DD156599A5 - PROCESS FOR PREPARING N, N'-BORED CARBOXYL ACID AMIDINES - 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

227 94 5 7 ^

* · L '. **' *. Berlin, July 10, 1981

AP C 07 C / 227 945 58 830 11

Process for the preparation of N ^ P-bridged carboxylic acid amidines

Applicatio _r ndungs gebie the invention t

The invention relates to a process for preparing H, N ^f bridged Carbonsäureamidine.

The compounds according to the invention have valuable pharmacological, in particular analgesic and anti-inflammatory properties. They are used as medicaments for the treatment of inflammatory diseases, especially those of the rheumatic or arthritic area, as anti-inflammatory drugs and / or as peripheral analgesics.

Characteristic of the known technical solutions

There is no information available which compounds have hitherto been used for the treatment of inflammatory diseases, as anti-inflammatory drugs and / or as peripheral analgesics. There are also no data available on methods for preparing H, N ^f -bridged carboxylic acid amidines.

Object of the invention '''

The aim of the invention is the provision of new analgesic and anti-inflammatory active compounds.

Explanation of the essence of the invention

The invention has for its object to find compounds with the desired properties and processes for their preparation.

According to the invention, new amidines, in particular ΪΓ, ΪΡ-bridged carboxylic acid amidines of the general formula

 10th · 7th 1981

AP C 07 C / 227 945

58 830 11

Ph- '

(I)

prepared, v / orin R _{1 is} an aromatic radical R ₉ represents optionally esterified or amidated _p 1-Carbozyniederalkyl, Ph'gegebenenfalls substituted 1,2-phenylene and alk represents an imino group of the metal "thin group by 1 to 3 C -Atoms separating aliphatic hydrocarbon radical, and their salts, processes for their preparation, pharmaceutical compositions containing them and their use as active pharmaceutical ingredients.

An aromatic radical may be carbocyclic or heterocyclic and substituted and is for example optionally substituted by lower alkyl, lower alkoxy, optionally halogen-containing alkylthio, lower alkaniline or lower alkanesulfonyl, optionally substituted sulfamoyl and / or halogen-substituted phenyl or optionally z. Substituted by lower alkyl, lower alkoxy and / or halogen substituted heteroaryl. Substituted sulfamoyl is, for example, U-mono- or di-, N'-di-lower alkyl-sulfamoyl.

227945 7

^v 'Heteroaryl is for example monocyclic, preferably 5- or 6-membered heteroaryl and has as heteroatoms nitrogen, oxygen or sulfur or nitrogen and additionally sulfur or oxygen. Such 5-membered radicals are, for example, pyrrolyl, such as 2-pyrrolyl, furyl, such as 2-furyl, thienyl, such as 2- or 3-thienyl, or thiazolyl, such as 2-thiazolyl. 6-membered heteroaryl contains at least one N atom and is, for example, pyridyl, such as 2-, 3- or 4-pyridyl, or pyrimidyl, such as 2-pyrimidyl.

Esterified carboxy-1 has as esterified carboxy • _v * group, for example lower alkoxycarbonyl on which also

optionally substituted aryl, such as phenyl or pyridyl, mono- or polysubstituted by hydroxy, halogen or lower alkoxy mono- or polysubstituted, such as optionally substituted by hydroxy, lower alkoxy and / or halogen-substituted lower alkoxycarbonyl, for example mono- or __ Dihydroxyniederalkoxy, halogenated or lower alkoxy-lower alkoxycarbonyl, or lower-alkyl, lower-alkoxy and / or halogen-substituted phenyl-lower alkoxycarbonyl.

Amidated 1-carboxy-lower alkyl has as amidated carboxy group, for example, carbamoyl which is optionally monosubstituted by hydroxy or amino, by lower alkyl or hydroxy lower alkyl once or twice or by 4- to 7-membered lower alkylene or '-' 3-oxa, 3-thia- or 3-azaalkylene may be substituted twice.

Examples which may be mentioned are: N-hydroxy, N-amino, N-mono- or Ν, Ν-di-lower alkyl or N-mono- or Ν, Ν-dihydroxyalkylcarbamoyl. By 4- to 7-membered lower alkylene, twice N-substituted carbamoyl is e.g. Pyrrolidino or piperidinocarbonyl or morpholino, thiomorpholino, piperazino or N-lower alkyl, such as N-methylpiperazino-carbonyl.

1,2-phenylene is optionally additionally mono- or polysubstituted, e.g. substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl.

The rest alk is, for example, the methine group from the imino group by 1 to 3 C-atoms separating lower alkylene such as ethylene, _1} 2- or especially 1,3-propylene, or the methine group from the imino group by 2 carbon atoms separating vinyl radical.

In the present specification, "lower" organic radicals and compounds are preferably to be understood as meaning those containing up to and including 7, especially up to and including 4, carbon atoms.

In the context of the present description, the general definitions used above and below have the following meanings.

Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, sec-butyl, tert-butyl, furthermore a pentyl, hexyl or heptyl radical.

Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy or tert-butyloxy.

Lower alkylthio is e.g. Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or n-heptylthio, Niederallcansulfinyl or sulfonyl is eg Methane, ethane or n-propanesulfinyl or -sulfonyl.

N-lower alkylsulfamoyl or N, N-di-lower alkylsulfamoyl is e.g. N-methyl, N-ethyl, N-propyl, Ν, Ν-dimethyl, N, N-diethyl, Ν, Ν-methylethyl or Ν, Ν-dipropyl-stilfamoyl.

Halogen is e.g. Halogen up to and including atomic number 35, such as fluorine, chlorine or bromine.

7 94 5 Ί: <·

-Λ-

Halo-lower alkylthio is e.g. Chloromethyl, chloroethyl or chloropropylthio or one of the corresponding fluoro or Broraniederalkylthio groups.

Halo-lower alkanesulfinyl or -sulfonyl is e.g. Chlonnethan-, Chlorethan- or Chlorpropansulfinyl or -sulfonyl and the corresponding fluoro or Bromniederalkansulfinyl- or -niederalkansulfonylgruppen.

tv, lower alkoxycarbonyl is e.g. Methoxy, ethoxy, n-propyl

oxycarbonyl, further a butyloxy, pentyloxy, hexyloxy or oxycarbonyl.

Phenyl- or pyridyl-lower alkoxycarbonyl is, for example, phenylmethoxycarbonyl, phenylethoxycarbonyl, 2-, 3- or 4-pyridylmethoxycarbonyl.

Hydroxy-lower alkoxycarbonyl or dihydroxy-lower alkoxycarbonyl is e.g. 1- or 2- ^ rdroxyethyl-, 1- or 3-hydroxypropyl or 1- or 4-a ^ droxybutylcarbonyl or 2,3-Dihydroxypropyloxycarbonyl, 2,3-, 2,4- or 3,4-Dihydroxybutyloxycarbonyl.

Lower alkoxy lower alkoxycarbonyl is e.g. 2-Methoxyethyloxy-, 1- or 2-Etho ^ ethyloxy-, 2- or 3-Methoxypropyloxy- or 2-, 3- or 4-Methoxybutyloxycarbonyl.

Hydroxyalkyl is e.g. Hydroxymethyl or hydroxyethyl, further hydroxypropyl or hydroxybutyl. :

N-lower alkylcarbamoyl or Ν, Ν-di-lower alkylcarbainoyl is e.g. N-methyl, N-ethyl, N-propyl, naphthyl, N-butyl-carbamoyl or Ν, Ν-dimethyl or Ν, Ν-diethyl or NjN-Methyletbylcarbanjoyl.

N-hydroxy-lower alkylcarbamoyl or Ν, Ν-dihydroxy-lower alkylcarbamoyl is e.g. N-hydroxymethyl or N ~ 2-hydroxyethylcarbamoyl-or. N, N-2,3-Dihydroxypropylcarbamoyl.

Salts of compounds of the formula I according to the invention are preferably pharmaceutically acceptable salts, such as corresponding acid addition salts and / or, when R 1 is carboxy-lower alkyl, internal salts or salts with bases. Suitable acid addition salts include, 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 additionally substituted by hydroxyl or additionally oxo and / or carboxy-containing carboxylic acids, or sulfonic acids, mineral acids are, for example, sulfuric acid or hydrohalic acids, such as bromine or hydrochloric acid. As optionally unsaturated dicarboxylic acids are e.g. Oxalic acid, malonic, fumaric or maleic acid, as optionally substituted by hydroxy additionally substituted or additionally oxo and / or carboxy-containing carboxylic acids are e.g. Wine, apple, pyruvic or citric acid used. Sulfonic acids are e.g. Benzene, p-toluene or methanesulfonic acid.

Suitable salts with bases include, for example, metal salts such as alkali 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, thiomorpholine, piperidine, pyrrolidine, such as mono-, di- or tri-lower alkylamines or mono-, di -, or Trihydroxyniederalkylaminen, eg Mono-, di- or triethanolamine. Mono-lower alkylamines are, for example, ethyl or tert-butylamine. Diniederalkylamines are e.g. Diethyl or dipropylamine, and as tri-lower alkylamines, e.g. Triethyl-, tributylamine or dimethylpropylamine into consideration. ·.

7 945 7

'·. ·'':' ·: -, - - Ψ - '.-' y --- .'-- ^: '- ' -. '. , ; . ';..,; / ':> .. «-, ν; ... .- -;,. '- -. ·'. .-.

The compounds of the formula I have valuable pharmacological properties. In particular, they have a pronounced antinociceptive (analgesic) effect, for example, on the basis of the acetic acid writhing syndrome in rats in the dose range of about 1 to about 30 mg / kg p.o. and in phenyl-p-benzoquinone-writhing. Test on the mouse in the dose range of about 1 to about 30 ml / kg p.o. show.

') Furthermore, they have a marked anti-inflammatory and

antiarthritic effect, which is characterized by inhibition of kaolin paw edema in the normal rat in the dose range of about 10 to 100 mg / kg p.o. and can also be detected in the inhibition of rat carrageenin footpad analogously to the method described by Pasquale et al., Agents and Actions, 5, 256 (1976) at doses of from about 3 to about 300 mg / kg p.o. show.

In addition, compounds of the formula I in curative administration inhibit four times administration of about 10 to 100 mg / kg p.o. the adjuvant arthritis rat kaolin pawing oedem.

) The compounds of the formula. I are therefore excellently suited

as a medicament for the treatment of inflammatory diseases, especially those of the rheumatic or arthritic area, as anti-inflammatory drugs and / or as peripheral analgesics.

The invention relates to e.g. Compounds of formula I in which R is optionally substituted by lower alkyl, lower alkoxy, optionally halogen-containing lower alkylthio, lower alkanesulfinyl or lower alkanesulfonyl, optionally substituted by lower alkyl optionally mono- or disubstituted sulfamoyl and / or halogen-substituted phenyl or optionally lower alkyl, lower alkoxy and / or halogen-containing 5- or 6-membered and as a heteroatom nitrogen, oxygen or

227945

Is sulfur or nitrogen and additionally sulfur or oxygen-containing, monocyclic heteroaryl, R_ 1-Carboxyniedcralkyl the formula -CH (R,) - R ', in the R' carboxy, optionally by lower alkyl. Lower alkoxy i'oder halogen-containing phenyl or pyridyl, hydroxy or lower alkoxy-substituted lower alkoxycarbonyl or optionally by hydroxy or amino, mono-, or by lower alkyl or hydroxy lower alkyl. is di-substituted by 4- to 7-membered lower alkylene or 3-oxa, 3-thia or 3-Azaalkylen twice-substituted carbamoyl, R, hydrogen or lower alkyl, Ph optionally by lower alkyl, lower alkoxy, halogen and / or Trif luormethyl substituted 1,2-phenylene and al'kdie. Methine of the imino group by 1-3 C atoms separating lower alkylene or by 2 C atoms separating lower alkenylene, and their salts, especially pharmaceutically acceptable salts.

These include, for example, compounds of formula I wherein R is optionally phenyl substituted by lower alkyl, lower alkoxy, lower alkylthio, lower haloalkylthio, lower alkanesulphinyl, halo-lower-alkanesulphinyl, lower alkanesulphonyl, halo-lower alkanesulphonyl, sulfamoyl, N-mono- or Ν, Ν-di-lower alkylsulfamoyl and / or halogen or optionally substituted by lower alkyl, lower alkoxy and / or halogen-substituted pyrrolyl, furyl, thienyl, thiazolyl, pyridyl or pyrimidyl, R _{2 is} a group of the formula -CH (R _) - R ', in the Rl carboxy, optionally by lower alkyl, Lower alkoxy or halogen substituted phenyl or Pyridylniederalkoxycarbonyl, hydroxy or NiederaIkoxyniederaIkoxycarbonyl, lower alkoxycarbonyl, carbamoyl, N-hydroxy or N-aminocarbamoyl, N-mono- or N, N-di-lower alkylcarbamoyl or -hydroxyniederalkylcarbamoyl or by 4- to 7-membered lower alkylene is substituted carbamoyl or 3-0xa-, 3-thia- or 3-azaalkyleneaminocarbonyl, R- Is hydrogen or lower alkyl, Ph is optionally substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl substituted 1,2-phenylene

227945 7

, and alk is the methine of the imino group by 1 to 3 C-atoms of the lower alkylene or by 2 C atoms separating lower alkenylene, and their salts, in particular pharmaceutically acceptable salts.

The invention relates in the first place to compounds of the formula I in which R. is optionally substituted by lower alkyl having bis and 4 C atoms, such as methyl, lower alkoxy having up to and containing 4 C atoms, such as methoxy, halo, low alkylthio with bis and with 4 carbon atoms such as chloromethylthio, lower alkylthio having up to and including 4 carbon atoms, such as _r methylthio, HaIogenniederalkansulfinyl having up to and including 4 carbon atoms, such as Chlormethansulfinyl, lower alkanesulphinyl having up to and including 4 carbon atoms, such as methanesulfinyl, halogen lower as Chloromethanesulfonyl, lower alkanesulfonyl with bis and with 4 C-atoms, such as methanesulfonyl, sulfamoyl, N-mono- or N, N-di-lower alkanesulfamoyl each having up to and 4 C atoms in the alkyl, such as N-methane or N, N -Diethyi, sulfamoyl, and / or by halogen with atomic number to and with 35, such as chlorine, substituted phenyl or optionally by lower alkyl having up to and with 4 Cr atoms, such as methyl, by lower alkoxy with up to and with 4 C atoms, such as methoxy, and / or halogen with atom nunmer to and with 35, such as chlorine, substituted pyridyl, such as 2-, 3- or 4-pyridyl, or thienyl, such as 2-thienyl, R "is a group of the formula -CH (RJ-R ', in which R 'carboxy, optionally substituted by lower alkyl having up to and with 4 C atoms, such as methyl, lower alkoxy with bis and with 4 C atoms, such as methoxy, and / or halogen, such as chlorine, substituted phenyl or Pyridylniederalkoxycarbonyl such as , 3- or 4-pyridyl-lower alkoxycarbonyl, lower alkoxycarbonyl, such as methoxycarbonyl, mono- or dihydroxy-lower alkoxycarbonyl, such as 2-hydroxyethoxy- or 2,3-dihydroxypropyloxycarbonyl, lower alkoxy-lower alkoxycarbonyl, such as 2-methoxyethoxycarbonyl, N-hydroxy and N-amino, respectively -carbamoyl, N-mono or N, N-di-lower alkoxycarban K) yl, such as N-methyl or N, N-diethylcarbamoyl ,. or carbamoyi, R is hydrogen or lower alkyl with bis and

22 7 94 5.7

AQ

with 4 C atoms, such as methyl, Ph is optionally represented by lower alkyl having up to and including 4 C atoms, such as methyl, lower alkoxy having up to and including 4 C atoms, such as methoxy, and / or halogen up to and including atomic number 35, such as fluoro, substituted 1,2-phenylene and alk. L, 2- 'is ethylene, as well as their salts, especially pharmaceutically acceptable salts.

The invention relates in the first place to compounds of the formula I in which R is optionally halogen, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, halo-lower alkylthio and / or sulfamoyl-substituted phenyl, pyridyl or thienyl, R is a group of the formula -CH-Ri, in R 'is carboxy, lower alkoxycarbonyl or carbamoyl, Ph is 1,2-phenylene optionally substituted by lower alkoxy, lower alkyl and / or halogen and alk is 1,2-ethylene or vinylene, and their salts, especially pharmaceutically acceptable salts.

The invention preferably relates to compounds of the formula I in which R is optionally substituted by halogen having an atomic number up to and including 35, such as chlorine, lower alkylthio having up to and including 4 C atoms, such as methylthio, lower alkanesulfinyl having up to and containing 4 C atoms, such as methanesulfinyl, Halo-lower alkylthio with bis and with 4 C atoms, such as chloromethylthio, and / or sulfamoyl-substituted phenyl, pyridyl, in particular 2-pyridyl, or thienyl, in particular 2-thienyl, R "is a group of the formula -CH-R ', in which R 'is carboxy, lower alkoxycarbonyl having up to and containing 5 C atoms, such as ethoxycarbonyl, or carbamoyl, Ph optionally substituted by lower alkoxy having up to and containing 4 C atoms, such as methoxy, lower alkyl having up to and containing 4 C atoms, such as Methyl, or halogen of atomic number to and including 35, such as fluorine, substituted 1,2-phenylene and alk is 1,2-ethylene or vinylene, and their salts, especially pharmaceutically acceptable salts.

227945 7

ΛΑ

- YYYY -,

^{In a} particularly preferred embodiment, the invention relates to compounds of the formula I in which R. is optionally substituted by. Halloweralkylthio with bis and with 4 C-atoms, such as chloromethylthio, lower alkylthio with bis and with 4 C-atoms, such as methylthio, lower alkanesulfinyl with bis and with 4 C-atoms, such as methanesulfinyl, or halogen with atomic number to and with 35, such as chlorine , in p-position or by sulfamoyl in 3-position and additionally by halogen with atomic number to and with. 35, such as chlorine, 4-substituted phenyl, pyridyl, in particular 2-pyridyl, or thienyl, in particular 2-thienyl, R "means a group of the formula -CH - R ', in which R' is carboxy, lower alkoxycarbonyl with to and with 5 C atoms, such as ethoxycarbonyl, or carbamoyl, Ph optionally with respect to the attached nitrogen atom in the 4-position by lower alkoxy with bis and with 4 C atoms, such as methoxy, in 3- and 5-position by lower alkyl with bis and with 4 C atoms, such as methyl, or in the 4-position by halogen with atomic number to and with 35, such as fluorine, substituted 1,2-phenylene and alk is 1,2-ethylene or vinylene, and their salts , In particular pharmaceutically acceptable salts.

The invention particularly preferably relates to compounds of the formula I in which R is optionally in the p position by lower alkylthio containing up to and including 4 C atoms, such as methylthio, by lower alkanesulfinyl having up to and including 4 C atoms, such as methanesulfinyl, or halogen, bis and with Atom number 35, such as chlorine, substituted phenyl, R "is lower alkoxycarbonylmethyl, Ph optionally substituted in p-position to the nitrogen atom by lower alkoxy with up to and with 4 C atoms, such as methoxy, or halogen up to and including atomic number 35, such as fluorine, substituted 1 , 2-phenylene and alk is 1,2-ethylene, and their salts, in particular their pharmaceutically acceptable salts.

4%

-U-

Outstanding subject of the invention are compounds of formula I, wherein R optionally in the p-position by lower alkylthio with bis and with 4 C-atoms, such as methylthio, by lower alkanesulfinyl with up to and with 4 C-atoms, such as methanesulfinyl, or halogen to and with atomic number 35 R 'is carboxymethyl,' Ph is optionally substituted in p-position to the nitrogen atom by lower alkoxy having up to and with 4 C atoms, such as methoxy, or halogen to and having atomic number 35, such as fluorine, substituted 1, 2-phenylene and alk is 1,2-ethylene, and their salts, in particular their pharmaceutically acceptable salts.

The invention relates in particular to the compounds of the formula III mentioned in the examples and their salts, in particular their pharmaceutically usable salts.

The compounds of the formula I and their salts can be prepared by methods known per se, for example by reacting compounds of the general formulas

alk (II) or Y alk (III)

wherein Z .. optionally functionally modified hydroxy or Mer-r

22 7 94 5 7

capto, or salts thereof with the introduction of an additional bond HZ cleaves and, if desired, a compound obtainable according to the invention into another compound of the formula I or a free compound obtainable according to the invention in a salt or a salt obtainable according to the method in the free compound or in transferred another salt.

Functionally modified hydroxy or mercapto is exemplified by a lower alkanol such as methanol or ethanol, or an optionally substituted aromatic alcohol such as phenol, etherified hydroxy or mercapto, or an inorganic acid such as a mineral acid, e.g. Hydrohalic acid, such as hydrochloric acid, esterified .Hydroxy and means, for example, lower alkoxy, such as methoxy, or optionally substituted aryloxy, such as phenoxy, lower alkylthio, such as methylthio, or halogen, such as chlorine or bromine.

The cleavage of H-Z .. takes place in a customary manner, for example spontaneously, thermally, i. under heating, and / or in the presence of a catalytic agent. The thermal cleavage usually proceeds in a temperature range of about 50 ° to about. 200 ° C. As catalytic agents are used e.g. basic or acidic catalysts, wherein as bases, for example, alkali metal hydroxides, amides or hydrides, such as potassium hydroxide, sodium amide or sodium hydride, metal oxides, such as alumina, especially organic nitrogen bases, such as tertiary amines, e.g. Pyridine, quinoline or Ν, Ν-dimethylaniline, and as acidic catalysts, for example, mineral acids or acid salts or anhydrides thereof, such as sulfuric acid or phosphoric acids, hydrogen sulfates, such as alkali metal hydrogen sulfates, e.g. Potassium hydrogensulfate, phosphorus pentoxide or mineral acid halides such as sulfuric acid halides, e.g. Sulfuryl chloride, are used. If necessary, it is carried out in the presence of an inert solvent or diluent, in a closed vessel and / or under inert gas, e.g. Nitrogen.

22794

-S

Itxerte solvents or diluents are optionally substituted hydrocarbons, such as optionally halogenated alipha- ,. or aromatic hydrocarbons, e.g. Chloroform or chlorobenzene, ethers, such as aliphatic, cycloaliphatic or aromatic ethers, e.g. Diethyl ether, dioxane, tetrahydrofuran, diphenyl ether or anisole, ketones such as aliphatic ketones, e.g. Acetone or methyl ethyl ketone, amides such as dialkylamides, e.g. Dimethylformamide, or sulfoxides such as dilower alkyl sulfoxides, e.g. Dimethyl sulfoxide.

Starting materials Formain II and III can be prepared by methods known per se, for example by reacting compounds of the formula

(IVa)

^X l '

or salts thereof, wherein X is hydrogen and Y is a group of the formula -alk-NR-C O = Zj) (R) or X ₁ -CC = Zp (R ₁ ) and Y _{1 is} a group of the formula -alk If appropriate, a free compound of the formula H 3 which is obtainable in this way is converted into another free compound or a salt obtainable in a salt or a process according to the invention in the free compound or in another salt.

Functionally modified oxo is, for example, thioxo, ketalized or thioketalized oxo, esterified dioxy or imino. For example, ketalized lower alkanols such as methanol or ethanol or lower alkanediols such as ethylene glycol or propylene glycols, e.g. with 1,3-dihydroxypropane, and thioketals are, for example, thioketals with lower alkanethiols, e.g. Methanethiol or ethanethiol, or lower alkanedithiols such as 1,2-ethanedithiol or propanedithiols, e.g. with propane-1,3-dithiol.

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Imino is, for example, optionally imino substituted by lower alkyl or phenyl, such as N-lower alkyl, e.g. N-propylimino.

The cyclization takes place in a known manner, for example in the presence of catalysts such as acidic 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 sulfonic acids, such as benzene, p-toluene or methanesulfonic acid. If necessary, it is carried out in one of the above-mentioned inert solvent or diluent, preferably under heating, e.g. in the temperature range of about 20 ° to about 200 ° C, in a closed vessel and / or under inert gas, e.g. Nitrogen.

In an advantageous embodiment of the method described above, starting from compounds of formula IVa and leads the cyclization to compounds of formula II and the elimination of HZ. from the compounds of formula II without isolation of the intermediates in situ .

A particularly advantageous embodiment of the above process which proceeds via compounds of the formula II consists, for example, in reacting compounds of the formula

Ll * I

Y ^Bz

(IVD)

wherein Bz is an optionally substituted a-phenyl-lower alkyl, preferably benzyl, in particular quaternized with benzyl bromide, by means of cyanides, such as alkali metal cyanides, e.g. Sodium cyanide which cleaves the bond on the quaternary nitrogen and in a resulting compound of formula IVe

/ Jö

(IVe)

the cyano group is solvolysed as desired, the benzyl groups are hydrogenolysed in the presence of a hydrogenation catalyst, e.g. of palladium, splits off and the now free amino compound with a compound of formula

in which Z 'optionally, functionally modified oxo,

and halo halogen, reacted and finally by means of a cyclizing agent, preferably a mineral acid halide, such as phosphorus oxychloride or phosphorus chloride, to give a compound of formula II.

The compounds of the formula I or salts thereof can be further prepared by reacting compounds of the formula

alk. (V)

V ·

wherein R 'is optionally esterified or amidated carboxy, or salts thereof isomerized and, if desired, a free compound of formula I thus obtained in another free compound or in a salt or a method according to available salt in the free compound or converted into another salt ,

The isomerization of compounds of formula V to compounds of formula I is carried out in the usual way, if necessary with the aid of acids, such as mineral acids, e.g. Sulfuric acid, of bases such as alkali metal hydroxides or carbonates, e.g. sodium hydroxide

227945 7

or potassium carbonate, or as of organic amines, e.g. tertiary amines, such as pyridine, or by the addition of energy, such as at temperatures above 100 ° C, optionally in the presence of a catalytic agent, such as a borate or phosphate, e.g. an alkali metal borate or phosphate and, if necessary, in a diluent, in a closed vessel and / or under inert gas, e.g. Nitrogen.

Inert solvents or diluents are optionally substituted hydrocarbons, such as optionally halogenated aliphatic or aromatic hydrocarbons. e.g. Chloroform or chlorobenzene, ethers, such as aliphatic, cycloaliphatic or aromatic ethers, e.g. Diethyl ether, dioxane, diphenyl ether or anisole, ketones such as aliphatic ketones, e.g. Acetone or methyl ethyl ketone, amides such as dialkylamides, e.g. Dimethylformamide, or sulfoxides such as dilower alkyl sulfoxides, e.g. Dimethyl sulfoxide.

Starting materials of the formula V or salts thereof can be prepared by methods known per se, for example by reacting compounds of the formula

alk (via),

wherein X. Oxo or thioxo, with compounds of the formula P (Z ₂ ) ₃ = C (R ₃ ) -Rj or X ₁ -P (Z ₃ ) ₂ -CH (R ₃ ) -Rj, which both as Phosphonium Ylides and may be present as phosphoranes, and wherein X _{1 is} oxo or thioxo, Z. alkyl and / or phenyl, Z is alkyl and / or phenyl or alkoxy and / or phenoxy and R is hydrogen or lower alkyl. Starting materials of the formula V or salts thereof can also be prepared, for example, by the reaction of compounds of the formula

- W-

alk (VIb),

r / V

wherein X _{2 is} a group of the formula -C (R 1 = X 1) and X 'is optionally functionally modified oxo, with hydrogen cyanide or a salt, eg an alkali metal salt thereof After optionally subsequent solvolysis, the resulting intermediates of the formula ## STR5 ## are cleaved

3

 alk (VII),

r /

wherein Z. optionally present in salt hydroxy or thio

Θ © Q tind Z ₅ ZJ ₂ -O, Z is a radical of the formal -P (Z ^ ₃ or -P ₍₄ are hydrogen and Z is hydroxy or mercapto, a compound of formula

Z -Z_ from

 4 5

Alkoxy is, for example, lower alkoxy, such as methoxy, ethoxy, propyloxy or a butyloxy. Optionally, functionally modified oxo means oxo, thioxo or optionally substituted by lower alkyl or phenyl imino.

22 7945 7

In an advantageous embodiment of the above-described process for the preparation of compounds of the formula I, for example starting from compounds of the formula VII, the preparation of compounds of the formula V and the isomerization according to the invention can be carried out in situ .

The splitting off of Z, -Z_ takes place in a customary manner, for example by supplying energy, e.g. a reaction temperature of about 50 ° to about 200 ° C, or in the presence of a catalytic agent. Such are, for example, basic or acidic catalysts, wherein as bases, for example, alkali metal hydroxides, amides, carbonates or hydrides, such as potassium hydroxide, sodium amide, potassium carbonate or sodium hydride, metal oxides, such as alumina, or organic nitrogen bases, such as tertiary amines, e.g. Pyridine, quinoline or N, N-dimethylaniline, and as acidic catalysts, for example, mineral acids such as sulfuric acid, hydrogensulfates such as alkali metal hydrogensulfates, e.g. Potassium hydrogensulfate, polyphosphoric acid, mineral acid anhydrides such as phosphorus pentoxide, or mineral acid halides such as sulfuric acid halides, e.g. Sulfuryl chloride, are used.

In the procedure for the formation of starting materials of formula V is carried out, if necessary, in the presence of an inert solubilizing or Verdiinnungsmittels, in a closed vessel and / or under inert gas, e.g. Nitrogen.

In turn, compounds of the formulas VIa or VIb can be prepared by analogous processes known per se. For example, by making compounds of the formulas

_Ρ _Λ _vh A

ⁿ j · (VId) or ^r "Π (VIe)

V \ lk

"Ι ι 2

condensed in the presence of a condensing agent. As the condensing agent are, for example acids, such as mineral acids, for example sulfuric acid, polyphosphoric acid, hydrogen halide such as hydrochloric acid _/ or phosphoric acid halides, such as phosphorus oxychloride or phosphorus trichloride.

Phosphoranes of the formula P (Z ₀ ) C (R -) - R 'or their phosphonium ylides can be prepared by methods known per se, for example by reaction of phosphines of the formula P (Z ₀ ), with

^Δ Q ^Δ * tertiary ammonium bases of the formal R'-CH (R,) -N (alk '), B, wherein alk ^{1 is} a

Alkyl radical, such as a lower alkyl radical, and B represents an anion, such as halide or hydroxyl anion, and by subsequent reaction with strong bases, such as alkali metal organyls, e.g. Butyllithium or phenyllithium. The corresponding quaternary ammonium bases are also obtained by reaction of phosphines P (Z ")" with known compounds of the formula R-Hal in the presence of bases such as alkali metal hydroxides. -lower alkanolates, hydrides or amides, ζ.B- sodium hydroxide, sodium methoxide, potassium hydride or potassium acid amide.

Compounds of the formula X =P (ZJ ₂ -CH (R ₃ ) -R 'can be prepared, for example, by reacting compounds of the formula P (Z-) in which Z 1 is alkoxy or phenoxy with compounds of the formula: Hal-GH (R -) - R ', in which Hal is halogen, is reacted.

Compounds of formula VId are obtainable by acylation of compounds of the formula

Bh- / ¹

\ lk IIH M _n

22 7945 7

af

- 2Θ-

with compounds of formula \ - < wherein X _{4 is} halogen or acyl.

The compounds of the formula I or salts thereof can also be prepared by, for example, a compound of the general formula

(VIII), llk.

wherein Z. optionally functionally modified hydroxy or mero

capto or amino, or a salt thereof cyclized and, if desired, a free compound of the formula I obtainable in this way into another free compound or into a salt or a salt obtainable according to the method into the free compound or into another salt. ".

Functionally modified hydroxy or mercapto is exemplified by lower alkanol, such as methanol or ethanol, or an optionally substituted aromatic alcohol, such as phenol, etherified hydroxy or mercapto or with a suitable anhydride, such as acetic anhydride, with an organic acid, such as sulfonic acid, e.g. Lower alkyl or optionally substituted arylsulfonic acid, such as methanesulfonic acid or p-toluenesulfonic acid, or with an inorganic acid, such as a mineral acid, e.g. Hydrohalic acid, such as hydrochloric acid, esterified hydroxy or mercapto, and represents, for example, lower alkoxy, such as methoxy, or optionally substituted aryloxy, such as phenoxy, lower alkylthio, such as methylthio, or lower alkanoyloxy, such as acetyloxy, Niederalkansulfonyloxy or

optionally substituted arylsulfonyloxy, such as methanesulfonyloxy, or p-toluenesulfonyloxy, or halogen, such as chlorine or bromine.

The cyclization takes place in a manner known per se, for example in the presence of a condensing agent, such as an acid condensing agent. These include, for example, acids, such as mineral acids, for example sulfuric acid or polyphosphoric acid, aryl halides, such as phosphoric acid halides, eg phosphoroxychloride, phosphorus tribromide or phosphorus pentachloride, The reaction is required in a solvent or .. diluent at a temperature range of about 20 ° to about 200 ⁰ C, in a closed vessel and / or under an inert gas, eg nitrogen.

Inert solvents or diluents are optionally substituted hydrocarbons, such as aliphatic. or aromatic halohydrocarbons, e.g. Chloroform or chlorobenzene,

- j

optionally mixed ethers, such as aliphatic, cycloaliphatic or aromatic ethers, e.g. Diethyl ether, dioxane, diphenyl ether or anisole, ketones, such as aliphatic ketones, such as acetone or methyl ethyl ketone. Amides, such as dialkylamides, e.g. Dimethylformamide, or sulfoxides such as lower alkyl sulfoxides, e.g. dimethyl sulfoxide,

The starting materials of the formula VIII can be prepared by a method known per se, for example by reacting in compounds of the formula

(IX)

\ lk

¹ Ah ₀

H ^z

227945 7

the primary amino group is substituted by means of alkali metal nitrites in the presence of acids by hydroxyl, this optionally esterified reactive, acylated the indole nitrogen with a compound of the formula R -COOH or a functionally modified derivative thereof and then forms the corresponding amidine with ammonia.

The acylation of the indole nitrogen takes place in a manner known per se, for example by reaction with optionally functionally modified carboxy derivatives, such as acids, acid anhydrides or activated esters. Anhydridised carboxy is e.g. with inorganic acids such as hydrohalic acid, with hydrazoic acid, with hydrocyanic acid or with organic acids such as optionally halogen-substituted lower alkanoic acids, e.g. Acetic acid, anhydride. These include e.g. Acid halides, e.g. Acid chlorides, corresponding acid azides, acid nitriles or acyloxycarbonyl.

The acylation with a compound of the formula R-COOH or an optionally functionally modified derivative thereof is carried out in a customary manner. Starting from one. Anhydride, especially an acid halide, it is preferred in the presence of a strong base,

, 7 ·

". ' for example, an alkali metal hydride, for example sodium hydride, an alkali metal amide, for example sodium amide, or an alkali metal alcoholate, for example Kaliummethylau performed.

The acylation, such as the subsequent reaction with ammonia, is e.g. in an inert solvent, such as in an alkylated amide, e.g. N, N-dimethylformamide, an optionally halogenated hydrocarbon, e.g. Chloroform or chlorobenzene, or a nitrile, e.g. Acetonitrile, or a mixture thereof, if necessary at reduced or elevated temperature and / or in an inert gas atmosphere.

The compounds of the formula IX can in turn be prepared by processes known per se, for example analogously to Fischer's synthesis by treatment of phenylhydrazones or correspondingly 1,3-substituted 4-piperidones with acids, such as with ethanolic hydrochloric acid, or by acylation and condensation of appropriately substituted a-hydroxyketones with optionally substituted anilines.

The compounds of formula IX can also be. in a preferred embodiment, for example, by compounds of the formula

(IVd)

which Bz. an optionally substituted a-Phenylniederalkylrest, preferably benzyl, in particular quaternized with benzyl bromide _y and by means of a nucleophile, preferably with cyanides, the bond cleaves on the quaternary nitrogen thus obtained and in an obtainable as an intermediate compound of formula

Ph - </ ^N CN

y (iv)

the cyano group is solvolysed as desired, and the benzyl groups are hydrogenolysed, for example, in the presence of a hydrogenation catalyst, e.g. of palladium, splits off.

22 7 94 5 7

- 2ft - '

The compounds of general formula I or salts thereof can also be prepared by, for example, in a compound of the formula

π (X),

alk

^R l

wherein R ° is a group of the formula -CH (R ₃ ) -R "and wherein R is hydrogen or lower alkyl and R" is a functionally different carboxy other than R i, a group of the formula -Ci = O) -N ₂ B, where B the anion of a mineral acid, for example chloride, bromide or tetrafluoroborate, or optionally methyl-oxidized to the level of formyl, or salts thereof R solvolytically or oxidatively converted into the group R, and, if desired, a free compound of the formula I thus obtained another free compound or in a salt or a salt obtainable according to the process into the free compound or into another salt. Functionally changed

λ delte and of R ¹ different, functionally modified carboxy

j '. , ,

compounds are, for example, optionally functionally modified orthoester groups, such as trihalo, Halogendiniederaikoxy- or Trinie.deralkoxymethylgruppen, anhydridesiertes carboxy, such as cyano, a group of formula = C = Q, cyano, azido or halocarbonyl, acyloxycarbonyl, such as acetyloxycarbonyl or derivatives of Carboxy of the formula R 'or R "in which oxo is optionally replaced by thio or optionally substituted imino, such as optionally esterified thiocarboxy, such as lower alkylthiocarboxy, for example ethylthiocarboxy, amidated thiocarboxyl, imino esters, such as imide or Amidhalogenidgruppierungen, for example iminochlor or aminodichloromethyl, imino ether groups, such as lower alkyl or lower alkyleneimino ether groups, for example methoxy or ethoxyiminomethylene, or amidino groups, such as amidino or lower alkyl, for example methylamidino.

Up to the stage, the formyl-oxidized methyl or functionally modified groups thereof are, for example, optionally esterified or etherified hydroxymethyl or optionally functionally modified formyl, such as hydroxymethyl, mono- or dihalomethyl, lower alkoxymethyl, formyl or formimino.

Functionally modified carboxy compounds, such as optionally functionally modified orthoesters, anhydridized carboxy or acyloxy carbonyl, can be solvolysed directly or in several solvolysis steps to give free, esterified or amidated carboxy.

The solvolysis of R "in a known manner, for example by hydrolysis with water, by ammonolysis with ammonia, by aminolysis with a desired primary or secondary ¹ amine or by alcoholysis with a corresponding alcohol. It is necessary in the presence of a catalyst, in a Lösungsbzw Diluent, in a closed vessel, in a temperature range of about 0 ° to about 150 ⁰ C and / or under inert gas, for example nitrogen worked.

Examples of catalysts are basic condensing agents, such as alkali metal or alkaline earth metal hydroxides, for example sodium, potassium or calcium hydroxide, or tertiary organic amines, such as pyridine or trialkylamines, for example triethylamine, or acidic hydrolyzers, such as mineral acids, for example hydrohalic acids, such as hydrochloric acid, or organic Carboti or sulfonic acids, such as ^: • ^: Lower alkanecarboxylic acids or optionally substituted benzenesulfonic acids, for example acetic acid or p-toluenesulfonic acid.

Optionally oxidized to the stage of formyl methyl, such as methyl, hydroxymethyl or formyl, or functionally modified

22 7 94 5 7

Derivatives thereof, such as halomethyl, e.g. Chloromethyl, mercaptomethyl, thioformyl or optionally substituted formimino can be oxidized, for example, directly via a plurality of oxidation steps, optionally via hydroxymethyl or formyl, to give carboxy. Ether ether hydroxymethyl, preferably lower alkoxymethyl, e.g. Ethoxymethyl is oxidized in the presence of an oxidizing agent to esterified carboxy, especially lower alkoxycarbonyl. The reaction of formyl to carbamoyl is carried out, for example, with the aid of an amino compound in the presence of an oxidizing agent, such as a transition metal oxide, e.g. Manganese dioxide, and if necessary in the presence of a nucleophile, in particular a cyanide, performed.

Oxidation of R "is carried out in the usual way, for example using the customary oxidizing agents, for example optionally catalytically excited oxygen, alkali metal salts of chromates or manganates, such as sodium chromate or potassium permanganate, or transition metal oxides, such as manganese dioxide or chromium trioxide in an inert solvent ^ in a closed vessel and / or under cooling barren heating, for example * at about 0 ° to about 150 ⁰ C.

The starting materials of the formula X can be prepared by analogous methods, for example by reacting compounds of the formula

alk (VIa)

wherein X. Oxo or thioxo, with compounds of formula H ^Z 2 ^ 3 ~ ^R 2 ' ^{wellowie SOWOQ} 1 ^a ls phosphonium ylides and may be present as phosphoranes, or X = P (Z,) ₂ " ^R 2 » ^And in which Z-alkyl and / or phenyl and Z" are alkyl and / or phenyl or alkoxy, such as lower alkoxy,

and / or phenoxy and R '' of Ri different functionally modified carboxy, a group of the formula -C ( ³¹ O) N ₅ B or optionally to the stage of formyl oxidized methyl, reacting, optionally obtainable intermediates of the formula

y · 7

¹ ^ ⁴

Phr- * - C - R "

v ^%

3 (VIh):

alk

/ V

ν ν

Θ Θ Θ

in which X'-0 or -S and Z.sup. a radical of the formula -P (Z _) _ or

-P (X ') (Z), a compound of the formula X = P (Z.) Or X = P (X') (Z.,) - cleaved and isomerizes a compound thus obtained to a compound of formula X. ,

The unit is usually carried out in an inert solvent, for example 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 of about 20 ° to about 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-butoxide. ·.

In a preferred embodiment, the starting materials of the formula X in which R ° is a solvolytic or oxidative radical convertible into R "are used, for example compounds of the formula ## STR5 ##

_Ph _./yBz

H, wherein Bz is an optionally substituted oc-phenyl-lower alkyl

22 7 94 5 7

tert, preferably benzyl, means quaternary the tertiary nitrogen atom, in particular with benzyl chloride, cleaves the bond on the quaternary nitrogen atom with the aid of a strong base, such as with cyanides, e.g. Sodium cyanide, and converted in a compound of the formula thus obtained

(IVe)

the cyano group in R °, for example by solvolysis to carboxy or lower alkoxycarbonyl and subsequent reduction to hydroxymethyl or lower alkoxymethyl, cleaves the Bz groups hydrogenolytically in the presence of a hydrogenation catalyst. Subsequently, the compound thus obtained is reacted with a compound of the formula

Z ¹ RC ^, wherein Z 'optionally functionally modified oxo and

Hai ^l Hai halogen means, and performs the cyclization to corresponding compounds of formula X in the presence of a conventional cyclization agent, such as mineral acid halide, for example phosphorus oxychloride, by.

The compounds of the formula I in which R represents amidated 1-carboxymethyl can also be prepared by addition of water and removal of a proton to compounds of the formula

'-CH ₂ -C = NR ₅

(XIa)

which in situ by rearrangement of compounds of the formula

ao

Ph.

^X 6 Il

alk. (XIb).

in which R_ is optionally substituted lower alkyl or phenyl and X _{fi is} a radical of the formula = ΪΤ-ΟΗ or = NN = N1.

The reaction is carried out in a conventional manner, for example in the presence of an acidic catalyst such as a mineral acid, e.g. Sulfuric acid or phosphoric acid, and optionally with heating.

The starting materials of the formula XIb can be prepared by analogous processes, for example by reacting compounds of the formula

^X l Il

r / V

wherein X represents oxo or thioxo, with hydroxylamine or an acid addition salt thereof or with an azide such as an alkali metal azide, e.g. Sodium azide.

Compounds of the formula I in which R is esterified or

amidated 1-carboxy-lower alkyl and alk is vinylene, are prepared, for example, by reacting corresponding compounds of the formula

227 94 5 7

: Il

in which alk is ethylene, dehydrated with elimination of hydrogen with simultaneous formation of an additional bond and, if desired, a compound obtainable according to the invention into another compound of the formula I or a free compound of the formula I obtainable according to the invention in a salt or a salt obtainable according to the method in the free Compound of formula I or converted into another salt.

The dehydrogenation is carried out in manner known per se, especially at elevated temperature, for example in a temperature range of about 100 ° to about 300 ⁰ C, and using a dehydrating agent., As such means, for example, come dehydrogenation catalysts, for example transition elements, preferably subgroup VIII, such as palladium or platinum, or their salts, such as ruthenium triphenyl phosphide chloride, into consideration, wherein the catalysts are optionally applied to a suitable support material, such as carbon, aluminum oxide or silicon dioxide. Further dehydrating agents are, for example, quinones, such as p-benzoquinones, for example tetrachloro-p-benzoquinone or 2,3-dichloro-5,6-dicyano-p-benzoquinone, or anthraquinones, for example phenanthrene-9,10-quinone. The reaction is carried out in an inert, optionally high-boiling solvent, such as in an ether, for example diphenyl ether, if necessary under pressure, in a closed vessel and / or under an inert gas, for example nitrogen.

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

An invention obtainable compound of formula I can be converted in a conventional manner into another compound of formula I.

If the group R 1 contains a free carboxy, this can be converted into corresponding esterified carboxy by esterification methods known per se, for example by reacting optionally modified carboxy or a salt thereof by alcoholysis with a desired alcohol, for example a reactive derivative thereof or one thereof derived olefin, or by alkylation with Diazoniederalkan.

Suitable reactive functional carboxy derivatives are, for example, anhydrides, and as anhydrides in particular mixed anhydrides, e.g. those with inorganic acids, such as hydrohalic acids, e.g. Hydrochloric acid, such as hydrogen chloride or hydrocyanic acids, or with organic carboxylic acids, such as lower alkanoic acids, e.g. Acetic acid, used.

Reactive derivatives of an alcohol include, for example, carboxylic, phosphoric, sulfuric or carbonic esters, e.g. Lower alkane carboxylic acid ester, tri-lower alkyl phosphite, dilower alkyl sulfite or pyrocarbonate, or mineral or sulfonic acid esters, e.g. Chlorine, bromine or sulfuric acid esters, benzene, toluene or. Methanesulfonic, the relevant alcohol.

The esterification of free carboxy is carried out in the presence of a condensing agent. Catalytically dehydrating agents for the esterification with alcohols are e.g. Acids, for example protic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, boron, benzenesulfonic and / or toluenesulfonic acid, or Lewis acids, such as boron trifluoride etherate, in question. Common water-binding condensing agents are e.g. substituted by hydrocarbon radicals

22 794 5 7

-SS-

te carbodiimides, for example N, N'-diethyl, Ν, Ν-dicyclohexyl or N-ethyl-N ^f - (3-dimethylaminopropyl) carbodiimides. Condensation agents for the esterification with reactive esters are, for example, basic condensation agents, such as inorganic bases, for example alkali metal or alkaline earth metal hydroxides or carbonates, such as sodium, potassium or calcium hydroxide or carbonate, such as organic nitrogen bases, for example tertiary organic amines, such as triethylamine or pyridine. The esterification is advantageously carried out with an excess of alcohol used. In this case, it is preferable to work in an anhydrous medium, if necessary in the presence of an inert solvent, such as in halogenated hydrocarbons, for example chloroform or chlorobenzene, in ethers, for example tetrahydrofuran or dioxane.

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

Furthermore, free carboxy or reactive functional carboxy derivatives by solvolysis with ammonia or a primary or secondary amine, which also hydroxylamine or hydrazines can be used, in a conventional manner with dehydration, optionally in the presence of a condensing agent in a desired convert amidated form. As the condensate, bases are preferably used, for example, inorganic bases such as alkali metal hydroxides, e.g. Sodium or potassium hydroxide, organic nitrogen bases such as tertiary amines, e.g. Pyridine, tributylamine or N-dimethylaniline, or tetrahalosilanes such as tetrachlorosilane.

a »

Furthermore, compounds of the formula I which are obtainable according to the invention, in which R ₂ contains carboxy esterified as a substituent, can be transesterified in the customary manner, for example by reaction with a corresponding alcohol or a metal salt thereof, such as an alkali metal salt, for example the sodium or potassium salt, if necessary. in the presence of a catalyst, for example a strong base, such as an alkali metal hydroxide, amide or alcoholate, for example potassium hydroxide, sodium amide or methylate, or a strong acid, such as a mineral acid, for example sulfuric acid, phosphoric acid or hydrochloric acid, or as an organic acid Sulfonic acid, for example, an aromatic sulfonic acid, such as p-toluenesulfonic acid.

Esterified carboxy may also be prepared by known methods, e.g. be converted by hydrolysis in the presence of a catalyst in the free carboxy group. As catalysts there are preferably used bases, e.g. Alkali metal! Hydroxides, such as sodium or potassium hydroxide in question. Esterified carboxy can be further in a conventional manner, for example by solvolysis, optionally in the presence of a catalyst, for example an acidic or basic agent in carboxy, by ammonia lysis or aminolysis, with ammonia or with a primary or secondary Amin.in amidated carboxy convert. As bases find, for example, alkali metal hydroxides, such as sodium or potassium hydroxides, and acids, for example, mineral acids, such as sulfuric acid, phosphoric acid or hydrochloric acid, use. Likewise, compounds of the formula I obtainable according to the invention, in which the group R contains the carboxy-substituted carboxy substituent, can cleave the amide bond according to methods known per se and thus convert the carbamoyl into free carboxy. For this purpose 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. ~

22 7 94 5 7

If the group R_ of the formula I contains an esterified carboxy group, it can be converted into an amidated carboxy group, for example by conventional solvolysis, advantageously by an excess of ammonia or at least one hydrogen atom-containing amine, if appropriate in the presence of a catalyst. It is used as. Catalysts, for example, acids, such as mineral acids, e.g. Hydrochloric, sulfuric or phosphoric acid, or bases such as alkali metal hydroxides, e.g. Sodium or potassium hydroxide.

Contains the group R "of formula I as a substituent amidated carboxy, this can be converted, for example, by conventional solvolysis with an alcohol in the presence of a catalyst in esterified carboxy. For example, acid catalysts such as mineral acids, e.g. Phosphoric acid, hydrochloric acid or sulfuric acid.

If the substituent R. of the formula I is substituted by lower alkylthio, it can be oxidized in the usual way to corresponding NiederalkansuIfinyl or -sulfonyl. Suitable oxidizing agents for the oxidation to the sulfoxide stage include, for example, inorganic peracids, such as peracids of mineral acids, e.g. Periodic acid or persulfuric acid, organic peracids, such as corresponding percarboxylic or persulfonic acids, e.g. Peramaisen, Peressig, Trifluorperessigbzw. Perbenzoic acid or p-toluenesulfonic acid, or mixtures of hydrogen peroxide and acids, e.g. Mixture of hydrogen peroxide with acetic acid, into consideration.

Frequently, the oxidation is carried out in the presence of suitable catalysts, suitable acids as catalysts, such as optionally substituted carboxylic acids, e.g. Acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of VII subgroup elements, e.g. Vanadium, molybdenum or tungsten oxide may be mentioned. The oxidation is under mild conditions, e.g. at temperatures of about -50 ° to about + 100 ° C, carried out.

The oxidation to the sulfone can also be carried out with dinitrogen tetroxide as a catalyst in the presence of oxygen at low temperatures, as well as the direct oxidation of Niederalkylthio to Niederalkansulfonyl. However, in this case usual ore is used in excess of the oxidizing agent.

\

Compounds of Formal I, wherein R. represents an aromatic radical substituted by lower alkylsulfinyl or -sulfonyl, can also be reduced to lower alkanesulfinyl by methods known per se for the corresponding lower alkylthio compounds starting from lower alkanesulfony! Derivatives; Suitable reducing agents are, for example, catalytically activated hydrogen, where noble metals or oxides, such as palladium, platinum or rhodium or their oxides, are used, optionally applied to 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 HE or tungsten III compounds, hydrogen halides, such as chlorine, bromine or hydrogen iodide, Hydrides, such as complex metal hydrides, eg Lithium aluminum, sodium borohydride, tributyltin hydride, phosphorus compounds such as phosphorus halides, e.g. Phosphorus trichloride, bromide, phosphorus pentachloride or phosphorus oxychloride, phosphines, such as triphenylphosphine, or phosphorus pentasulfide-pyridine, or sulfur compounds, such as mercaptans, thioacids, such as thiophosphoric acids or dithiocarboxylic acids, dithionite or sulfur-oxygen complexes, such as iodine-pyridine-sulfur dioxide complex in question.

Salts obtained can be converted into the free compounds in a manner known per se, e.g. by treating with an acidic reagent, such as a mineral acid, or a base, e.g. Lye ..

The new compounds may, depending on the choice of starting materials and procedures, in the form of one of the possible isomers or mixtures thereof, e.g. depending on the number of asymmetric

227 94 5 7

Carbon atoms as pure optical isomers -, such as antipodes or mixtures of isomers, such as racemates.,. Diastereoisomeric mixtures or racemate mixtures ,. available.

Obtained Diastereomeresgemische and Racematgemische can be separated in a known manner in the pure isomers, diastereomers or racemates due to the physico-chemical differences of the constituents, for example by. Chromatography and / or fractional crystallization.

Obtained racemates can also be broken down by known methods in the optical antipodes, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by reacting an acidic end product with one with the racemic. Acid salts forming optically active base and separation of the salts thus obtained, e.g. due to their different solubilities, decomposed into the diastereomers from which the antipodes can be released by the action of suitable agents. Advantageously, one isolates the more effective of the two antipodes.

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

As a result of the close relationship between the novel compounds in free form and in the form of their salts, the corresponding salts or free compounds are to be understood as meaningful and expedient in the preceding and following among the free compounds or their salts.

The invention also relates to those embodiments of the method according to which a

- as -

proceeds as intermediate compounds and performs the missing steps or uses a starting material in the form of a salt or in particular, forms the reaction conditions.

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described above as being particularly valuable. New starting materials and processes for their preparation also form an object of the invention.

The pharmaceutical preparations according to the invention which contain compounds of the formula I or pharmaceutically acceptable salts thereof are. those for enteral, such as oral or rectal, and parenteral administration and for topical administration to warm blood (s) containing the pharmacological agent alone or together with a pharmaceutically acceptable carrier material. The dosage of the active substance depends on the species of warm-blooded animals, the age and the individual condition, as well as on the mode of administration. Normally, an approximately daily dose of about 30-300 mg, advantageously distributed in several equal partial doses, should be estimated for a warm-blooded animal weighing about 75 kg when administered orally.

The new pharmaceutical preparations contain, for example, from about 10 Z to about 80%, preferably from about 20% to about 60% of the active ingredient. Pharmaceutical preparations according to the invention for enteral or parenteral administration are, for example, those in unit dosage forms, such as dragees, tablets, capsules or suppositories, and also ampoules. These are produced in a manner known per se, for example by means of conventional mixing, granulation, coating, solution or lyophilization processes. Thus, one can obtain pharmaceutical preparations for oral use by solidifying the active ingredient

22 7 945 7

Carriers combined, optionally granulated a resulting mixture, and the mixture or granules, if desired or necessary, after addition of suitable excipients, processed into tablets or dragee cores.

^; · Suitable carriers are in particular. Fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, furthermore binders, such as starch pastes using -J, for example, corn, wheat, rice or potato starch, gelatin, tragacanth , Methylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the above-mentioned starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow, regulating and lubricating agents, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores will be

with suitable, optionally gastric juice-resistant coatings. comparable

see .u.a. concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate used. The tablets or dragee coatings may contain dyes or pigments, e.g. for the identification or labeling of different doses of active substance.

Other orally applicable pharmaceutical preparations are gelatin capsules, as well as soft, closed capsules of gelatin and a plasticizer, such as. Glycerine or sorbitol. The capsules may contain the active ingredient in the form of granules, e.g. in a mixture

with fillers, such as lactors, binders, such as starches, and / or lubricants, such as Takl or magnesium stearate, and optionally of stabilizers. In soft capsules, the active ingredient is preferably dissolved in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols or suspended, wherein stabilizers may also be added.

As rectally applicable pharmaceutical preparations are, for example, suppositories into consideration, which consist of a combination of the active substance with noble Suppositoriengrundmasse. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatin rectal capsules which contain a combination of the active ingredient with a basic mass! as basic materials there are e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question,

For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, e.g. a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, whereby suitable lipophilic solvents or vehicles such as fatty gels, e.g. Sesame oil, or synthetic fatty acid esters, e.g. Ethyl oleate or triglycerides used or aqueous injection suspensions containing viscosity increasing agents, e.g. Sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally also stabilizers.

As topically applicable pharmaceutical preparations are primarily cream, ointments, pastes, foams, tinctures and solutions in question, which contain from about 0.5 to about 20% of the active ingredient.

Creams are oil-in-water emulsions that have more than 50 Z of water. The oily basis used is primarily fat

22 7 94 5 7

alcohols, e.g. Lauryl, cetyl or stearyl alcohol ,. Fatty acids, e.g. Palmitic or stearic acid, liquid to solid waxes, e.g. Isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, e.g. Vaseline (petrolatum) or paraffinol. Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, e.g. Fatty acid esters of polyhydric alcohols or ethylene oxide adducts thereof, such as polyglycerin acid esters or polyoxyethylene sorbitan acid esters (tweens), polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, e.g. Sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, usually in the presence of fatty alcohols, e.g. Catyl alcohol or stearyl alcohol. Additives to the water phase are u.a. Agents that reduce dehydration of the cream. e.g. Polyalcohols, such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, furthermore preservatives, fragrances, etc.

Ointments are water-in-oil emulsions containing up to 70%, but preferably from about 20% to about 50% water or aqueous phases. The fatty phase is primarily hydrocarbons, e.g. Vaseline, paraffinol and / or hard paraffins in question, the preferred hydroxy compounds for improving the water binding capacity, such as fatty alcohols or esters thereof, e.g. Cetyl alcohol or wool wax alcohols or wool wax included. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), e.g. Sorbitan oleate and / or sorbitan isostearate. Additives to the water phase are u.a. Humectants, such as polyalcohols, e.g. Glycerol, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances, etc.

Fatty ointments are anhydrous and contain, in particular, hydrocarbon, e.g. Paraffin, vaseline and / or liquid

22 7 94 5 7

Paraffins, moreover natural or partial synthetic fat, e.g. Coconut fatty acid triglyceride, or preferably hardened oils, e.g. hydrogenated peanut or castor oil, further fatty acid partial ester of clycerol, e.g. Glycerol mono- and distearate, as well as e.g. those mentioned in connection with the ointments, the water absorption ability increasing fatty alcohols, emulsifiers and / or additives.

Pastes are cream and ointments with secretion-absorbing powder components, such as metal oxides, e.g. Titanium oxide or zinc oxide, further talc and / or aluminum silicates, which have the task of binding existing moisture or secretions.

Foams are administered from pressure vessels and are aerosolized liquid oil-in-water emulsions wherein halogenated hydrocarbons such as chlorofluoro-lower alkanes, e.g. Dichlorodifluoromethane and. Dichlorotetralfuorethan be used as a blowing agent. The oil phase used u.a. Hydrocarbons, e.g. Paraffin oil, fatty alcohols, e.g. Cetyl alcohol, fatty acid esters, e.g. Isopropyl myristate, but not other waxes. As emulsifiers u.a. Mixtures of those having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those having predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). There are also the usual additives, such as preservatives, etc. ,

Tinctures and solutions most often have an aqueous ethanolic base, which i.a. Polyalcohols, e.g. Glycerol, glycols, and ethylene glycol or polyethylene glycol as humectants to reduce evaporation, and replenishers such as fatty acid esters with low polyethyleneglycols, i. soluble in aqueous mixture, lipophilic substances as a substitute for the skin with the ethanol extracted fatty substances, and, if necessary, other auxiliaries and additives are added.

22 7

10..7. 1981

AP C 07 C / 227 945

58 830 11

The production of the topically usable pharmaceutical preparations is carried out in a conventional manner, for. By dissolving or suspending the active ingredient in the base or in a TdI thereof, if necessary. When processing the active ingredient as a solution this is usually solved by the emulsification in one of the two phases; when processed as a suspension, it is mixed after emulsification with part of the base and then added to the remainder of the formulation.

The present invention also relates to the use of the compounds of formulas I and the salts of such compounds having salt-forming properties, preferably for the treatment of inflammation, primarily of inflammatory diseases of the rheumatic type, especially of chronic arthritis.

Exemplary embodiment ......

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees Celsius.

The designation of the linkage sites in the pyrimidoindole ring system on which the compounds of the formula I are based

Ίτ Γ 1 A

is inconsistent in the literature *

Thus, the older references the linkages in the ring system with / 3,4-a /, while recently the designation / 1,6-a / is used.

22 79Λ5 7

HV

For reasons of principle, the following nomenclature is preferred below for the above ring skeleton.

Pyriraido [1,6-a] indole

Example 1; 7-Methoxy-l (p-chlorophenyl) -3,4-dihydro-pyrimido [1,6-a] indole-S-acetic acid ethyl ester hydrochloride '

165 g (0.4 mol) of ethyl 2 - [(p-chlorobenzoylamino) -ethyl] -5-methoxy-indole-3-acetate are refluxed in 825 ml of phosphorus trichloride for 3 hours and then the excess phosphorotirchloride at a bath temperature of Distilled off at 60 ° under a slight vacuum. The residue is dissolved in 1500 ml of methylene chloride, stirred with 2000 ml of ice water, by adding 500 ml of conc. Ammonia made alkaline and separated after brief stirring, the methylene chloride phase. It is washed neutral with water, dried over Na 2 SO 4, and the 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 treated with 100 ml of an approximately 4-normal hydrogen chloride solution in ether. The hydrochloride of the 7-methoxy-l- (p-chlorophenyl) -3,4-dihydro-pyrimido [l, 6-a] indole-acetic acid ethyl ester crystallizes out.

CH "0 y · CH.-COOC → H! IT IJ

ί · HCl

/ VV

Il

c / V

It is filtered off with suction and washed with acetone / ether 1:10: yellowish crystals of mp. 204-208 °, after recrystallization from methanol / acetone mp. 205-208 °.

227945 7

The starting product can be prepared as follows:

a) 131 g (0.45 mol) of 3-benzyl-6-methoxy-tetrahydro ~ Y-carboline are dissolved in 1300 ml of acetonitrile at 40 ° with stirring and added within 10 minutes 94 g (0.55 mol) of benzyl bromide. After a short time, the Benzylammoniumderivat begins to crystallize. It is stirred for a further 15 hours at room temperature, then cooled in an ice bath and filtered with suction from Kristall'isat. Mp 150-151 °.

"Λ b) 464 g (1 mol) of the thus prepared N, N-dibenzy 1-6-methoxy

tetrahydro-Y-carboliminium bromide are dissolved in 4250 ml of methanol with heating to 65 ° and added within 5 minutes, a solution of 196 g '(4 mol) of sodium cyanide in 500 ml of water with stirring. The solution is refluxed for 3 hours under reflux. Upon cooling, after inoculation, 2- (dibenzylamino-ethyl) -3-cyanomethyl-5-methoxy-indole crystallizes in colorless crystals, mp. 102-104 °.

c) 220 g (0.537 mol) of the nitrile prepared according to b) are dissolved in 300 ml of abs. Dissolved ethanol and the solution at -5 ° saturated with dry hydrogen chloride. The mixture is then stirred for 5 1/2 days at 20 °. The precipitated crystals are allowed to settle, decanted from the supernatant solution, the sediment is dissolved in 2000 ml of ice water and stirred for about 3 hours at 20 °. Then, with ice cooling with conc. Made alkaline 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 ToluoIs remains a light brown OeI, which is subjected without further purification of the hydrogenation according to d).

'te'

d) 181.3 g of 2) obtained according to c) 2-dibenzylamino-5-methoxyindole-3-acetic acid ethyl ester in 1500 ml of abs. Alcohol dissolved, and hydrogenated with the addition of 18 g of Pd / C (5%) at atmospheric pressure and 20-35 °. After uptake of 12500 ml of EL again 18 g of catalyst are added and further hydrogenated to a standstill of BL intake of 17300 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 seeding, the 2-aminoethyl-5-methoxy-indole-3 = acetic acid ethyl ester crystallized in colorless crystals of mp. 79-80 °. ,

e) 61.7 g (0.223 mol) of the 2-aminoethyl-5-methoxy-indole-3-acetic acid ethyl ester prepared according to d) are dissolved in 600 ml of methylene chloride and the solution is covered with 150 ml of 2N sodium hydroxide solution. With vigorous stirring, a solution of 43 g (0.245 mol) of p-chlorobenzoyl chloride is added at 0-5 ° within 2 1/2 hours and then stirred for 1 hour. The methylene chloride phase is then separated, washed with water, dried over MgSO 4, and evaporated to dryness. The residue crystallizes on ingestion in ether in colorless crystals of the mp. 136-138 ° 2- [(p-chlorobenzoyl-amino) -ethyl] -5-methoxy-indole-3-acetic acid ethyl ester.

Example 2 : 1-Phenyl-3,4-dihydro-pyrimido [1,6- isindole-S-acetic acid ethyl ester]

54 g (0.154 mol) of 2- (benzoylamino-ethyl) -indole-3-acetic acid ethyl ester are refluxed in 250 ml of phosphorus oxychloride for 3 hours. The excess phosphorus oxychloride is then distilled off at 60 ° in vacuo and the residue is stirred with 1000 ml of ice water. The aqueous solution is transferred by filtration

22 7 94 5 7

Hyflo clarified, with conc. Ammonia made alkaline and extracted with 500 ml of ether. The ether phase is dried over sodium sulfate and concentrated to dryness. The residue is dissolved in 200 ml of acetone and mixed with 25 ml of an approximately 4-normal hydrogen chloride solution in ether. After inoculation, the hydrochloride of 1-phenyll-3,4-dihydro-pyrimido [i, 6-a3indole-5-acetic acid ethyl ester crystallizes in yellowish crystals of mp. 172-175 °, which can be recrystallized from IN hydrochloric acid (mp 187-189 °). The base liberated from the salt melts after recrystallization from ether at 83-84 °.

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

Example 3: In an analogous manner, as described in Example 2, obtained from 2 - [(p-methylthio-benzoyl-amino) -ethyl] -5-fluoro-indolessigsäureethylester, mp. 157-158 °, the 7-fluoro-l - (p-methylthiophenyl-3,4-dihydro-pyrimidine [1,6-a] indole-5-acetic acid ethyl ester, mp. 119-120 °.

Example 4: In a manner analogous to that of 2-benzoyl-aminoethyl-4,5-dimethyl-indole-3-acetic acid ethyl ester, mp. 183-184 °, the 6,8-dimethyl-l-phenyl-3,4-dihydro- pyrimido [l, 6-a] indole-5-acetic acid ethyl ester of the mp 142-143 °.

EXAMPLE 5 The 2- (3-sulfamoyl-4-chlorobenzoyl-amino) -ethyl-indole-3-acetic acid ethyl ester of the mp 212-213 ° C. isobtained in an analogous manner with the 1- (3-sulphamoyl-4-) chloro-phenyl) -3,4-dihydro-pyrimido [l, 6-a] indole-5-acetic acid ethyl ester of mp. 227-228 °.

Example 6; In an analogous manner, from 2- (2,6-Dichlorbenzoylaminoethyl) -indol-3-acetic acid ethyl ester of mp. 125-126 ° den

227

92-93 ° (hydrochloride mp. 138-142 °) 1- (2,6-dichlorophenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid, mp.

Example 7; In an analogous manner, 2- (2-picolinoyl-aminoethyl) -indole-3-acetic acid ethyl ester, mp. 117-118 ° gives the 1- (2-picolinyl) -3,4-dihydro-pyrimido [1,6-a ] indole-5-ethyl acetate, mp. 113-114 °, (hydrochloride 194-204 °).

Example 1 >: The hydrochloride of 1- (2-thienyl) -3,4-dihydro-pyrimido is obtained in an analogous manner from 2- (2-thienylamino-ethyl) -indole-3-acetic acid ethyl ester of mp 140-141 ° [1,6-a] indole-5-acetic acid ethyl ester of mp. 153-157 °.

Example 9: 7-Methoxy-1- (p-chlorophenyl) -3,4-dihydro- [1,6-a] -indol-1-acetic acid

In a solution of 550 g of potassium hydroxide in 200 ml of water and

117.2 g (0.27 mol) of 7-methoxy-1- (p-chlorophenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid ethyl ester hydrochloride are added with stirring to 1500 ml of methanol. Man stirred for 10 hours at room temperature, the methanol is distilled off in vacuo, the residue is dissolved in 1500 ml of ice water and the solution is added under ice-cooling with 700 ml of conc. Hydrochloric acid. It is suctioned off from the precipitated hydrochloride and recrystallized from 2300 ml of 50% ethanol. In this case, 7-methoxy-1- (p-chlorophenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid hydrochloride in the form of yellowish crystals of mp. 225-228 ° (with decomposition) to.

Example 10; In an analogous manner, the hydrochloride of 1-phenyl-3,4-dihydro-pyrimido [l, 6-a] indole-5-acetic acid of mp 235-240 ° (dec.) Is obtained from the corresponding ethyl ester.

227945 7

Example 11; The hydrochloride of 7-fluoro-1- (p-methylthio-phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid of the mp 220- is obtained in an analogous manner from the corresponding ethyl ester. 222 ° (decomp.).

Example 12; In an analogous manner, the hydrochloride of 7-fluoro-1- (p-methylsulfinylphenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid of the corresponding ethyl ester is obtained. 210 ° (decomp.) ·

Example 13: In an analogous manner, the hydrochloride of the corresponding ethyl ester gives the hydrochloride of the α-dimethyl-1-phenyl-1,3-dihydropyrimido [1,6-α] indole-5-acetic acid, mp 212-220 ° (dec.). , The corresponding hemihydrate melts at over 210 °.

Example 14; The hydrochloride of 1- (3-sulfamoyl-4-chloro-T-phenyl) -3,4-dihydro-pyrimido [l, 6-a] indole-5-acetic acid of the corresponding ethyl ester is obtained in an analogous manner 216-220 ° (decomp.).

Example 15; The hydrochloride of 1- (2,6-dichlorophenyl) -3,4-dihydropyrimido [1,6-a] indole-5-acetic acid, mp. 270-277 °, is obtained in an analogous manner from the corresponding ethyl ester (decomp. ).

Example 16; In an analogous manner, the hydrochloride of 1- (2-thienyl) -3,4-dihydro-pyrimido- [1,6-a] indole-5-acetic acid of melting point 230-235 ° (dec. ). From the aqueous solution of the hydrochlorides crystallized at pH 6-7, the l- (2-thienyl) -3,4-dihydro-pyrimido [l, 6-a] indole-5-acetic acid as the inner salt, mp 187-189 ° ,

so

Example 17 : 1-Pheny 1-3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid amide

1 g (0.003 mol) of 1-phenyl-3,4-dihydro-yrunido [l, 6-a] indole-5-acetonitrile is heated at 100 ° in 10 g of polyphosphoric acid for 30 minutes. The reaction mixture is dissolved in 100 ml of water, the solution under ice cooling by addition of conc. Ammonia made alkaline and the reaction product: extracted with methylene chloride. The methylene chloride phase is washed neutral with water, dried over Na 2 SO 4, and the solution is evaporated to dryness. The remaining as residue solid 1 ~ phenyl-3,4-dihydro-pyrimido [i, 6-a] indole-5-acetic acid amide is recrystallized from methanol: colorless crystals, mp. 239-240 °. The corresponding hydrochloride melts at 253-260 ° Fcerg).

The starting material 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 about 60 minutes at 100 °. Pour to 1 kg of ice, put through. Addition of conc. Ammonia alkaline and extracted with ether. After washing, drying and evaporation of the ether phase, 2- (dibenzylamino-ethyl) -indole-3-acetamide is obtained as a syrup, which can be crystallized from a small amount of ether. Mp 135-136 °. '

b) 120 g (0.3 mol) of 2- (dibenzylamino-ethyl) -indole-3-acetamide are added with the addition of. 12 g. Hydrogenated 5% Pd / C in 1.2 1 methanol at atmospheric pressure and 30-35 °. After uptake of 14.4 1 of hydrogen, the hydrogenation is stopped, filtered off from the catalyst and the solution concentrated in vacuo to dryness. The residue is recrystallized from 100 ml of ethanol with addition of 250 ml of ether. The resulting 2-aminoethyl-indole-3-acetamide melts at 156-157 °.

22 7 945 7

• 'c) 21.7 g (0.1 mol) of 2-aminoethyl-indole-3-acetamide are added in a mixture of 200 ml of ether and 100 ml of water with good stirring and cooling to about 5 ° with 17.5 ml (0.15 mol) of benzoyl chloride and gradually added dropwise 100 ml of 2N NaOH. The reaction is complete after about 1 hour. The mixture is stirred for a further 1 hour at 0-5 ° and filtered from the deposited 2- (benzoylamino-ethyl) -indol-3-acetamide of mp. 223-225 °.

d) 1.6 g (0.005 mol) of 2- (benzoylamino-ethyl-indole-3-acetamide are refluxed in 16 ml of phosphorus oxychloride for 2 hours The excess of phosphorus oxychloride is distilled off, the oily residue is taken up in water and by-products are removed Reaction by extraction with ether The aqueous phase is combined with concentrated ammonia while cooling and extracted with ether After washing, drying and evaporation of the ether phase, 1-phenyl-3,4-dihydro-pyrimido [1,6-a] is obtained. 5-acetonitrile as a yellowish OeI by

Dissolve in methanol and treatment with ethereal hydrochloric acid in a crystalline hydrochloride, mp 195-205 ° can be converted.

Example 18: In an analogous manner as described in Example 17, obtained from 1- (3-sulfamoyl-4-chloro-phenyl) -3,4-dihydro-pyrimido- [l, 6-a] indole-5-acetonitrile from 280 to 280 ° C, the hydrochloride of the 1- (3-sulfamoyl-4-chlorophenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetamide, mp. 249-257 ° ( dec.).

Example 19: 12 g (0.03 mol) of 1- (p-methylthio-phenyl) -3,4-dihydropynmido [1,6-a] indole-5-acetic acid ethyl ester are dissolved in 120 ml of glacial acetic acid and mixed with 4 ml of 30% Hydrogen peroxide added. One leaves approx.

Stand at room temperature for 20 hours, pour into 1 liter of ice-water, adjust with conc. Ammonia alkaline and extracted with ethyl acetate. The ethyl acetate phase is washed, dried and evaporated. The obtained! - (p-Methylsulfoxy-phenyD-S ^ -dihydro-pyrimidoCl.ö-aJindol-5-acetic acid ethyl ester crystallized from ether in yellowish crystals, mp. 150-151 °.

227945 7

sz

Example 20: In an analogous manner as described in Example 1, starting from 2 - [(p-methylthio-phenyl-amino) -ethyl] -5-fluoroindole-5-acetic acid ethyl ester, the hydrochloride of 7-fluoro-l- (pmethylthio -phenyl) -3,4-dihydro-pyrimido [l, 6-a] indole-3-acetic acid ethyl ester of the mp 210 ° (dec.) and starting from 2 - [(p-chloromethylthio-phenyl-amino) - ethyl] -5-fluoro-indole-3-acetic acid ethyl ester, the hydrochloride of 7-fluoro-1- (p-chloromethylthio-phenyl) -3,4-dihydropyrimido [l, 6-a] indole-5-acetic acid ethyl ester, mp. 198-202 °.

Example 21 : The hydrochloride is obtained in a manner analogous to that described in Example 19 starting from 7-fluoro-1- (p-methylthio-phenyl) -3,4-dihydropyrimido [1,6-a] indole-5-acetic acid ethyl ester hydrochloride of 7-fluoro-1- (p-methylsulfoxyphenyl) -3,4-dihydro-pyrimido- [1,6-a] indole-5-acetic acid ethyl ester of mp 261-264 °.

Example 22: In a manner analogous to Example 9, the 7-fluoro-1- (7-fluoro-3r (p-methylthio-phenyl) -pyrimido [l, 6-a] indole-5-acetic acid ethyl ester is obtained by saponification. p-methylthio-phenyl) -pyrimido- [l, 6-a] indole-5-acetic acid of mp. 213-220 ° (dec.).

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-pyrimido [l, 6-a] indole-5-acetic acid ethyl ester are dissolved in 20 ml of diphenyl ether with 0.5 g of palladium / carbon (10 %) with stirring to reflux. To

2 hours more 0.5 g of palladium / carbon are added and again

Heated for 3 hours. After filtering off the catalyst, the reaction mixture is concentrated in vacuo, the residue taken up in a little ethyl acetate and chromatographed on silica gel. With hexane (ethyl acetate (9: 1)) obtained fractions, which after evaporation and recrystallization from ether 7-fluoro-l- (p-methylthio-phenyl) -pyrimido [l, 6-a] indole-5-acetic acid ethyl ester of mp. 120-122 ° deliver.

22 7 94 5 7

/ V ^C00C 2 ^H 5

I Il Il

^V Y ^X , ·

/ VV

In an analogous manner are obtained:

l-Phenyl-pyrimido [l, 6-a] indole-5-acetic acid ethyl ester, mp. 59 ° -62 °) 7-methoxy-l- (p-chlorophenyl) pyrimido [1,6-a] indol-5 ethyl acetate, mp 130-131 °.

Example 24: 1.0 g (0.003 mol) of 1-phenyl-3,4-dihydro-pyrimido [1,6-a] -indole-5-acetonitrile is dissolved in 50 ml of abs. Ethanol and 50 ml of hydrogen chloride saturated ethanol for 48 hours at 0 °. Then, the solvent is removed under reduced pressure abdestil lier t. The remaining, crude hydrochloride of the 1-phenyl-3,4-dihydro-pyrimido [1,6-a] indole-5-acetiminoethyl ether is suspended in 10 ml of water and heated to 40 ° with stirring for 15 minutes. After cooling, the l-phenyl-3,4-dihydro-pyrimido [l, 6-a] indole-5-acetic acid ethyl ester hydrochloride crystallizes, which, after recrystallization from IN hydrochloric acid crystals of mp. 187-189 °.

Example 25: 3.84 g (0.01 mol) of ethyl 7-fluoro-1- (p-methylsulfoxy-phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid are dissolved in 500 ml ml of ethyl acetate with 40 g of deactivated Raney nickel with stirring . Heated under reflux for 2 hours. Then, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue, after crystallization from ether, gives ethyl 7-fluoro (p-methylthio-phenyl) -3j, 4-dihydro-pyrimido [1,6-a] indole-5-acetic acid of melting point 119-120 °.

Example 26 Tablets containing 25 mg of active ingredient, for example 7-fluoro- (1- (pmethylthiophenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid or a salt, for example the hydrochloride , of which, can be produced as follows:

Ingredients (for 1000 tablets):

Active 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

demineralised water q.s.

Preparation: All solid ingredients are first driven through a sieve of 0.6 mm mesh size. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water. The resulting starch paste is added to the bulk and the mixture is granulated, if necessary with the addition of water. The granules are dried overnight at 35 °, driven through a sieve with 1.2 mm Masebenweite and yerpresst to both sides concave tablets of about 6 mm in diameter.

227945 7

In an analogous manner, tablets containing in each case 25 mg of one of the compounds of the formula I mentioned in Examples 1 to 19 can also be prepared, the compounds also being in the form of acid addition salts, such as hydrochlorides, and compounds in which R _{9 is} 1-carboxymethyl, also in the form of salts and bases, such as sodium, potassium or zinc salts may be present.

Example 27: Chewable tablets containing 30 mg of active ingredient, eg 7-fluoro-1- (p-methylthio-phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid or a salt, eg Hydrochloride thereof may, for example, as follows. getting produced:

Composition (for 1000 tablets):

active substance 30.0 g All solid ingredients 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 5% gelatin solution q.s. production:

driven with 0.25 mm mesh size. The mannitol and lactose are mixed, granulated with the addition of gelatin solution, passed through a 2-mesh sieve, dried at 50 ° and again passed through a sieve of 1.7 mm mesh size. The active ingredient, the glycine and the saccharin are mixed thoroughly, the mannitol, the lactose granules, the stearic acid and the talcum added, the whole thoroughly mixed and pressed to both sides concave tablets of about 100 mm diameter with breaking groove on the top.

227945 7

In an analogous manner, chewable tablets containing in each case 30 mg of one of the compounds of the formula I mentioned in Examples 1 to 19 can also be prepared, the compounds also being in the form of acid addition salts, such as hydrochlorides, and compounds in which R 1 is carboxymethyl, may also be in the form of salts with bases such as sodium, potassium or zinc salts. _e

Example 2 8: Tablets containing 100 mg of active ingredient, eg 7-eluor-1- (p-methylthio-phenyl) -3,4-dihydro-pyrimido [1,6-a] indole-5-acetic acid

j -. '

acid or a salt, e.g. the hydrochloride thereof can be prepared as follows:

Composition (for 1000 tablets):

Active ingredient 100.0 g

Lactose 248.5 g

Cornstarch 17 »5 g

Polyethylene glycol 6000 5.0 g

Talc 15.0 g

Magnesium stearate 4.0 g

demineralised water q.s.

Preparation : The solid ingredients are first driven through a sieve with 0.6 mm mesh. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are intimately mixed.

22 7 94 5 7.

The other half of the starch is suspended in 65 ml of water and this suspension added to a boiling solution of the polyethylene glycol in 260 ml ^; Added water. The resulting paste is added to the powdery substances, the whole is mixed and granulated, if necessary with the addition of water. The granules are dried overnight at 35 °, driven through, a sieve with 1.2 um mesh size and pressed on both sides concave tablets of about 10 mm diameter with score on the top.

In an analogous manner, tablets containing 100 mg

a compound of the formula I according to Examples 1 to 25, where compounds are also available in the form of acid addition salts, such as hydrochlorides, and compounds in which R 1 is carboxymethyl, also in the form of salts with bases, such as sodium and potassium salts. or zinc salts may be present.

Claims (7)

58 830 11 Erfindun ^ sanepruch 1. Process for the preparation of If, U ^f - »bridged Carbonsäureamidine the general formula py, A 2. Il \ _alk (D, / v / orin R-, is an aromatic radical, R _{2 is} optionally esterified or amidated 1-carboxy-lower alkyl, Ph is optionally substituted 1,2-phenylene and alk is an aliphatic hydrocarbon radical which separates the imino group from the methine group by 1 to 3 C atoms and their salts, characterized in that compounds of the general formulas. _ Ph- S ^a - Ph JJ (II) or \! -H * \ \ ^ V H ^Ί v / orin Z ^ as modified hydroxy or mercapto, or salts thereof with introduction of an additional bond H »Z. splits off or Compounds of the formula Ph = C (Rj-EU ι 3 2 f ^X alk : u - 7 94 5 7 ¹⁰ - ⁷ · ¹⁹⁸¹ AP C 07 C / 227 945 58 830 11 wherein R * is optionally esterified or amidated carboxy, or salts thereof isomerized or a compound of the general formula Eh (VIII) , R _n - C = UH ^b wherein Zr is optionally functionally modified hydroxy or mercapto or amino, or a salt thereof cyclized or
in a compound of the formula wherein Ro is a group of the formula -CH (R ₀ ) -R "and c. ic wherein R is hydrogen or lower alkyl and R "is different from R 'functionally modified carboxy, a group of the formula -C (= O) -I ^ E ^, wherein B ^ is the anion of a mineral acid, or' optionally up to the stage of formyl oxidized methyl, or salts thereof R_ solvolytisph or oxidatively in, the group R »converted, or for the preparation of compounds of formula I, wherein R _{2 is} amidated 1-carboxymethyl and Ph, R and alk have the above meanings, by addition of water and cleavage of a proton to compounds of the formula 279457 ¹ ° · ⁷ ' ¹⁹⁸¹ AP C 07 C / 227 $ 0 58 830 11 Ph. _0-CH -C = NR ^ I! ^{2 5} I / ^alk (XIa), LJ ₁ J. where R is optionally substituted lower alkyl or phenyl and Xg is a radical of the formula = N-OH or, S = N-H = IiI, the compound of the formula I is or for the preparation of compounds of the formula I in which R "is esterified or amidated 1-carboxy-lower alkyl, alk is vinylene and R ₁ and Ph have the above meanings, compounds of the formula JrXi "'# Il alk * alk in which alk is ethylene, dehydrated with elimination of hydrogen with simultaneous formation of an additional bond and, if desired, a compound obtainable according to the invention into another compound of the formula I or a free compound of the formula I obtainable according to the invention in a salt or a process according to the invention available salt in the free compound of formula I or »transferred to another salt. A process according to item 1 for the preparation of compounds of the formula I in which R.sup.4 is optionally mono- or lower alkylthio, lower alkanesulfinyl or lower alkanesulfonyl optionally substituted by lower alkyl, lower alkoxy, optionally lower halogen, optionally mono- or by lower alkyl 2 2 7 10. 7, 1981 64 AP C 07 C / 227 945 - 6θ - 58 830 11 disubstituted sulfamoyl and / or halogen-substituted phenyl or optionally mederalkyl, mederalkoxy and / or halogen-containing 5- or 6-membered heteroatom nitrogen, oxygen or sulfur or nitrogen and additionally having sulfur or oxygen, monocyclic heteroaryl, R _? 1- Carboxyniederalkyl the formula -CH (Ro) -HX is in the R 'carboxy, optionally by Mederalkyl, Mederalkoxy or halogen-containing phenyl or pyridyl, hydroxy or Mederalkoxy substituted Mederalkoxycarbonyl or optionally by hydroxy or amino simple, by Mederalkyl or * Hydroxyniederalkyl mono- or disubstituted, by 4- to 7-membered Mederalkylen or 3-oxa -, - 3-thia- or 3 ~ azaalkylene di-substituted carbamoyl, R_ is hydrogen or alkylalkyl, Ph optionally by alkyl, Mederalkoxy, halogen and / or trifluoromethyl-substituted 1,2-phenylene and alk is the methine of the imino group by 1 to 3 C-atoms separating lower alkylene or, by 2 C-atoms separating Hiederalkenylen, and. their salts, characterized in that starting from compounds of the formulas II or III, V, VIII, X, XIa or I, wherein the variables have the meanings given in point 1. A process according to item 1 for the preparation of compounds of the formula I in which R. is optionally substituted by alkyl, mideoxy, alkylthio, halo-lower alkylthio, mediankanesulfinyl, halo-lower alkanesulfinyl, mediankanesulfonyl, halo-lower alkanesulfonyl, sulfamoyl, U-mono- or N, N-di-lower alkylsulfamoyl and / or Halogen-substituted phenyl or pyrrolyl optionally substituted by alkyl, medercoxy and / or halogen, furyl, thienyl, thiazolyl, pyridyl or pyrimidyl, R 'is a group of the formula -CH (Ro) -R ^, ¹ ° · 7 ·· 1981 AP C 07 C / 227 945 - 58 830 11 in the R 'carboxy, optionally substituted by lower alkyl, lower alkoxy or halogen-substituted phenyl or, Pyridylniederalkoxyearbonyl, hydroxy or »Niederalkoxyniederalkoxycarbonyl, Niederalkoxycarbonyl, carbamoyl, N ~ hydroxy or N-Aminocarb moyl, N ~ mono- or * NN-Di - 'lower alkylcarbamoyl or -hydroxyniederalkylcarbamoyl or substituted by 4 ~ or 7-güedriges lower alkylene. Carbamoyl or 3-oxa, 3-thia- or 3-Azaalkylenaminocarbonyl, R ~ is hydrogen or lower alkyl, Ph is optionally substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl-substituted 1,2-phenylene and alk the methine of the imino group by 1 to 3 C-atoms separating lower alkylene or is separating lower-alkenylene by 2 C atoms, and their salts, characterized in that the starting compounds of the formulas II or III, V, VIII ₉ X, XIa, or I in which the variables have the meanings given in point 1, 4 # Method according to item 1 for the preparation of compounds of formula I, wherein R ₁ optionally by alkyl with bis and with 4 C atoms, lower alkoxy with bis and with 4 C atoms, Halogenniederalkylthio with bis and with 4 C-atoms, lower alkylthio with up to and with 4 C atoms, halogeno-lower alkanesulfinyl with up to and including 4 C atoms, lower alkanesulfinyl with up to and with 4 C atoms, halo-lower alkanesulfonyl, lower alkanesulfonyl with up to and with 4 C atoms, sulfamoyl, N-mono- or N, respectively , N-di-lower alkanesulfamoyl having in each case up to and including 4 C atoms in the alkyl and / or by halogen having an atomic number up to and including 35 or optionally lower alkyl having up to and including 4 C atoms, lower alkoxy having up to and including 4 C atoms Atoms, and / or halogen of atomic number to and substituted by 35 pyridyl or thienyl, Rp is a group of the formula. -CH (R ") ~ R £, in the R ^ July 10, 1981 AP C 07 C / 227 945 58 830 11 Carboxy, optionally substituted by lower alkyl with bis and with 4 C atoms, Uiederalkoxy with bis and with 4 C-atoms, and / or halogen substituted phenyl or Pyridylniederalkoxycarbonyl, ÜTiederalkoxycarbonyl, mono- or dihydroxy-lower alkoxycarbonyl, Niederalkoxyniederalkoxycarbonyl, H-hydroxy - or N-aminocarbamoyl, N-mono- or Ν, ΐϊ-di-lower alkoxycarbamoyl or carbamoyl, R-hydrogen or lower alkyl having up to and with 4 C atoms, Ph is optionally substituted by lower alkyl with up to and 4 C atoms , Mederalkoxy with up to and with 4 C-atoms and / or halogen to and atomic number 35 substituted 1,2-phenylene and alk is 1,2-ethylene, and their salts, characterized in that one of compounds of the formulas II or Ill, V, VIII, X or XIa, where the variables have the meanings given in point 1. 5. A process according to item 1 for the preparation of compounds of the formula I in which R ₁ is phenyl, pyridyl or thienyl which is unsubstituted or substituted by halogen, alkylthiothio, mederalkansulfine 1, lower alkanesulphonyl, halo-lower alkylthio and / or sulphamoyl, R ₁ is a group of the formula -CHP- R * is where R 'is carboxy, lower alkoxycarbonyl or carbamoyl, Ph is 1,2-phenylene optionally substituted by medialkoxy lower alkyl and / or halogen and alk is 1,2-ethylene or vinylene, and their salts, characterized by that starting from compounds of the formulas II or III, V, VIII, X, XIa or I, v / orin the variables have the meanings given in point 1, 6, method of item 1 for the preparation of compounds of formula I, wherein R. optionally substituted by halogen atomic number to and with 35, Hiederalkylthio with bis and 7 94 5 7 ^io ' ⁷ · ¹⁹⁸¹ AP C 07 C / 227 945 58 830 11 with 4 C atoms, Mederalkansulfinyl with bis and with 4 C-atoms, halo-lower alkylthio with up to and 4 C-atoms and / or sulfamoyl-substituted phenyl, pyridyl or thienyl, R _{2 is} a group of the formula -CHp-Rp ^ ⁸ ^ "3- ⁿ and ^he Kp carboxy, lower alkoxycarbonyl with bis and with 5 C atoms or carbamoyl, Ph optionally by Mederalkoxy with up to and with 4 C-atoms, lower alkyl with up to and with 4 C-atoms or halogen with atomic numbers to and with 35 substituted 1,2 ~ phenylene and alk is 1,2-ethylene or vinylene, and their salts, characterized in that starting from compounds of the formulas II or III, V, VIII, X, XIa or I, wherein the variables have the meanings given in point 1, 7 «method according to item 1 for the preparation of compounds of formula I, wherein R ^ is optionally substituted by Halogenniederalkylthio with bis and with 4 C-atoms, such as chloromethylthio, Hiederalkylthio with bis and with 4 C-atoms, lower alkanesulfinyl with bis and with 4 C Atoms, or halogen having an atomic number up to and including 35, in the p ~ position or by sulfamoyl in the 3 ~ position and additionally by halogen having the atomic number up to and containing 35 in the 4-position, pyridyl or thienyl, Rp is a group of the formula CHp-R ', in which R' is carboxy, ITiederalkoxycarbonyl with bis and with 5 C-atoms or carbamoyl, Ph optionally with respect to the attached nitrogen atom in the 4-position by Hiederalkoxy with bis and with 4 C-atoms in 3- and 5-position by Uiederalkyl with up to and with 4 C-atoms or in 4 ~ position by halogen with atomic number to and substituted with 35-substituted 1,2-phenylene and alk is 1,2-ethylene or vinylene, and their salts, characterized that one of Compounds of the formulas II or III, V, VIII, X, XIa or I, where the variables have the meanings given in point 1. 10th · 7th 1981 AP C 07 C / 227 945 58 830 11 8, process according to item 1 for the preparation of compounds of formula I, wherein R ^ optionally substituted in p-position by lower alkylthio with up to and 4 C atoms by Niederalkansulfinyl with up to and with 4 C-atoms or halogen to and with atomic number 35 substituted Phenyl means R _? Uiederalkoxycarbonylmethyl with bis and with 6 C-atoms, Ph optionally in p-position to the nitrogen atom by lower alkoxy with up to and with 4 C-atoms or halogen to and atomic number 35 substituted 1,2-phenylene and alk 1,2-ethylene and their salts, characterized by starting from compounds of the formulas II or III, IV, VIII, X or XIa, in which the variables have the meanings given in point 1. 9 # Method according to item 1 for the preparation of compounds of formula I, wherein R. optionally substituted in the p-position by Mederalkylthio with bis and with 4 C-atoms by Uiederalkansulfinyl with up to and with 4 C-atoms or halogen to and having atomic number 35 substituted Phenyl, R ^ is carboxymethyl, Ph is optionally in p-position to the nitrogen atom represented by Mederalkoxy with up to and with 4 C-atoms or halogen to and with atomic number 35 substituted 1,2-phenylene and alk is 1,2-ethylene, and their salts, characterized by starting from compounds of the formulas II or III, V, VIII, X or XIa, in which the variables have the meanings given in point 1 * 10, the method of item 1 for the preparation of 7-methoxy-1- (p-chlorophenyl) -3,4 ~ dihydropyrimido ^ * 1,6-a_7indol-5-acetic acid or a salt thereof, characterized in that one of compounds of the Formulas II or III, V, VIII, X or XIa. 10. 7. 1981 AP C 07 C / 227 945 - 65 - 58 830 11 11. Method according to item 1 for the preparation of 7-fluoro-1- (p-methylthio-phenyl) -3-> 4-dihydroxy-pyrimido / fj, α-α / indole-5-acetic acid or a salt thereof, characterized in that the compounds of the formulas II or III , V, VIII, X or XIa. 12. The method according to item 1 for the preparation of 7-fluoro-1- (p-methylthiophenyl) -3,4-dihydro-pyrimido / 1,6 ~ a / indol ~ 5-acetic acid ethyl ester or a salt thereof, characterized in that starting from compounds of the formulas II or III, V, VIII, X or XIa. Process according to any one of items 1 to 12, characterized in that it starts from an intermediate obtainable at any stage of the process and carries out the missing steps or uses a starting material in the form of a salt or, in particular, forms it under the reaction conditions.