HU187471B - Process for preparing n-acyl-triptamine derivatives and pharmaceutical compositions containing them as active agents - Google Patents

Abstract

Prepn. of N-acyl tryptamine derivs. of formula (I) is carried out by reacting a carboxylic acid of formula R3COOH (II) with an alkyl chloroformate in the presence of triethylamine, adding a tryptamine cpd. of formula (III) or an acid-addn. salt of (III) and triethylamine, and isolating (I) and opt. converting it to a nontoxic salt (where R1 is H or MeO; R2 is H or Me; R3 is pyridyl, iodomethylpyridyl, chloromethylpyridyl or 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl). The calimed process includes the use of trimethoxybenzoic acid as (II) (prepn. of N-3,4,5-trimethoxybenzoyltryptamine is disclosed), and the halomethylpyridine derivs. are disclosed as being pyridine methohalide derivs. Cpds. (I) are useful as antiinflammatory, analgesic and antipyretic agents. The process gives high yields (e.g. 50-81%) under mild conditions using readily available starting materials (cf. PL 81695).

Description

The present invention relates to a novel process for the preparation of partially novel N-acyltryptamine derivatives and their acid addition salts, and to pharmaceutical compositions containing them as active ingredients.

In the general formula (I)

R 1 is hydrogen or methoxy,

R ₂ is hydrogen or methyl,

R ₃ is pyridyl, trimethoxyphenyl, or 1- (chlorobenzoyl) -5-methoxy-2-methyl-3-methyleneindole.

The N-acyl derivatives of tryptamine (I) are potent anti-inflammatory agents and exhibit more analgesic and antipyretic activity than Phenylbutazone in various models of inflammation (Carragenin, Serotonin tests, Formalin and kaolin edema, Dinitrochlorobenzene and Tuberculin test) ) animals. Their acute and chronic toxicity is significantly lower than that of Phenylbutazone. For example, for N-pyridoyl 3-tryptamine the following LD ₅₀ values can be measured:

mouse rat (intraperitoneal (intraperitoneally) Hsan)

N-pyridoyl-3- 1250-1450 2000 mg / kg tryptamine mg / kg

Phenylbutazone 330 mg / kg 230 mg / kg

The chronic toxicity of N-pyridoyl-3-tryptamine is also very low. Prolonged experimentation in rats at a dose of 250 mg / kg (intraperitoneally, for 7 days) did not induce gastric mucosal lesions, whereas Phenylbutazone in the comparative study showed a single ulcerogenic effect at 115 mg / kg.

A process for the preparation of N-pyridoyltryptamine by reaction of tryptamine with pyridine carboxylic acid is known from Polish patent application No. 81,695, but acid chloride is known to be very difficult and extremely difficult to carry out on a large scale.

Until now, however, compounds containing trimethoxyphenyl or 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-methylene-indole having R ₃ were not known. These compounds can be shown to be far superior to the already known N-pyridoyl tryptamine in pharmacological action.

The process of the present invention provides for the easy and simple preparation of N-acyltyptamine from readily available starting materials and solvents, and can be carried out in good yields at room temperature.

It has now been found that N-acyl derivatives of tryptamine (1) can be prepared in which R 1, R ₂ and R ₃ are as defined above when a carboxylic acid, in this case nicotinic acid, trimethoxybenzoic acid or l- (p-chlorobenzoyl) ) -5-Methoxy-2-methylindolyl-3-acetic acid is reacted with an alkyl chloroformate in the presence of triethylamine, followed by reaction of a tryptamine derivative (II) wherein R and R ₂ is as defined above or, after prior addition of triethylamine, its acid addition salt with a mineral acid is guided. The excellent N-acyl derivative of tryptamine is optionally converted into a pharmaceutically acceptable, non-toxic acid addition salt.

The reaction is carried out in a solvent, preferably an aromatic hydrocarbon such as benzene, or a mixture of an aromatic hydrocarbon and a chlorinated hydrocarbon, preferably methylene chloride, at a temperature between 15-25 ° C.

N-acyl derivatives of tryptamine of the invention are generally poorly water soluble but are well absorbed from the gastrointestinal tract.

These are shooting examples

Example 1

To a suspension of 100 g (0.81 mol) of nicotinic acid and 1000 ml of dry benzene is added 150 ml (1.0 mol) of triethylamine at room temperature with stirring. After the solution was clear, 97 mL (1 mol) of ethyl chloroformate in 400 mL of benzene was added over 10 minutes. The reaction mixture was stirred for half an hour at 15-25 ° C and the precipitated triethylamine hydrochloride was filtered off. The filtrate, which is a mixture of nicotinic acid and ethoxy formic anhydride, is poured into 100 ml (0.5 mole) of pure tryptamine hydrochloride in benzene (600 ml) and triethylamine (130 ml). The brown reaction mixture turns to beige in 10-20 minutes. The reaction mixture was stirred at room temperature for 8-10 hours and then filtered. The filtered crude product was recrystallized from ethanol / water 1: 1. Thus, 108 to 110 g (81% of theory) of N-nicotinoyl-tryptamine is obtained having a purity of 99.65%, mp: 151-153 ° C, molecular formula: C H _{I5 BC} ONJ, molecular weight: 265.3.

The resulting N-nicotinoyltryptamine is converted to the hydrochloride salt as follows:

Dissolve Ν-nicotinoyltryptamine in boiling ethanol. To the clear solution was added 33% ethanolic hydrogen chloride solution (20 mL) while the reaction mixture cooled automatically. After half an hour, the precipitated hydrochloride salt was filtered off and washed with ethanol. Thus 45.25 g (93.9%) of salt, m.p., 151-153 empirical formula during ° C dec: C ₁₆ H ₃ ON _I5 -HC1 H ₂ O, molecular weight: 319, 78th

N-nicotinoyl tryptamine with methyl iodide forms crystalline iodomethylate in acetone (formula: C ₁₇ H ₁₀ O ₃ J, molecular weight 406.2), m.p. 205-207 ° C. This jódmetilátot spent Amberlite JR-4B or Wofatit SBKval column is reacted with methyl chloride, the product obtained is 182-185 ° C melted with decomposition molecular formula: C _I7 H ₁₀ ON ₃ C1, molecular weight:

187,471

315.8. Both salts are highly soluble in water.

The above procedure may be repeated with the same results, if instead of chloroformic acid ethyl ester, chloroformic acid methyl or propyl ester application ^he used.

Example 2 To 1 g of nicotinic acid suspended in 1 ml of benzene, 1.5 ml of trimethylamine was added with stirring at room temperature. After clearing the solution, add 1 ml of ethyl chloroformate in 10 ml of benzene. After stirring for half an hour, the precipitated triethylamine hydrochloride is filtered off and 0.5 g of 5-methoxy-tryptamine is added to the filtrate, which is a mixed anhydride of nicotinic acid and ethoxy formic acid.

The reaction mixture is stirred for 4 hours at room temperature and the crude product is filtered off. Recrystallization from ethanol gave 0.5 g (64.9% of theory) of N-nicotinoyl-5-methoxy-tryptamine, m.p. 159-162 ° C, C ₁₇ H ₁₈ O ₂ N ₃ , molecular weight 295 , third

Example 3

1-Methyl-tryptamine and nicotinic acid are obtained in analogy to Example 2 using 1: 1 benzene / methylene chloride as the reaction medium and isolated as the oxalate dihydrate, m.p. 151-153 ° C. m.p., C ₁₇ H ₁₈ ON ₃ · C ₂ H ₂ O ₄ -2H ₂ O, molecular weight 405.4.

Example 4

Tryptamine hydrochloride was prepared and 3,4,5-trimetoxibenzoesavból of Example 1 analogously N-3,4,5-trimethoxybenzoyl-tryptamine is obtained, mp 159-162 ° C, yield 65%, molecular formula: C ₂₀ H ₂₂ O ₄ N ₂ , molecular weight 365.5.

Claims (4)

A process for the preparation of the N-acyl tryptamine derivatives of the formula I and their acid addition salts comprising the following: R 1 is hydrogen or methoxy, R ₂ is hydrogen or methyl, R ₃ is pyridyl, trimethoxyphenyl, or 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-methyleneindole, characterized in that one of the carboxylic acids is nicotinic acid, trimethoxy- benzoic acid or 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid is reacted with an alkyl chloroformate in the presence of triethylamine, followed by reaction with a tryptamine derivative of the formula After the addition of triethylamine, R ₁ and R ₂ are added to the mineral acid addition salt thereof, or, if desired, the reaction product, after separation, is converted into a pharmaceutically acceptable acid addition salt. Process according to claim 1, characterized in that the reaction is carried out in an aromatic hydrocarbon, preferably benzene, or in a mixture of an aromatic and chlorinated hydrocarbon, preferably benzene and methylene chloride, at a temperature of from 15 to 25 ° C. 3. A process for the preparation of antiinflammatory and analgesic pharmaceutical compositions, wherein the N-acyl derivative of the formula I according to claim 1, wherein R 1, R ₂ and R ₃ are as defined in claim 1, except N-pyridoyl-3-tryptamine, or an acid addition salt thereof, is admixed with a pharmaceutically acceptable carrier and / or pharmaceutical excipient, and the mixture is formulated for administration. 2 pieces of figure Example 5 From tryptamine hydrochloride and 1- (p-chlorobenzoyl) - 50 From 5-methoxy-2-methylindole-3-acetic acid (indomethacin), N- [1- (chlorobenzoyl) -5-methoxy-2-methylindole-3-acetyl] -tryptamine was obtained analogously to Example 1. m.p. 154-156 ° C, 50% yield, 55 C ₂₅ H ₂₆ O ₃ N ₃ Cl, molecular weight 499.96.