CS211327B1 - 3-+l 2-alcoxyphenoxy+p -3-phenylpropylamines and the salts thereof - Google Patents

Description

(54,3- (2-Alkoxyphenoxy) -3-phenylpropylamines and their salts)

This invention relates to novel 3- (2-alkoxy-phenoxy) -3-phenylpropylamine of formula I ___ OR ^{* 1}

Q ^^ OCHCHjCKjR C ₆ H ₅ wherein R know the rest of 4-methyl-piperazinyl or 4-benzyl-1-piperazinyl and R ¹ is methyl, ethyl or benzyl, or wherein the residue R is methylamino or dimethylamino, and R ¹ is only benzyl, and their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula I and their salts have. therapeutically useful locally anesthetic and spasmolytic efficacy, of which they are technically important. They are suitable for the removal of spasms of smooth muscles, especially the digestive tract. The intensity of their effects is indicated by the following specific data:

1- (3- (2-Methoxyphenoxy) -3-phenylpropyl) -4-benzylpiperazine was tested as the dihydrochloride. Acute toxicity in mice by intravenous administration, LD ^ q = 15 mg / kg. At a concentration of 0.1 to 0.5%, this substance causes complete anesthesia of the cornea of the eye in 50% of the rabbits in the experiment (a concentration of 1% for trimecaine as standard is required to achieve the same effect).

At a concentration of 1 µg / ml, it reduces acetylcholine-induced contractions of isolated rat duodenum by 50%, and at a concentration of 1 to 10 µg / ml, it has a similar effect to barium chloride contractions (this is virtually as intense as papaverine for

ED = 5 µg / ml). 1- (3- (2-Ethoxyphenoxy) -3-phenylpropyl) -4-benzylpiperazine was also tested as the dihydrochloride. Acute toxicity, LDc ₀ = 12,5 mg / kg iv This substance is also active

211327 2 in the corneal anesthesia test (ED = 0.1 to 0.5%) and acts by spasmolytiocy against both aeytelcholine (ED = 1 to 10 µg / ml) and barium chloride contractions (ED = 1 to 10 µg / ml) isolated rat duodenum.

The processes for the preparation of the compounds of the formula I according to the invention are described in the examples. They consist primarily in the reactions of the alkali salts of guaiacol, 2-ethoxyphenol (E. Klarmann et al., J. Amer. Chem. Soo. 54. 1204 1932) and 2-benzyloxyphenol (JH Jones, GT Young, J. Chem. Soc. (C) 1968. 436) and halide derivatives of the general formula II,

CICHCHgCHgR (ii) ^C 6 ^H 5 wherein R is the residue of dimethylamine, 4-methyl-piperazinyl or 4-benzyl-1-piperazinyl, in boiling ethanol. Of the starting chloro derivatives of formula II, only 1-phenyl-3-dimethylaminopropyl chloride has been described in the literature (B. B. Mol'loy and K. K. Schmiegel, US 4,018,895; Chem. Abstr. 87, 134, 520, 1977). The preparation of others is given in the examples.

The compound of the invention of formula I wherein R = methylamino and R ¹ = benzyl is prepared by another method. This is based on the dimethylamino derivative of the formula III, >> CH ₂ C ₆ H ₅ 'ochch ₂ ch ₂ n (ch ₃ ) ₂

5 4 ^H (III) obtained in this way first, který'se partially demethylated by treatment with ethyl chloroformate in refluxing benzene. The product is a carbamate of formula IV, Y 2 ^CH 2 ^C 6 ^H 5

CH, ochch ₂ ch ₂ Ng ₆ h ₅

The COOC3 H6 (IV) which is isolated as a neutral substance and in the second stage is hydrolysed alkaline, preferably by a very concentrated solution of potassium hydroxide in ethanol at the boiling point of this solution. In this way the desired compound of formula I is obtained, wherein R = methylamino and r '= benzyl.

The substances according to the invention are bases insoluble in water. For the performance of pharmacological tests or for the preparation of dosage forms, salts of these bases are substantially more preferred than the free bases. These salts are part of the invention and are prepared by neutralizing bases with pharmaceutically acceptable inorganic or organic acids. Particularly preferred and crystalline well are the hydrochlorides.

The identity of the compounds according to the invention and the novel intermediates was ensured both analytically and by means of spectra (UV, IR, 1 H-NMR, MS).

Examples:

1- (3- (2-Methoxyphenoxy) -3-phenylpropyl) -4-methylpiperazine

3.5 g of sodium hydroxide and 4.5 g of guaiacol are successively dissolved in 140 ml of ethanol.

While stirring, 8.15 g of 1-phenyl-3- (4-methylpiperazino) propyl chloride dihydrochloride is added and the reaction mixture is refluxed for 12 hours with stirring. Ethanol was then distilled off, 50 ml of 1M-NaOH was added to the residue, and the base was isolated by extraction with ether. The extract was dried over potassium carbonate and evaporated under reduced pressure. The crude base obtained is dissolved in 25 ml of ethanol and the solution is neutralized with a slight excess of anhydrous HCl in ether. After addition of 25 ml of ether, the dihydrochloride of the title compound precipitates in a yield of 7.9 g (74%), mp 189-191 ° C. Crystallization from a mixture of 2-propanol, ethyl acetate and ether affords a completely pure material, m.p. According to analysis, this product is a hemihydrate.

The required 1-phenyl-3- (4-methylpiperazino) propyl chloride dihydrochloride is a novel compound which is prepared by the following procedure:

To a solution of 14.2 g of 37 (4-methylpiperazino) propiophenone (A-Lespagnol et al., 9th Congr. Soc. Pharm. France, Clermont-Ferrand 1957, 185; Chem. Abstr. Gg, 21,929, 1959) at 100 4.6 ml of sodium borohydride are slowly added with stirring to the ml of ethanol, and the mixture is refluxed for 3.5 hours. The ethanol was evaporated, the residue was quenched with 100 ml of water and extracted with benzene. The extract was washed with 15% sodium chloride solution, dried over potassium carbonate and evaporated. 13.0 g (91%) of oily 1-phenyl-3- (4-methylpiperazino) propanol are obtained. Neutralization with anhydrous hydrogen chloride in ethanol / ether yields 11.7 g of crystalline dihydrochloride, which crystallizes from ethanol and melts in the pure state at 198-199 ° C.

A solution of 30.8 g of thionyl chloride in 18 ml of chloroform is added dropwise to the stirred suspension of 11.7 g of the preceding dihydrochloride in 150 ml of chloroform over a period of 20 minutes at 30 to 35 ° C. The mixture was stirred at 40-45 ° C for 20 min and then refluxed for 3 h. It is evaporated to dryness under reduced pressure, acetone is added to the residue and, after standing for 1 h, the precipitated 1-phenyl-3- (4-methylpiperazino) propyl chloride dihydrochloride is filtered off with suction. Yield: 11.8 g (95%), mp 245-253 ° C. Crystallization from ethanol gave the pure product, mp 251.5-254 ° C.

2. 1- (3x (2-Methoxyphenyl) -3-phenylpropyl) -4-benzylpiperazine

3.6 g of sodium hydroxide and 5.0 g of guaiacol are successively dissolved in 120 ml of ethanol and 10.0 g of 3- (4-benzylpiperazino) -1-phenylpropyl chloride dihydrochloride are added with stirring. The mixture was refluxed under stirring for 10 h, the ethanol was distilled off, 70 ml of 1M-NaOH was added to the residue, and the product was extracted with ether. The extract was washed with water, dried over potassium carbonate and evaporated. 9.9 g (95%) of a crude oil base are obtained, which is neutralized, as in the previous case, with a solution of hydrogen chloride in ether. 1 g, 1 g (89%) of the dihydrochloride is obtained, which crystallizes as a sesquihydrate from wet 2-propanol, m.p.

Mp 207-209 ° C.

The starting material 3- (4-benzylpiperazino) -1-phenylpropyl chloride dihydrochloride is a novel compound and is prepared as follows:

To a solution of 7.8 g of 3- (4-benzylpiperazino) propiophenone (K. Lányi et al., Pharmazie 2g,

189, 1970) in 60 ml of ethanol was slowly added 1.9 g of sodium borohydride and the mixture was refluxed under stirring for 3.5 hours. Then the ethanol is evaporated, the residue is diluted with water and extracted with benzene. Work-up of the extract gave 7.2 g (93%) of the crystalline base of 3- (4-benzylpiperazino) -1-phenylpropanol, m.p. 65-75 ° C. Crystallization from petroleum ether gave a pure base, mp 78.5-80 ° C. Neutralization with hydrogen chloride in ethanol / ether yields crystalline dihydrochloride which melts in pure state at 200 to 201 ° C (ethanol).

Similar to the procedure described in Example 1 above, 41.5 g of the previous dihydrochloride were reacted with 71.5 g of thionyl chloride in 470 ml of chloroform. There was obtained 41.7 g (96%) of 3- (4-benzylpiperazino) -1-phenylpropyl chloride dihydrochloride, m.p. 226 DEG C. Crystallization from aqueous ethanol gave the pure product, m.p. 225-228 DEG C. with decomposition.

3. 1- (3- (2-Ethoxyphenoxy) -3-phenylpropyl) -4-methylpiperazine

As in the previous cases, 6.0 g of 2-ethoxyphenol (cited) are reacted with 7.1 g of 1-phenyl-3- (4-methylpiperazino) propyl chloride dihydrochloride in a solution of 3.5 g.

LZZil sodium hydroxide in 110 ml ethanol. The mixture is boiled for 7 hours and worked up as before. The crude oily base was converted directly to neutralization with anhydrous hydrogen chloride in an ethanol / ether mixture to give the dihydrochloride in a yield of 7.4 g (80%). It crystallizes from wet 2-propanol as a monohydrate and melts in the pure state at 182-186 ° C.

4th 1 - (3 "/ 2-Ethoxyphenoxy / ^-3-a, a-phenylpropyl) -4-benzylpiperazine

Similarly to the previous cases, 5.54 g of 2-ethoxyphenol are reacted with 10.05 g of 3- (4-benzylpiperazino) -1-phenylpropyl chloride dihydrochloride in a solution of 3.6 g of sodium hydroxide in 120 ml of ethanol. The mixture was refluxed for 10 h and worked up as before. The crude base is directly neutralized with hydrogen chloride in a mixture of ethanol and ether; 11.4 g (91%) of the dihydrochloride are obtained, which crystallizes from wet 2-propenol as the monohydrate melting at 201 ° C.

5. 1- (3- (2-Benzyloxyphenoxy) -3-phenylpropyl) -4-methylpiperazine

As in the previous cases, 6.0 g of 2-behzyloxyphenol (literature cited) is reacted with 7.1 g of 1-phenyl-3- (4-methylpiperazino) propyl chloride dihydrochloride in a solution of 3.0 g of sodium hydroxide in 110 ml of ethanol. The oily base obtained was converted to the dihydrochloride (8.1 g, 76%), m.p. 204-205.5 ° C (2-propanol).

6. 1- (3- (2-Benzyloxyphenoxy) -3-phenylpropyl) -4-benzylpiperazine

As in the previous cases, 7.0 g of 2-benzyloxyphenol are reacted with 10.1 g of 3- (4-benzylpiperazino) -1-phenylpropyl chloride dihydrochloride in a solution of 3.5 g of sodium hydroxide in 140 ml of ethanol. The oily base obtained is converted, as in the previous cases, to the dihydrochloride (yield 81%); crystallizes from a mixture of wet 2-propanol and ether as a hemihydrate and melts in the pure state at 91-193 ° C.

7. N, N-Diraethyl-3- (2-benzyloxyphenoxy) -3-phenylpropylamine

Benzyloxyphenol (14.0 g) is dissolved in a solution of 4.8 g of sodium hydroxide in 170 ml of ethanol, 11.7 g of 1-phenyl-3-dimethylaminopropyl chloride hydrochloride (US 4,018,895) is added to the solution, and the mixture is stirred and The ethanol was distilled off, 100 ml of IM-NaOH was added to the residue, and the product was extracted with ether. The precipitated solid was filtered off, the extract was washed with water, dried over potassium carbonate and evaporated. 17.8 g (98%) of crude base is obtained, which crystallizes slowly from cyclohexane, m.p. 65-69 ° C. Crystallization from petroleum ether gave the pure product, mp 70-72 ° C. Acid neutralization provides hydrochloride melting at 158-161 ° C (2-propanol-ethyl acetate) and hydrogen oxalate, m.p. 148-150 ° C (2-propanol-ethyl acetate).

8. N-Methyl-3- (2-benzyloxyphenoxy) -3-phenylpropylamine

A solution of 2.1 g of ethyl chloroformate in 20 ml of benzene is added dropwise over a period of 50 minutes to a stirred solution of 7.0 g of the preceding base in 32 ml of benzene at 70-75 ° C. The mixture was then refluxed for 1.5 h, diluted with 50 mL of benzene and washed with 25 mL of 2.5M HCl. The separated organic layer was evaporated under reduced pressure and the residue was chromatographed on a column of 160 g of neutral alumina (activity II). Benzene eluted first with 1.4 g of the least polar contaminant and then with 1.2 g of homogeneous oily ethyl N-methyl-N- (3- (2-benzyloxyphenoxy) -3-phenylpropyl) carbamic acid ethyl ester.

A mixture of 4.5 g of crude carbamate, 5.6 g of potassium hydroxide and 7 ml of ethanol is refluxed for 1.5 h in a bath at 105-115 ° C. The mixture was then diluted with water and extracted with benzene. The extract is shaken with 100 ml of 1M-HCl, but the hydrochloride formed does not enter the aqueous phase and is obtained by evaporating the benzene solution; 4.0 g of an oil which crystallized slowly when dissolved in 10 ml of 2-propanol. It is the hydrochloride of the title compound and melts at 152 to 153.5 ° C (2-propanol) in pure form.

Claims (2)

SUBJECT OF THE INVENTION 3- (2-Alkoxyphenoxy) -3-phenylpropylamines of formula (I) OR ¹ ochch ₂ ch ₂ r ^{(I) C} 6 ^H S wherein R represents a 4-methyl-1-piperazinyl or 4-benzyl-1-piperazinyl radical and R ¹ is methyl, ethyl or benzyl, or wherein the radical R is methylamino or dimethylamino ar is benzyl only, and their salts with pharmaceutically acceptable inorganic or organic acids. Severography. n. p „plant 7. Most