NL8105139A - Prepn. of N-acyl tryptamine derivs. - by reacting carboxylic acid with alkyl chloroformate and then with tryptamine cpd. - 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

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Short designation: Process for preparing N-acyl derivatives of tryptamine.

The invention relates to a process for preparing N-acyl derivatives of tryptamine of general formula 1, wherein R 1 is hydrogen or a methoxy residue, R 1 is hydrogen or a methyl residue, R 1 is a pyridyl residue, iodomethylpyridyl residue, chloromethyl-pyridyl residue or N-1 (p-chlorobenzoyl) -5-methoxyindoyl-2-methyl-3-methylene moiety, and its salts.

The said N-acyltryptamine compounds have a strong anti-inflammatory activity as well as analgesic and anti-pyretic activity which is stronger than phenylbutazone in various inflammatory models (Carrageenin, serotonin tests, formalin as well as kaolin edema, also in dinitrochlorobenzene as well as tuberculin tests) in 15 animals. These compounds also have even lower acute and chronic toxicity, which is considerably lower than phenylbutazone.

For example, the LD1 value for mice when intraperitoneal administration of N-pyridoyl-3-tryptimine is 1250-1450 mg / kg while this value is 330 mg / kg for phenylbutazone. The LD_n value for rats at

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Intraperitoneal administration is greater than 2000 mg / kg while this value is 230 mg / kg with phenylbutazone.

N-pyridoyl-3-tryptamine also has a lower chronic toxicity in experiments continued for longer periods in rats at a dose of 250 mg / kg causing changes in the mucous layer during an intraperitoneal administration for 7 days of the stomach, while comparative testing using phenylbutazone at a single dose of 115 mg / kg when administered intraperitoneally gave a marked ulcerogenic effect.

A method of preparing N-pyridoyltryptamine is known from Polish Patent 81,695, according to which method pyridine carboxylic acid chloride is allowed to act on tryptamine. The preparation of this acid chloride is, however, as is known, very laborious and, in particular, in larger quantities difficult to carry out.

According to the invention, an easy process is possible for the preparation of N-acyltryptamine using readily usable starting materials as well as solvents, whereby a good yield is obtained at room temperature.

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The process according to the invention for the preparation of N-acyl derivatives of tryptamine and the salts thereof of general formula 1, wherein a hydrogen atom is a methoxy residue, R2 is hydrogen or a methyl group, R1 is a pyridyl residue, iodomethylpyridyl residue, chloro-methylpyridyl residue or N-1- (p-chlorobenzoyl) -5-methoxyindolyl-2-methyl-3-methylene radical is characterized in that a carboxylic acid such as nicotinic acid, trimethoxybenzoic acid, 1- (p-chlorobenzoyl) -5-methoxy-2-methylindolyl-3 acetic acid reacts with chloroteric acid alkyl ester in the presence of trimethylamine and tryptamine 10 of formula 2 is added to the reaction mixture, wherein R 1 and R 2 have the same meaning as indicated above or an addition salt of tryptamine with a mineral acid after triethylamine is first added, after which the reaction mixture, after separation, can be converted into a pharmaceutically permitted toxic salt.

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

The N-acyl derivatives of tryptamine obtained according to the invention are generally sparingly water-soluble, but are well absorbed by the digestive tract.

The invention is further illustrated by the following examples.

Example I

To a suspension of 100 g (0.81 mol) of nicotinic acid 25 in 1000 ml of dry benzene, 150 ml (1.0 mol) of triethylamine was added with stirring at room temperature. After the solution was clear, a solution of 97 ml (1 mole) of chloroformic acid ethyl ester or an equivalent amount of chloroformic acid methyl or propyl ester in 400 ml of dry benzene was added for about 10 minutes.

The reaction mixture was stirred at a temperature of 15-25 ° G for half an hour and the separated triethylamine hydrochloride was filtered off. The filtrate, which is a solution of mixed nicotinic acid and alkoxy formic anhydride, was poured into a mixture of 100 g (0.5 mol) of pure tryptamine hydrochloride and 130 ml of triethyl-35 amine in 800 ml of benzene. The reaction mixture turned brown and after 10-20 minutes became clear again and was colored beige. To complete the reaction, the mixture was stirred at room temperature for an additional 8-10 hours. The filtered crude reaction product was recrystallized in a mixture of ethanol / water 1: 1 recrystallized 8105139 t <rc -3-22245 / Vk / mb.

The yield was 108-110 g (about 8L) of N-nico-tinoyltryptamine with 99.65% pure content with a melting range of 151-153 ° C.

The total formula was C ^ H ^ ON ^ and the molecular weight 265.3-

The N-niootinoyltryptamine obtained was converted into the hydrochloride as follows. 40 g of N-nicotinoyltryptamine were dissolved in ethanol at its boiling point. . To the clear solution was added a 33% ethanol solution of 20 ml of hydrochloric acid, whereby the reaction mixture was cooled. After 30 minutes, the separated hydrochloride was filtered and washed with ethanol. There was thus obtained 45.25 g (93.9% yield) of N-nicotinoyltryptamine hydrochloride hydrate, m.p. (decomposing) 151-153 ° C. The total formula 15 was C.H1Q0N2 · .HCl.Hp0 with a molecular weight of 319.78. N-nicotinoyl-tryptamine, with methyl iodide in acetone, formed a crystalline iodomethylate with a total formula of C 1 -F 1 -ON 2 J and a molecular weight of 406.2. The decomposition melting point was 205-207 ° C.

The latter salt was introduced into a column of 20 Amberlite JR-4B or Wofat SBK by means of methochloride.

This substance melted at a temperature of 182-185 ° C (with decomposition). The total formula was C 1 H 1 ON 1 Cl and the molecular weight 315.8. Both salts were easily soluble in water.

Example II

To a suspension of 1 g of nicotinic acid in 10 ml of benzene was added 1.5 ml of trimethylamine with stirring at room temperature. After a clear solution was formed, 1 ml of chloroformic acid ethyl ester in 10 ml of benzene was poured into this solution. After 30 minutes, the separated triethylamine hydrochloride was filtered off and 0.5 g of 5-methoxytryptamine was added to the filtrate, which is a solution of a mixed acid anhydride of nicotinite ethoxymic acid.

The reaction was then continued under stirring at room temperature for 4 hours. The crude reaction product was filtered off.

After recrystallization from ethanol, 0.5 g (yield 64.9%) of 35 N-nicotinoyl-5-methoxytryptamine with a melting range of 159-162 ° C were obtained.

The total formula was C H 2 O N N and molecular weight 295.3.

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Example III

Starting from N-methyltypyptamine and nicotinic acid, N-methyl-9-N-niootinoyltryptamine was obtained in the form of a benzene / methylene chloride 2: 1 as reaction medium according to the procedure described in Example II, using a 2: 1 reaction medium. oxalate dihydrate. The melting point was 151-153 ° C (with decomposition). The total formula was Gi7Hi80N3 "C2H2 ° 4" 2 and the molecular weight 405.4.

Example IV

According to the method described in example I

10 N-3,4,5-trimethoxybenzoic acid N-3,4,5-trimethoxybenzoyltryptamine was obtained from a melting range of 159-162 ° C in a yield of 65 ^ from N 2 -methyltryptamine hydrochloride. The total formula was C20H22 ° 4N2 and the molecular weight 355.5.

Example V

From tryptamine hydrochloride and 1- (p-chlorobenzoyl) -5-methoxy-2-methylindolyl-3-acetic acid (Indomethacin), M-1- (p-chlorobenzoyl) -5-methoxy-2 was analogously reported in Example 1 -methyl-indolyl-3-acetyltryptamine obtained with a melting point of 154-156 ° C.

The yield was more than 50%.

The total formula was C-rtHOi; O-11-Cl and the molecule 29 2 3 3 weight 499.96.

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Claims (2)

A process for the preparation of N-acyl derivatives of tryp-tamine of general formula 1, wherein R 1 is hydrogen or a methoxy radical, hydrogen is a methyl group, is a pyridyl radical, iodiuromethylpyridyl radical, chloromethylpyridyl radical or N-1- (p- chlorobenzoyl) -5-methoxyindolyl-2-methyl-3-methylene radical, characterized in that a carboxylic acid such as nicotinic acid, trimethoxybenzoic acid, 1- (p-chlorobenzoyl) -5-methoxy-2-10 methylindolyl-3-acetic acid in the presence of triethylamine with chloroformic alkyl ester and to the reaction mixture tryptamine of formula 2, wherein and R 2 have the above meaning or an addition salt of tryptamine with. a mineral acid after first adding triethylamine, after which the reaction product, after separation, can be converted into a pharmaceutically permitted, non-toxic salt. 2. Process according to claim 1, characterized in that the reaction is effected in a medium of aromatic hydrocarbons, in particular in benzene, or in a mixture of aromatic and chlorinated hydrocarbons, in particular in methylene chloride, at a temperature of 15- 25 ° C. Eindhoven, November 1981 8105139 -6- 22245 / Vk / mb r i FORMULA SHEET. Ri - / \ __ ch2- ch2-nh - co-r3 w R2 __rCH2 ~ CH2-NH2 \ λΝ / R2 2.8105139