DK157757B - METHOD OF ANALOGY FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE PYRIMIDOOE 1,6-AAA INDOL-5-ACETIC ACID DERIVATIVES OR SALTS THEREOF - Google Patents

Abstract

Novel amidines, especially N,N'- bridged carboxylic acid amidines of the general formula <IMAGE> in which R1 represents an aromatic radical, R2 represents optionally esterified or amidated 1-carboxy- lower alkyl, Ph represents optionally substituted 1,2-phenylene and alk represents an aliphatic hydrocarbon radical separating the imino group from the methane group by from 1 to 3 carbon atoms, and their salts, have, inter alia, anti-inflammatory activity and can be used as active medicament substances in pharmaceutical preparations. They are produced according to methods known per se.

Description

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in

The present invention relates to an analogous process for the preparation of novel therapeutically active pyrimido / 1,6-a-indole-5-acetic acid derivatives of the formula CH9-R'9 5 Ph in 1 (I)

R-L

wherein R 1 means unsubstituted or once or twice with halogen, lower alkoxy, lower alkyl thio, halogen low alkyl thio, lower alkanesulfinyl, lower alkanesulfonyl and / or sulfamoyl substituted phenyl, picolinyl or thienyl, R 2 represents carb-oxy, low alkoxycarbonyl or carbamoyl, 1.2 the phenylene ring Ph is unsubstituted or substituted once or twice by halogen, lower alkyl and / or lower alkoxy, and the dotted line means that a double bond may also exist, the "low" groups having at most 4 C-15 atoms, or their salts.

The process of the invention is characterized in that a) a compound of the formula ^ CH2-R'2

Ph 1] II (IVa) 2 Y 1 X 1 wherein Ph, R 2 and R 2 have the above meanings, represent hydrogen, and represent a group of the formula -CH 2 CH 2 NH-C 2 OJ-R 1 or -CH = CH-NH-C (= O) -Rx, or a salt thereof cyclized in the presence of an acidic catalyst, or

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2 b) in a compound of the formula

. CHO R

_ / 2 2

Ph I

(X) i j

Rx wherein Ph and R 2 have the above meanings, and R "2 means from R'2 different functionally modified carboxy, or in a salt thereof, R" 2 / ° m necessary by means of an acid or base is transferred by hydrolysis to carboxy R'3, by alcohols with a lower alkanol to lower alkoxycarbonyl R'2 or by ammonolysis to carbamoyl R'2, or c) to prepare compounds of formula I wherein R'2 means lower alkoxycarbonyl or carbamoyl, the dotted line means that a double bond is present and R 1 and Ph have the above meanings, a compound of the formula

Ph [1 f (I,) or a salt thereof using a dehydrogenating agent while decomposing hydrogen by simultaneously forming an additional bond, or d) to prepare compounds of formula I wherein R 1 is carboxy, and R 1 and Ph have the above meanings, a compound of formula I is hydrolyzed, wherein R 2 is lower alkoxycarbonyl or carbamoyl, or a salt thereof, if necessary by an acid or base, or e) to prepare compounds of the formula Wherein R'2 is lower alkoxycarbonyl or carbamoyl, and R4 and Ph

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have the above meanings, esterified or amidated with ammonia a compound of formula I or a salt thereof, wherein R 2 represents carboxy, or f) for the preparation of compounds of formula I wherein 5 means lower alkylthio substituted phenyl, and R

Ph has the above meanings, a compound of formula I wherein R 1 is reduced by lower alkanesulfinyl or sulfonyl substituted phenyl, or a salt thereof by a reducing agent, or 10 g) to prepare compounds of formula I wherein R means with lower alkanesulfinyl or sulfonyl substituted phenyl, and R 2 and Ph have the above meanings, a compound of formula I is oxidized, wherein R 4 is substituted with low alkylthio substituted phenyl, or a salt thereof by an oxidizing agent, where desired , a free compound of formula I is converted to a salt or salt is converted to a free compound of formula I or to another salt.

Thienyl is 2- or 3-thienyl, and picolinyl is e.g. 2-, 3- or 4-picolinyl.

Salts of the present compounds of formula I are preferably pharmaceutically useful salts, such as corresponding acid addition salts and / or, when meaning 1-carboxyl-a-alkyl, internal salts or salts with bases. 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 acids, such as hydrogen bromide or hydrochloric acid. As optionally unsaturated dicarboxylic acids may be mentioned, for example, 4

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oxalic acid, malonic acid, fumaric acid or maleic acid, optionally used with hydroxy further substituted or additional oxo and / or carboxy containing carboxylic acids, for example tartaric acid, malic acid, pyruvic acid or citric acid. Sulfonic acids are e.g. 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, ethyl or tert-butylamine. Dilavalkylamines are, for example, diethyl- or dipropylamine, and as examples of trilavalkylamines may be mentioned triethyl-, tributyl- or dimethyl-propylamine.

The compounds of formula I have valuable pharmacological properties. In particular, they have a pronounced antinociceptive (analgesic) effect, which can be detected, for example, by the acetic acid-twisting syndrome in rats in the dose range of about 10%. 1 to approx. 30 mg / kg p.o. and by the phenyl-β-benzoquinone torsion test on mice in the dose range of ca. 1 to approx. 30 mg / kg p.o.

Furthermore, the compounds have a pronounced anti-inflammatory and anti-arthritic effect, which can be demonstrated by inhibiting the kaolin paw edema in normal rats in the dose range from ca. 10 to approx. 100 mg / kg p.o., and which can also be detected by inhibiting the carrageenin paw edema in rats by analogy to the method of Pasquale et al., Agents and Actions, 5, 256 (1976), at doses of from ca. 3 to approx. 300 mg / kg p.o.

In addition, the compounds of formula I inhibit curative application by 4-fold administration of ca. 10 to approx. 100 mg / kg 35 p.o. kaolin paw edema in adjuvant arthritis rats.

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The compounds of formula I are therefore very suitable as drugs for the treatment of inflammatory diseases, primarily those of rheumatic or arthritic, as antiphlogistics and / or as peripheral analgesics.

Process a)

The cyclization is carried out in a known manner, e.g. in the presence of catalysts such as acidic catalysts. Examples of acidic catalysts include mineral acids such as sulfuric acid or polyphosphoric acid, mineral acid halides such as sulfuryl chloride or phosphorus halides, e.g. phosphorus pentachloride, or organic sulfonic acids such as benzene, p-toluene or methanesulfonic acid. If necessary, the reaction is carried out in one of the above-mentioned inert solvents or diluents, preferably under heating, e.g. in the temperature range from approx. 20 to approx. 200 ° C, in a closed container and / or under an inert gas atmosphere, e.g. a nitrogen atmosphere.

A particularly advantageous embodiment of method a) 20 consists, for example, in that in compounds of formula <ivd) I!

H

wherein Bz represents an optionally substituted α-phenyllavalkyl group, preferably benzyl, quaternizes in particular 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 prepared compound of the formula

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6

-. ^^ CN

Ph i

(IVe) f

H S

Ν '

Bz ^^ Bz solvolyses the cyano group to R * or R ", the benzyl group hydrolyzes off hydrogenolytically in the presence of a hydrogenation catalyst, for example, palladium, and converts the now free amino compound to a compound of the formula

> Z; L

Rn “C

Hal is oxo, and Hal is halogen, and finally is reacted by a cyclizing agent, preferably a mineral acid halide such as phosphorus oxychloride or phosphorus chloride.

Method b)

For example, functionally modified and different from R * 2, functionally modified carboxy are optionally functionally modified orthoester groups, such as trihalogenated, halogenated dilavalkoxy or trilavalkoxymethyl groups, anhydrided carboxy such as cyano, a group having the formula = C = O, azido or halocarbonyl, acyloxycarbonyl such as acetyloxycarbonyl, or derivatives of carboxy of formula R 1 or R 2 in which oxo is optionally substituted with thio or optionally substituted imino such as optionally esterified thiocarboxy such as lower alkylthiocarboxy, f eg ethylthiocarboxy, amidated thiocarboxyl, imino esters such as imide or amide halide groups, eg imino chloro or amino dichloromethyl, imino ether groups such as low alkyl or low alkylene imino ether groups, eg methoxy oxy or ethoxyiminomethylene, or amidino groups such as amidino or lower alkylamidino, for example methylamidino.

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Functionally modified carboxy compounds, such as optionally functionally converted orthoesters, anhydrided carboxy or acyloxycarbonyl, can be solvoluted directly or in several solvolysis steps for free, esterified or amidated carboxy.

The solvolysis of R "is carried out in a known manner, for example by hydrolysis with water, by ammonia lysis with ammonia, by aminolysis with a desired primary or secondary amine or by alcoholysis with a corresponding alcohol. The reaction is carried out if necessary in the presence of a catalyst, in a solvent or diluent, in a sealed container, in a temperature range of about 0 to 150 ° C and / or under an inert gas atmosphere, for example a nitrogen atmosphere.

Examples of catalysts include basic condensing agents such as alkali metal or alkaline earth metal hydroxides, e.g. sodium, potassium or calcium hydroxide, or tertiary organic amines such as pyridine or trialkylamines, e.g. triethylamine, or acidic hydrolysis agents such as mineral acids, e.g. hydrogen halide acids, such as hydrochloric acid, or organic carboxylic or sulfonic acids, such as lower alkane carboxylic acids or optionally substituted benzenesulfonic acids, e.g. acetic acid or p-toluenesulfonic acid.

The reaction is usually carried out in an inert solvent, for example in an optionally halogenated hydrocarbon such as an aromatic hydrocarbon, e.g. benzene or toluene, an ether such as tetrahydrofuran or dioxane, or an amide, e.g. dimethylformamide, in a temperature range of from ca. 20 to 150 ° C and / or optionally in the presence of a catalyst such as a base, e.g. an alkali metal alcoholate such as potassium tert-butylate.

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Process c)

Dehydrogenation is carried out in a manner known per se, especially at higher temperature, e.g. in a temperature range of approx. 100 to approx. 300 ° C, and using a dehydrogenating agent. As a dehydrogenating agent, for example, dehydrogenation catalysts, e.g. elements of the side groups, preferably of side group VIII, such as palladium or platinum, or their salts, such as ruthenium triphenyl-1-phosphide chloride, the catalytically active substances being optionally placed on a suitable support material such as carbon, alumina or silica. Other dehydrogenating agents are, for example, guinones, such as tetrachloro-β-benzoguinone or 2,3-dichloro-5,6-dicyano-β-benzoguinone, or such as anthraguinones, e.g. phenanthrene-9,10-guinon. 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 atmosphere, e.g. a nitrogen atmosphere.

The compounds of formula I used as starting materials can be prepared using the methods described above.

A compound of formula I prepared can be converted into another compound of formula I -25 I known per se.

Free carboxy R'2 can be transferred into corresponding esterified carboxy, e.g. by reacting optionally reactively converted carboxy or a salt thereof by alcoholysis with a desired alcohol, e.g. a reactive derivative thereof or an olefin derived therefrom, or by alkylation with diazolavalkane.

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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 acid, or with organic carboxylic acids such as lower alkanoic acids, e.g. acetic acid.

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

The esterification of the free carboxy group is carried out in the presence of a condensing agent. As catalytic water-scavenging agent for the esterification with alcohols, for example, acids, e.g. protonic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, boric, benzenesulfonic and / or toluenesulfonic, or Lewis acids such as boron trifluoride etherate. Conventional water-binding condensing agents are e.g. hydrocarbon groups substituted with hydrocarbon groups, e.g. N, N1-diethyl, N, N-dicyclohexyl or N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimides. Condensation agents for the esterification with reactive esters are e.g. 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, organic nitrogen bases, e.g. tertiary organic amines such as triethylamine or pyridine. The esterification is preferably carried out with excess alcohol used. The reaction is preferably carried out in an anhydrous medium, if necessary in the presence of an inert solvent, such as in halogenated hydrocarbons, e.g. chloroform or chlorobenzene, or in ethers, e.g. tetrahydrofuran or dioxane.

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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-toluene sulfonic acid, or, first of all, a basic catalyst, e.g. sodium or potassium hydroxide, advantageously in an inert solvent such as in an ether, e.g. in diethyl ether or tetrahydrofuran.

Furthermore, free carboxy R'2 or reactive functional carboxy derivatives can be transferred to a desired amide form by solvolysis with ammonia in the usual manner during dehydration, e.g. in the presence of a condensing agent. As a condensing agent, bases, for example inorganic bases such as alkali metal hydroxides, e.g. sodium or potassium hydroxide, organic nitrogen bases such as tert-amines, e.g. pyridine, tributylamine or N-dimethylaniline, or tetrahalogen silanes such as tetrachlorosilane.

Furthermore, the compounds of formula I wherein R'2 is esterified carboxy may be transesterified in the usual manner, e.g. by reaction with a corresponding alcohol or metal salt thereof, such as an alkali metal salt, e.g. sodium or potassium salts, if necessary in the presence of a catalyst, e.g. a strong base such as, an alkali metal hydroxide, alkali metal amide or alkali metal alcoholate, e.g. potassium hydroxide, sodium amide or 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.

Furthermore, esterified carboxy can be transferred into the free carboxy group in a manner known per se, e.g. by hydrolysis in the presence of a catalyst. Preferably, as catalysts, bases, e.g. alkali metal hydroxides such as sodium or potassium hydroxide. Furthermore, esterified carboxy can be converted to carboxy, e.g. by solar volysis, optionally in the presence of a catalyst, e.g. an acidic or

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a basic agent, or for amidated carboxy by ammonolysis or aminolysis with ammonia or with a primary or secondary amine. As bases, for example, alkali metal hydroxides such as sodium or potassium hydroxide may be used, and as acids, for example, mineral acids such as sulfuric acid, phosphoric acid or hydrochloric acid may be used. Also, in compounds of formula I wherein the substituent contains amidated carboxy, the amide bond known in the art can be cleaved and in this way carbamoyl is transferred into free carboxy. This reaction is carried out in the presence of a catalyst, e.g. a base such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. sodium, potassium or calcium hydroxide or carbonate, or an acid such as a mineral acid, e.g. hydrochloric acid, sulfuric acid or phosphoric acid.

When the group R'2 of the compounds of formula I is an esterified carboxy group, it can be transferred into an amidated carboxy group, e.g. by conventional solvolysis, advantageously with an excess of ammonia, optionally in the presence of a catalyst. As catalysts, for example, acids such as mineral acids, e.g. hydrochloric acid, sulfuric acid or phosphoric acid, or bases such as alkali metal hydroxides, e.g. sodium or potassium hydroxide.

When the group R'2 of the compounds of formula I is amidated carboxy, it can be transferred into esterified carboxy e.g. by conventional solvolysis with an alcohol in the presence of a catalyst. For this purpose, for example, acidic catalysts such as mineral acids, e.g. phosphoric acid, hydrochloric acid or sulfuric acid.

When the substituent of the compounds of formula I is substituted with lower alkylthio, this group can be oxidized in the usual way to corresponding lower alkanesulfinyl or sulfonyl. As suitable oxidizing agents for the oxidation to the sulfoxide step, for example, inorganic peracids such as peracids of mineral acids, e.g. periodic

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or persulfuric acid, organic peracids such as corresponding percarboxylic or persulfonic acids, e.g. permyric acid, peracetic acid, trifluoroacetic acid or perbenzoic acid or p-toluene persulfonic acid, or mixtures of hydrogen peroxide and acids, e.g. mixtures of hydrogen peroxide with acetic acid.

The oxidation is often carried out in the presence of suitable catalysts, suitable catalysts such as optionally substituted carboxylic acids, e.g. acetic acid or trifluoroacetic acid, or transition metal oxides such as oxides of the elements of side group VII, e.g. vanadium, molybdenum or tungsten oxide. The oxidation is carried out under mild conditions, e.g. at temperatures of approx. -50 to 100 ° C.

The oxidation to the sulfone step can also be carried out correspondingly with nitrous oxide as the catalyst in the presence of oxygen at low temperatures in the same way as the direct oxidation of low alkylthio to low alkanesulfonyl.

Here, however, the oxidizing agent is usually used in excess of 20 shots.

Compounds of formula I, in which a lower alkylsulfinyl or sulfonyl substituted aromatic group, can be reduced in known manner to the corresponding lower alkylthio compounds, by the lower alkanesulfonyl derivatives of lower alkanesulfinyl. As a reducing agent, for example, catalytically activated hydrogen can be used, using noble metals or oxides thereof, such as palladium, platinum or rhodium or their oxides, optionally on a suitable support material such as activated carbon or barium sulfate. Furthermore, reducing metal cations such as tin II, lead II, copper I, manganese II, titanium II, vanadium II, molybdenum III or tungsten III compounds, hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide can be used. hydrides such as complex metal hydrides, e.g. lithium aluminum, sodium boron, tributyltinborohydride, phosphorus compounds such as phosphorus halides,

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eg. phosphorus trichloride, bromide, phosphorus pentachloride or phosphorus oxychloride, phosphines such as triphenylphosphine, or phosphorus pentasulfide pyridine, or sulfur compounds such as mercaptans, thios acids, such as thiophosphoric acid or dithiocarboxylic acids, dithionic acid, sulfuric acid or sulfuric oxygen sulfuric anhydride complex.

Prepared salts can be converted into the free compounds in a manner known per se, e.g. by treatment with an acidic reagent such as a mineral acid, or a base, e.g. alkali limetalhydroxidopløsning.

The compounds of this invention may, depending on the choice of starting materials and reaction conditions, 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, diastereoisomeric mixtures or racemate mixtures.

Prepared diastereomer mixtures and racemate mixtures 20 can, due to the physicochemical differences of the constituents, be separated in known manner into the pure isomers, diastereomers or racemates, for example by chromatography and / or fractional crystallization.

Furthermore, produced racemates can be separated into the 25 optical antipodes in a manner known per se, e.g.

by recrystallizing an optically active solvent, by microorganisms or by reacting an acidic final product with an optically active base which forms salts with the racemic acid, and separating the salts thus prepared, e.g. due to various solubilities, in the diastereomers from which the antipodes are released by the action of a suitable agent. Preferably, the most effective of the two antipodes is isolated.

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The compounds and their salts can also be obtained in the form of hydrates or contained other solvents used for the crystallization.

Since the compounds in question in free form and in the form of their salts are closely related, in the foregoing and subsequent, the free compounds or their salts are equivalent to the corresponding salts or free compounds.

The invention also relates to such embodiments of the process, according to which starting from any step of the process as intermediates are made and implementing the missing steps or using a starting material in the form of a salt or, in particular, forming it under the reaction conditions.

The pharmaceutical compositions containing the compounds of formula I or their pharmaceutically acceptable salts are preparations for enteral, such as oral or rectal, and parenteral administration, as well as for topical use in warm blooded animals. The compositions contain the pharmacologically active substance alone or in admixture with a pharmaceutically useful carrier. The dosage of the active substance depends on the nature of the warm-blooded animal, its age and individual condition, and the mode of administration. In normal cases, an oral daily dose of 25 approx. 30-300 mg, advantageously divided into several sub-doses, for a warm-blooded animal with a body weight of 75 kg.

The pharmaceutical compositions contain e.g. from approx. 10 to approx. 80, preferably from ca. 20 to approx. 60% active substance. The present compositions for enteral or parenteral administration are e.g. such in dosage unit forms, such as dragees, tablets, capsules or suppositories, furthermore ampoules. These are manufactured in a manner known per se, e.g. by conventional mixing, granulation, coating, dissolution or lyophilization processes

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15 ways. Thus, pharmaceutical compositions for oral administration may be prepared when the active ingredient is combined with solid carriers and the granulated preparation optionally granulated, whereupon the mixture or granulate, if desired, or if necessary, after the addition of suitable excipients, is processed into tablets or drill cores.

The process according to the invention is further illustrated in the following examples.

The terms used in the literature for binding sites in the pyrimido indole ring system .7 in which form the compounds of formula I are not uniform. Thus, in older literature, the binding sites in the ring system are denoted by [3,4-a], while in recent literature, the term [1,6-a] is used,

For reasons of principle, the term pyrimido [1, β-a] indole is used hereinafter for the above ring system.

Example 1 7-Methoxy-1 (p-chlorophenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester hydrochloride 165 g (0.4 mol) 2 - [(p-chlorobenzoyl) -amino) -ethyl] -5-methoxy-indole-3-acetic acid ethyl ester is heated to boiling in 825 ml of phosphorus trichloride for 3 hours under reflux, after which excess phosphorus trichloride is distilled off at a bath temperature of 60 ° C under low vacuum. The residue is dissolved in 1500 ml of methylene chloride, stirred with 2000 ml of ice-cream.

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16 water is made basic by adding 500 ml of concentrated ammonia water and after a short stirring the methylene chloride phase is isolated. Wash with water for neutral reaction, dry over Na 2 SO 4 and then the methylene chloride is distilled off. The residue (136.7 g) is dissolved in 120 ml of acetone and 500 ml of ether, and to the solution is added 100 ml of ca. 4 N hydrogen chloride solution in ether. Thereby, hydrochloro-crystallization of 7-methoxy-1- (p-chlorophenyl) -3,4-dihydro-pyrimido [1,6-a] indole acetic acetic acid ethyl ester crystallizes.

CH-0 CHn-C00 COH [-

Vv / 10 vv \ I. HCl

Ay

Cl

The compound is suctioned off and washed with a mixture of acetone and ether in the 1:10 mixture ratio to give odd crystals of m.p. 204-208 ° C, which after recrystallization from a mixture of methanol and acetone has m.p. 205-208 ° C.

The starting compound can be prepared as follows: a) 131 g (0.45 mol) of 3-benzyl-6-methoxy-tetrahydro-γ-carboline are dissolved with stirring in 1300 ml of acetonitrile at 40 ° C and added over 10 minutes. 94 g (0.55 mol) of benzyl bromide. After a short time, the benzylammonium-20 derivative begins to crystallize. Stir for a further approx. 15 hours at room temperature, after which the mixture is cooled in an ice bath and the crystalline product is suctioned, m.p. 150-151 ° C.

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B) 464 g (1 mole) of the N, N-diben2-yl-6-methoxy-tetrahydro-Y-carboliminium bromide thus prepared are dissolved in 4250 ml of methanol with heating to 65 ° C and added over 5 minutes under stirring a solution of 5 196 g (4 moles) of sodium cyanide in 500 ml of water. The solution is heated to reflux for 3 hours. Upon cooling, after inoculation, 2- (dibenzylamino-ethyl) -3-cyano-methyl-5-methoxy-indole crystallizes out as snip colorless crystals. 102-104 ° C.

C) 220 g (0/537 mol) of the nitrile prepared according to b) is dissolved in 300 ml of absolute ethanol and the solution is saturated at -5 ° C with dry hydrogen chloride. The solution is then stirred for 5 1/2 days at 20 ° C. The precipitated crystals are allowed to settle, decant the above solution, dissolve the precipitate in 2000 ml of ice water and stir the solution at ca. 3 hours at 20 ° C. The solution is then made basic with concentrated ammonia solution under ice-cooling and stirred with 1500 ml of toluene / ice water.

The separated toluene phase is washed with water, dried over 23 sodium sulfate and filtered over 1000 g of alumina (activation step 3) and then washed with toluene. After distillation of the toluene, a residual yellow brominated oil is obtained which is subjected to hydrogenation without further purification in the subsequent step d).

D) 181.3 g of the 2-dibenzylamino-5-methoxy-indole-3-acetic acid ethyl ester prepared in c) are dissolved in 1500 ml of absolute alcohol and hydrogenated under the addition of 18 g of Pd / C (5%) at normal pressure. and 20-35 ° C. After uptake of 12500 ml, an additional 18 g of catalyst is added, 30 and the hydrogenation is continued until the hydrogen uptake is stopped, with a total of 17300 ml being taken up. After filtering off the catalyst and washing with methylene chloride, the solution is evaporated to dryness and the residue is dissolved in 250 ml of ether. After grafting, 2-amino-ethyl-5-methoxy-indo-3-acetic acid ethyl ester crystallizes. form of father velous crystals with m.p. 79-80 ° C.

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E) 61.7 g (0.223 mol) of the 2-aminoethyl-5-methoxy-indole-3-acetic acid ethyl ester prepared in d) are dissolved in 600 ml of methylene chloride and the solution is poured over 150 ml of 2N sodium hydroxide solution. With vigorous stirring, at 0-5 ° C, a solution of 43 g (0.245 mole) of p-chlorobenzoyl chloride is added over 2 1/2 hours, then stirred for another 1 hour. The methylene chloride phase is isolated, washed with water, dried over MgSO4 and evaporated to dryness. The residue crystallizes on admission 10 in ether in colorless crystals, m.p. 136-138 ° C, 2 - [(p-chlorobenzoyl-amino) -ethyl] -5-methoxy-indole-3-acetic acid ethyl ester.

Example 2 1-Phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester 54 g (0.154 mol) 2- (benzoylaminoethyl) indole-3-acetic acid ethyl ester is heated to reflux for 3 hours in 250 ml of phosphorus oxychloride. Excess phosphorus oxychloride is distilled off in vacuo at 60 ° C and the residue 20 is stirred in 1000 ml of ice water. The aqueous solution is clarified by filtration over hyflo, basified with concentrated ammonia water and extracted with 500 ml of ether. The ether phase is dried over sodium sulfate and evaporated to dryness. The residue is dissolved in 200 ml of acetone and 25 ml 25 of a ca. 4 N hydrogen chloride solution in ether. After grafting, the hydrochloride of 1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester crystallizes in yellow crystals, m.p. 172-175 ° C, which can be recrystallized from 1N hydrochloric acid (mp 187-189 ° C). The base released from the salt 30 melts after recrystallization from ether at 83-84 ° C.

The 2- (benzoylamino-ethyl) -indole-3-acetic acid ethyl ester used as a starting material, m.p. 162-163 ° C can be prepared by analogy with the procedures described in Examples 1a) - e).

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Example 3

Analogous to the procedure described in Example 2, is prepared from 2 - [(p-methylthio-benzoylamino) -ethyl] -5-fluoro-indole-acetic acid ethyl ester, m.p. 157-158 ° C 7-Fluoro-1- (p-methylthio-phenyl-3,4-dihydro-pyrimidine [1,6-a] indole-5-acetic acid ethyl ester, mp 119-120 ° C.

Example 4

Analogous to the above process is prepared from 2-benzoylaminomethyl-4,5-dimethyl-indole-3-acetic acid ethyl ester with m.p. 183-184 ° C 6,8-Dimethyl-1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester, m.p. 142-143 ° C.

Example 5

Analogously to the above process, is prepared from 2- [(1-sulfamoyl-β-chlorobenzoyl-aminoO-ethyl] -indole-3-acetic acid ethyl ester, mp 212-213 ° C 1- (3-sulfamoyl-4-chloro-phenyl) ) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester, mp 227-228 ° C.

Example 6 Analogous to the above process prepared from 2- (2,6-dichlorobenzoylaminoethyl) -indole-3-acetic acid ethyl ester, m.p. 125-126 ° C 1- (2,6-Dichlorophenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester, m.p. 92-93 ° C (hydrochloride / mp 138-142 ° C).

Example 7

Analogous to the above process is prepared from 2- (2-picolinoylamino-ethyl) -indole-3-acetic acid ethyl ester with m.p. 117-118 ° C 1- (2-picolinyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester, m.p. 113-114 ° C (hydrochloride, mp 194-204 ° C).

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20

Example 8

Analogous to the above process is prepared from 2- (2-thienylamino-ethyl) -indole-3-acetic acid ethyl ester with m.p. 140-141 ° C hydrochloride of 1- (2-thienyl) -3,4-di-5-hydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester, m.p. 153-157 ° C.

Example 9 7-Methoxy-1- (p-chlorophenyl) -3,4-dihydro- [1,6-a] indole-5-acetic acid 10 To a solution of 550 g of potassium hydroxide in 200 ml of water and 1500 ml of methanol is added. with stirring 117/2 g (0.27 mol) of 7-methoxy-1- (p-chlorophenyl) -3,4-dihydro-pyrimido [1,6-a] indo 1-5-acetic acid ethyl ester hydrochloride. The mixture is stirred for 10 hours at room temperature, then the methanol is distilled off in vacuo and the residue is dissolved in 1500 ml of ice-water and 700 ml of concentrated hydrochloric acid are added under ice-cooling. The separated hydrochloride is extracted and recrystallized from 2300 ml of 50% ethanol. In this way, 7-methoxy-1- (p-chlorophenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid hydrochloride is obtained in the form of yellow crystals, m.p. 225-228 ° C (dec.).

Example 10

Analogous to the above process, the hydrochloride of 1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid is obtained from the corresponding ethyl ester, m.p. 235-240 ° C (dec.).

Example 11

Analogous to the above process, the hydrochloride of 7-fluoro-1- [3- (p-methylthio-phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid, m.p. 220-222 ° C (dec.).

2, DK 157757B

Example 12

Analogous to the above process, the hydrochloride of 7-fluoro-1- (p-methylsulfinyl-phenyl) -3,4-dihydro-pyrimido [1,6-a] 5-indole-5-acetic acid is prepared from the corresponding ethyl ester. 208-210 ° C (dec.).

Example 13

Analogous to the above process, the hydrochloride of 6,8-dimethyl-1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid 10 is prepared from the corresponding ethyl ester, m.p. 212-220 ° C (dec.). The corresponding hemihydrate melts at a temperature above 210 ° C.

Example 14

Analogous to the above process, the hydrochloride of 1- (3-sulfa-1-methyl-4-chloro-phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid with mp. 216-220 ° C (dec.).

Example 15

Analogous to the above process, the hydrochloride of 1- (2,6-20 dichlorophenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid, m.p. 270-277 ° C (dec.). .

Example 16

Analogously to the above process, the hydrochloride of 1- (2-thienyl) -25 3,4-dihydro-pyrimido- [1,6-a] indole-5-acetic acid, m.p.

230-235 ° C (dec.). From an aqueous solution of the hydrochloride crystallizes at pH 6-7 1- (2-thienyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid as the inner salt, m.p. 187-189 ° C,

DK 157757 B

22

Example 17 1-Phenyl-3,4-dihydro-pyrimido [1,6-aj indole-5-acetic acid iodide 1 g (0.003 mol) 1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole 5-Acetonitrile is heated to 100 ° C in 10 g of polyphosphoric acid 5 for 30 minutes. The reaction mixture is dissolved in 100 ml of water, the solution is made basic under ice-cooling by the addition of concentrated ammonia water and the reaction product is extracted with methylene chloride. The methylene chloride phase is washed neutral with water, dried over sodium sulfate and the solution is evaporated to dryness. As the residue, solid 1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid amide is obtained, which is recrystallized from methanol. Colorless crystals are obtained with m.p. 239-240 ° C. The corresponding hydrochloride melts at 253-260 ° C (dec.).

The starting material can be prepared as follows: a) 38 g (0.1 mole) of 2- (dibenzylamino-ethyl) -indole-3-acetonitrile is added to 300 g of polyphosphoric acid and the mixture is heated to 100 ° C with stirring for approx. 60 minutes.

Then the mixture is poured into 1 kg of ice which is made basic 20 by the addition of concentrated ammonia water and then extracted with ether. After washing, drying and evaporating the ether phase, 2- (dibenzylaminoethyl) -indole-3-acetamide is obtained in the form of a syrup which can be recrystallized from a bit of ether, m.p. 135-136 ° C.

B) 120 g (0.3 mol) of 2- (dibenzylamino-ethyl) -indole-3-acetamide are hydrogenated with the addition of 12 g of 5% Pd / C in 1.2 liters of methanol at normal pressure and a temperature of 30 g. -35 ° C. After uptake of 14.4 liters of hydrogen, the hydrogenation is stopped, the catalyst is filtered off and the solution is evaporated to dryness in vacuo. The residue is recrystallized from 100 ml of ethanol with the addition of 250 ml of ether. The 2-aminoethyl-indole-3-acetamide thus prepared melts at 156-157 ° C.

23 DK 157757B

c) To 21.7 g (0.1 mole) of 2-aminoethyl-indole-3-acetamide in a mixture of ether (200 ml) and water (100 ml) is added with good stirring and cooling to ca. 5 ° C 17.5 ml (0.15 mol) of benzoyl chloride and gradually add 5 100 ml of 2 N sodium hydroxide solution. The reaction is completed after approx. 1 hour. The mixture is then stirred for an additional 1 hour at 0-5 ° C, after which the separated 2- (benzoylamino-ethyl) -indole-3-acetamide is extracted with m.p. 223-225 ° C.

D) 1.6 g (0.005 mol) of 2- (benzoylamino-ethyl) -indole-3-acetamide are heated in 16 ml of phosphorus oxychloride for 2 hours under reflux. Excess phosphorus oxychloride is distilled off, the oily residue is taken up in water, and by-products formed by the reaction are removed by extraction with ether. Concentrated ammonia water is added to the aqueous phase and then extracted with ether. After washing, drying and evaporating the ether phase, 1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetonitrile is obtained in the form of a yellowish oil which, when dissolved in meth-20 anole and addition of ethereal hydrochloric acid can be transferred into a crystalline hydrochloride with m.p. 195-205 ° C.

Example 18

Analogous to the procedure described in Example 17, is prepared from 1- (3-sulfamoyl-4-chloro-phenyl) -3,4-dihydro-pyrimido- [1,6-a] indole-5-acetonitrile, m.p.

280-285 ° C hydrochloride of 1- (3-sulfamoyl-4-chloro-phenyl) - 3,4-dihydro-pyrimido [1,6-a] indole-5-acetamide, m.p.

249-257 ° C (dec.).

Example 19 12 g (0.03 mol) of 1- (p-methylthio-phenyl) -3,4-dihydropyrimido [1,6-a] indole-5-acetic acid ethyl ester are dissolved in 120 ml of glacial acetic acid and 4 are added. 30% hydrogen peroxide. The mixture is left to stand for approx. 20 hours at the living room

DK 157757 B

At 24 ° C, it is poured into 1 liter of ice water, the mixture is basified with concentrated ammonia water and extracted with ethyl acetate. The ethyl acetate phase is washed, dried and evaporated. The prepared 1- (p-methylsulfoxy-5-phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester crystallizes from ether in yellow crystals, m.p. 150-151 ° C.

Example 20

Analogous to the procedure described in Example 1, 2 - [(p-methylthio-phenylamino) -ethyl] -5-fluoro-indole-5-acetic acid ethyl ester hydrochloride of 7-fluoro-1- ( methylthio-phenyl) -3,4-dihydro-pyrimido [1,6-a] -indole-3-acetic acid ethyl ester, m.p. 210 DEG C. (decomposition) and from the 2 - [(p-chloromethyl-thio-phenyl-amino) -ethyl] -5-fluoro-indole-3-acetic acid ethyl ester hydrochloride of 7-fluoro-1- (p-chloromethylthio) phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester, m.p. 198-202 ° C.

Example 21 Analogous to the procedure described in Example 19 is prepared from the 7-fluoro-1- (p-methylthiophenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester hydrochloride hydrochloride of 7-fluoro-1- (p-methylsulf-oxyphenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester with m.p. 261-264 ° C.

Example 22

Analogous to the procedure described in Example 9, is prepared by saponification of 7-fluoro-1- (p-methylthio-phenyl) -pyrimido [1,6-a] indole-5-acetic acid ethyl ester 7-fluoro-1-30 (p-methylthio -phenyl) -pyrimido- [1,6-a] indole-5-acetic acid, m.p. 213-220 ° C (dec.).

DK 157757B

25

Example 23 7-Fluoro-1- (p-methylthio-phenyl) -pyrimido [1,6-a] indole-5-acetic acid ethyl ester 2 g of 7-fluoro-1- (p-methylthio-phenyl) -3,4-dihydro-1 pyrimido 5 [1,6-a] indole-5-acetic acid ethyl ester is heated to reflux in 20 ml of diphenyl ether with 0.5 g of palladium / carbon (10%) with stirring. After 2 hours, an additional 0.5 g of palladium / coal is added and the mixture is heated for an additional 3 hours. After filtering off catalyst 10, the reaction mixture is evaporated in vacuo, the residue is taken up in a little ethyl acetate and chromatographed over silica gel. With hexane / ethyl acetate (9: 1) are obtained fractions which after evaporation and recrystallization from ether give 7-fluoro-1- (p-methylthio-phenyl) -pyrimido [1,6-a] indole-5-ed-diacetic acid ethyl ester with m.p. 120-122 ° C.

F CHo-C00CoHc ΎυΥ

By analogy, 1-phenyl-pyrimido [1,6-a] indole-5-acetic acid ethyl ester is prepared, m.p. 59-62 ° C and 7-methoxy-1- (p-chlorophenyl) pyrimido [1,6-a] indole-5-acetic acid ethyl ester, m.p. 130-131 ° C.

Example 24 1.0 g (0.003 mol) of 1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetonitrile is stirred in 50 ml of absolute ethanol and 50 ml of hydrogen chloride saturated ethanol for 48 hours. by

DK 157757B

26 + 3 ° C. Then the solvent is distilled off under reduced pressure. The remaining crude hydrochloride of 1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetiminoethyl ether is suspended in 10 ml of water and heated under stirring for 15 minutes to 40 ° C. After cooling, 1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester hydrochloride crystallizes, which, after recrystallization from 1N hydrochloric acid, gives crystals of m.p. 187-189 ° C.

Example 25 3.84 g (0.01 mole) of 7-fluoro-1- (p-methylsulfoxy-phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester are heated at reflux in 500 ml of ethyl acetate with 40 g of deactivated Raney nickel with stirring for 2 hours.

The catalyst is then filtered off and the filtrate is evaporated under reduced pressure. The residue is recrystallized from ether to give 7-fluoro-1- (p-methylthio-phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester, m.p. 119-120 ° C.

Example 26 20 Tablets containing 25 mg of active substance, e.g. 7-fluoro-1- (p-methylthio-phenyl) -3,4-dihydro-pyrimido- [1,6-a] indole-5-acetic acid or a salt thereof, e.g. hydrochloride, can be prepared as follows:

Ingredients (for 1000 tablets): 25 Ingredient 25.0 g

Lactose 100.7 g

Wheat starch 7.5 g

Polyethylene glycol 6000 5.0 g

Talc 5.0 g Magnesium stearate 1/8 g

Demineralized water e.g.

DK 157757 B

27

manufacturing

All solid components are first screened through a screen having a mesh width of 0.6 mm. Then, the active substance, lactose, talc, and magnesium stearate are mixed with half the starch. The other half of the starch is suspended in 40 ml of water and the suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water.

The starch paste prepared is added to the bulk and the mixture is 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 pressed into double concave tablets with a diameter of approx. 6 mm.

Similarly, tablets 15 containing 25 mg of one of the compounds of formula I mentioned in Examples 1 to 19 may also be prepared, the compounds also being used in the form of acid addition salts such as hydrochlorides and compounds wherein R 2 is 1-carboxylic acid. methyl, also in the form of salts with bases such as sodium, potassium or zinc salts.

Example 27

Chewable tablets containing 30 mg of active substance, e.g.

7-fluoro-1- (p-methylthio-phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid or a salt thereof, e.g.

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.

DK 157757B

28

manufacturing

All solids are first sieved 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 with a 2 mm mesh, dried at 50 ° C and pressed again through a sieve with a 1.7 mm mesh. The active substance, glycine and saccharin are thoroughly mixed, the mannitol, lactose granulate, stearic acid and talc are added, and the whole is thoroughly mixed and compressed into double concave tablets of approx. 100 mm and with split notch on the upper side.

Similarly, chewable tablets containing 30 mg of one of the compounds of formula I mentioned in Examples 1 to 19 may also be prepared, the compounds 15 also being used in the form of acid addition salts such as hydrochlorides and compounds wherein 1 is carboxymethyl , also in the form of salts with bases such as sodium, potassium or zinc salts.

Example 28 20 Tablets containing 100 mg of active substance, e.g. 7-fluoro-1- (p-methylthio-phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid or a salt thereof, e.g. hydrochloric acid, may be prepared as follows:

Composition (for 1000 tablets): Active substance 100.0 g

Lactose 248.5 g

Corn starch 17.5 g

Polyethylene glycol 6000 5.0 g

Talc 15.0 g Magnesium stearate 4.0 g

Demineralized water q.s.

manufacturing

The solid components are sieved through a sieve with a mesh width of 0.6 mm. Thereafter, thorough mixing of the active substance, lactose, talc, magnesium stearate and

DK 157757 B

29 half of the starch. 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 prepared adhesive is added to the powdered substances, all mixed and granulated, if necessary, with the addition of water. The granulate is dried overnight at 35 ° C, sieved through a sieve with a mesh width of 1.2 mm and pressed into double concave tablets with a diameter of approx. 10 mm and with split notch on the upper side.

Analogously, tablets containing 100 mg of a compound of formula I prepared according to Examples 1 to 25 can also be prepared, the compounds also being used in the form of acid addition salts, such as hydrochlorides, and compounds wherein 1-15 carboxymethyl also means in form of salts with bases such as sodium, potassium or zinc salts.

Claims (6)

An analogous process for the preparation of therapeutically active pyrimido / 1,6-a-indole-5-acetic acid derivatives of the formula [beta] - CH2-R'2 Ph [] I5 (I) i 'wherein R ^ is unsubstituted or once or twice with halogen , lower alkoxy, low alkylthio, haloalkylthio, low alkanesulfinyl, low alkanesulfonyl and / or sulfamoyl substituted phenyl, picolinyl or thienyl, R with halogen, lower alkyl and / or lower alkoxy, and the dotted line means that there may also be a double bond, the "low" groups having at most 4 ΟΙ 5 atoms, or their salts, characterized in that a) a compound of the formula ^ ch 2 -R'2 Ph II (IVa) X1 wherein Ph, R 2 and R 2 have the above meanings, represents hydrogen, and means a group of the formula -CH 2 -CH 2 -NH "C (= O) - Or -CH = CH-NH-C (= O) -Rx, or a salt thereof cyclized in the presence of n acidic catalyst, or DK b) in a compound of the formula CH 2 -R "2 Ph IL JL (x) j wherein Ph and R 2 have the above meanings and R" 2 means from R'2 different functionally modified carboxy, or in a salt thereof, R 2 is transferred, if necessary by acid or base, by hydrolysis to carboxy R'2, by alcoholysis with a low alkanol to low alkoxycarbonyl R'2 or by ammonolysis to carbamoyl R'2, or c) for the preparation of compounds of formula I wherein R'2 means lower alkoxycarbonyl or carbamoyl, the dotted line means that there is a double bond, and R4 and Ph have the above meanings, a compound of the formula ^ CH2-R, 2 Ph I in (I ') Rx 15 is dehydrogenated. or a salt thereof using a dehydrogenating agent while decomposing hydrogen by simultaneously forming an additional bond, or d) for the preparation of compounds of formula I wherein R 2 is carboxy and R 2 and Ph are as defined above. 20, a compound of formula I wherein R'2 is lower alkoxycarbonyl or carbamoyl, or a salt thereof, if necessary by an acid or base, or hydrolysed to prepare compounds of formula I wherein R '2 means lower alkoxycarbonyl or carbamoyl and R 1 and Ph have the above meanings, esterified or amidated with ammonia a compound of formula I or a salt thereof, wherein R 2 is carboxy, or f) for the preparation of compound r of the formula I wherein R 1 represents lower alkylthio substituted phenyl and R 2 and Ph have the above meanings, a compound of formula I wherein R 1 is lower alkanesulfinyl or 10-sulfonyl substituted phenyl, or a salt thereof by by means of a reducing agent, or g) for the preparation of compounds of formula I wherein R 2 is lower alkanesulfinyl or sulfonyl substituted phenyl, and R 2 and Ph have the above meanings, a compound of formula I wherein R means a lower alkylthio substituted phenyl, or a salt thereof by an oxidizing agent, whereupon, if desired, a free compound of formula I is converted to a salt or a salt is converted to a free compound of formula I or to another salt . Process according to claim 1 for the preparation of 7-methoxy-1- (p-chlorophenyl) -3,4-dihydro-pyrimido / 1,6-a7 ~ 5-acetic acid or a salt thereof, characterized in that starting from compounds of formulas IVa, X, 1 'or 25 L or a salt thereof. Process according to claim 1 for the preparation of 7-fluoro-1- (p-methylthiophenyl) -3,4-dihydro-pyrimido [1,6-a7in-dol-5-acetic acid or a salt thereof, characterized in that are taken from compounds of formulas IVa, X, 1 '30 or I or a salt thereof. Process according to claim 1 for the preparation of 7- fluoro-1- (p-methylthiophenyl) -3,4-dihydro-pyrimido / 1,6-§7in-dol-5-acetic acid ethyl ester or a salt thereof, characterized by , starting from compounds of formulas IVa, X, 1 'or I or a salt thereof. Process according to claim 1 for the preparation of 7- 5 fluoro-1- (p-methylthiophenyl) -pyrimido / 1,6-§7indole-5-acetic acid, the ethyl ester or a salt thereof, characterized in that starting from compounds with formulas IVa, X, 1 'or I or a salt thereof. Process according to claim 1 for the preparation of 1- (2-10 thienyl) -3,4-dihydro-pyrimido / L, 6-a-indole-5-acetic acid or a salt thereof, characterized in that starting from compounds with formulas IVa, X, 1 'or I or a salt thereof.