DE2325328A1 - 1-trifluoromethoxy derivs - and 1-trifluoromethylthio-phenyl derivs of 2-aminopropanes, anoretcis - Google Patents

Abstract

Cpds. of formula (I) and their salts are new: where R' and R2 = H or 1-5C ALKYL; OR NR'R2 = a heterocyclic residue opt. contg. a further heteroatom; and A = O or S. Anoretics with no CNS or cardiovascular activity. EtNH2 (2 ml) was added to HCO2H (1.85 g) to 0 degree, followed by 1-(3'trifluoromethylthiophenyl) propan-2-one (2.85 g) at 20 degrees. The mixture was heated 14 hrs. at 160-170 degrees, HCl (2ml) and H2O (2 ml) added, refluxed 3 hrs., 2 ml. HCl added, refluxed 2 hrs., diluted with H2O, and extracted with Et2O (50 ml). The H2O phase was basified, extracted with Et2O (3 x 50 ml), the Et2O washed, dried, evapd., and the oil (1.4g) treated with HCl-Et2O, giving 1-(3'-trifluoromethylthiophenyl)-2-ethylaminopropane HCl (30% yield), m.p. 130 degrees (recryst. from EtOAc).

Description

825 n / wa

Synthelabo, Paris / Prankreich

New phenylethylamine derivatives

The invention relates to new phenylethylamine derivatives of the general formula (i)

309882/1448

wherein R, and R "are identical or different and either represent a hydrogen atom or a straight-chain or branched alkyl radical having 1 to 5 carbon atoms, where 'R, and R_ and the nitrogen atom together can form a heterocyclic radical which optionally comprises one or more further heteroatoms, for example a piperidine, morpholine, thiomorpholine radical etc., and A is either a sulfur or an oxygen atom.

Due to the presence of an asymmetrical carbon atom in the molecule of compounds (i) understands the compounds (i) according to the invention include the racemates and their optical isomers.

The invention also includes the addition salts which the compounds (i) with any mineral or organic pharmaceutically acceptable acid.

The invention also relates to a process for the preparation of the amines of the general formula (i), the is characterized by the fact that one is a phenyl-1-propanone-2 of the general formula (II), in which A has the same meaning as in the general formula (i), with an amine of the general formula (! Ql), wherein R-, and R_

309882/1448

mean the same radicals as in formula (1).

- C

(II)

HN. '(III) ^l 2

ACF

This condensation is heated in the presence of formic acid · using a large excess' at <^ xtiLn (ill) is carried out, preferably being at an elevated temperature between 16O and 170 ⁰ C and at this temperature for 10 to 20 hours, preferably 14 hours holds. The amine (I) is isolated either in the form of a base or in the form of a salt, preferably a hydrochloride.

The invention also includes the preparation of a phenyl-I propanone-2 of the formula (II) included, which is obtained by using a phenyl · -! nitro-2-propene of the general formula (IV ")" ·

.CH.

= C

(IV)

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in which A has the same meaning as in general formula (i), for example reduced by means of a mixture of iron and hydrochloric acid in the presence of iron chloride. This reduction is preferably carried out at 90 ^° C. by heating to this temperature for a few hours. Phenyl-1 nitro-2 · propeh-1 (IV) is obtained by steam distillation after the reaction mixture has been made alkaline.

The preparation of a phenyl-1 nitro-2 propene of the formula (IV) is also included in the invention. It consists in getting a benzaldehyde of the general Formula (V)

(V)

wherein A has the same meaning as in the general formula (i), with a nitroethane in the presence a catalytic amount of an aliphatic amine, for example n-butylamine, condensed.

This reaction / is caused by heating the mixture Reflux temperature of nitro.ethane and by decanting of the water depending on the formation.

The preparation of the aldehyde (V) is also in the Invention included »It consists in that one

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a benzoic acid chloride of the general formula (VI)

(VI)

wherein A has the same meaning as in the general formula (i) by means of a hydrogen stream reduced in toluene in the presence of a catalytic amount of palladium / barium sulfate. The reaction temperature represents the reflux temperature of the used Solvent, the reaction time 10 to 15 Hours, preferably 12 hours.

The aldehyde (V) is isolated by reacting it with Sodium hydrogen sulfite, after which the adduct obtained is heated in water in the presence of potassium carbonate decomposed and the aldehyde (V) isolated by steam distillation.

The invention also includes the separation of the amines (i) included in their optical antipodes by any known method. This separation is preferred carried out by an optically active acid, preferably d-tartaric acid or d-dibenzoyltartaric acid.

The following examples illustrate the invention without restricting them.

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Example 1: (TrIfluormethylthio -3>'phenyl) -! ethylamino-2- propane.

1.85 g (* i-0 tnmol) of formic acid are introduced into a 50 ml two-necked flask equipped with an air cooler and a dropping funnel. It is cooled by means of an ice bath and 2 ml of ethylamine are added drop by drop. The reaction mixture is allowed to rise again to room temperature and 2.85 g (10 mmol) (trifluoromethylthio-3 ¹ phenyl) -! propanone-2 added. The contents of the flask are heated to ΙβΟ to 170 ° for 14 hours, 2 ml of concentrated hydrochloric acid and 2 ml of water are added and the mixture is heated to reflux temperature for 3 hours. Another 2 ml of concentrated hydrochloric acid is added and the mixture is brought to reflux again for 2 hours. It is allowed to cool, water is added, extracted once with 50 ml of ether, the aqueous phase is made alkaline with soda solution, extracted three times successively with 50 ml of ether, the combined ethereal extracts are washed several times with water, dried over sodium sulfate, filtered and the ether is evaporated of the filtrate on a water bath in vacuo. The 1.4 g of the oily residue are dissolved in anhydrous ether and ethereal hydrochloric acid is added until the precipitation has ended.

The (trifluoromethylthio-3 ¹ phenyl) -1 ethylamino-2 propane ₇ h ^ odilorid. Recrystallized from ethyl acetate, is in the form of a white crystallized, water-soluble compound that melts ^{at 0 C.} Yield 30 %.

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Analysis: C ₁ 2H ₁₇ ClF ₅ N 07 (2 99, ö. ) N 4, , 67 Cl 11 / 83. Calculates $: C 48, 19th H 5 , 71 4, , 66 11 , 97 Found %: ■ 48, 15th 5 , 67 _— - ■ · * ■ 11 , 87 48, '5 , 62 (Trifluoromethylthip ~ 3 'phenyl) - * ■ -1 propanone-2 Example 2:

13.2 g (50 mmol) (trifluoromethylthio-3 * phenyl) -! nitro-2 ~ propene, 19.6 g (0.35 gAT / g) iron in powder form and 0.25 g iron (Hl) chloride and the mixture is heated to 80 to 90 ° in an oil bath. It is added through the dropping funnel with stirring 13 * 5 ml of concentrated hydrochloric acid are added drop by drop over 7 hours, the temperature being kept at 90 ^° C. It is allowed to cool, the reaction mass is made alkaline using soda solution and the ketone is dragged through water. damp distillation. The distillate is extracted twice successively with 100 ml of ether, the two ethereal extracts are combined, these are dried over sodium sulfate, filtered and the solvent of the filtrate is evaporated on a water bath in vacuo. The residue is rectified.

7.1 g (yield 60.5 %) of (trifluoromethyl-thio-3'-phenyl) -1-propanone-2 are obtained in this way in the form of a colorless oil which passes over at 138 to 146 ° / 25 to 30 μm, n ^ = 1.489.

Analysis: C ₁₀ HgF ^ OS (234)

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- ■ 8 - ·

Calculated % -. C 51.28 H 3.88

.Found % ·. 50.99 ■ 3j90

51.29 3.66

Example 3: (Trifluoromethylthio- ^ 'phenyl) -! nltro-2 propene-1

33.3 g (16 mmol) of trifluoromethylthio-3-benzaldehyde, 43.3 ml of nitroethane and 2 ml of n- Butylamine. This mixture is refluxed for 4 hours and rectified. After the nitroethane has been eliminated, 26.8 g (64 % yield) of (trifluoromethylthio-3 'phenyl) -1 nitro-2-propene-1, which passes over at 130-138 ° / 8-9 mm, are obtained this in petroleum ether (35 to 70 °) and leaves a compartment in the ice. The compound is ultimately in the form of a crystallized solid. Melting point 48 °.

Analysis: C ₁₀ H ₈ F ₃ NO 2 ^S ' (263) 06 Calculates $ : C 45 , 63 H 3, 13th Found # : 45 , 35 3, 85 45 , 50 2,

Example 4: (trifluoromethylthio-3 benzaldehyde)

In a 1 liter three-necked flask with a cooler, a

ORIGINAL “9

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J ö ä QOI f 11 <%% i $

mechanical stirrer and a gas inlet tube, a solution of 56.9 S (257 mmol) of trifluoromethylthio-3-benzoic acid chloride in 285 ml of anhydrous toluene and 5 * 7 S 5 / ^ strength palladium / barium sulfate is introduced. The mixture is heated to reflux temperature for 12 hours while stirring, with a gentle stream of hydrogen being blown in. The catalyst is filtered off, which is washed with ether, and 125 ml of a sodium hydrogen sulfite solution (d = 1.33) are added to the piltrate. The mixture is left to stand with vigorous stirring for 24 hours, the bisulfite is filtered, this is washed with ether *, this is introduced into a three-necked flask and a solution of 80 g of potassium carbonate in 500 ml of water is added. The mixture is then heated to the boil and the aldehyde is recovered by steam distillation to the extent that it is formed. The distillate is extracted twice successively with ether, the combined ethereal phases are dried over sodium sulfate and filtered, the solvent is evaporated off on a water bath in vacuo and the residue is rectified. So obtained 33.3 g (exploitation 'te $ 67) trifluoromethylthio-benzaldehyde 3 in the form of an oil which lll ° to passes 30 to 38 mm at I08 /.

Analysis:· ö 5 3 46, (206, ) H • 2, 45 Calculates ^c / U c ■ 46, 60 2, 41 Found it ? U 54 2, 46 35

Through pharmacological examination of the hydrochloride the compounds (i) were found to have strong appetite suppressant properties.

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In contrast to most of the amphetamine derivatives they lack

1. a stimulating central activity, in particular at the level of the cortex,

2. cardiovascular effect ·., Such as the Taohycardia and the increase in arterial pressure.

These properties give compounds (i) and their salts are of great therapeutic importance, especially in the treatment of various forms of fat * corporeality.

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Claims (8)

P 23 25 328.3 - 13 November 1973 patent claims 1. "New phenylethylamine derivatives of the general Formula (I) CH ₂ -CH-N CH,. ^ Ro ' ( ^χ ) ACP. wherein R ₁ and R _{p are} identical or different and represent either a hydrogen atom or a straight-chain or branched alkyl radical having 1 to 5 carbon atoms, wherein R ₁ and Rp and the nitrogen atom can together form a heterocyclic radical which optionally comprises one or more further heteroatoms and A is either a sulfur or an oxygen atom * in racemic form or as optical isomers. 2. Addition salts of the compounds (I) with any pharmaceutically acceptable. Mineral or organic acid. 3. (Trifluoromethylthio-3 'phenyl) -! ethylamino-2 propane in the form of the racemate or the optical isomer and its hydrochloride. - - _ 4. (Trifluoromethoxy-3 'phenyl) -1 ethylamino-2 propane in the form of the racemate or the optical isomer and its hydrochloride. 5. (Trifluoromethylthio-3 'phenyl) -amino-2 propane in the form of the racemate or the optical isomer and its hydrochloride Mo) Si £ & $ // £ φ® *> ° ² - ^ - SS JS SZ 8 WAOHGER EiOHTf 6. Process for the preparation of the amines of the general formula (i), characterized in that one is a phenyl-1-propanone-2 of the general formula (II), wherein A has the same meaning as in the general formula (I), with an amine of the general formula (III), in which R 1 and R p are the same radicals as in formula (I). (II) (in) ACF, 7. The method according to claim 6, characterized in that the reaction is carried out in the presence of formic acid using a large excess of amine (III). 8. Pharmaceutical agent with effect against obesity, characterized by a content of at least one of the compounds (I) and / or their pharmaceutically suitable salts, optionally together with customary ones Auxiliary and / or carrier materials. 303