DK159152B - Analogy process for preparing therapeutically active pyrimido(1,6-a)indole derivatives or salts thereof - Google Patents

Description

DK 159152 B

The present invention relates to an analogous process for the preparation of novel therapeutically active pyrimido [1,6-a] indole derivatives of the general formula R3 \ s \ / CH2-c ° OR2 I il Γι 5 VYSi.

r / V

wherein R 2 is optionally at the β-position with alkoxy of not more than 4 carbon atoms or alkanesulfinyl of not more than 4 carbon atoms substituted phenyl, unsubstituted thienyl or unsubstituted pyridyl, R 2 means hydrogen or lower alkyl of not more than 4 carbon atoms, R 3 means hydrogen, lower alkoxy of not more than 4 carbon atoms or halogen, with the exception that R 2 is different from ethyl when R 3 is hydrogen and R 1 is phenyl or when R 3 is methoxy and R 1 is p-chlorophenyl, or salts thereof.

15 The general definitions used in the foregoing and hereafter have, in the context of the present description, primarily the following meanings.

Low alkyl means methyl, moreover ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

Low alkoxy is methoxy, moreover, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, sec-butyloxy or tert-butyloxy.

Low alkanesulfinyl is e.g. sulfinyl, methanesulfinyl, ethanesulfinyl or n-propanesulfinyl.

Halogen is, for example, halogen having an atomic number not exceeding 35, such as fluorine, furthermore chlorine or bromine.

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2

Salts of the compounds of formula I are preferably pharmaceutically useful salts such as corresponding acid addition salts and / or, when R 2 is hydrogen, internal salts or bases salts. Suitable acid addition salts are, for example, salts with inorganic acids such as mineral acids, or organic acids such as sulfamic acids, e.g. cyclohexylsulfamic acid, optionally unsaturated dicarboxylic acids, or optionally with hydroxy further substituted or additional oxo and / or carboxy containing carboxylic acids, or sulfonic acids. Mineral acids are, for example, sulfuric acid or hydrogen halide acid, such as hydrobromic acid or hydrochloric acid. As optionally unsaturated dicarboxylic acids may be mentioned, for example, oxalic acid, malonic acid, fumaric acid or maleic acid, and as optionally hydroxy further substituted or additional oxo and / or carboxy containing carboxylic acids may be mentioned for example tartaric acid, malic acid, pyruvic acid or citric acid.

Sulfonic acids are, for example, benzene, p-toluene or methanesulfonic acid.

Suitable salts with bases are, for example, metal salts such as alkali metal or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts, transition metal salts such as zinc or copper salts, or salts with ammonia or substituted organic amines such as morpholine, thio-morpholine, piperidine, pyrrolidine such as mono-, di- or trilavalkylamines or mono-, di- or trihydroxyl of alkylamines, e.g. mono-, di- or triethanolamine. Monolavalkylamines are, for example, ethylamine or tert-butylamine. Dilavalkylamines are, for example, diethylamine or dipropylamine, and as examples of trilavalkylamines may be mentioned triethylamine, tributylamine or dimethylpropylamine.

The compounds of formula I have valuable pharmacological

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3 properties. In particular, they have a pronounced antinociceptive (analgesic) effect that can be detected, for example, by the acetic acid-twisting syndrome in rats in the 5 dose range from ca. 1 to approx. 30 mg / kg p.o. and in the phenyl-β-benzoquinone torsion test in mice in the dose range of from ca. 1 to approx. 30 mg / kg p.o.

Furthermore, the compounds of the present invention have a distinct anti-infl animator in sk and anti-arthritic effect, which can be demonstrated by inhibiting the kaolin paw edema in normal rats in the dose range of from ca. 10-100 mg / kg p.o., and can also be detected by the inhibition of carrageenin paw edema in rats analogous to the method described by Pascal et al., Agents and Actions, 5, 256 (1976) at doses of 15 3 to approx. 300 mg / kg p.o.

Furthermore, the compounds of the formula I inhibit the kaolin paw edema of adjuvant arthritis rats by curative application by four times administration of from ca. 10 to 100 mg / kg p.o.

Similarly, the compounds of formula I are 3,4-dihydro-pyrimido [1,6-ajindole compounds superior in efficacy in at least one of the above-mentioned pharmacological models. In general, they are also more hydrolysis resistant and thus have better storage stability. The compounds of the present invention are therefore particularly suitable as drugs for the treatment of inflammatory disease states, primarily in the rheumatic or arthritic field, as antiphlogistics and / or as peripheral analgesics.

The process of the invention is characterized in that a) dehydrogenates a compound of the formula

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4

r. CH - COOR

3 \ ^ \ / 2 2

1 II H

Vy \ (XI) p x V '

R 1 s or a salt thereof while decomposing hydrogen to form a further bond or 5 b) hydrolyzing a compound of formula I or a salt thereof wherein R 2 represents alkyl of not more than 4 carbon atoms, or c) ester a compound having the formula I or a salt thereof, wherein R 2 represents hydrogen and, if desired, 10 converts a formed free compound of formula I into a salt thereof or converts a prepared salt into the free compound of formula I or to another salt.

The dehydrogenation according to process a) is carried out in a manner known per se, especially at elevated temperature, e.g. in a temperature range of approx. 100 to approx. 300 ° C, and using a dehydrogenating agent. For example, as dehydrogenation agent, dehydrogenation catalysts, e.g. side group elements, preferably from side group VIII, such as palladium or platinum, or salts thereof, such as ruthenium triphenylphosphide chloride, the catalysts optionally being mounted on a suitable support material such as carbon, alumina or silica. Other dehydrogenating agents are, for example, quinones such as p-benzoquinones, e.g. tetrachloro-β-benzoquinone or 2,3-dichloro-5,6-dicyano-β-benzoquinone, or such as anthraquinones, e.g. phenanthrene-9,10-quinone. The reaction is carried out in an inert, possibly high boiling solvent, such as an ether, e.g. diphenyl ether, if necessary under pressure, in a closed container and / or under an inert gas, e.g. nitrogen.

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5

The compounds of formula XI used as starting materials can be prepared by starting from compounds of formula

Ph_2 \ | I (ivd1) 5

H

wherein Bz represents an optionally substituted α-phenyl lower alkyl group, preferably benzyl, and quaternizing this group with benzyl bromide, cleaves the bond at the quaternary nitrogen atom by cyanides such as alkali metal cyanides, e.g. sodium cyanide, and in a formed compound of the formula

Ph - V N X (IVe)

i J

Bz Xz solvolyses the cyano group as desired, the benzyl group decomposes hydrogenolytically in the presence of a hydrogenation catalyst, e.g. palladium, and reacting the resulting free amino compound with a compound of the formula

Zi *

Rl ~ C

Hal 20 wherein Z 2 represents oxo and Hal means halogen, which is finally reacted with a cyclizing agent, preferably a mineral acid halide, such as phosphorus oxychloride or phosphorus chloride, to form a compound of formula I.

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6 When the group -COOR2 is a free carboxy group, it can be converted into corresponding esterified lower alkoxycarbonyl 5 -COOR2, using R 2 which is C (1-4) -alkyl, e.g. reacting optionally reactively derived carboxy or a salt thereof by alcoholysis with a corresponding lower alkanol, e.g. a reactive derivative thereof or an olefin derived therefrom or by alkylation with a corresponding diazolavalkane.

Suitable reactive functional carboxy derivatives are, for example, anhydrides, in which mixed anhydrides are used, such as anhydrides, e.g. those with inorganic acids such as hydrogen halide acids, e.g.

Hydrochloric acid, such as hydrogen azide or hydrogen cyanide or with organic carboxylic acids such as 1-valanoic acids, e.g. acetic acid.

Reactive alcohol derivatives are, for example, carboxylic acid esters, phosphoric acid esters, sulfuric acid esters · or carbonic esters, e.g. lower alkane carboxylic acid esters, trilavalkyl phosphite, dilavalkyl sulfite or pyrocarbonate, or mineral or sulfonic acid esters, e.g. chloro, bromo or sulfuric acid esters, benzene, toluene or methanesulfonic acid esters of the alcohol concerned.

The esterification of a free carboxy group -COOR2 is carried out if necessary in the presence of a catalytic or water-splitting agent or condensing agent. As the catalytic water decomposing agent for the esterification with corresponding alcohols, for example, acids, e.g. protonic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, boric acid, benzenesulfonic acid and / or toluenesulfonic acid, or Lewis acids such as boron trifluoride etherate. Conventional water-binding condensing agents are, for example, substituted with hydrocarbon groups of 35 carbodiimides, e.g. N, Ν'-diethyl-, N, N-dicyclohexyl-

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7 or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide.

Condensing agents for the esterification with reactive esters are, for example, basic condensing agents, such as inorganic bases, e.g. alkali metal or alkaline earth metal hydroxides or carbonates such as sodium, potassium or calcium hydroxide or carbonate, or, for example, organic nitrogen bases, e.g. tertiary organic amines such as triethylamine or pyridine. The esterification is advantageously carried out in excess of the alcohol used. Preferably, it is worked in an anhydrous medium, if necessary in the presence of an inert solvent such as halogenated hydrocarbons, e.g. chloroform or chlorobenzene, or in ethers, e.g. tetrahydrofuran or dioxane.

For example, the reaction with an olefin can be carried out in the presence of an acidic catalyst, e.g. a Lewis acid, e.g. boron trifluoride, a sulfonic acid, e.g. p-toluenesulfonic acid, or first of all a basic catalyst, e.g. sodium or potassium hydroxide, advantageously in an inert solvent such as an ether, e.g. in diethyl ether or tetrahydrofuran.

Furthermore, one can re-esterify the compounds of formula I wherein -COOR 2 is lower alkoxycarbonyl and R 2 is C (1-4) alkyl, in the usual manner, e.g. by reaction with a corresponding lower alkanol or metal salt thereof, such as an alkali metal salt, e.g. the sodium or potassium salt, if necessary in the presence of a catalyst, e.g. a strong base such as an alkali metal hydroxide, an alkali metal amide or an alkali metal alcoholate, e.g. potassium hydroxide, sodium amide or sodium methylate, or a strong acid such as a mineral acid, e.g. sulfuric acid, phosphoric acid or hydrochloric acid, or an organic sulfonic acid, e.g. an aromatic sulfonic acid such as p-toluenesulfonic acid.

Low alkoxycarbonyl-COOR 2 wherein R 2 is C 1-4 alkyl can

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8 further in a known manner, e.g. by hydrolysis, optionally in the presence of a catalyst, e.g. an acid or alkaline agent, is transferred into carboxy -COOR 2 - As bases, for example, alkali metal hydroxides such as sodium or potassium hydroxide can be used, and as acids, for example, mineral acids such as sulfuric acid, phosphoric acid or hydrochloric acid can be used.

Produced salts can be converted in the known manner to the free compounds, e.g. by treatment with an acidic reagent such as a mineral acid, or a base, e.g. alkali metal hydroxide solution.

The compounds of the invention may, depending on the choice of starting compounds and process, be in the form of the possible isomers or as mixtures thereof, e.g. depending on the number of asymmetric carbon atoms as pure optical isomers such as antipodes or as isomer mixtures such as racemates, diastereoisomer mixtures or racemate mixtures. Produced diastereomer blends and racemate mixtures can be separated into the pure isomers, diastereomers or racemates, for example, due to the physicochemical differences of the components. by chromatography and / or fractional crystallization.

Furthermore, prepared racemates can be cleaved in known manner in the optical antipodes, e.g. by recrystallization from an optically active solvent, by microorganisms or by reacting an acidic final product with an optically active base which forms salt with the racemic acid, and separating the 30 salts thus prepared, e.g. due to their different solubilities, in the diastereomers from which the antipodes can be released by the action of suitable agents. Advantageously, one isolates the most effective of the two antipodes.

The compounds, including their salts, can also be obtained in form

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9 of hydrates or may contain other solvents used for crystallization.

As a result of the close relationship between the compounds in question in free form and in the form of their salts, the prior and subsequent compounds or their salts may optionally also mean the corresponding salts or compounds.

The process of the invention is further illustrated in the following 10 examples.

In the literature, different terms are used for the bonding positions of the pyrimido indole ring system ΰ I 9a 10 .7 A 3.

which forms the basis of the compounds of formula I.

15 In older literature, the binding sites in the ring system are thus denoted by [3,4-a], while the term [1,6-a] is now used.

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10

Example 1.

38 g of 7-fluoro-1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester are heated in 200 ml of diphenyl ether in the presence of 10 g of palladium / carbon (10%) with stirring. for 50 minutes to 260 ° C. The phenyl ether is removed under reduced pressure, the evaporation residue is taken up in diethyl ether, the catalyst is filtered off and the filtrate is evaporated to begin crystallization. The mixture is then stirred with hexane and a little diethyl ether and suction filtration is carried out. In this way, 7-fluoro-1-phenyl-pyrimido [1,6-a] indole-5-acetic acid ethyl ester is obtained, m.p. 91-93 ° C.

For example, the starting material can be prepared as follows: a) 131 g (0.45 mole) of 3-beitzyl-6-fluoro-tetrahydro-γ-carboline 15 are dissolved in 1300 ml of acetonitrile at 40 ° C with stirring, and over 10 minutes 94 g (0.55 mol) of benzyl bromide are added. After a short time, the benzylammonium derivative of crystallize begins. Stirring is continued for approx. 15 hours at room temperature, then the mixture is cooled in an ice bath, 20 and the crystalline product is suctioned off.

b) Dissolve 464 g (1 mole) of the N, N-dibenzyl-6-fluoro-tetrahydro-Y-carboliminium bromide thus prepared in 4250 ml of methanol with heating to 65 ° C and add a solution of 196 g (4 moles) of sodium cyanide in 500 ml of water with stirring. The solution is heated for 3 hours to reflux. Upon cooling, after inoculation, 2- (dibenzylamino-ethyl) -3-cyano-methyl-5-fluoro-indole crystallizes out as colorless crystals.

c) Dissolve 220 g (0.537 mol) of the nitrile 30 of b) in 300 ml of absolute ethanol and saturate it at -5 ° C with dry hydrogen chloride. Then stir for 5 1/2 days at 20 ° C. The precipitated crystals are allowed to settle, decant the above solution, dissolve the precipitate in

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11 2000 ml ice water and stir for approx. 3 hours at 20 ° C. Then, under ice-cooling with concentrated ammonia solution, make basic with stirring with 1500 ml of toluene / ice water.

The isolated toluene phase is washed with water, dried over sodium sulfate and filtered over 1000 g of alumina (activity step 3) and washed with toluene. After distillation of the toluene, there is obtained as a residue a light brown oil which is subjected to hydrogenation without further purification as described below under (d).

D) 181.3 g of the 2-dibenzylamino-5-fluoro-indole-3-acetic acid ethyl ester prepared in c) are dissolved in 1500 ml of absolute alcohol and then hydrogenated while adding 18 g of Pd / C (5%) at normal pressure and 20-35 ° c. After uptake of 12500 ml H2, an additional 18 g of catalyst is added and hydrogenation is continued until hydrogen uptake ceases after a total uptake of 17300 ml. The catalyst is filtered off and washed with methylene chloride, the solution is evaporated to dryness and the residue is dissolved in 250 ml of ether. After grafting, 2-aminoethyl-5-fluoro-20-indole-3-acetic acid ethyl ester crystallizes in the form of colorless crystals.

e) 61.7 g (0.223 mol) of the 2-amino-ethyl-5-fluoro-indole-3-acetic acid ethyl ester prepared in d) are dissolved in 600 ml of methylene chloride and the solution is poured into 150 ml of 2 N sodium hydroxide solution. With vigorous stirring, at 0-5 ° C, a solution of benzoyl chloride (43 g (0.245 mole)) is added over 2 1/2 hours, then stirred for an additional 1 hour. The methylene chloride phase is then isolated, washed with water, dried over MgSO 4 and evaporated to dryness. The residue crystallizes upon uptake into ether. In this way, 2- (2-benzoylaminoethyl) -5-fluoro-indole-3-acetic acid ethyl ester is obtained.

37 g (0.154 mol) of 2- (2-benzoylamino-ethyl) -5-fluoro-indole-3-acetic acid ethyl ester are heated to reflux in 160 ml of phosphorus oxychloride for 3 hours. Phosphorus excess

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12

Phoroxychloride is then distilled off in vacuo at 60 ° C and the residue is stirred with 650 ml of ice water. The aqueous solution is clarified by filtration through diatomaceous earth, made basic by the addition of concentrated ammonia solution and extracted with 400 ml of ether. The ether phase is dried over sodium sulfate and evaporated to dryness. The residue is dissolved in 150 ml of acetone, to which 16 ml of ca. 4 N ethereal hydrochloric acid. After grafting, the hydrochloride of 7-fluoro-1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester crystallizes in the form of yellow crystals which can be recrystallized from 1 N

hydrochloric acid. The base released from the salt melts after recrystallization from ether at 56-58 ° C.

Example 2.

Analogous to the procedure described in Example 1, 2-aminoethyl-5-fluoro-indole-3-acetic acid ethyl ester and p-methanesulfinylbenzoyl chloride are prepared from 7-fluoro-1- (p-methanesulfinylphenyl) -3,4-amine. dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester (m.p. for the hydrochloride 208-210 ° C) 7-fluoro-1- (p-methanesulfinylphenyl) pyrimido [1,6-a] indole 20 acetic acid ethyl ester with m.p. 133-135 ° C.

Example 3

Analogous to the process described in Example 1, is prepared from 2-aminoethyl-indole-3-acetic acid ethyl ester and 2-thenoyl chloride over 1- (2-thienyl) -3,4-dihydro-pyrimido [1,6-25 a] indole. 5-acetic acid ethyl ester (m.p. for the hydrochloride 153-157 ° C) 1- (2-thienyl) -pyrimido [1,6-a] indole-5-acetic acid ethyl ester, m.p. 94-95 ° C.

Example 4

Analogous to the procedure described in Example 1, is prepared from 2-aminoethyl-5-methoxy-indole-3-acetic acid ethyl ester and 2-picolyl chloride over 7-methoxy-1- (2-picolinyl) - DK 159152 8 13 3,4-dihydro-pyrimido [1,6-a] indole-acetic acid ethyl ester 7-methoxy-1- (2-picolinyl) -pyrimido [1,6-a] indole-5-acetic acid ethyl ester, m.p. 103-104 ° C.

Example 5

12.2 g of 1-phenyl-pyrimido [1,6-a] indole-5-acetic acid ethyl ester (mp 59-62 ° C) prepared from 2-aminoethyl-indole-3-acetic acid ethyl ester and benzoyl chloride over 1-phenyl 3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester (mp 83-84 ° C) is stirred with 30 ml of ethanol and 40 ml of 1 N sodium hydroxide solution for 3 hours at room temperature. The mixture is acidified with concentrated hydrochloric acid to pH 3 and 30 ml of propylene oxide are added with stirring. After a short time, 1-phenyl-pyrimido [1,6-a] crystallizes out indole-5-acetic acid. It is filtered off and recrystallized from 90% ethanol to give a m.p. at 198-204 ° C (dec.). -

Example 6 «

Analogous to the procedure described in Example 5 is prepared from 7-fluoro-1- (p-methanesulfinyl) pyrimido [1,6-a] indole-5-acetic acid ethyl ester 7-fluoro-1- (p-methanesulfinyl) pyrimido [1,6-a] indole-5-acetic acid, m.p. 218-224 ° C (dec.).

Example <7.

Analogous to the procedure described in Example 5, is prepared from 7-fluoro-1-phenyl-pyrimido [1,6-a] indole-5-acetic acid ethyl ester 7-fluoro-1-phenyl-pyrimido [1,6-a ] indole-5-acetic acid, m.p. 217-220 ° C.

Example .8.

Analogous to the procedure described in Example 5, 1- (2-thienyl) pyrimido [1,6-a] indole-5-acetic acid is prepared from

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14 acid ethyl ester 1- (2-thienyl) pyrimido [1,6-a] indole-5-acetic acid, m.p. 196-200 ° C (dec.).

Example 9

Analogous to the procedure described in Example 5, is prepared from 7-methoxy-1- (2-picolinyl) pyrimido [1,6-a] indole-5-acetic acid ethyl ester 7-methoxy-1- (2-picolinyl) -pyrimido [1,6-a] indole-5-acetic acid, m.p. 20l-206 ° C.

Example 1.0 In the same manner as described in Examples 1 and 5, 10 7-fluoro-1- (p-methoxyphenyl) -pyrimido [1,6-a] indole-5-acetic acid is also prepared, m.p. 220-225 ° C.

Example 11

Tablets containing 25 mg of active substance, e.g. 7-fluoro-1- (p-methylthio-phenyl) -pyrimido [1,6-a] indole-5-acetic acid or a salt thereof, e.g. the hydrochloride, can be prepared as follows:

Ingredients (for 1000 tablets):

Active substance 25.0 g

Lactose 100.7 g 20 Wheat starch 7.5 g

Polyethylene glycol 6000 5.0 g

Talc 5.0 g

Magnesium stearate 1.8 g

Demineralized water q.s.

*

Preparation:

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15

All solid components are first pressed separately through a screen having a mesh width of 0.6 mm. Then the active ingredient, the lactose, talc, the magnesium stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water. The resulting starch paste is added to the bulk and the mixture is granulated, if necessary, with the addition of water. The granule is dried overnight at 35 ° C, pressed through a screen having a mesh width of 1.2 mm, and compressed into double concave tablets having a diameter of approx. 6 mm.

Similarly, tablets each containing 25 mg of one of the other compounds of formula I mentioned in 15 Examples 1-1C and 14 may also be prepared, the compounds also being in the form of acid addition salts such as hydrochlorides and compounds wherein hydrogen means. also in the form of salts and bases such as sodium, potassium or zinc salts.

Example 12

Chewable tablets containing 30 mg of active substance, e.g. 7-Fluoro-1- (p-methylthio-phenyl) -pyrimido [1,6-a] indole-5-acetic acid or a salt thereof, e.g. for example, the hydrochloride can be prepared as follows: Composition (for 1000 tablets):

Active substance 30.0 g

Mannitol 267.0 g

Lactose 179.5 g

Talc 20.0 g Glycine 12.5 g

Stearic acid 10.0 g

Saccharin 1.0 g of 5% gelatin solution q.s.

preparation; 16

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All the solid components are first pressed separately through a sieve with a mesh width of 0.25 mm. The mannitol and lactose are mixed, granulated with the addition of gelatin solution, pressed through a sieve of 2 mm mesh, dried at 50 ° C and pressed again through a sieve of 1.7 mm mesh. The active substance, glycine and saccharin are thoroughly mixed, the mannitol, lactose granulate, stearic acid and talc are added, all thoroughly mixed and compressed into double concave tablets of approx. 100 mm with split notch on the upper side.

Similarly, chewable tablets containing 30 mg of one of the other compounds of formula I mentioned in Examples 1 to 10 and 14 may also be prepared, the compounds also being 15 in the form of acid addition salts such as hydrochlorides and compounds. wherein hydrogen is also in the form of salts with bases such as sodium, potassium or zinc salts.

Examples 13, 20 Tablets containing · 100 mg of active substance, e.g. 7-Fluoro-1- (p-methylthio-phenyl) -pyrimido [1,6-a] indole-5-acetic acid ethyl ester can be prepared as follows:

Composition (for 1000 tablets):

Active substance 100.0 g 25 Lactose 248.5 g

Corn starch 17.5 g

Polyethylene glycol 6000 5.0 g

Talc 15.0 g

Magnesium stearate 4.0 g 30 Demineralized water q.s.

Preparation:

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17

The solid components are first pressed separately through a screen having a mesh width of 0.6 mm. Then, thorough mixing of the active substance, lactose, talc, magnesium stearate and half of the starch is made. The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting paste is added to the powdered ingredients, all mixed and granulated, if necessary, with the addition of water. The granulate is dried overnight at 35 ° C, pressed through a sieve with a mesh width of 1.2 mm, and compressed into double concave tablets with a diameter of approx. 10 mm with split notch on the upper side.

Similarly, tablets containing 100 mg of one of the other compounds of Formula I of Examples 1-10 and 14 may also be prepared, the compounds also being in the form of acid addition salts such as hydrochlorides and compounds wherein R 2 is hydrogen, also in the form of salts with bases such as sodium, potassium 20 or zinc salts.

Example 14

To 100 ml of anhydrous ethanol saturated with hydrogen chloride gas is added 3.02 g of 1-phenyl-pyrimido [1.6 ~ a] indole-5-acetic acid.

The mixture is heated at reflux for 15 hours, then cooled and evaporated to dryness under reduced pressure. After recrystallization from ether, 1-phenylpyrimidof 1,6-a] indole-5-acetic acid ethyl ester is obtained, m.p. 59-62 ° C.

30 Trial Report

Using the phenyl-β-benzoquinone torsion test as a test model, the antinociceptive (analgesic) effect is determined for the following compounds:

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7 - Fluoro-1- (2-thienyl) -pyrimidof 1,6-a] indole-5-acetic acid ethyl ester (I) 1-phenyl-pyrimidof-1,6-a] indole-5-acetic acid (II) 5 - 1- (2-Thienyl) -pyriraido [1,6-a] indole-5-acetic acid (III)

Test Method

The test is conducted analogously to that of L.C. Hendershot and J. Forsaith in J. Pharmacol, exp. Therap. 125, 237 (1959) published the method with the following modifications: 10 albino mice (MAG females, 18-25 g, 2 groups of 4 animals), which have not been fed overnight, are injected intraperitoneally with 0.25 ml of a fresh 0.03% suspension of phenyl-β-benzoquinone in tragic 0.4% 55 minutes after oral application of the comparative compound. Instead of the active substance, control animals are given the carrier tragically 0.4%. Five minutes after the intraperitoneal injection of the irritant, the antinociceptive response is determined by counting the stretching movements for a period of 10 minutes ter.

The antinociceptive effect (EDsg value) of the test compounds is determined by calculating the dose at which a 50% decrease in stretching movements is observed compared to the control group.

Test Results 25 Compound ED50 (mg / kg) I 0.2 II 0.6 III 0.2 30 -

Claims (4)

1. Analogous process for the preparation of therapeutically active pyrimido [1,6-aindole derivatives of the general formula * 3 \ A 1. ii ii VY> ,. R 'V' wherein optionally at the p-position with alkoxy having at most 4 carbon atoms or alkanesulfinyl having at most 4 carbon atoms substituted phenyl, unsubstituted thienyl or unsubstituted pyridyl, R2 means hydrogen or lower alkyl having not more than 4 carbon atoms, R3 4 is carbon or halogen, with the exception that R 2 is different from ethyl when R 3 is hydrogen and R 1 is phenyl or when R 3 is methoxy and R 2 is p-chlorophenyl, or salts thereof, characterized in that a) dehydrogenating a compound of formula * 3 \ A / "2-COOR2 in II H Vy \ R-V or a salt thereof while decomposing hydrogen to form a further bond or b) hydrolyzing a compound of formula I or a salt thereof, wherein R 2 represents alkyl of not more than 4 carbon atoms, or c) ester a compound of formula I or a salt thereof wherein R 2 represents hydrogen and, if desired, converts a formed free compound of formula I into a salt or convert a prepared salt to the free compound of formula 1 or to another salt. Process according to claim 1 for the preparation of 5 7-fluoro-1- (2-thienyl) -pyrimido [1,6-a] indole-5-acetic acid or a salt thereof, characterized in starting from a compound of formula (XI) or (I) or a salt thereof. Process according to claim 1 for the preparation of 10 1- (2-thienyl) -pyrimido [1,6-a] indole-5-acetic acid or a salt thereof, characterized in starting from a compound of formula (XI) ) or (I) or a salt thereof. Process according to claim 1 for the preparation of 1- (2-thienyl) -pyrimido [1,6-a] indole-5-acetic acid ethyl ester or a salt thereof, characterized in that a compound of formula (XI) is used. ) or (I) or a salt thereof.