic acid (d = 1.22), the mixture became less viscous and heated to 30-100 ° C. for 1 hour to give a solution. After cooling, 100 ml of ice water was added, acidified to pH 1 with concentrated hydrochloric acid, and extracted three times with 50 ml of ether.

The acidic phase was alkalized with concentrated sodium hydroxide solution and extracted three times with 75 ml of ether. The obtained ether phase was treated by a known method and the oily residue obtained after evaporation of the ether was crystallized in 150 ml of hexane. The white crystalline product was filtered dried.

Weight: 19.45 g Yield: 92.3%

Melting Point: 55 ℃

¹ H-NMR (CDCl ₃ ): 0.95 (s, 3H), 1.10 (t, 3H), 2.30 (s, 3H), 2.55 (d, 2H), 2.65 (s, 2H), 3.00 (s wide, 1H Exchangeable), 3.25 (d, 2H), 6.90-7.45 (m, 3H).

Hydrochloride: Yield = 64.4% Melting Point = 192 ° C. (ethanol)

Elemental Analysis for C ₁₃ H ₂₀ Cl ₃ NO:

Theoretical value (%): C; 49.94, H; 6.45, Cl; 34.02, N; 4.48, 0; 5.12

Found (%): C; 49.83, H; 6.35, Cl; 33.93, N; 4.38, O; 5.21

Example 12

(±) 2-methyl-2- [N-methyl, N- (2-phenyl) -ethyl] -amino-3- (3,4-dichlorophenyl) -propanol (JO 1457)

General formula (I): R ₂ = CH ₃ ; R ₂ = CH ₃ ;

R ₃ = CH ₂ -CH ₂ -C ₆ H ₅

The product was prepared according to the method of Example 1 using 8.9 g (26.3 mmol) of aminoalcohol prepared in Example 10B (JO 1456) as a starting material. The product was in the form of a viscous oil.

Weight: 8.8 g Yield: 95.0%

TLC: C; 0.55

¹ H-NMR (CDCl ₃ ): 0.85 (s, 3H), 2.20 (s wide, 1H interchangeable), 2.25 (s, 3H), 2.40-2.75 (m, 6H), 3.10 (d, 2H), 6.85 -7.35 (m, 8 H).

Hydrochloride: Yield = 65.3% Melting point = 212 ° C. (ethanol-ether)

Elemental Analysis for C ₁₉ H ₂₄ Cl ₃ NO:

Theoretical value (%): C; 58.70, H; 6.22, Cl; 27.36, N; 3.60, 0; 4.11

Found (%): C; 58.62, H; 6.17, Cl; 27.31, N; 3.57, O; 4.03

Example 13

(±) 2-methyl-2- (N-methyl, N-allyl) -amino-3- (3,4-dichlorophenyl) -propanol (JO 1581)

General formula (1): R ₁ = CH ₃ ; R ₂ = R ₃ = CH ₂ -CH = CH ₂

The product was prepared according to the method of Example 11 using 3.8 g (13.8 mmol) of aminoalcohol obtained in Example 7. The product was obtained in the form of a pale yellow viscous oil.

Weight: 3.8g Yield: 95.5%

TLC: B; 0.60

¹ H-NMR (CDCl ₃ ): 0.95 (s, 3H), 2.25 (s, 3H), 2.70 (s, 2H), 2.90 (s, 1H exchangeable), 3.15 (d, 2H), 3.25 (d, 2H), 5.25 (d, 2H), 5.55-5.95 (m, 1H), 6.95-7-45 (m, 3H).

Hydrochloride: Yield = 86.5% Melting Point = 190 ° C. (Ethyl Acetate)

Elemental Analysis for C ₁₄ H ₂₀ Cl ₃ NO:

Theoretical value (%): C; 51.79, H; 6.21, Cl; 32.76, N; 4.31, O; 4.93

Found (%): C; 51.73, H; 6.21, Cl; 32.68, N; 4.26, 0; 5.05

Example 1A (JO 1275), 1B (JO 1307) and 1C aminoalcohol were reacted with formaldehyde and formic acid to give the products of Examples 14A, 14B and 14C, respectively. The products of Examples 15 and 16 were also prepared from the aminoalcohols of Examples 2 and 3, respectively.

Manufacturing method

0.1 mole of aminoalcohol was added to 24.6 ml of 37% formaldehyde solution (wt / v), i.e. 9.0 g (0.3 mole). The reagents are mixed vigorously, in order to obtain a uniform gum, sometimes slightly lukewarm and slowly adding 18.9 ml (0.5 mole) of 99-100% formic acid (d = 122) with cooling as necessary. The viscous mixture is left in a boiling bath for 11/2 hours, cooled to 20 ° C. and then 125 ml of water is added.

The solution is acidified to pH 1 with concentrated hydrochloric acid and extracted three times with 50 ml of ether. The ether phase is removed and the acidic phase is alkalized to pH 12 with concentrated sodium hydroxide solution and extracted three times with 75 ml of ether. This mixed ether phase is treated by known methods.

Example 14

14A- (±) 2-methyl-2-dimethylamino-3- (3,4-dichlorophenyl) -propanol (JO1017)

Formula (I): R ₁ = R ₂ = R ₃ = CH ₃ White crystal

Yield: 79.2% Melting Point = 88 ° C (hexane)

TLC: A; 0.4-0.5

¹ H-NMR (CDCl ₃ ): 0.90 (s, 3H), 2.30 (s, 6H), 2.65 (s, 2H), 3.10 (s, wide, 1H exchangeable), 3.20 (s, 2H), 6.95- 7.45 (m, 3 H).

Hydrochloride: Yield = 84.0% Melting Point = 177 ° C (ethanol)

Elemental Analysis for C ₁₂ H ₁₈ Cl ₃ NO:

Theoretical value (%): C; 48.26, H; 6.07, Cl; 35.62, N; 4.69, O; 5.36

Found (%): C; 48.35, H; 6.04, Cl; 35.47, N; 4.70, O; 5.43

14B-(-) 2-methyl-2-dimethylamino-3- (3, 4-dichlorophenyl) -propanol (JO 1239)

Formula (I): R ₁ = R ₂ = R ₃ = CH ₃

Oil: yield = 53.1% TLC: A; 0.4-0.5

=-6.5°(C=1%, 에탄올)

= -6.5 ° (C = 1%, ethanol)

¹ H-NMR (CDCl ₃ ): same as the product of Example 14A.

Hydrochloride: Yield = 79.2% Melting Point = 192 ° C (ethanol)

Elemental Analysis for C ₁₂ H ₁₈ Cl ₃ NO:

Theoretical value (%): C; 48.26, H; 6.07, Cl; 35.62, N; 4.69, O; 5.36

Found (%): C; 48.21, H; 6.09, Cl; 35.55, N; 4.63, O; 5.39

14C-(+) 2-methyl-2-dimethylamino-3- (3, 4-dichlorophenyl) -propanol (JO 1240)

Formula (I): R ₁ = R ₂ = R ₃ = CH ₃

Oil: yield = 53.1% TLC: A; 0.4-0.5

=+6.2°(C=2%, 에탄올)

= + 6.2 ° (C = 2%, ethanol)

¹ H-NMR (CDCl ₃ ): same as the product of Examples 14A and B.

Hydrochloride: Yield = 79.7% Melting Point: 193 ° C (ethanol)

Elemental Analysis for C ₁₂ H ₁₈ Cl ₃ NO:

Theoretical value (%): C; 48.26, H; 6.07, Cl; 35.62, N; 4.69, O; 5.36

Found (%): C; 48.16, H; 6.12, Cl; 35.61, N; 4.57, O; 5.45

Example 15

(±) 2-isopropyl-2-dimethylamino-3- (3,4-dichlorophenyl) -propanol (JO 1580)

General formula (I): -R ₁ = CH (CH ₃ ) ₂ ; R ₂ = R ₃ = CH ₃

Oil: yield = 96.6% TLC: A; 0.65

¹ H-NMR (CDCl ₃ ): 0.80-1.20 (m, 6H), 1.65-2.20 (m, 1H), 2.40 (s, 6H), 2.75 (s, 2H), 3.20 (s, 1H exchangeable), 3.45 (s, 2 H), 7.00-7.45 (m, 3 H).

Hydrochloride: Yield = 92.9% Melting Point = 178 ° C (acetone)

Elemental Analysis for C ₁₄ H ₂₂ Cl ₃ NO:

Theoretical value (%): C; 51.47, H; 6.79, Cl; 32.56, N; 4.29, O; 4.89

Found (%): C; 51.56, H; 6.59, Cl; 32.53, N; 4.26, O; 4.98

Example 16

(±) 2-pentyl-2-dimethylamino-3- (3,4-dichlorophenyl) -propanol (JO 1564)

General formula (I): —R ₁ = (CH ₂ ) ₄ CH ₃ ; R ₂ = R ₃ = CH ₃

Oil: yield = 92.5% TLC: A; 0.65

¹ H-NMR (CDCl ₃ ): 0.80 (t, 3H), 1.30 (s, 8H), 2.35 (s, 6H), 2.65 (s, 2H), 3.25 (s, 1H interchangeable in 3H), 6.85- 7.35 (m, 3 H).

Hydrochloride: Yield = 92.7% Melting Point = 160 ° C (Ethyl Acetate)

Elemental Analysis for C ₁₆ H ₂₆ Cl ₃ NO:

Theoretical value (%): C; 54.17, H; 7.38, Cl; 29.98, N; 3.95, O; 4.51

Found (%): C; 54.15, H; 7.26, Cl; 29.82, N; 3.88, 0; 4.60

Example 17

(±) 2-methyl-2- (1-piperidyl) -3- (3,4-dichlorophenyl) -propanol (JO 1467)

General formula (I): R ₁ = CH ₃ ; NR ₂ -NR ₃ = piperidyl

5 g (21.3 mmol) of aminoalcohol and 5.14 g (22.3 mmol) of 1,5-dibromopentane obtained in Example 1A were dissolved in 40 ml toluene in a moisture proof reactor.

The solution was refluxed for 1 hour with stirring and then cooled to room temperature. Then, 4.58 g (43.2 mmol) of sodium carbonate was added, and the suspension obtained was again refluxed for 20 hours. After cooling, 100 ml of 2N hydrochloric acid was added slowly and the insolubles were filtered off and washed with toluene.

The filtrate was removed and the insolubles obtained were dissolved in 500 ml of water. 10 N sodium hydroxide was added to the obtained suspension and alkalized to pH 12. This mixture was extracted three times as 250 ml of ether. The mixed ether phases were treated by known methods. After evaporation, a white amorphous solid product was obtained.

Weight 2,2 g Yield = 34.2%

Melting point = 94 ° C. TLC: A; 0.6

¹ H-NMR (CDCl ₃ ): 0.95 (s, 3H), 1.55 (s wide, 6H), 2.50-2.75 (m, 6H), 2.90 (s, H exchangeable), 3.30 (q, 2H), 6.90 -7.45 (m, 3 H).

Elemental Analysis for C ₁₅ H ₂₁ Cl ₂ NO:

Theoretical value (%): C; 59.61, H; 7.00, Cl; 23.46, N; 4.63, O; 5.29

Found (%): C; 59.42, H; 6.99, Cl: 23.58, N; 4.74, 0; 5.30

Example 18

(±) 2-methyl-2- (4-morpholinyl) -3- (3,4-dichlorophenyl) -propanol (JO 1565)

General formula (I): -R ₁ = CH ₃ ; NR ₂ -R ₃ = morpholine

23.4 g (0.1 mole) of aminoalcohol obtained in Example 1A was dissolved in 300 ml of dimethylformamide in a moisture proof reactor.

While stirring, 15.7 g (0.110 mole) of bis-2-chloroethyl ether and 18.5 g (0.220 mole) of sodium bicarbonate were added sequentially.

The suspension was stirred at 100 ° C. for 48 hours. Insolubles were filtered off and the dimethylfo was removed by vacuum distillation. The residue obtained was dissolved in ether and then this solution was extracted three times in turn with 150, 100 and 100 ml of N HCl solution.

The mixed hydrochloric acid phase was alkalized to pH 12 by addition of caustic soda solution. The mixture was then extracted with ether. This mixed ether phase was washed with saturated sodium chloride solution and then dried over Na ₂ SO ₄ . The ether was distilled off. The residue obtained was 33.0 g.

The residue was purified by silica column chromatography. Elution with methylene chloride-methanol mixture 95: 5 (v / v) afforded the above product.

Weight 14.5g Yield = 47.7%

TLC: C; 0.75

Hydrochloride: Yield = 76.9% Melting Point = 232 ° C (Methanol-Ether)

Elemental Analysis for C ₁₄ H ₂₀ Cl ₃ NO ₂ :

Theoretical value (%): C; 49.36, H; 5.92, Cl; 31.32, N; 4.11, O; 9.39

Found (%): C; 49.38, H; 5.88, Cl; 31.17, N; 4.03, O; 9.49

Example 19

(±) 2-methyl-2- (1- (4-methyl) -piperazinyl) -3- (3, 4-dichlorophenyl) -propanol (JO 1566)

46.8 g (0.200 mole) and 42.2 g (0.220 mole) of aminoalcohol of Example 1A were prepared using N-methyl-bis- (2-chloroethyl) -amine hydrochloride and 54 g (0.640 mole) of sodium bicarbonate as starting materials. The product was obtained according to the method of Example 18.

Weight 6.2g Yield = 9.8%

Melting point = 118 ° C. (ethyl acetate) TLC: D; 0.45

Elemental Analysis for C ₁₅ H ₂₂ Cl ₂ N ₂ :

Theoretical value (%): C; 56.71, H; 6.99, Cl; 22.35, N; 8.83, 0; 5.04

Found (%): C; 56.73, H; 6.82, Cl; 22.28, N; 8.74, 0; 5.20

¹ H-NMR (CDCl ₃ ): 1.05 (s, 3H), 2.40 (s, 3H), 2.45-3.05 (m, 10H), 3.05-3.65 (m, 1H exchangeability in 3H), 6.95-7.50 (m , 3H).

Weight 2.2g Yield = 34.2%

Melting point = 94 ° C. TLC: A; 0.6

¹ H-NMR (CDCl ₃ ) = 0.95 (s, 3H), 1.55 (s wide, 6H), 2.50-2.75 (m, 6H), 2.90 (s, H exchangeable), 3.30 (q, 2H), 6.90 -7.45 (m, 3 H).

Elemental Analysis for C ₁₅ H ₂₁ Cl ₂ NO:

Theoretical value (%): C; 59.61, H; 7.00, Cl; 23.46, N; 4.63, O; 5.29

Found (%): C; 59.42, H; 6.99, Cl; 23.58, N; 4.74, 0; 5.30

Pharmacological studies of the product according to the present invention show very interesting properties, especially for the central nervous system (S.N.C.), which has analgesic activity. In addition, their toxicity was also measured. The details of this study are presented below and the results obtained indicate the therapeutic activity of these products as well as their usefulness as a medicament.

Acute toxicity was studied by oral administration to male rats. For this purpose, the product was administered in an aqueous solution of 2ml / 100g ratio. The animals were observed for 3 hours after dosing and then daily for 14 days, lethal and necropsied.

LD ₅₀ values (fatality killing 50% of animals) were measured according to the methods of Reed JL and Muench H (Am. J. Hyg. 1939, 27, 493). This value is generally between 750 and 1200 mg / kg and may sometimes be greater than the latter value.

Activity against S.N.C.

This activity was measured as a tail suspension experiment in mice according to the method by Thierry et al. (Behavioral and Neural Biology, 1984, 41, 180-189), in which animal models for screening products with activity against S.N.C. were proposed.

The experiment was carried out in batches of 10 male rats for each dose of each product, the material to be tested was orally administered as an aqueous solution 1 hour prior to measurement, and the control batch was fed only distilled water.

The measurement results are expressed as percentage of activity compared to the control.

Analgesic activity

This was measured and studied in rats by acetic acid test according to the method of Troster R. (Fed. Proc. 1959. 18, 412).

Twenty hours before the test, the animals were fasted for food and water. The test product was then orally administered at a rate of 2 ml of solution for 100 g of body weight, followed by intraperitoneal administration of 0.25 ml of 0.25% acetic acid solution (wt / v) maintained at 37 ° C. after 30 minutes. Thirty minutes after the injection, the number of abdominal cramps experienced by the animal is counted every 10 minutes.

The pain is considered to be alleviated when the analgesic number of the animal is less than 1/2 of the mean value of the spasms according to the control experiment.

The results obtained by administering the product at a dose of 30 mg / kg ratio are expressed as the percentage of animals with pain relief. For any product, several doses were administered and the ED ₅₀ (the dose at which 50% of the animals alleviate pain) was determined in log probability units.

The results of the two experiments are summarized in Tables (1) and (2).

TABLE 1

Results of Pharmacological Experiment

TABLE 2

As can be seen from these results, the product according to the present invention shows much greater activity against the central nervous system when compared to clomipramine when the doses of 32 and 128 mg / kg are administered.

The analgesic of the product according to the invention is clearly demonstrated upon oral administration of 30 mg / kg. ED ₅₀ values indicate superior activity compared to the known analgesic Noramidopyrine used as reference.

Thus, the products according to the invention have activity as psychotropic and analgesic agents which are useful in contract form for livestock and human therapeutic purposes.

Among them, these agents are especially prescribed for the treatment of various etiological pains as well as psychopathological and neuropathological diseases.

They are used in patients with mental and neurological disorders, i.e. patients with prognosis, such as variations in temperament, memory, psychomotor tension and any organic function.

Moreover, due to the combined activity of the product as a psychotropic and analgesic agent, the present formulation can be used in any clinic as well as in the treatment of insomnia, headache, migraine or ocular pain.

The product according to the invention, or a pharmaceutically acceptable salt thereof, is administered in a form suitable for the nature of the disease to be treated, the form of the composition according to the suitable route of administration, and according to the desired route of administration.

Due to the relatively low toxicity of these products, the daily dose in humans is about 1 g. Typical daily dosages are between 0.010 and 0.500 g and this amount can be divided into several unit doses.

The pharmaceutical composition according to the present invention comprises 1 to 40% by weight of the active ingredient consisting of one or more compounds of the general formula (I) or salts thereof and 99 to 99 pharmaceutical carriers according to the physical form of the desired composition. 60 weight percent.

The compositions are prepared by known methods and their form corresponds to the route of administration. Examples include tablets, dragees, capsules, powders, injectable or drink solutions, gels and suppositories. These preparation methods will be described below as non-limiting methods for preparing an isotonic solution or tablet for injection of the active ingredient according to the present invention.

refine

Formulation

5-75 mg of active ingredient according to Example 10A

2 mg polyvinyl pyrrolidone

Carboxymethyl Starch 8mg

Magnesium Stearate 3mg

Lactose 60-76 mg

Monocrystalline Cellulose 12 2-76mg

Manufacturing method

Polyvinyl pyrrolidone is dissolved at a concentration of 0.1 to 1.0% by weight in water or low molecular weight alcohols such as ethanol or hydroalcohol mixtures.

The active ingredient, lactose, half of the crystalline cellulose and carboxymethyl starch are thoroughly mixed and then humidified with the polyvinyl pyrrolidone solution obtained above.

The paste obtained is granulated on a vibrating granulator and the granules are dried on an oven or a flowing air bed. The obtained particles are separated on a screen, and magnesium stearate, the remainder of the microcrystalline cellulose and the carboxymethyl starch are added. After sufficient mixing, the tablets are purified at a rate of 200 mg per tablet.

Isotonic Solution for Injection

Formulation

10 mg of active ingredient (hydrochloride form) according to Example 1A

Sodium chloride 9mg

Distilled Water (Equivalent) 1.0ml

The isotonic solution is injected into an appropriate volume of ampoule, sealed and sterilized by a known heat treatment method, or the solution is sterilized by filtration and then divided into an ampoule under sterilization and sealed. In the latter case, it is preferable to add 1% benzyl alcohol as the disinfectant or 10 mg of the alcohol to the formulation for 1 ml of solution.

Claims (10)

Aminoalcohol of the following general formula (I) and acid addition salt thereof.

Wherein R ₁ is lower alkyl, R ₂ is H or lower alkyl, R ₃ is H, lower alkyl, lower alkenyl, lower phenylalkyl or lower cyclo alkylalkyl having 3-6 carbon atoms in the ring, or R ₂ When H, lower alkanoyl, lower phenyl alkanoyl or cycloalkyl carbonyl having 3-6 carbon atoms in the ring, R ₂ and R ₃ together with the nitrogen atom to which they are attached form a heterocycle saturated with 5-7 chains. Wherein said heterocycle may comprise oxygen, sulfur or nitrogen as a second heteroatom not directly linked to said nitrogen atom, wherein said latter nitrogen heteroatom is alkyl of C ₁ -C ₄ It may have a substituent. The aminoalcohol according to claim 1, wherein R ₁ is methyl. The aminoalcohol according to claim 1 or 2, wherein R ₂ is hydrogen or methyl. The aminoalcohol according to any one of claims 1 to 3, wherein R ₃ is hydrogen or methyl. The aminoalcohol according to claim 1, which is 2-methyl-2-amino-3- (3,4-dichlorophenyl) -propanol and salts thereof. The aminoalcohol according to claim 1, which is 2-pentyl-2-amino-3- (3,4-dichlorophenyl) -propanol and salts thereof. The aminoalcohol according to claim 1, which is 2-methyl-2-methylamino-3- (3,4-dichlorophenyl) -propanol and salts thereof. The aminoalcohol according to claim 1, which is 2-methyl-2- [N-methyl, N- (2-phenyl) ethyl] -amino-3- (3,4-dichlorophenyl) -propanol and salts thereof. . The aminoalcohol according to claim 1, which is 2-methyl-2-dimethylamino-3- (3,4-dichlorophenyl) -propanol and salts thereof. An analgesic agent having an activity in the central nervous system comprising 1 to 40% by weight of aminoalcohol of the general formula (I) and acid addition salt thereof, or a salt thereof and 99 to 60% by weight of a pharmaceutically acceptable carrier.

Wherein R ₁ is lower alkyl, R ₂ is H or lower alkyl, R ₃ is H, lower alkyl, lower alkenyl, lower phenylalkyl or lower cyclo alkylalkyl having 3-6 carbon atoms in the ring, or R ₂ When H, lower alkanoyl, lower phenyl alkanoyl or cycloalkyl carbonyl having 3-6 carbon atoms in the ring, R ₂ and R ₃ together with the nitrogen atom to which they are attached form a heterocycle saturated with 5-7 chains. In this case, the second hetero atom which is not directly connected to the nitrogen atom may include oxygen, sulfur or nitrogen atom, wherein the latter nitrogen hetero atom has an alkyl substituent of C ₁ -C ₄ It may be.