NO134744B - - Google Patents

Description

The present invention relates to the production of new, therapeutically effective 1,3,8-triazaspiro(4,5)-decane derivatives with the general formula:

where R is hydrogen or C 1 -C 4 alkyl and R is hydrogen or a

2 2

group of the formula -COR , where R is C 1 -C 4 -alkyl or phenyl, or an acid addition salt thereof.

The new compounds of formula I have an outstanding effect on the central nervous system or the autonomic nervous system. The compounds have anxiolytic, antipsychotic, antiemotional, anticonvulsant, antipsychotic, sedative, analgesic and antihypertensive effects.

According to the present invention, the new compounds of formula I are prepared by a compound of the general formula:

where R.- and R-;, has the.abovef' or. : '-indicated meaning,, is reacted with an oxidizing agent to obtain a compound of the general formula:

where R 1 and R 2 have the above meaning, or an acid addition salt thereof, and, if desired, the resulting compound is hydrolyzed.

The aminophenyl ketone derivatives in question with formula (I) are prepared according to the synthesis core below:

Form (A)

If R ii is C-j-C 4 -alkyl, R <8> is C-j-C-j-alkyl, A is halogen, alkylsulfonyloxy or i

arylsulfonyloxy and R 1 and R 2 have the same meaning as indicated above.

The p>-(3-indolyl)propionic acid derivative of formula (VIII), used as an intermediate, can be prepared from an o-nitro-benzyl ketone derivative of formula (V) according to the method shown under scheme (A), which consists in reducing an o-nitrobenzyl ketone (V) to an indole derivative of formula (VI), transfer the indole (VI) to its Grignard reagent by reacting the former with an alkylmagnesium halide (denoted by R Mg.haloene) react the Grignard reagent with £>-halopropionitrile to the |>>-(3-indolyl)-propionitrile derivative of formula (VII), hydrolyze the resulting (V-(3-indolyl)propionitrile (VII) to the appropriate compound of formula (VIII'), and if necessary alkylate or arylate the compound (VIII<1>) to the corresponding compound of formula (VIII").

The substituent R1 in the compound of formula (VIII") can also be introduced by alkylation or arylation of the compound (VI) or (VII).

The reduction, the first step of the process, is carried out in a suitable organic or inorganic solvent with different reducing agents. Examples of preferred reducing agents are e.g. hydrogen in the presence of a catalyst catalyst such as palladium, nickel, platinum etc. and a metal such as iron, zinc, tin or a salt of these in an acidic environment. The reduction is easily carried out at temperatures between approx. 10°C and the boiling point of the solvent, and the relevant compound (VI) is usually obtained in high yield.

The Grignard reaction, the next step of the process, is easily carried out as is known for Grignard reactions. The above-mentioned Grignard reagent of the indole (VI) can be prepared as is well known in the field, and the Grignard reaction is carried out in a suitable solvent such as e.g. ether, tetrahydrofuran, dioxane, anisole, benzene, toluene etc, at a temperature of between approx. -10°C and the solvent's boiling point. After hydrolysis of the product, the relevant compound (VII) can usually be isolated in good yield, or the compound can be used for the following hydrolysis step without purification.

The hydrolysis of the compound (VII) can be carried out in an acidic or alkaline environment according to usual hydrolysis methods, and the corresponding ^-(3-indolyl)propionic acid (VIII<1>) is usually obtained in high yield %-IN^-alkyl no or N^-ary and none of the indole compounds (VIII'), (VI) or (VII) are carried out with a suitable alkylating or arylating agent such as e.g. alkyl halide, aryl halide, dialkyl sulfate, alkyl p-toluenesulfonate etc, in the presence of a basic reagent or a condensing agent such as e.g. sodium amide, potassium amide, sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, alkyllithium, phenyllithium, cuprocyanide etc. The reaction is usually carried out in a suitable solvent such as ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, dimethylformamide, alcohols, liquid ammonia or similar at temperatures of between approx. 0 and 140°C, and the relevant compound is usually obtained in high yield.

o-nitrobenzyl ketones of formula (V), which are the starting materials used for the present method, are easily prepared from readily available substances. The following reaction kernel shows one of the examples:

The 3-(7T-piperidinopropyl)indole derivative of formula (IV) used as an intermediate according to the method is prepared from a f*-(3-indolyl)-propionic acid derivative (VIII) via the two routes shown under scheme (B) . First, the compound (VIII) is reduced to an alcohol derivative (IX) which is transferred to the halide or sulphonate of formula (X), and then the compound (X) is reacted with a piperidine derivative (XI) which gives the desired compound (IV). The reduction is carried out in a suitable organic solvent such as e.g. diethyl ether, di-n-butyl ether, tetrahydrofuran, dioxane, methylal, N-ethylmorpholine, benzene, toluene, etc., and lithium aluminum hydride is used as reducing agent, which gives the desired alcohol derivative (IX) in high yield. The conversion of the alcohol derivative (IX) into a compound (X) is carried out in a known manner, e.g. by using phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride etc. in a suitable inert solvent, by the action of alkyl- or aryl-sulfonyl chloride in pyridine, or by using triphenylphosphine carbon tetrahalide or triphenylphosphine dihalide. The halide derivative is also obtained from the sulfonate derivative by the action of lithium halide, sodium halide, calcium halide, magnesium halide, etc.; The condensation reaction between the compound (X) and the piperidine derivative (XI) can be carried out in a suitable inert solvent such as dimethylformamide, dimethyl sulfoxide, an aromatic hydrocarbon such as benzene, toluene or xylene, a lower alkanol such as ethanol, propanol or butanol, a lower alkane such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a halogenated hydrocarbon such as dichloroethane or chloroform, an ether such as diethyl ether, di-n-butyl ether, tetrahydrofuran or dioxane, or an ester such as ethyl acetate or butyl acetate. In certain cases, the reaction can be accelerated at an elevated temperature and advantageously by adding a basic reagent or condensing agent. The desired 3-(γ-piperidinopropyl)indole derivative (IV) is usually obtained in high total yield. ;The compound of formula (XII) is prepared by reacting the compound of formula (VIII) or its functionally active derivative with a piperidine (XI). Said functional derivative is e.g. an acid halide, acid anhydride, mixed acid anhydride, p-nitrophenyl ester or the like, and the mixed acid anhydride mentioned above includes substances prepared by treating the compound (VIII) with ethyl chloroformate, isobutyl chloroformate or the like. In most cases, the reaction is advantageously carried out in the presence of a basic reagent or a condensing agent such as triethylamine, pyridine, sodium carbonate, dicyclohexylcarbodiimide, etc.j in a suitable inert organic solvent. ;The compound of formula (XII) is converted into the relevant compound (IV) by reduction. Although different reducing agents can be used for the reduction, it is particularly advantageous to use a metal halide such as lithium aluminum hydride in an inert organic solvent such as e.g. ether, tetrahydrofuran, dioxane, benzene, toluene, etc. The thus produced 3-(Y-piperidinopropyl)indole compounds of formula (IV) can be transferred to the corresponding inorganic or organic acid addition salts in a known manner. Aminophenyl ketones of formula (II) can be prepared by bringing the above 3-Y~piperidino-propylindoles of formula (IV) or an acid addition salt thereof, into contact with an oxidizing agent. For the oxidative cleavage reaction, it is preferred to use an oxidizing agent such as ozone, hydrogen peroxide, permauric acid, peracetic acid, perbenzoic acid, chromic acid, potassium permanganate or sodium periodate, although the oxidizing agent used is not limited to these examples. ;Generally, the reaction proceeds easily at room temperature, but the temperature can be higher or lower if necessary to achieve the desired reaction control. The oxidizing agent is preferably chromic acid or ozone. The reaction is preferably carried out in the presence of a solvent. The choice of solvent depends on the chosen oxidizing agent and can consist of water, acetone, carbon tetrachloride, chloroform, acetic acid, formic acid, sulfuric acid and the like. The oxidizing agent is used in a stoichiometric amount or less. The reaction temperature varies depending on the oxidizing agent chosen. When the oxidation is carried out with chromic acid in the presence of acetic acid, it is advantageous that the chromic acid is used in 2 - 3 times the equimolar amount and that the reaction is carried out at room temperature. A 3-(%-piperidinoprolyl)indole derivative or an acid addition salt thereof is dissolved or suspended in a solvent and the oxidizing agent is added to the solution or suspension with stirring. In general, the reaction is completed within approx. 24 hours. When the oxidation is carried out using ozone, the reaction is advantageously carried out at room temperature. A 3- -pipery*. dinopropyl)indole derivative or an acid addition salt thereof is dissolved or suspended in a solvent such as formic acid, acetic acid, carbon tetrachloride or the like and ozonized oxygen is bubbled through the solution or suspension while stirring.

The desired aminophenyl ketone derivative (II) can be separated from the reaction mixture in crude form by extraction or filtration with or without prior neutralization. The product is further purified if desired by recrystallization from a suitable solvent such as ethanol, isopropanol or the like in a known manner.

The prepared compound of formula (II) can be hydrolyzed to the corresponding deacylated compound of formula (III). The hydrolysis is carried out in an acidic or alkaline environment in a known manner for hydrolyses.

The prepared aminophenylketone derivative of formula (i)

can be transferred to the corresponding inorganic or organic acid addition salts in a known manner. Such salts may include pharmaceutically usable salts of the type hydrochlorides, hydrobromides, sulfates, phosphates, sulfamates, citrates, lactates, maleates, malates, succinates, tartrates, cinnamates, acetates, benzoates, gluconates, ascorbates and the like.

The aminophenyl ketones of formula (I) or their pharmaceutically usable acid addition salts have powerful effects on the central nervous system or the autonomic nervous system.

Pharmacological investigations have shown that the compounds exhibit a number of depressant effects on the central nervous system or the autonomic nervous system. Some of the compounds in question are more effective at "conditioned avoidance response" in rats than chlorpromazine. They also have anti-apomorphine and anti-methamphetamine effects that are higher than those of chlorpromazine.

While the compounds of formula I have many beneficial effects, they show hardly any toxic symptoms, and one can safely say that these substances are of great importance in practical use. Each of the pharmaceutically active compounds can be incorporated, e.g. in tablets as the only active ingredient for oral administration and can be very useful as an anxiolytic, antipsychotic, antiemotional, anticonvulsant, antipsychotic or analgesic drug. A typical tablet is made of from 1 - 2% binder such as tragacanth, from 3 - 10% lubricant such as talc, from 0.25 - 1.0% lubricant such as magnesium stearate, a medium dose of active ingredient and q.s. 100% filler such as lactose. Usual oral dosage is 1 - 100 mg per us daily.

The following examples illustrate the invention in more detail.

Reference example

(A) To a stirred solution of potassium ethylate (prepared

from 6.73 g of potassium and 57 ml of anhydrous ethanol) in 180 ml of anhydrous ether

25.1 g of diethyl oxalate were added dropwise at a temperature below 15°C. After the addition was finished, 23>3 g of 4-fluoro-2-nitrotoluene was added dropwise at a temperature below 20°C.

While the reaction mixture was stirred for 20 hours, the potassium salt of ethyl-o-nitrophenylpyruvate was separated which was filtered and washed with anhydrous ether until the filtrate was colorless. Yield of dry salt was 40 g.

(B) A mixture of the potassium salt of ethyl-o-nitrophenylpyruvate (32.0 g), 30 ml of 10% aqueous potassium hydroxide solution

and 150 ml of water was stirred for 2 hours at room temperature. Under vigorous stirring, 108 ml of 30 µg aqueous solution were added dropwise

hydrogen peroxide solution at a temperature below 15°C and the mixture was stirred at room temperature approx. 20 hours. After filtering off insoluble substances, the filtrate was acidified with 20% aqueous sulfuric acid. The precipitate was filtered off and gave 19.0 g of 4-fluoro-2-nitrophenylacetic acid with m.p. 150°C. (C) After stirring a mixture of 16.0 g of 4-fluoro-2-nitrophenylacetic acid and 25 ml of thionyl chloride for 3 hours at room temperature and heating for 4 hours at 50-60°C, the excess of thionyl chloride was evaporated under reduced Print. After volatile substances had been removed by addition of benzene portions (3 x 30 ml) and subsequent evaporation, 4-fluoro-2-nitrophenyl-acetyl chloride was obtained as an oily residue. To a stirred solution of the magnesium ethoxy derivative of diethyl malonate, prepared from 2.92 g of magnesium, 14 ml of anhydrous ethanol and 19.2 g of diethyl malonate according to known methods, in 15 ml of anhydrous ether, a solution of the above acid chloride in 25 ml of anhydrous benzene was added dropwise at 30 - 35°C After the reaction mixture was refluxed for 2 hours, it was decomposed by the addition of aqueous sulfuric acid at below 20°C. After separation of the organic layer, the aqueous layer was extracted with portions of ether. The combined organic layers were washed with water and evaporated to a crude product of diethyl-(4-fluoro-2-nitro-phenyl)-acetylmalonate as an oil. (D) The above diethyl-(4-fluoro-2-nitrophenyl)acetylmalonate was dissolved in a solution of 30 ml of acetic acid, 20 ml of water and 5 ml of concentrated sulfuric acid and gently refluxed until no more carbon dioxide was evolved. After cooling, the reaction mixture was made alkaline by the addition of aqueous sodium hydroxide and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization of the solid residue from aqueous ethanol gave 4-fluoro-2-nitrophenylacetone with m.p. 60 - 61°C.

Example 1

Stage I

To a solution of 78.9 g of 4-fluoro-2-nitrophenylacetone in 800 ml of 80 µg (v/v) acetic acid, 140 g of zinc dust was added in portions at a temperature of 70 - 80°C. After the addition was finished, the temperature of the bath was increased to 85 - 90°C and the heating continued for 1 hour. The hot mixture was filtered and the zinc precipitate washed with a little ethanol and ether. The filtrate was diluted with 1 liter of water to 6-fluoro-2-methylindole, m.p. 97 - 99°C.

Step 2

To a stirred ether solution of ethyl magnesium iodide, which was prepared from 9.8 g of magnesium, 62.7 g of ethyl iodide and 100 ml of dry ether, a solution of 40.0 g of 6-fluoro-2-methylindole in 130 ml of dry ether was added dropwise at a temperature of 2 - 5°C. After the addition was complete, the mixture was refluxed until ethane evolution ceased. The mixture was cooled to 5°C and a solution of 24.5 g of 3-chloropropionitrile in 50 ml of dry ether added dropwise at a temperature below 5°C. The temperature of the mixture was raised gradually to the boiling point of ether. After refluxing was continued for 4 hours, the precipitated complex product was decomposed by adding moist ether (50 ml), water (50 ml) and 2N acetic acid (40 ml). The ether layer was filtered off, washed with water and concentrated to g-(6-fluoro-2-methylindolyl)propionitrile as a crude oil. I.R.

Y C=N 2230 cm<-1>.

Step 3

A mixture of 54.0 g of crude 3-(6-fluoro-2-methyl-3-indolyl)propionitrile and 500 ml of 20 µg aqueous potassium hydroxide solution was refluxed until ammonia evolution ceased. After the mixture had cooled, insoluble matter, which constituted recovered 6-fluoro-2-methylindole, was filtered off, and the filtrate acidified by slow addition of concentrated hydrochloric acid with vigorous stirring. The separated substance was filtered off and dried to g-(6-fluoro-2-methyl-3-indolyl)propionic acid with m.p. 131 - 133°C

Step 4

A solution of ethyl chloroformate (5 .43 g) in tetrahydrofuran (20 ml) at a temperature below 5°C. After stirring for a further 10 min. the reaction mixture was added to a solution of 4-oxo-1-phenyl-1,3,8-triazaspiro(4,5)-decane (11.57 g) in chloroform (250 ml) at a temperature below 5°C.< After continued stirring for 5 hours at room temperature, the reaction mixture was washed thoroughly with water, dilute aqueous sodium carbonate solution and a saturated sodium chloride solution. Evaporation of the organic solvent gave 8-[g-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5] -decane as a crystalline powder with m.p. 100 - 105°C.

Step 5

To a stirred mixture of 10.54 g of lithium aluminum hydride and 40 ml of dry ether, a solution of 16.0 g of 8-[g-(6-fluoro-2-methyl-3-indolyl)propyl]-4-oxo- 1-phenyl-1,3,8-triazaspiro [4,5]-decane in 220 ml of dry tetrahydrofuran under gentle reflux. Stirring and refluxing were continued for a further 5 hours and the reaction mixture was gradually treated with a mixture of water and tetrahydrofuran under ice cooling. The mixture was dried with the addition of anhydrous sodium sulfate with stirring and filtered. The filtrate was evaporated to give 8-[γ-(6-fluoro-2-methyl-3-indolyl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]-decane as a crystalline powder which melted at 165 - 168°C.

Example 2

Step 1

To a stirred mixture of 5.72 g of lithium aluminum hydride and 200 ml of dry ether, a solution of 22.1 g of g-(6-fluoro-2-methyl-3-indolyl)propionic acid in 200 ml of dry ether was added dropwise under gentle reflux. Stirring and refluxing were continued for 5 hours and the reaction mixture was added dropwise to a mixture of water and ether under ice cooling. The ether layer was separated and evaporated to dryness. The remaining oil was distilled under reduced pressure and this gave 6-fluoro-2-methyl-3-(γ-hydroxypropyl)indole with b.p. 180 - 190°C (0.7 mm Hg) which was set aside for solidification, m.p.: 66.5 68.5°C.

Step 2

To a stirred solution of 10.35 g of 6-fluoro-2-methyl-3-(γ-hydroxypropyl)indole in 100 g of pyridine was added 19.0 g of p-toluenesulfonyl chloride at a temperature below 30°C. After stirring for 2 hours at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was

washed with dilute hydrochloric acid and evaporated under reduced pressure to 6-fluoro-2-methyl-3-(γ-p-toluenesulfonyloxypropyl)indole as a crude oil.

This tosylate was dissolved in dimethylformamide (150 ml) and 10.5 g of lithium chloride was added at a temperature below 4o°C with stirring. After stirring for several hours, the mixture was poured into ice-cooled water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to 6-fluoro-2-methyl-3-(Y~chloropropyl)indole as an oil, bp. 172 - 176°C (1.3 mm Hg).

Step 3

A stirred mixture of 6-fluoro-2-methyl-3-(γ-chloropropyl)-indole (11.28 g) 4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]-decane ( 11.57 g), sodium carbonate (5.3 g), potassium iodide (0.2 g) and dimethylformamide (100 ml) were heated at 90-100°C for 12 hours. The reaction mixture was then poured into ice-cooled water and the separated solid was filtered off and recrystallized from ethanol to 8-[y-(6-fluoro-2-methyl-3-indolyl)propyl J-4-oxo-1-phenyl- 1,3,8-triazaspiro [4,5]-decane, with m.p. 210 - 213°C.

Example 3

To a solution of 4.0 g of 8-[γ-(6-fluoro-2-methyl-3-indolyl)propyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]- decane in 60 ml of acetic acid, an oxygen stream containing approx. 3% ozone at a temperature of 15 - 20°C until the dark solution became clear. The reaction mixture was diluted with water and made alkaline by slow addition of aqueous sodium hydroxide solution with vigorous stirring, and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to 8-[γ-(2-acetamino-4-fluorobenzoyl)-propyl]-4-oxo-1-phenyl-1,3,8-triazaspiro [4,5 ]-decan, sm.p. 190 - 192.5°C.

Example 4

In a similar manner as described in example 2 or 3, the following compounds can be prepared: 8-[y-(l-ethyl-2-methyl-6-fluoroindolyl)propyl]-4-oxo-l-phenyl-1j3j8-triazaspiro [4 ,5]-decane, caramel-like solid, I.R. 1700 cm<-1>, 1620 cm<-1> (weak),

8-[γ-(2-phenyl-6-fluoroindolyDpropyl]-4-oxo-1-phenyl-1,3,8-tri-azaspiro[4,5]-decane, mp 218°C.

Example 5

In a similar way as described under example 4, the following substances can be prepared: 8-[y-(2-N-ethylacetamino-4-fluorobenzoyl)-propyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[ 4,5]-decane, brown oily substance, I.R. 1700 cm"<1>, 1640 cm<-1>,

8-[γ-(2-benzoylamino-4-fluorobenzoyl)propyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]-decane, m.p. 198 - 200.5°C.

Example 6

A solution of 2.25 g of 8-[γ-(2-acetamino-4-fluoro-.benzoyl)propyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,51-decane in 100 ml of ethanol was heated under reflux with 10 ml of concentrated hydrochloric acid for 1 hour. The reaction mixture was cooled and the ethanol distilled off. The residue was diluted with water, made alkaline by the addition of an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water and evaporated to dryness. Recrystallization of the residue gave 8-[γ(2-amino-4-fluorobenzoyl)propyl]-4-oxo-1-phenyl-1,3,8-triazaspiro [4,5]-decane, m.p. 195°C.

Example 7

In a similar manner to that described in example 5, the following compounds were prepared: 8-[γ-(2-ethylamino-4-fluorobenzoyl)propyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,5 ]-decan, sm.p. 168.5 - 175.5°C, 8-[y-(2-methylamino-4-fluorobenzoyl)propyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]-decane, sm.p. 209 - 211°C.

Claims (1)

Analogous process for the preparation of therapeutically effective 1,3,8-triazaspiro(4,5)-decane derivatives with the general formula: where R is hydrogen or C 1 -C 1 -alkyl and R is hydrogen or a group of the formula -COR 2 where R 2 is C 1 -C 2 -alkyl or phenyl, or an acid addition salt thereof, characterized in that a compound with the general formula: 1 2 where R and R have the meaning stated above, is reacted with an oxidizing agent to obtain a compound with the general formula: where R 1 and R 2 have the above meaning, or an acid addition salt thereof, and, if desired, the resulting compound is hydrolyzed.