NO156012B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY EFFECTIVE PYRIMIDO (1,6-A) INDOL-5-ACETIC ACID DERIVATIVES. - 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

The invention relates to an analogous process for the preparation of new, therapeutically effective pyrimido/1,6-a/indole-5-acetic acid derivatives with the formula

in which means unsubstituted or singly or disubstituted by halogen, lower alkoxy, lower alkylthio, halolower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl and/or sulfamoyl substituted phenyl, picolinyl or thienyl^ means carboxy, lower alkoxycarbonyl or carbamoyl, the 1,2-phenylene ring Ph is unsubstituted or a - or doubly substituted with halogen, lower alkyl and/or lower alkoxy and the dashed line shall express that there may also be a double bond, since residues designated as "lower" may have up to 4 C atoms, as well as their salts, characterized by that

a) a compound with formula

wherein Ph, R'^ and R^ have the above meanings and X, means

hydrogen and means a group of formula

-CH2-CH2-NH-C(=0)-R1 resp. -CH=CH-NH-C (=0) - R-^ or a salt thereof is cyclized in the presence of an acidic catalyst, or

b) in a connection with formula

wherein Ph and R, have the above-mentioned meanings, and R^' and R2' mean variously functionally modified carboxy or a salt thereof, R!} is transferred, if necessary by means of an acid or base, by hydrolysis to carboxy R2, by alcoholysis with a lower alkanol to lower alkoxycarbonyl R 2 or by ammonolysis to carbamoyl R 2', or c) for the preparation of compounds of formula I, in which R 2 means lower alkoxycarbonyl or carbamoyl and the dashed line shall express the presence of a double bond, and R^ and Ph has the above-mentioned meaning, a compound of formula or a salt thereof is de-hydrogenated using a dehydrogenating agent while splitting off hydrogen with the simultaneous formation of an additional bond, or d) for the preparation of compounds of formula I, in which R2 means carboxy and R .^, Ph has the above-mentioned meanings, a compound of formula I is hydrolyzed, in which R^ means lower alkoxycarbonyl or carbamoyl, or a salt thereof if necessary d with the help of an acid or base, or e) for the preparation of a compound of formula I, in which lower alkoxycarbonyl means resp. carbamoyl, and R^, Ph have the above meanings, are esterified resp. a compound of formula I or a salt thereof, in which R^ means carboxy, is amidated with ammonia, or f) for the preparation of compounds of formula I, in which R^ means lower alkylthio substituted fehyl, and R^, Ph has the above-mentioned meaning, is reduced a compound of formula I, in which R^ means with lower alkanesulfinyl or -sulfonyl substituted phenyl, or a salt thereof by means of a reaction agent, or g) for the preparation of compounds of formula I, in which R^ means with lower alkanesulfinyl or -sulfonyl substituted phenyl

and R^, Ph have the above-mentioned meanings, a compound of formula I, in which R^ denotes phenyl substituted with lower alkylthio or a salt thereof, is oxidized by means of an oxidizing agent,

and if desired, a compound of formula I is transferred to a salt or a salt is transferred to the free compound of formula 1 or to another salt.

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

Salts of compounds of formula I are preferably pharmaceutically usable salts corresponding to acid addition

salts and/or if means 1-carboxyleveralkyl,

internal salts or salts with bases. Suitable acid addition salts are, for example, salts with inorganic acids such as mineral acid or organic acids, such as sulfamic acid, e.g. cyclohexylsulfamic acid, optionally unsaturated dicarboxylic

acids, or optionally substituted with hydroxy in addition, resp. in addition ozo, and/or carboxylic carboxylic acid, or sulphonic acid, mineral acid is, for example, sulfuric acid or hydrohalic acids such as bromic or chlorohydrogen

acid. As possibly unsaturated dicarboxylic acids, there are e.g. in consideration of oxalic acid, malonic, fumaric or maleic acid, which optionally with hydroxy additionally substituted

respectively in addition, oxo and/or carboxylic carboxylic acids are used, e.g. tartaric, malic, grape or citric acid. Sulfonic acids are e.g. benzene, p-toluene or methanesulfonic acid.

Suitable salts with bases are, for example, metal, such as alkali or alkaline earth metal salts, e.g. sodium, potassium

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 of substituted organic amines such as morpholine, thiomorpholine, piperidine, pyrrolidine, as mono-, di- resp. trilower alkylamines or mono-, di- or trihydroxy lower alkylamines, e.g. mono-, di- or triethanolamine. Mono-lower alkylamines are, for example, ethyl or tert-butylamine. Dilave alkylamines are e.g. diethyl or dipropylamine, and as trilower alkylamines there are e.g. considering triethyl, tributylamine or dimethylpropylamine.

The compounds of formula I have valuable pharmacological properties. In particular, they have a pronounced natinociceptive (analgesic) effect, which can, for example, be shown by means of the acetic acid wiggle syndrome in rats in the dose range from approx. 1 to approx. 30 mg/kg p.o. and in the phenyl-p-benzoquinone wiggle test on mice in the dose range from approx. 1 to approx. 30 ml/kg p.o.

Furthermore, it has a clear anti-inflammatory and antiarthritic effect, which can be demonstrated by inhibition of kaolin paw edema in normal rats in dose ranges from approx. 10 to 100 mg/kg p.o., and which can also be shown in the inhibition of carrageenan paw edema in rats analogous to the methods discussed by Pasquale et al., Agents and Actions, 5, 256 (1976) in doses from approx. 3 to approx. 300 mg/kg p.o.

Moreover, compound with formula I in curative applications inhibits by 4 times administration from approx. 10 to 100 mg/kg p.o., kaolin paw edema of adjuvant arthritis rat.

The compounds of formula I are therefore preferably suitable as drugs for the treatment of inflammatory diseases above all such, of the rheumatic, resp. arthritic area, as antiphlogistics and/or as peripheral analgesics.

Variant_a£

The cyclization takes place in a known manner, for example in the presence of catalysts, such as acid catalysts. Such are, for example, 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 sulphonic acids, such as benzene, p-toluene or methanesulphonic acid. Thereby, one works, if necessary, in one of the above-mentioned inert dissolution or diluents, preferably under heating, e.g. in the temperature range from approx. 20°C to approx. 200°C in a closed vessel, and/or under inert gas, e.g. nitrogen.

A particularly advantageous embodiment of the above in relation to compound with formula I and X proceeding method consists, for example, in connection with formula

in which Bz means an optionally substituted α-phenyl lower alkyl residue, preferably benzyl, especially quaternized with benzyl bromide is cleaved with the aid of cyanides, such as alkali metal cyanides, e.g. sodium cyanide, the bond with it. quaternary nitrogen and in a formed compound of formula IVe, the cyano group is solvolysed to R' or R", the benzyl group is hydrogenolytically split off in the presence of a hydrogenation catalyst, e.g. palladium, and the now free amino compound is reacted with a compound of formula

where Z| means oxo, and Hal means halogen, and finally reacted with the aid of a cyclizing agent, preferably a mineral acid halide such as phosphorus oxychloride or phosphorus chloride.

Variant_b^

Functionally modified and different from R2 functionally modified carboxy are, for example, optionally functionally modified orthoester groups such as trihalogen, halogen dilave- alkoxy or trivareal oxymethyl groups, anhydrous carboxy as cyano, a group of formula =C=0, cyano-,

azido- or halocarbonyl, acyloxycarbonyl or as acetyloxycarbonyl or derivatives of carboxy, with the formula R2' or R^', in which oxo is optionally replaced by thio,

respectively optionally imino as optionally esterified thiocarboxy as lower alkylthiocarboxy, e.g. ethylthiocarboxy, amidated thiocarboxyl, iminoesters such as imide- or amide halide groups, e.g. iminochloro- or aminodichloromethyl, iminoether groups such as lower alkyl or lower alkylene iminoether groups, e.g. methoxy- or ethoxyimino-methylene or amidino groups such as amidino or lower alkyl-, e.g. methylamidino.

Functionally modified carboxy compounds such as optionally functionally modified orthoester, anhydrous carboxy or acyloxycarbonyl can be solvolyzed directly or in several solvolysis steps to free, esterified or amidated carboxy.

The solvolysis of RiJ takes place in a known manner, for example by hydrolysis with water, by ammonolysis with ammonia or by alcoholysis with a corresponding alcohol. Thereby, if necessary, work is carried out in the presence of a catalyst in a solution or diluent in a closed vessel in a temperature range from approx. 0°C to approx. 150°C and/or inert gas,

e.g. nitrogen.

Catalysts are, for example, basic condensation 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 acid, e.g. halohydrogen acid, such as hydrochloric acid, or organic carboxylic or sulfonic acids such as lower alkanecarboxylic acid or optionally substituted benzenesulfonic acid, e.g. acetic acid or p-toluenesulfonic acid.

The reaction usually takes place in an inert solvent, e.g. an optionally halogenated hydrocarbon such as an aromatic e.g. benzene or toluene, an ether such as tetrahydrofuran or dioxane, or an amide, e.g. dimethylformamide, in a temperature range from approx. 20°C to approx. 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.

Variant_c:

The dehydrogenation takes place in a manner known per se,

especially at excessively high temperatures, for example in a temperature interval from approx. 100° to approx. 300°C, and using a dehydrogenating agent. Examples of such agents include dehydrogenation catalysts,

e.g. subgroup elements, preferably of subgroup VIII,

such as palladium or platinum or their salts, such as ruthenium triphenyl phosphide chloride, the catalyst possibly being supported on a suitable support material such as coal, aluminum oxide or silicon dioxide. Further dehydrogenating agents are, for example, quinones such as p-benzoquinones, e.g. tetrachloro-p-benzoquinone or 2,3-dichloro-5,6-dicyano-p-benzoquinone, or as anthraquinones, e.g. phenathrene-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 vessel, and/or under inert gas, e.g. nitrogen.

The compounds of formula that can be used as starting materials

I, can be produced according to the above methods.

A compound of formula I obtained according to the invention can be converted in a manner known per se into another compound of formula I.

Free carboxy can be transferred in and of itself

known esterification methods i.correspondingly esterified carboxy, for example by reacting possibly reactive modified carboxy or a salt thereof by means of alcoholysis with a desired alcohol, for example a reactive derivative thereof, or an olefin derived thereof, or by alkylation with diazolaveralkane.

Suitable reactive functional carboxy derivatives are, for example, anhydrides, as the anhydrides used are particularly mixed anhydrides, e.g. those with inorganic acids such as halogen hydrogen acids, e.g. hydrochloric acid,

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

Examples are reactive derivatives of an alcohol

a carboxylic, phosphoric, sulfuric or carboxylic acid esters,

e.g. lower alkane carboxylic acid esters, tri-lower alkyl phosphite, di-lower alkyl sulphite or pyricarbonate or mineral

respectively sulphonic acid esters, e.g. chloro, bromo or sulfuric acid esters, benzene, toluene or methanesulphonic acid esters of the alcohol in question.

The esterification of free carboxy is carried out in the presence of

a condensation agent. As a catalytic water-releasing agent for the esterification of alcohols, e.g. in terms of acids, for example protonic acids such as hydrochloric acid, hydrogen bromic acid, sulphurous acid, phosphoric acid, boronic acid, benzene sulphonic acid

and/or toluenesulfonic acid, resp. Lewis acid, such as boron trifluoride etherate. Common water-binding condensation agents are e.g. with hydrocarbon residues. substituted carbodiimides, for example N,N<1->diethyl-, N,N-dicyclohexyl- or N-ethyl-N'-(3-

dimethylaminopropyl)-carbodiimides. Condensing 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, resp. -carbonates, such as sodium, potassium or calcium hydroxide, resp. -carbonate,

as organic nitrogen bases, e.g. tart. organic amines such as triethylamine or pyridine. The esterification is preferably carried out with an excess of used alcohol. Thereby, one preferably works in an anhydrous medium, if necessary in the presence of an inert solvent such as in halo-generated hydrocarbons, e.g. chloroform or chlorobenzene in ethers, e.g. tetrahydrofuran or dioxane.

The reaction with an olefin can, for example, take place in the presence of

of an acid catalyst, e.g. a Lewis acid, e.g. of boron trifluoride, a sulphonic acid, e.g. of p-toluenesulfonic acid, or above all a basic catalyst, e.g. of sodium or potassium hydroxide, preferably in an inert solvent such as an ether, e.g. diethyl ether or tetrahydrofuran.

Furthermore, one can transfer free carboxy RI resp. reactive functional carboxy derivatives by means of solvolysis with ammonia in the usual way under dehydration, optionally in the presence of a condensing agent to a desired amidated form. Bases are preferably used as condensation agents, 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, tri-butylamine or N-dimethylaniline, or tetrahalosilanes such as tetrachlorosilane.

Furthermore, compounds of formula I obtained according to the invention can be transesterified in the usual manner, in which R 1 is esterified carboxy, for example by reaction with a corresponding alcohol, resp. a metal salt thereof such as an alkali metal salt, e.g. sodium or potassium salts if necessary in the presence of a catalyst, for example a strong base, such as an alkali metal hydroxide amide or 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 as an organic sulphonic acid, e.g. an aromatic sulfonic acid such as p-toluenesulfonic acid.

Esterified carboxy can further according to known methods, e.g. by means of hydrolysis in the presence of a catalyst is transferred to the free carboxyl group. As catalysts, there are preferably tall bases, e.g. alkali metal hydroxides such as sodium or potassium hydroxide. The esterified carboxyl can further be converted in the usual way, for example by means of solvolysis, possibly in the presence of a catalyst, for example an acid or basic agent to carboxy by means of ammonolysis with ammonia to amidated carboxy.

Alkali metal hydroxides such as sodium resp. potassium hydroxide, and which acidify, for example, mineral acids such as sulfuric acid, phosphoric acid or hydrochloric acid. Likewise, according to the invention, compounds of formula I obtained, in which the group Rj is carboxy, can be cleaved by methods known per se to cleave the amide bond, and thus transfer carbamoyl to free carboxy. For this, one works in the presence of a catalyst, for example 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.

Does the group R^ in formula I mean an esterified carboxy group,

then this can, for example, be transferred by ordinary solvolysis, preferably by an excess of ammonia, possibly in the presence of a catalyst to an amidated carboxy group. Thereby, acids are used as catalysts, for example

such as mineral acids, e.g. hydrochloric, sulfuric or phosphoric acid or bases, such as alkali metal hydroxides, e.g. sodium or potassium hydroxide.

If the group R~ in formula I represents amidated carboxy as substituents, then this can be transferred, for example, by ordinary solvolysis with an alcohol in the presence of a catalyst in esterified carboxy. Thereby, for example, acid catalysts such as mineral acids are used, e.g. phosphoric acid, hydrochloric acid or sulfuric acid.

If the substituent R 1 with formula I is substituted with lower alkylthio, this can be oxidized in the usual way in the corresponding lower alkanesulfinyl or resp. -sulfonyl. Suitable oxidizing agents for the oxidation to the sulphoxide step include, for example, inorganic peracids, such as peracid of mineral acid, e.g. periodic acid or persulphuric acid, organic peracids such as corresponding percarboxylic or persulfonic acids, e.g. permauric acid, peracetic acid, trifluoroperacetic acid, resp. perbenzoic acid or p-toluenepersulphonic acid or mixtures of hydrogen peroxide and acids, e.g. mixture of hydrogen peroxide with acetic acid.

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

The oxidation to the sulfone step can also be carried out with dinitrogen tetroxide as catalyst in the presence of oxygen at low temperatures in a similar manner to the direct oxidation of lower alkylthio to lower alkanesulfonyl. However, an oxidizing agent is usually used here

in surplus.

Compounds of formula I, in which R-^ means one with lower alkyl-sulfinyl, resp. sulfonyl substituted aromatic residue, can be reduced according to methods known per se to the corresponding lower alkylthio compounds, starting from lower-alkanesulfonyl derivatives also to lower-alkanesulfinyl. Catalyzed activated hydrogen is suitable as a reducing agent, for example, since precious metals or oxides such as palladium, platinum or rhodium, resp. their oxides are used, possibly on a suitable support material, such as activated carbon or barium sulphate. Furthermore, reducing metal cations such as

tin II-, lead II-, copper I-, manganese II-, titanium II-, vanadium II-, molybdenum III- or tungsten III-compounds, halogen hydrogens, such as chlorine bromine or hydrogen iodo, hydrides such as complex metal hydrides, e.g. lithium aluminum, sodium boron, tributyltin hydride, phosphorus compounds, such as phosphorus halogenides, e.g. phosphorus trichloride, bromide, phosphorus pentachloride or phosphorus oxychloride, phosphines such as triphenylphosphine or phosphorus pentasulfide-pyridine, or sulfur compounds such as mer-captans, thioacids, such as thiophosphoric acid or dithiocarboxylic acids, dithionite or sulfur-oxygen complexes, such as iodine-pyridine-sulfur dioxide complex.

Formed salts can be transferred in a manner known per se

the free connections, e.g. by treatment with an acidic reagent such as a mineral acid, resp. a base, e.g. alkali lye.

The new compounds can depend on the choice of starting materials

and working methods exist in the form of one of the possible isomers or as mixtures thereof, e.g. depending on the number of asymmetric carbon atoms, as pure optical isomers, as antipodes or as isomeric mixtures such as racemates, diastereoisomer mixtures or racemate mixtures.

Formed diastereomer mixtures and racemate mixtures can, due to physicochemical differences of the components, be divided in a known manner into the pure isomers, diastereomers or racemates, usually by chromatography and/or fractional crystallization.

Formed racemates can be further separated into the optical antipodes according to known methods, for example by recrystallization from an optically active solvent with the help of microorganisms or by reaction of an acidic final substance with an optically active base that forms salts with the racemic acid, separation of the salts formed in this way,

e.g. due to their different solubilities in the diastereomers, the antipodes of which are released by the action of suitable agents. Preferably, the most effective of the two antipodes is isolated.

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

Because of the narrow relationship between the new connections

in free form and in the form of their salts, in the foregoing and the following, free compounds and their salts possibly also mean the corresponding salts, resp. free connections.

The invention also relates to the embodiments and methods according to which one proceeds from one or other step of the method as an intermediate formed compound, and carries out the missing step or uses a starting material in the form of a salt, or forms especially under the reaction conditions.

In the method according to the invention, such starting materials are preferably used which lead to the compounds mentioned at the outset as particularly valuable. New starting materials and methods for their production are also covered by the invention.

Pharmaceutical preparations, which contain compounds of formula I or pharmaceutically usable salts thereof, are those for enteral as oral or rectal and parenteral administration, as well as for topical use on warm-blooded animals, which contain the pharmacologically active substance alone or together with a pharmaceutically usable carrier material . The dosage of the active substance depends on the warm-blooded type, age and individual condition, as well as on the method of application. In normal cases, it is for approx. 75 kg warm-blooded animals to suggest by oral application an approximate daily dose of approx. 30

- 300 mg, preferably divided into several such partial doses.

The following examples will explain the invention in more detail, where the temperature is indicated in degrees Celsius.

The designation of the joining sites in the pyrimido-indole ring system underlying the compounds of formula I

is inconsistent in the literature.

Thus older literature designates the joining points in the ring system with /3,4-a/, in more recent times the designation ^I,6-a/ is used.

For reasons of principle, the following nomenclature is preferred for the above-mentioned ring structure:

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-chlorobenzoylamino)-ethyl7-5-methoxy-indole-3-acetic acid ethyl ester are heated in 825 ml of phosphorus trichloride for 1 3 hours under reflux to boiling, and there-

after, excess phosphorus trichloride is distilled off at a bath temperature of 60°C under a weak vacuum. The residue is dissolved in 1500 ml of methylene chloride, stirred with 2000 ml of ice water, made alkaline by the addition of 500 ml of concentrated ammonia, and after brief stirring the methylene chloride phase is separated. It is washed neutrally with water, dried over Na2S0^, and methylene chloride is distilled off. The residue (136.7 g) is dissolved in 120 ml of acetone and 500 ml of ether, and the solution is mixed with 100 ml of an approx. ^--normal hydrogen chloride solution in ether. Hydrochloride of 7-methoxy-1-(p-chlorophenyl)-3,4-dihydro-pyrimido/1,6-a_/indole-acetic acid ethyl ester is thereby crystallized.

It is suctioned off and washed with acetone/ether 1:10 yellowish crystals of m.p.. 204.-208°, after recrystallization from methanol/acetone m.p. 205 - 208°C.

The starting product can be produced as follows:

a) 131 g (0.4-5 mol) of 3-benzyl-6-methoxy-tetrahydro-Y-carboline is dissolved in 1300 ml of acetonitrile at 4-0°C, with stirring, and during 10 minutes 94 - g (0.55 mol) benzyl bromide. After a short time, the benzylammonium derivative begins to crystallize. It is still stirred approx. 15 hours at room temperature, then cooled in an ice bath, and suctioned off from the crystallisate. Sm.p. 150-151°C. b) 4°4-g (1 mol) of the thus prepared N,N-di-lbenzyl-6-methoxy-tetrahydro-γ-carboliminium bromide is dissolved

in 4-250 ml of methanol while heating to 65°C, and during

After 5 minutes, a solution of 196 g (4 mol) of sodium cyanide in 500 ml of water is added while stirring. The solution is heated for 3 hours under reflux to boiling. On cooling, after grafting, 2-(dibenzylamino-ethyl)-3-cyanomethyl-5-methoxy-indole crystallizes out in colorless crystals of m.p. 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. It is then stirred for 5 1/2 days at 20°C. The separated crystals are allowed to settle from decanting the above solution, the bottom deposit is dissolved in 2000 ml of ice water, and stirred for approx. 3 hours at 20°C. It is then made alkaline under ice-cooling with concentrated ammonia solution and stirred with 1500 ml of toluene-ice water. The separated toluene phase is washed with water, dried over sodium sulphate and filtered over 1000 g of aluminum oxide (act. step 3) and washed with toluene. After distilling off the toluene, a light brown oil remains which, without further purification, is subjected to hydrogenation according to point d). d) 181.3 g of the 2-dibenzylamino-5-methoxy-indole-3-acetic acid ethyl ester formed according to c) is dissolved in 1500 ml of absolute alcohol, and hydrogenated with the addition of 18 g of Pd/C (5%) at normal pressure and 20 -35°C. After absorption of 12,500 ml of H2, 18 g of catalyst is added and it is further hydrogenated to a standstill of absorption of a total of 17,300 ml. 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-aminoethyl-5-methoxy-indole-3-acetic acid ethyl ester crystallizes in colorless crystals of m.p. 79-80°C.

e) 61.7 g (0.233 mol) of the 2-aminoethyl-5-methoxy-indole-3-acetic acid ester produced according to d)

is dissolved in 600 ml of methylene chloride and the solution is checked with 150 ml of 2N sodium hydroxide solution. With vigorous stirring, a solution of 4-3 g (0.245 mol) of p-chlorobenzoyl chloride is added at 0-5° over 2 1/2 hours and then stirred for a further 1 hour. The methylene chloride phase is then separated and washed with water, dried over MgSO. and evaporated to dryness. The residue is crystallized by absorption in ether in colorless crystals of m.p. 136-138 oC 2l(p-chlorobenzoyl-amino)-ethyl_7-5-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) of 2-(benzoylamino-ethyl)-indole-3-acetic acid ethyl ester are heated ± 250 ml of phosphorus oxychloride in 3

hours under reflux to boil. The excess phosphorus oxychloride is then distilled off at 60°C in a vacuum, and the recurrence is carried out with 1000 ml of ice water. The aqueous solution is clarified by filtration over hyflo, made alkaline with concentrated ammonia and extracted with 500 ml of ether. Ether-

the phase is dried over sodium sulfate and evaporated to dryness. The residue is dissolved in 200 ml of acetone and mixed with 25 ml

of an approx. 4.N hydrogen chloride solution in ether. After grafting, the hydrochloride of 1-phenyl-3»4-dihydro-pyrimido /"i , 6-α_/indole-5-acetic acid ethyl ester crystallizes in yellowish crystals of m.p. 172-175°C which can be recrystallized in 1-N hydrochloric acid,

(m.p. 187-189°C). The base released from the salt then melts

recrystallization from ether from 83-84°C.

The 2-(benzoylamino-ethyl)-indole-3-acetic acid ethyl ester used as starting material, m.p. 162-163°C, can be prepared analogously to example 1 a) - e).

Example 3

In an analogous way as mentioned in example 2, 2-/"(p-methylthio-benzoyl-amino)-ethyl_7-5-fluoro-indole acetic acid ethyl ester of m.p. 157-158°C will be obtained 7 -fluoro-1-(p-methylthiophenyl-3,4-dihydro-pyrimido/1»6-a_/indole-acetic acid ethyl ester of m.p. 119-120°C.

Example 4-

Analogously, 2-benzoyl-aminoethyl-i,5-dimethyl-indole-3-acetic acid ethyl ester of m.p. 183-184°C obtain 6,8-dimethyl-1-phenyl-3>i 4-dihydro-pyrimido/l, 6- aj indole-5-acetic acid ethyl ester of m.p. 1 4-2-14-3°C.

Example 5

Analogously, from 2-β-sulfamoyl-4-chlorobenzoyl-amino)-ethyl_7-indole-3-acetic acid ethyl ester of m.p. 212-213°C

get 1 - (3-sulfamoyl -4-- chloro-rf enyl) -3. 4-dihydro-pyrimidino/l, 6-α7 indole-5-acetic acid ethyl ester of m.p. 227-228°C.

Example 6

Analogously, 2-(2,6-dichlorobenzoyl-aminoethyl)-indole-3-acetic acid ethyl ester of m.p. 125-126^0 obtain 1 -(2,6-dichloro-phenyl)-3,4-dihydro-pyrimido/i,e-a/indole-5-acetic acid methyl ester of m.p. 92-93°C (hydrochloride m.p . 1 38-U2°C ).

Example 7

Analogously, 2-(2-picolinoyl-aminoethyl)-indole-3-acetic acid ethyl ester of m.p. 117-118°C obtain 1 - (2-picolinyl)-3, 4-dihydro o^pyrimido/l, 6-^a_/indole-5-acetic acid ethyl ester of m.p. 113-1U°C, (hydrochloride 194-204°C).

Example 8

. Analogously, 2-(2-thienylamino-ethyl)-indole-3-acetic acid ethyl ester of m.p. 14.0-14-1°G gives hydrochloride of 1 - (2 - thienyl ) -3. 4-dihydro-pyrimido/"1,6-a_/indole-5-acetic acid - ethyl ester of m.p. 153-157°C.

Example 9

7-Methoxy-1-(p-chlorophenyl)-3'4-dihydro-pyrimido-[1,6-α7-indole-5-acetic acid

Into a solution of 550 g of potassium hydroxide in 200 ml of water and 1500 ml of methanol, while stirring, 117.2 g (0.27 mol) of 7-methoxy-1-(p-chlorophenyl)-3'4-dihydro-pyrimido/i are introduced, 6- ajindole-5-acetic acid ethyl ester hydrochloride. The mixture is stirred for 10 hours at room temperature, the methanol is distilled off in a vacuum, the residue is dissolved in 1500 ml of ice water and the solution is mixed under ice-cooling with 700 ml of concentrated hydrochloric acid. Secreted hydrochloride is suctioned off and recrystallized from 2300 ml of 50% ethanol. This results in 7-methoxy-1-(p-chlorophenyl)-3,4-dihydro-pyrimido/1,6-a_/indole-5-acetic acid hydrochloride in form of yellowish crystals of sm. p. 225-228°C (under cleavage).

Example 10

In a similar way, the corresponding ethyl ester gives hydrochloride of 1-phenyl-3. 4-dihydro-pyrimido[1,6-a_]indole-5-acetic acid of m.p. 235-24.0uC with cleavage.

Example 11

In an analogous way, the corresponding ethyl ester will yield hydrochloride of 7-fluoro-1-(p-,ethylthio-phenyl)-3,4-dihydro-pyrimido/1,6-a_/indole-5-acetic acid of sm .p. 220-222<w>C during cleavage.

Example 12

Analogously, the corresponding ethyl ester will yield hydrochloride of 7-fluoro-1-(p-methylsulfinyl-phenyl)-3,4-dihydro-pyrimido[i,6-a_7indole-5-acetic acid of m.p. 208-210°C during cleavage.

Example 13

Analogously, from the corresponding ethyl ester, the hydrochloride of 6,8-dimethyl-1-phenyl-3»4-dihydropyrimido/l, 6-aJ indole-5-acetic acid of m.p. 212-220°C during decomposition. The corresponding hemihydrate melts at over 210°C.

Example 14.

Analogously, from the corresponding ethyl ester, the hydrochloride of 1-(3-sulfamoyl-4-chloro-phenyl)-3,4-dihydro-pyrimido/l, 6-a_7indole-5-acetic acid of m.p. 216-220°C during decomposition.

Example 15

Analogously, from the corresponding ethyl ester, the hydrochloride of 1-(2,6-dichlorophenyl)-3,4-dihydro-pyrimido/1,6-aJ indole-5-acetic acid of m.p. 270-277°C during decomposition.

Example 16

Analogously, the corresponding ethyl ester gives hydrochloride of 1-(2-thienyl)-3'4-dihydro-pyrimido-[1,6-a_7indole-5-acetic acid of m.p. 120-235°C during decomposition. From the aqueous solution of hydrochloride' crystallizes at pH

6- 7. 1-(2-thienyl)-3,4-dihydro-pyrimido/1,6-a/indole-5-acetic acid-as inner salt of m.p. 187-189°C.

Example 17

1-phenyl-3,4-dihydro-pyrimido/1,6-a/indole-5-acetic acid amide. 1 g (0.003 mol) of 1-phenyl-3'4-dihydro-pyrimido[1,6-a_]indole-5-acetonitrile is heated in 10 g of polyphosphoric acid for 30 minutes at 100°C. The reaction mixture is dissolved in 10 ml of water, and the solution is made alkaline under ice-cooling by the addition of concentrated ammonia, and the reaction product is extracted with methylene chloride. The methylene chloride phase is washed neutral with water, dried over Na2SO4 and the solution is evaporated to dryness. The residue remaining solid 1 -phenyl-3»4-dihydro-pyrimido/1,6-a_7indole-5-acetic acid amide is recrystallized from methanol: colorless crystals of m.p. 239-140° C. The corresponding hydrochloride melts at 253-260° C with decomposition Starting materials can be prepared as follows: a) 38 g (0.1 mol) of 2-(dibenzylamino-ethyl)-indole-3-acetonitrile are introduced into 300 g of polyphosphoric acid and the mixture is heated with stirring for approximately 60 minutes at 100° C. Man

■ .pour onto 1 kg of ice, adjust alkaline by adding concentrated ammonia and extract with ether. After washing, drying and evaporation of the ether phase, 2-(dibenzylamino-ethyl)-indole-3-acetamide is obtained as syrup, which can be crystallized from a little ether, m.p. 135-136°C.

b) 120 g (0.3 mol) of 2-(dibenzylamino-ethyl)-indole-3-acetamide is hydrogenated while adding 12 g of 5% Pd/C in 1.2 1

methanol at standard pressure and 30-35°C. After absorption of 14.4 1 hydrogen, the hydrogenation is interrupted, filtered off from the catalysts and the solution is evaporated to dryness in a vacuum. The residue recrystallizes from 100 ml of ethanol while adding 250 ml of ether. The 2-aminoethyl-indole-3-acetamide thus formed melts at 156-157°C.

c) 21.7 g (0.1 mol) of 2-aminoethylindole-3-acetamide are mixed in a mixture of 200 ml of ether and 100 ml of water under good stirring

stirring and cooling at approx. 5°C with 17.5 ml (0.15 mol) of benzoyl chloride, and gradually 100 ml of 2N-NaOH are added dropwise. Reac-

The session ends after approx. 1 hour. It is stirred for a further 1 hour at 0-5°C, and suction from the separated 2 - (benzoylamino-ethyl)-indole - 3-acetamide of 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. M:an avde settles the excess of phosphorus oxychloride and absorbs the oil-active residue in water, and removes the by-products from the reaction by extraction with ether. The aqueous phase is mixed with concentrated ammonia while cooling, and extracted with ether. After washing, drying and evaporating the ether phase, 1-phenyl-3»4-dihydro-pyrimido /i,6-αJ-5-acetonitrile is obtained as a yellowish oil, which, by dissolving in methanol and mixing with ethereal hydrochloric acid, can be transferred into a crystalline hydrochloride of m.p. 195-205°C.

Example 18

In an analogous way as discussed in example 17, one will

of 1-(3-sulfamoyl-4-chloro-phenyl)-3,4-dihydro-pyrimido-[i,6-a_7 indole-5-acetonitrile of m.p. 280-285°C get the hydrochloride of 1-(3-sulfamoyl-4-chloro-phenyl)-3. 4-dihydro-pyrimido/"1,6-α_7indole-5-acetamide of m.p. 249-257°C with cleavage.

Example 19

12 g (0.03 mol) of 1-(p-methylthio-phenyl)-3,4-dihydro-pyrimido/1,6-ayindole-5-acetic acid ethyl ester are dissolved in 120 ml of glacial acetic acid and mixed with 4 ml of 30% hydrogen peroxide. Let it remain at room temperature for approx. 20 hours, rather on

1 liter of ice water, made alkaline with concentrated ammonia,

and extract with vinegar. The acetic ester phase is washed, dried and evaporated. The resulting 1-(p-methylsulfoxy-phenyl)-3'4-dihydro-pyrimido/'1,6-[]indole-5-acetic acid ester crystallizes from ether yellowish crystals of m.p. 115-151° C.

Example 20

Analogous to that discussed in example 1, when starting from 2-/"(p-methylthio-phenyl-amino)-ethyl_/-5-fluoro-indole-5-acetic acid ethyl ester, the hydrochloride of 7-fluoro- 1 - (p-methylthio-phenyl)-3,4-dihydro-pyrimido[1,6-a]-indole-3-acetic acid - ethyl ester of m.p. 210°C during cleavage, and starting from 2 -/~(p-chloromethyl-thio-phenyl.-amino)-ethyl 7-5-fluoro-indole-3-acetic acid ethyl ester get hydrochloride of 7-fluoro-1-(p-chloromethylthio-phenyl)- 3» 4-difluoro-pyrimido/l, 6-a_/indole-5-acetic acid ethyl ester of m.p. 198-202°C.

Example 21

Analogously as in example 19" one wants when walking

from 7-fluoro-1-(p-methylthio-phenyl)-3»4-dihydro-pyrimido /l, 6-a<_>/indole-5-acetic<y>reet<y>le ester -h< y>hydrochloride obtain the hydrochloride of 7-fluoro-1-(p-methylsulfoxyphenyl)-3,4-dihydro-pyrimido-/1, 6-a_/indole-5-acetic acid ethyl ester of m.p. 261-264°C.

Example 22

Analogous to example 9". you want by saponification

of 7-fluoro-1-(p-methylthio-phenyl)-3,4-dihydro-pyrimido/1,6-α7-indole-5-acetic acid ethyl ester obtain 7-fluoro-1-(p-methylthio-phenyl)-3 ,4-dihydro-pyrimido/1,6-α-7-indole-5-acetic acid of m.p. 119-120°C.

Example 23

7-fluoro-1-(p-methylthio-phenyl)-pyrimido/1,6-a/indole-5-acetic acid ethyl ester... 2 g 7-fluoro-1-(p-methylthio-phenyl)-3, 4 -dihydro-pyrimido/1,6-α_7indole-5-acetic acid ethyl ester is heated in 20 ml of diphenyl ether with 0.5 g of palladium/charcoal (10$) under reflux stirring. After 2 hours, a further 0.5 g of palladium/coal is added, and heated again for 3 hours. After filtration from the catalyst, the reaction mixture is evaporated in vacuo, the residue is taken up in a little vinegar, and chromatographed over silica gel.

With hexane-acetic ester (9:1) fractions are obtained which, after evaporation and recrystallization from ether, give 7-fluoro-1-(p-methylthio-phenyl)-pyrimido/1, 6-a_7indole-5-acetic acid ethyl ester of m.p. 120-122°C.

1-phenyl-pyrimido[1,6-a]indole-5-acetic acid ethyl ester

of sm.p. 59-62°C, 7-methoxy-1-(p-chlorophenyl)-pyrimido/l, 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_7-indole-5-acetonitrile is stirred in 50 ml of absolute ethanol and 50 ml of ethanol saturated with hydrogen chloride in 4- 8 hours at 0°C. The solvent is then distilled off under reduced pressure, the remaining crude hydrochloride of 1-phenyl-3-4-dihydro-pyrimido/_1,6-a_/indole-5-acetatiminoethyl ether is suspended in 10 ml of water, and heated with stirring for 15 minutes at 4-0°C. After cooling, 1-phenyl-3,4-dihydro-pyrimido/1,6-α_7 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 mol) 7-fluoro-1-(p-methylsulfoxy-phenyl)3t 4--dihydro-pyrimido/1,6-a_7-indole-5-acetic acid ethyl ester is heated in 500 ml ethyl acetate with 4-0 g of deactivated Raney-Nickel with stirring for 2 hours under reflux. It is then filtered off from the catalyst, and the filtrate is evaporated under

set pressure. The residue gives after crystallization from ether 7-fluoro-1-(p-methylthio-phenyl)-3, A-dihydro-pyrimido/1,6-ajindole-5-acetic acid ethyl ester of m.p. 119-120°C.

Claims (6)

1. Analogy method for the production of new therapeutically effective pyrimido^1,6-a/indole-5-acetic acid derivatives with formula wherein R-^ means unsubstituted or singly or twice with halogen, lower alkoxy, lower alkylthio, halolower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl and/or sulfamoyl substituted phenyl, picolinyl or thienyl, R2 means carboxy, lower alkoxycarbonyl or carbamoyl, The 1,2-phenylene ring Ph is unsubstituted or one or two times substituted by halogen, lower alkyl and/or lower alkoxy and the dashed line shall express at there can also be a double bond, since residues designated as "lower" can have up to 4 C atoms, as well as their salts, characterized in that a) a compound of formula in which Ph, R-^ and R^ have the above meanings and X^ means hydrogen and Y-^ means a group of formula -CH2-CH2-NH-C(=0)- R1 resp. -CH=CH-NH-C(=0)-R1, or a salt thereof, is cyclized in the presence of an acidic catalyst, orb) in a connection with formula in which Ph and R^ - have the above meanings and R2 means from R2 different functionally modified carboxy or a salt thereof, R<i>J is transferred if necessary by means of an acid or base by hydrolysis to carboxy R2, by alcoholysis with a lower alkanol to lower alkoxycarbonyl R2 or by ammonolysis to carbamoyl R2, or c) for the preparation of compounds of formula I, in which R^ means lower alkoxycarbonyl or carbamoyl and the dashed line shall express the existence of a double bond, and R^ and Ph have the above meaning, a compound of formula is dehydrogenated or a salt thereof using a dehydrogenating agent while splitting off hydrogen with the simultaneous formation of an additional bond, or d) for the preparation of compounds of formula I, in which R2 means carboxy, and R^, Ph have the above-mentioned meanings, a compound is hydrolyzed with formula I, in which R^ means lower alkoxycarbonyl or carbamoyl, or a salt thereof if necessary by means of an acid or base, or e) for the preparation of a compound of formula I, in which 1*2 means lower alkoxycarbonyl resp. carbamoyl and R^, Ph have the above meanings, are esterified resp. a compound of formula I or a salt thereof, wherein R^ means carboxy, is amidated with ammonia, or f) for the production of compounds of formula I, wherein R^ means lower alkylthio substituted phenyl and R£, Ph has the above meaning, is reduced a compound of formula I, in which R 1 means with lower alkanesulfinyl or - sulfonyl substituted phenyl or a salt by means of a reducing agent, or g) for the preparation of compounds of formula I, in which R^ means with lower alkanesulfinyl resp. - sulfonyl substituted phenyl and R£f Ph have the above-mentioned meanings, a compound of formula I, in which R^ means lower alkylthio-substituted phenyl or a salt thereof, is oxidized by means of an oxidizing agent, and if desired, a free compound of formula I is transferred to a salt or a salt is transferred to the free compound of formula I or to another salt.; 2. Method according to claim 1 for the preparation of 7-methoxy-1-(p-chlorophenyl)-3,4-dihydro-pyrimido/1,6-a/-5-acetic acid or a salt thereof, characterized in that from compounds of the formulas IVa, X, I' and I or a salt thereof.; 3. Process according to claim 1 for the preparation of 7-fluoro-1-(p-methylthiophenyl)-3,4-dihydro-pyrimido/1,6-a/-indole-5-acetic acid or a salt, characterized in that from compounds with the formulas IVa, X, I' and I or a salt thereof.; 4. Process according to claim 1 for the preparation of 7-fluoro-1-(p-methylthiophenyl)-3,4-dihydro-pyrimido/1,6-a/indole-5-acetic acid ethyl ester or a salt thereof, characterized in that from compounds with the formulas IVa, X, I' and I or a salt thereof.; 5. Method according to claim 1 for the preparation of 7-fluoro-1-(p-methylthiophenyl)-pyrimido/1,6-a/indole-5-acetic acid, the ethyl ester or a salt thereof, characterized in that the starting point is compounds with the formulas IVa, X, I<*> and I or a salt thereof. 6. Process according to claim 1 for the preparation of 1-(2-thienyl)-3,4-dihydro-pyrimido/1,6-a/indole-5-acetic acid or a salt thereof, characterized in that the starting point is compounds with the formulas IVa, X, I' and I or a salt thereof.