IE50985B1

IE50985B1 - Novel amidines,processes for their manufacture,pharmaceutical preparations containing them,and their use

Info

Publication number: IE50985B1
Application number: IE455/81A
Authority: IE
Original assignee: Ciba Geigy Ag
Priority date: 1980-03-04
Filing date: 1981-03-03
Publication date: 1986-09-03
Also published as: HK80086A; KR850000062B1; KR850000061B1; HU186385B; DD156599A5; DK157757B; KR850000044B1; AU6801681A; AU544236B2; ES8301989A1; NO810719L; EP0035474A1; ES8305763A1; ATE13673T1; JPH0338273B2; DK157757C; ZA811398B; FI74007B; FI74007C; CY1340A

Abstract

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

Description

The present invention relates to novel amidines, 5 processes for their manufacture, pharmaceutical preparations containing them, and their use.

The invention provides novel amidines, especially N,Ν'-bridged carboxylic acid amidines of the general formula in which represents aa aromatic radical, represents optionally esterified or amidated 1-carboxy-lower alkyl, Th represents optionally substituted 1,2-phenylene, alk and represents an aliphatic hydrocarbon radical separating the imino group from the aethine group by from ί to 3 carbon atoms. their salts, processes for their manufacture, pharmaceutical preparations- containing them and their use as an active substance in medicaments, An aromatic radical can be carbocyclic or heterocyclic and can be substituted and is, for example, phenyl optionally substituted by lower alkyl, by lower alkoxy, by optionally halogen-containing lower alkylthio, lower alkanesulphinyl or lower alkanesulphonyl, by optionally substituted sulphaaoyl, and/or by halogen, or heteroaryl optionally substituted, for example, by lower alkyl, lower alkoxy and/or halogen. Substituted sulphaaoyl is, for exanple, Ν-mono» or N,N-di-lower alkylsulphaaoyl.

Heteroaryl is, for exanple, monocyclic, preferably - or 6-membered heteroaryl and contains as hetero atom nitrogen, oxygen or sulphur,-or nitrogen and, in addition, sulphur or oxygen. . 5-membered radicals of this type are, for exanple, pyrrolyl, such as 2-pyrrolyl, furyl, such as 2-furyl, thienyl, such as 2- or 3-thienyl, or thiazolyl, such as 2-thiazolyl. d-membered heteroaryl contains at least one nitrogen atom and is, for exanple, pyridyl, such as 2-, 3- or 4-pyridyl, or pyrimidyl, such as 2-pyrimidyl.

Esterified 1-carboxy-lower alkyl contains as esterified carboxy group, for exanple lower alkoxycarbonyl, which may also be substituted once by optionally substituted aryl, such as phenyl or pyridyl, or one or more times by hydroxy, halogen or lower alkoxy, such as lower alkoxyearboayl optionally substituted by hydroxy, lower alkoxy and/or halogen, for exanple mono- or di-hydroxylower alkoxy, halogen- or lower alkoxy-lower alkoxycarbonyl, or phenyl-lower alkoxycarbonyl substituted by lower alkyl, lower alkoxy and/or halogen.

Amidated ί-carboxy-lower alkyl contains as amidated carboxy group, for exanple carbamoyl, which may optionally be substituted once by hydroxy or amino, once or twice by lower alkyl or hydroxy-lower alkyl,’or twice by 4- to 7-membered lower alkylene or 3-oxa-, 3-thia- or 3aza-aDsylene. The following may be mentioned as examples: Β-hydroxy-, Β-amino-, Jf-mono- or H,N-di-lower alkyl-, or B-aeno- or N,S-di-hydroxyalkylcarbamoyl. Carbamoyl H-substituted twice by 4— to 7-membered lower alkylene is, for example, pyrrolidine- or piperidino—carbonyl, or morpholino-, thiomorpholino-, piperazino- or N—lower alkylpiperazino-, such as Β-methylpiperazino-, carbonyl. 1,2-pbenylene is optionally additionally sub10 stituted one or more times, for example by lower alkyl, lower alkoxy, halogen or trifluoromethyl.

The radical alk is, for example, a lower alkylene radical separating the methine group from the imino group by from 1 to 3 carbon atoms, such as ethylene, 1.2- or especially 1,3-propylene, or.is.a vinylene radical separating the methine group from the imino group by 2 carbon atoms.

In the present description, by organic radicals and compounds referred to as lower* .there are to be understood those having up to and including 7, especially up to and including 4, carbon atoms.

The general defipttiapa used hereinbefore and hereinafter have, within the scope of the present description, especially the following meanings: lower alkyl is, for example, methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.butyl, and also a pentyl, hexyl or heptyl radical.

Lower alkoxy is, for example, methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy.

Lower alkylthio is, for example, methylthio, ethylthio, n-propylthio, isopropylthio, a-butylthio, isobutylthio, sec.-butylthio, tert.-butylthio, n-pentylthio, n-hexylthio or n-heptylthio, and lower alkanesulphinyl or -sulphonyl is, for example, methane-,ethane- or n-propanesulphinyl or -sulphonyl. 5098B Ϊ-Iower alkylsulphamoyl, is, for exanple, N-methylsulphaaoyl, H-ethylaulphaaoyl or N-propylaulphamoyl, and H.S-di-lower alkylsulphaaeyl is, for exanple, H,Sdiaethylsulphanoyl, Η,Η-dietbylsulphaaoyl, H,H-aethylethylsulphaaoyl or S,H-dipropylsulphamoyl.

Halogen is, for exanple, halogen having up to and including an atonic number of 35, such as fluorine, chlorine or bromine.

Halo-lower alkylthio is, for example, chlorometbylthio, chloroethylthio or chloropropylthio or one of the corresponding fluoro- or brono-lower alkylthio groups.

Halo-lower alkanesulphinyl or -sulphonyl is, for exanple. chloronethane-,. chloroethane- or ehlorgpropanesulphinyl or -sulphonyl and the corresponding fluoroor bromo-lower alkanesulphinyl or -lower alkanesulphonyl groups.

Lower alkoxycarbonyl is, for exanple, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, butoxycarhonyl, or a penfcyloxycarbonyl, hexyloxycarbonyl or heptyloxyearbonyl radical.

Phenyl- and pyridyl-lower alkoxycarbonyl are, for exanple, phenylmethoxycarbonyl, phenyletboxycarbonyl and 2-, 3- or 4-pyridylaethoxycarbonyl respectively.

Hydroxy-lower alkoxycarbonyl is, for exanple, 1- or 2-hydroxyethylcarbonyl, 1- or 3-hydroxypropylearbonyl or 1- or 4-hydroxybutylcarbonyl and dihydroxy-lower alkoxycarbonyl is, for exanple, 2,3-dihydroxypropoxycarbonyl, 2,3-, 2,4- or 3,4-dihydroxybutoxycarbonyl.

Lower alkoxy-lower alkoxycarbonyl is, for exanple, 2- nethoxyethcxycarbonyl, 1- or 2-ethoxyethoxycarbonyl, 2- or 3-nwthoxypropoxycarbonyl or 2-, 3- or 4-methoxybutoxyearbonyl.

Hydroxyalkyl is, for exanple, hydroxymethyl or hydroxyethyl, but also hydroxypropyl or hydroxybutyl.

S-lower alkylcarbaaoyl is, for exanple, H-aethylcarbaaoyl, B-ethylcarbaaoyl, B-propylearbamoyl, Nisopropylcarbeaoyl or B-butylcarbaaoyl and B,B-di-lower aUcylcarbamoyl is. for example. H,B-dimethylcarbamoyl, N,S-diethylcarbamoyl or H,N-methylethylcarbamoyl.

B-Hydroxy-lower aUcylcarbamoyl is, for exanple, B-bydroxymetbylcarbamoyl or N-2-hydroxyethylcarbamoyl and, S.H-dihydroxy-lower aUcylcarbamoyl is, for example, Η, 3-2,3-dihydroxypropylearbamoyl.

Salts of conpounds of tbe formula I according to tbe invention are preferably pharmaceutically acceptable salts, such as corresponding acid addition salts and/or, when r2 is 1-carboxy-lower alkyl, internal salts or salts with bases. Suitable acid addition salts are, for exanple, salts with -ίππτ-gan-i-g acids, such as mineral acids, or organic acids, such as sulphamie acids, for exanple cyclohexylsulphamic acid, optionally unsaturated dicarboxylic. acids,, or. earboxylie.acids optionally additionally substituted by hydroxy or additionally containing oxo and/or carboxy, or sulphonic acids. Mineral acids are, for example, sulphuric acid or hydrohalic acids, sueh as hydrobromie or hydrochloric acid. There come into consideration as optionally unsaturated dicarboxylic acids, for example oxalic aeid, malonic aeid, fumaric acid or maleic acid, and there are used as carboxylic acids optionally additionally substituted by hydroxy or additionally containing oxo and/or carboxy, for exanple tartarie acid, malic acid, pyruvic acid or citric acid. Sulphonic acids are, for exanple, benzenesulphonic, p-toluenesulphonic or methanesulphonic acid.

Suitable salts with bases are, for exanple, metal, such as alkali metal or alkaline earth metal, salts, for exanple sodium, potassium or magnesium salts, transition metal salts, such as zinc or copper salts, or sales with ammonia or salts of substituted organic amines such as morpholine, thiomorpholine, piperidine and pyrrolidine, such as mono-, di- or tri-lower alkylamines or mono-, di- or tri-hydroxy-Icwer alkylamines, for exanple mono-, di- or tri-ethanolamine. Mono-lower alkylamines are, for exanple, ethylamine or tert.-butylamine. Di-lower alkylamines ar·, for example. diethylamine or dipropylamine, and there come into consideration as tri-lower alkylamines, for exanple, triethylamine, tributylamine or diaethylpropylamixie.

She ceapanada of the formula I have valuable pharmacological properties. In particular they exhibit a pronounced antinociceptive {analgesic) activity, which may be demonstrated, for example, by the aeetic acidwrithing syndrome in rats in a dosage range of from approximately 4 to approximately 30 mg/kg p.o. and by the phenyl-p-benaoqainone-writhing test in mice in a mt dosage range of from approximately 1 te approximately 30 mg/kg p.o..

Zn addition, they have a marked anti-inflanmatory and anti-arthritic activity, which may be demonstrated by suppression of kaolin paw oedema in the normal rat in a dosage range of from approximately *<0 to 100 mg/kg p.o., and which, ia addition, may be demonstrated by the suppression of carrageenin paw oedema in the rat, analogously to the method described by Fasquale et al., Agents and Actions, 5, 256 (1976), in doses of approximately 3 te approximately 300 mg/kg p.o..

Furthermore, in curative administration with administration, four times, of approximately 10 to 100 mg/kg p.o., the compounds of the formula Z suppress kaolin paw oedema of the adjuvant-arthritis rat.

The cospounda of the formula Z are therefore excellently suitable as medicaments for the treatment of inflammatory disorders, especially those in the rheumatic and arthritic field, as antiphlogistlcs and/or as peripheral analgesics.

The invention relates, for exanple, to compounds of the formula Z in which represents phenyl optionally substituted by lower alkyl, by lower alkoxy, by optionally halogen-containing lower alkylthio, lower alkanesulphinyl or lower alkanesulphonyl, by sulphamoyl optionally mono5098B or di-subatituted by lower alkyl, and/or by halogen, or represents 5- or 6-membered monocyclic heteroaryl optionally containing lower alkyl, lower alkoxy and/or halogen and having as hetero atom nitrogen, oxygen or sulphur, or nitrogen and, in addition, sulphur or oxygen, Rj represents 1 -carboxy-lower alkyl of the formula -CHiR^)—R^, in which Rj represents carboxy, lower alkoxycarbonyl optionally substituted by lower alkyl-, lower alkoxy- or halogen-containing phenyl or pyridyl, by hydroxy or by lower alkoxy, or represents carbamoyl optionally substituted once by hydroxy or amino, once or twice by lower alkyl or hydroxy-lower alkyl, or twice by 4- to 7-membered lower alkylene or 3-oxa-, 3-thia- or 3-aza-alkylene, Rj is hydrogen or lower alkyl, Th is 1,2-phenylene optionally substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, and alk is lower alkylene separating the methine group from the imino group by from 1 to 3 carbon atoms or lower alkenylene separating the methine group from the imino group by 2 carbon atoms, and their salts, especially pharmaceutically acceptable salts.

Among the above there are included, for example, compounds of the formula X ia which Rg represents phenyl optionally substituted by lower alkyl, lower alkoxy, lower alkylthio, halo-lower alkylthio, lower alkanesulphinyl, halo-lower alkanesulphinyl, lower alkanesulphonyl, halo-lower alkanesulphoayl, sulphamoyl, N-mono- or N,N-di-lower alkylsulphawoyl and/or halogen, or represents pyrrolyl, furyl, thienyl, thiazolyl, pyridyl or pyrimidyl each optionally substituted by lower alkyl, lower alkoxy and/or halogen, Rj represents a group of the formula -CHiR^J-Rj in which Rj is carboxy, phenyl- or pyridyl-lower alkoxycarbonyl optionally substituted by lower alkyl, lower alkoxy or halogen, hydroxy- or lower alkoxy-lower alkoxycarbonyl, lower alkoxycarbonyl, carbamoyl, N-hydroxycarbamoyl, 2Γ-aminocarbamoyl, H-mono50985 or 5,5-di-lower alkylcarbamoyl or -hydroxy-lower alkylcarbamoyl, or carbamoyl stibatituted by 4- to 7-membered lower alkylene, or 3-oxa-, 3-thia- or 3-aza-alkyleneaoinoearbonyl, represents hydrogen or lower alkyl. Ph represents 1,2-phenylene optionally substituted by lower alkyl, lower alkoxy, halogen and/or trifluoronethyl and alk represents lower alkylene separating the nethine group iron the imino group by from i to 3 carbon atoms or lower alkenylene separating the sethine group from the imino group by 2 carbon atoms, and their salts, especially pharmaceutically acceptable salts.

She invention relates especially to compounds of the formula X in which represents phenyl optionally substituted by lower alkyl having up to and including 4 carbon atoms, such as methyl, by lower alkoxy having up to and jn^n^ng 4 carbon atoms, such as methoxy, by halo-lower alkylthio having tp to and including 4 carbon atoms, such as ehloromethylthio, by lower alkylthio having up to and including 4 carbon atoms, such as methylthio, by halo-lower alkanesulphinyl having tp to and including 4 carbon atoms, such as chlorcmethanesulphinyl, by lower »i Teyieeniphi nyt having up to and including 4 carbon atoms, such as methanesulphinyl, by halo-lower alkaneaulphonyl, such as chloromethanesulphonyl, by lower alkanesulphonyl having up to and including 4 carbon atoms, such as methanesulphonyl, by sulphamoyl, by S-βοηο- or H.H-di-lower alkanesulphamoyl each having up to and including 4 carbon atoms in the alkyl radical, such as B-metbanesulphamoyl or N,Hdiethylsulphamoyl, and/or by halogen having an atomic number of up to and including 35, such as chlorine, or represents pyridyl, such as 2-, 3- or 4-pyridyl, or thienyl, such as 2-thienyl, each optionally substituted by lower alkyl having up to and including 4 carbon atoms, such as methyl, by lower alkoxy having up to and including 4 carbon atoms, such as methoxy, and/or by halogen having an atomic number of up to and including 35, such as chlorine, Rg represents a group of tbe formula -CH(R3)-Rj in which Rj represents carboxy, phenyl- or pyridyl-lower alkoxyearbonyl, such as 2-, 3- or 4-pyridyl-lower alkoxycarbonyl, optionally substituted hy lower alkyl having up to and including 4 carbon atoms, such as methyl, by lower alkoxy having up to and including 4 carbon atoms, such as methoxy, and/or hy halogen, such as chlorine, lower alkoxyearbonyl, such aa methoxycarbonyl, mono- or di-hydroxylower alkoxycarbonyl, such as 2-hydroxyethoxy- or 2,3dihydroxypropoxycarbonyl, lower alkoxy-lower alkoxyearbonyl such as 2-methoxyethoxyearbonyl, N-hydroxy- or IT-aminocarbamoyl, H-aono- or N,N-di-lower alkoxycarbamoyl,, such as N-methyl- or Ν,Ν-diethylcarhamoyl, or carbamoyl,· Rg la hydrogen or' lower alkyl having up to and including 4 carbon atoms, such as methyl, Ph is 1,2-phenylene optionally · substituted by lower alkyl having up to and including 4 carbon atoms, such as methyl, by lower alkoxy having up to and including 4 carbon atoms, such as methoxy, and/or by halogen having up to and including an atomic number of 35, such as fluorine and alk is 1,2-ethylene, and their salts, especially pharmaceutically acceptable salts.

The invention relates first and foremost to compounds of the formula X in which R, represents phenyl, optionally substituted hy halogen, lower alkylthio, lower alkanesulphinyl, lower alkanesulphonyl, halo-lower alkylthio and/or sulphamoyl, or pyridyl or thienyl, Rg represents a group of the formula -CHg-Rj in which Rj represents carboxy, lower alkoxyearbonyl or carbamoyl, Ph represents 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 relates preferably to compounds of the formula X in which represents phenyl, optionally substituted by halogen having an atomic number of up to and including 35, such as chlorine, by lower alkylthio having up to and including 4 carbon atoms, such as methylthio, hy lower alkanesulphinyl having up to and including 4 carbon atoms, such as methanesulphinyl, by halo-lower alkylthio having up to and including 4 carbon atoms, such as ebloromethylthio and/or by sulphamoyl, pyridyl, especially 2-pyridyl, or thienyl, especially 2-thienyl, R^ represents a group of the formula -CHj-Rj in which R£ represents carboxy, lower alkoxycarbonyl having up to and including 5 carbon atoms, such as ethoxycarbonyl, or carbamoyl, Ph represents 1,2-phenylene optionally substituted by lower alkoxy having up to and including 4 carbon atoms,, such as methoxy,, by lower alkyl having up to and including-4 carbon atoms, such as methyl, and/ox ky halogen having an atomic number of up to and including 35, such as fluorine, and alk is 1,2ethylene or vinylene, and their salts, especially pharmaceutically acceptable salts.

The invention relates in an especially preferred manner to compounds of the formula I in which R^ represents phenyl optionally substituted in the p-position by halo-lower alkylthio having up to and including 4 carbon atoms, such as ebloromethylthio, by lower alkylthio having up to and including 4 carbon atoms, such as methylthio, by lower alkanesulphinyl having up to and including 4 carbon atoms, such as methanesulpbinyl, or by halogen having an atomic number of up to and including 35, such as chlorine, or in the 3-position by sulphamoyl and, in addition, in the 4-position by halogen having an atomic number of up to and including 35, such as chlorine, or pyridyl, especially 2-pyridyl, or thienyl, especially 2-thienyl, Rj represents a group of the formula -CH-j-Rj in which Rj represents carboxy, lower alkoxycarbonyl having up to and including 5 carbon atoms, such as ethoxycarbonyl, or carbamoyl. Ph represents 1,2-phenylene optionally substituted in the 4-position in relation to the bonded nitrogen atom by lower alkoxy having up to and including 4 carbon atoms, such as methoxy, in the 3and 5-position by lower alkyl having up to and including 4 carbon atoms, such as methyl, or in the 4-positioa by halogen having an atomic number of up to and including 35, such as fluorine, and alk is 1,2-ethylene or vinylene, and their salts, especially pharmaceutically acceptable salts.

The invention relates especially preferably to 10 compounds of the formula I in which R^ represents phenyl optionally substituted in the p-position by lower alkylthio having up to and including 4 carbon atoms, such as methylthio, by lower alkanesulphinyl having up to and including 4 carbon atoms,. such as methane15 The invention relates more especially to compounds of the formula I in which R^ represents phenyl optionally substituted in the p-position by lower alkylthio having up to and ineluding 4 carbon atoms, such as me thyl thio, by lower alkanesulphinyl having up to and including 4 carbon atcns, such as aethanesulphinyl, or by halogen having up to and including an atonic number of 35, such as chlorine, Rj represents carboxyaethyl, Ph represents 1,2-phenylene optionally substituted in the p-position to the nitrogen atcn by lower alkoxy having up to and including 4 carbon atoms, such as aethoxy, or by halogen having up to and including an atomic number of 35, such as fluorine, and represents 1,2-ethylene, and their salts, especially 10 their pharmaceutically acceptable salts.

The invention relates namely to the compounds of the formula X and their salts, especially their pharmaceutically acceptable salts, mentioned in the Examples.

The compounds of the formula I and their salts can 15 be produced, for example,by splitting off H-Z1 from compounds of the general formula Ph-Z 2 e\A '\l alk (IX) or Ί a Ph ί R2 I alk (III), in which Z^ represents optionally functionally modified hydroxy or mercapto, or from salts thereof, with the introduction of aa additional bond, and, if desired, converting a compound obtainable according to the invention into a different conpound of the formula I or converting a free compound obtainable according to the invention into a salt, or converting a salt obtainable according to the process into the free compound or into a different salt.

Fractionally modified hydroxy or mercapto is, for example, hydroxy or mercapto etherified by a lower alkanol, such as methanol or ethanol, or by an optionally substituted aromatic alcohol, such as phenol, or hydroxy esterified by an inorganic acid, such as a mineral aeid, for exanple a hydrohalic acid, such as hydrochloric acid, and represents, for example, lower alkoxy, sueh as methoxy, or optionally substituted aryloxy, such as phenoxy, lower alkylthio, such as methylthio, or halogen, sueh as chlorine or bromine. 3-2^ is split off in customary manner, for example spontaneously, by thermal means, i.e. hy heating, and/or in the presence of a catalytic agent. The thermal splitting reaction is usually carried out in ft temperature range of from approximately .50^ to approximately 200°C.

The catalytic agents used are, for exanple, basic or acidic catalysts, there being used as bases, for exanple alkali metal hydroxides, amides or hydrides, such as potassium hydroxide, sodium amide or sodium hydride, metal oxides, such as aluminium oxide, or especially organic nitrogen bases, such as tertiary amines, for exanple py*»' <33 np, quinoline or N.Jf-dimethylaniline, and as acidic catalysts, for exanple mineral acids or acidic salts or anhydrides thereof, such as sulphuric acid or phosphoric acids, hydrogen sulphates, such as alkali metal hydrogen sulphates, for exanple potassium hydrogen sulphate, phosphorus pentoxide, or mineral aeid halides, such as sulphuric acid halides, for exanple sulphuryl chloride. The process is, if necessary, carried out in the presence of an inert solvent or diluent, in a closed vessel and/or under an inert gas, for exanple nitrogen.

Inert solvents and diluents are optionally substituted hydrocarbons, such as optionally halogenated aliphatie or aromatic hydrocarbons, for exanple chlorofozm or chlorobenzene, ethers, such as aliphatic, cycloaliphatic or aromatic ethers, for exanple diethyl ether, dioxan, tetrahydrofuran, diphenyl ether or anisole, ketones, such aa aliphatic ketones, for example acetone or methylethylketone, amides, such as dialkylamidee, for example dimethylformamide, or sulphoxides, such as di-lower alkylsulphoxidea, for example dimethylsulphoxide.

Starting materials of the formulae IX and XXX can he produced according to processes known per se. for exanple by cyclising compounds of the formula or salts thereof, in which X, represents hydrogen and Y^ represents a group of the formula -alk-NH-C(»2J) (R,) or X^ represents -C(-ZJ)(R^) and represents a group of the formula -alk-NHg and ZJ represents optionally functionally modified oxo, and, if desired, converting a so-obtainable free canpound of the formula XX into a different free compound, or into a salt, or converting a salt obtainable according te the process into the free compound or into a different salt.

Functionally modified oxo is, for exanple, thioxo, ketalised or thio-ketalised oxo, esterified di oxy, or imino. Ketalised oxo compounds are, for exanple, ketals with lower alkanols, such as methanol or ethanol, or lower alkanediols, such as ethylene glycol or propylene25 glycols, for exanple 1,3-dihydroxypropane, and thioketals are, for exanple, thioketals with lower alkanethiols, for exaaple methanethiol or ethanethiol, or lower albanedithiols, such as 1,2-ethanedithiol, or propanedithiols, for exanple propane-1,3-dithiol.

Imino is, for exanple, imino optionally substituted hy lower alkyl or phenyl, such as S-lower alkylimino, for exanple B-propylimino.

The cyclisation is carried out is known manner, for exanple in the presence of catalysts, such as acidic catalysts. These are, for exanple, mineral acids, such as sulphuric acid or polyphosphoric acid, mineral acid halides, such as sulphuryl chloride, or phosphorus halides, for exanple phosphorus pentachloride, or organic sulphonic acids, such as henzenesulphonic, p-toluenesulphonic or methanesulphonic acid. The cyclisation is, if necessary, carried out in one of the above-mentioned inert solvents or diluents, preferably while heating, for exanple in a tenperature range of from approximately 20° to approximately 200°C, in a closed vessel and/or under inert gas, for exanple nitrogen.

In an advantageous embodiment of the afore-described process, compounds of the formula XVa are used as starting materials and cyclisation to compounds of the formula XX and splitting off Ξ-Z^ from the compounds of the formula XX are carried out in situ without isolation of the intermediates.

An especially advantageous embodiment of the afore-described process carried out by way of the compounds of the formula XX consists, for example, is quaternising, especially with benzyl bromide, conpounds of the formula _/’'Ή-8ζ Ph ii ι ι (XVd) , in which Bz represents an optionally substituted Phx\ 'CT V\ (XV«) . a»· as desired solvolysing the cyano group, splitting off the benzyl groups by hydrogenolysis in the presence of a hydrogenation catalyst, for example palladium, and reacting the then free amino conpound with a conpound of the formula R^-C' in which Z.J represents ^Bal optionally functionally modified oxo and Bal represents halogen, and finally reacting by means of a cyclising agent, preferably a mineral aeid halide, such as phosphorus oxychloride or phosphorus chloride, to form a conpound of the formula XX.

The compounds of the formula X or salts thereof may furthermore be produced by isoaerising conpounds of the formula ^-rC(R3)-4 I (V) , R The isomerisation of compounds of the formula V to compounds of the formula X is carried out in customary manner, if. necessary by means of acids, such as mineral acids, for example sulphuric acid, bases, such as alkali metal hydroxides or carbonates, for example sodium hydroxide or potassium carbonate, or such as by means of organic amines, for exanple tertiary amines, such as pyridine, or by applying energy, such as at temperatures of from 1OO°C, optionally in the presence of a catalytic agent, such as a borate or phosphate, for exanple an alkali metal borate or phosphate and, if necessary, in a solvent or diluent, in a closed vessel and/or under inert gas, for exasple nitrogen.

Inert solvents and diluents are optionally substituted hydrocarbons, such as optional ly halogenated aliphatic or aromatic hydrocarbons, for exasple chloroform or chlorobenrene, ethers, such as aliphatic, cycloaliphatic or aromatic ethers f for exasple diethyl ether, dioxan, diphenyl ether or anisole, ketones, such as aliphatic ketones, for example acetone or methylethylketoae, amides, such as dialkylaoides, for example dimethylformamide, or sulphoxides, such as di5 lower alkylsulphoxides, for exanple dimethylsulphoxide. Starting materials of the formula V or salts thereof can be produced according to methods known per se. for example by reacting compounds of the formula B ‘alk in which X^ represents oxo or thioxo, with compounds of the formula PiZ^-CtR^-Rj or X.,»P(Z3)2-CB(R3)-Rj respectively, which may be in the form of phosphonium ylides or in the form of phospboranes, and in which X^ represents oxo or thioxo, Z2 represents alkyl and/or phenyl, represents alkyl and/or phenyl, or alkoxy and/or phenoxy, and R2 represents hydrogen or lower alkyl. Starting materials of the formula V or salts thereof may likewise be produced, for example by reacting compounds of the formula alk (VIb) in which Xj represents a group of the formula -C(R3)»Xj and Xj represents optionally functionally modified oxo, with hydrogen cyanide or a salt, for example an alkali metal salt, thereof. After solvolysis, which then optionally follows, a compound of the formula VZ5 is split off from so-obtainable intermediates of the formula Ph\ Z4 25 I I 2 \ R3 (VII) , alk in which Z4 represents hydroxy or thio optionally present in salt form and Z$ represents a radical of.the © © Θ formula -P(Z2)3 or -RiZ^-Q , or Z4 represents hydrogen and Zs represents hydroxy or mercapto.

Alkoxy is, for example, lower alkoxy, such as methoxy, ethoxy, propoxy or butoxy. Optionally functionally modified-oxo is oxo, thioxo or imino optionally sub15 stituted by lower alkyl or phenyl.

Zn an advantageous embodiment of the abovedescribed process for the manufacture of compounds of the formula I, for example using compounds of the formula VIX as starting materials, the manufacture of compounds of the formula V and the isomerisation according to the invention can be carried out in situ.

Th· splitting off of Z^-Zj is carried out is customary manner, for exanple by the application of energy, for exanple a reaction tenperature of from approximately 50° to approximately 200°C, or in the presence of a catalytic agent. Such agents are, for example, basic or aeidie catalysts, there being used ae bases, for exanple alkali metal hydroxides, amides, carbonates or hydrides, such as potassium hydroxide, sodium amide, potassium carbonate or sodium hydride, metal oxides, such as aluminium lo oxide, or organic nitrogen bases, such as tertiary amines, for exanple pyridine, quinoline or B.S-dimethylaniline. and as acidic catalysts, for exanple mineral acids, such as sulphuric aeid, hydrogen, sulphates, such.as alkali metal hydrogen sulphates, for exanple potassium hydrogen sulphate, polypbosphoric acid, mineral acid anhydrides, sueh as phosphorus pentoxide, or mineral acid halides, such as sulphuric acid halides, for exanple sulphuryl chloride.

The method for the formation of starting materials of the formula V is, if necessary, carried out in the presence of an inert solvent or diluent, in a closed vessel and/or under inert gas, for exanple nitrogen.

Ccnpounds of the formulae Via or Vlb may, for their part, he produced according to analogous processes that are known per se. for example by condensing compounds of the formula Ph" .zXi -H 'V^alk I ixz . Av (Vid) or Κιχ Λ yx2 'alk (Vie) ia the presence of a condensing agent. Suitable condensing agents are, for exaaple, adds, such aa mineral acids, for example sulphuric add, polyphosphoric add or a hydrohalic add, for exanple hydrochloric add, or phosphoric add halides, such as phosphorus oxychloride or phosphorus trichloride.

Phosphoranes of the formula FfZglg-CfRgJ-Rj and their phosphonium ylides can he produced according to methods known per se, for exanple by reacting phosphines of the formula P(Zg)3 with quaternary ammonium bases of Θ Q the formula Rj-CH(Rg)-N(alk* in which alk’ represents an alkyl radical, such as a lcwer alkyl.- radical, and Βθ represents as anion, such.as a halide or hydroxyl anion, and by subsequent reaction with strong bases, such 15 as alkali metal organyls, for exanple butyllithium or phenyllithiusu The corresponding quaternary asoonium bases are obtained likewise by reaction of phosphines PCZglg with known compounds of the formula in the presence of bases, such as alkali natal hydroxides, lower alkanolates, 20 hydrides or amides, for example sodium hydroxide, sodium methanolate, potassium hydride or potassium amide. be produced, for exa^le, Ts? reacting compounds of the formula P(Z3)3 in which Zg represents alkoxy or phenoxy, with compounds of the formula Hal-CH(Rg)-Rj in which Sal represents halogen.

Conpounds of the formula Vid are obtainable by acylation of compounds of ths formula Ph--' (VIg) H EHg with compounds of th· formula R^-Οζ^ in which X4 represents halogen or acyl.

The compounds of the formula X or salts thereof can furthermore he produced, for exasple hy cyclising 5 a compound of the general formula Λ—ΓΓ r2 Ν7'*1* (VIII) , [ —β R^-OHB 6 in which Zg represents optionally functionally modified hydroxy or mercapto, or amino, or a salt thereof, and, if desired, converting a so-obtainable free compound of the formula X into a different free compound or intoa salt or converting a salt obtainable according to the process into the free compound or into a different salt.

Functionally modified hydroxy or mercapto is, for example, hydroxy or mercapto etherified by lower alkanol, such as methanol or ethanol, or by an optionally substituted aromatic alcohol, such as phenol, or hydroxy or mercapto esterified by a suitable anhydride, such as acetic anhydride, by an organic acid, such as sulphonic acid, for exasple lower alkylsulphonic or optionally substituted arylsulphoaie acid, such as methanesulphonic or p-toluenesulphonie acid, or by an inorganic acid, such as a mineral acid, for exasple hydrobalic acid, such as hydrochloric acid, and represents, for exasple, lower alkoxy, such as methoxy, or optionally substituted aryloxy, such as phenoxy, lower alkylthio, such as methy 1thio, or lower alkanoyloxy, such as aeetoxy, lower alkane5098S aulphonyloxy or optionally substituted arylsulphonyloxy, such as methanesulphonyloxy or p-toluenesulphonyloxy, or halogen, such as chlorine or bromine.

The cyclisation is carried out in a manner known per se. for exaaple in the presence of a condensing agent, such as an acidic condensing agent. Included among these are, for exaaple, acids, such as mineral acids, for exaaple sulphuric acid or polyphosphoric acid, and mineral acid halides, such as phosphoric acid halides, for exaaple phosphorus oxychloride, phosphorus tribromide or phosphorus pentaehloride. The reaction is, if necessary, carried out in a solvent or diluent, in a temperature range of from approximately 20° to approximately 200°C, in a closed vessel and/or under an inert gas, for axanple nitrogen.

Inert solvents and diluents. are optionally substituted hydrocarbons, such as aliphatic or aromatic halogenated hydrocarbons, for exaaple chloroform or chlorobenzene, optionally mixed ethers, such as aliphatic, cycloaliphatic or aromatic ethers, for example diethyl ether, dioxan, diphenyl ether or anisole, ketones, such as aliphatic ketones, such as acetone or aethylethylistone, amides, such as dialkylamides, for axanple dimethylformamide, or sulphoxides, such as lower alkylsulphcxides, for exasple dimethylsulphoxide.

The starting materials of the formula Till can be produced according to methods known per se. for exasple by substituting the primary amino group in compounds of the formula I H (IX) by means of alkali metal nitrites in the presence of acids, by hydroxy, optionally reaetively esterifying this group, acylating the indole nitrogen with a compound of the formula R^-COCB or with a functionally modified derivative thereof, and then forming the corresponding amidine with ammonia.

The acylation of the indole nitrogen is carried out according to a method known per se. for example by reaction with optionally functionally modified carboxy derivatives, such as acids, aeid anhydrides or activated esters. Anhydridised carboxy in this process is anhydridised, for example, by inorganic acids, such as a hydrohalie acid, by hydraxoie acid, by hydrocyanic acid or by organic acids, such as lower alkanoie acids optionally substituted by halogen, for exanple acetic acid· Included among these are, for example, aeid halides, for example acid chlorides, corresponding acid azides, acid nitriles or acyloxycarbonyl.

The acylation with a compound of the formula R^-COCB or an optionally functionally modified derivative thereof is carried out in customary manner, when using an anhydride, especially an acid halide, as starting material, the acylation is preferably carried out in the presence of a strong base, for example ac alkali metal hydride, for example sodium hydride, an alkali metal amide, for example sodium amide, or an alkali metal alcoholate, for example potassium methanolate.

The acylation, like the subsequent reaction with ammonia, is carried out, for example, in ac inert solvent, such as an alkylated amide, for example S,B-dimethylformamide, ac optionally halogenated hydrocarbon, for example chloroform or chlorobenzene, or a nitrile, for example acetonitrile, or in a mixture thereof, if necessary at reduced or elevated temperature and/or in an inert gas atmosphere.

The compounds of the formula XX may, for their part, be produced according to processes known per se. for exanple analogously to Fischer's indole synthesis by treating phenyl hydrazones or correspondingly 1,3substituted 4-piperidonea with acids, such as with ethanolic hydrochloric acid, or by acylation and eonden5 sation of correspondingly substituted a-bydroxyketones with optionally substituted anilines.

The compounds of the formula XX may furthermore, in a preferred ptnbodlment, be produced, for exanple, by quaternising starting conpounds of the formula /O\-Bz V/ Fh· (XVd) in which Sz represents an optionally substituted a-phenyl-lower alkyl radical, preferably benzyl, especially with benzyl bromide, and splitting the bond at the resulting quaternary nitrogen by means of a nucleophile, preferably by cyanides, and in a eonpound of the formula Ph—f (lve) H J B(Bz)2 obtainable as intermediate, as desired solvolysing the cyano group and splitting off the benzyl groups, for exanple by hydrogenolysis in the presence of a hydro20 genation catalyst, for exanple palladium.

The conpounds of the general formula X or salts thereof can furthermore he produced, for exanple, from a compound of the formula Mx.x * alk (X) . in which R^ represents a group of the formula -CHCR^J-RJ and in which Rj represents hydrogen or lower alkyl and RJ represents functionally modified carboxy different from RJ, or a group of tbe formula -C(«O)-sP, in which is the anion of a mineral aeid, for example chloride, bromide or tetrafluoroborate, or represents methyl optionally oxidised to the stage of io formyl, or salts thereof, by converting R^ by solvolysis or oxidation into the group R^ and, if desired, converting a so-obtainable free conpound of the formula Z into a different free conpound or into a salt, or converting a salt obtainable in accordance with the prooess into the free conpound or into a different salt. Functionally modified carboxy conpounds and functionally modified carboxy conpounds different from RJ are, for exanple optionally functionally modified ortho-ester groups, such as trihalo-, halo-di-lower alkoxy- or tri-lower alkoxymethyl groups, anhydridised carboxy, such as cyano, a group of the formula «C-Ο, cyano-, azido- or halooarbonyl, acyloxycarbonyl, such as acetoxycarbonyl, or derivatives of carboxy of tba formula RJ or RJ, in which oxo is optionally replaced by thio or optionally substituted imino, such as optionally esterified thioearboxy, such as lower alkylthioearboxy, for example ethylthioearboxy, amidated thiocarboxyl, Imino-eaters, such as imide- or amide-halide groupings, for example iminoehloromethyl or aminodichloromethyl, imino ether groupings, such as lower alkylimino ether or lower alkyleneimino ether groupings, for exanpie methoxyiminomethylene or ethoxyiminoaethylene, or ami dino groups, such as ami dino or lower alkylamidino, for exanpie methylami dino.

Methyl oxidised to the formyl stage, or functionally modified groups thereof are, for exanpie, optionally «actively esterified or etherified hydroxymethyl or optionally functionally modified formyl, such as hydroxymethyl, mono- or di-halomethyl, lower alkoxymethyl, formyl or fonaimino.

Functionally modified carboxy eonpounds, such as optionally functionally modified ortho-esters, anhydridised carboxy or acyloxycarbonyl can be solvolysed directly, or in several solvolysis steps, to free, esterified or amidated carboxy.

The solvolysis of Rj carried out in known manner, for example by hydrolysis with water, by ammonolysis with ammonia, by aminolysis with a desired primary or secondary amine or by alcoholysis with a corresponding alcohol. The process is carried out, if necessary, in the presence of a catalyst, in a solvent or diluent, in a closed vessel, in a temperature range of from approximately 0° to approximately 150°C and/or under inert gas, for exanpie nitrogen.

Catalysts are, for exanpie, 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 exanpie triethylamine, or acidic hydrolysing agents, such as mineral acids, for exanpie hydrobalic acids, such as hydrochloric acid, or organic carboxylic or sulphonic acids, such as lower alkanecarboxylic acids or optionally substituted benzenesulphonic acids, for exanpie acetic acid or p-tolueneaulphodc add.

Methyl optionally oxidised to the formyl stage, each as methyl, hydroxymethyl or formyl, or functionally modified derivatives thereof, such aa halomethyl, far example chlorcoethyl, mereaptcmethyl, thioformyl or optionally substituted form-1mino, may be oxidised directly or by way of several oxidation steps, optionally by way of hydroxymethyl or formyl, to carboxy. Etherified hydroxymethyl, preferably lower alkoxymetbyl, for example ethoxymethy1, is oxidised, in the presence of an oxidising agent, to form esterified carboxy, espedally lower alkoxycarbonyl. The reaction of formyl to form carbamoyl is carried out, for exasple by means of an amino compound in the presence of an oxidising agent, such as a transition metal oxide, for exasple manganese dioxide, and, if necessary, in the presence of a nucleophile, espedally a cyanide.

Oxidation of RJ is carried out in customary manner, for exasple using customary oxidising agents. These are, for exasple, optionally catalytically activated 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. The oxidation is carried out, if necessary, in an inert solvent, in a closed vessel and/or while cooling or heating, for exasple at approximately 0° to approximately 15O°C.

The starting materials of the formula X can he produced according to analogous processes, for exanple by reacting compounds of the formula (Via) , R. ia which represents exo or thioxo, with conpounds of the formula P(Zg)g-R|, which may be in the form either of phosphonium ylides or of phosphoranes, or X^=P(Z3)g—Rg, and in which Zg represents alkyl and/or phenyl and Zg represents alkyl and/or phenyl, or represents alkoxy, such as lower alkoxy, and/or phenoxy, and Rj represents functionally modified carboxy different frcm Ri, or a group of the 0)0) formyl stage, splitting off from intermediates of the formula Rj (VIh) Ψ alk /X/ optionally obtainable in this manner, in which XJ represents or -p and Z. represents a radical of the formula Θ Θ -P(Zg)g or -P(XJ)(Zg)g, respectively, a OOTEOund of the formula X1«P(Zg)g or X1«P(XJ)(Zg)g respectively, and isomerising a compound obtained in this manner to a canpound of the formula X.

The reaction is usually carried out in an inert solvent, for exaaple an optionally halogenated hydrocarbon, such as an aromatic compound, for example benzene or toluene, an ether, such as tetrahydrofuran or dioxan, or an amide, for example dimethylformamide, in a tenperature range of from approximately 20° to approximately 15O°C and/or optionally in the presence of a catalyst, such as a base, for example an alkali aetal alcoholate, such as potassiua tert, -butanolate.

In a preferred eabodlaent, the starting materials of the formula X in which is a radical that can be converted by solvolysis or oxidation into R? obtained, and starting, for example, froe coepounds of the formulaPh—S Ji-az (ivd) w H in which Bz represents an optionally substituted a-phenyllower alkyl radical, preferably benzyl, the tertiary nitrogen atoa is quaternised, especially with benzyl chloride, the bond at the quaternary nitrogen atoa is split by means of a strong base, such as by a_ cyanide,, for example sodium cyanide, and in a resulting conpound of the formula Pfc—j cs V\ I /* (IVe) Bz^Bz the cyano group is converted into Rj, for exasple by solvolysis to carboxy or lower alkoxyearbonyl and then reduction to hydroxymethyl or lower alkoxyaethyl respectively, and the Bz groups are split off by hydro20 genolysis in the presence of a hydrogenation catalyst.

The conpound obtained in this manner is then reacted with a compound of the formula -C , in which Zj ^Bai represents optionally functionally modified oxo and Hal represents halogen, and cyclisation to corresponding esnpounds of the formula X is carried out in the presence of a customary cyclising agent, such as a mineral acid halide, for example phosphorus oxychloride.

The compounds of the formula X in which Rg represents amidated 1 carhcxymethyl can further be produced by adding water and splitting off a proton in lo compounds of the formula which are produced in situ by rearrangement of compounds of the formula Ph—«- CHg-O-r \y*\ f alk (XXb), in which Rg represents optionally substituted lower alkyl or phenyl and Xg represents a radical of the The reaction is carried out in customary manner, for exanple in the presence of an acidic catalyst, such as a mineral acid, for exanple sulphuric or phosphoric acid, and optionally while heating.

The starting materials of the formula Xlb can be produced according to analogous precesses, for example by reacting compounds of the formula r ti 2 \/\ γ alk lo in which Xj represents oxo or thioxo, with hydroxylamine or an acid addition salt thereof, or with an azide, such as an alkali metal azide, for exanple sodium azide.

Conpounds of the formula I in which Rj represents esterified or amidated 1-carboxy-lower alkyl and alk represents vinylene are produced, for exanple by dehydrogenating appropriate ccnpounds of the formula (I) . in which alk represents ethylene, with the splitting off of hydrogen with simultaneous formation of an additional bond, and, if desired, converting a compound obtainable according to the invention into a different ccnpound of the formula I or converting a free compound of the formula I obtainable according to the invention into a salt, or converting a salt obtainable according to the process into the free canpound of the formula I or into a different salt.

The dehydrogenation is carried out in a manner known per se. especially at elevated temperature, for example in a temperature range of from approximately 100° to approximately 300°C, and with the use of a dehydrogenating agent. Such agents are, for exasple, dehydrogenation catalysts, for exanple sub-group elements, preferably of the sub-group VIII, such as palladium or platinum, or salts thereof, such as rutheniumtriphenyl-phosphide-chloride, the catalysts optionally being supported on a suitable carrier, such as carbon, aluminjam oxide or silicon dioxide. Other dehydrogenating agents are, for exasple, quinones, such as pbenaoquinone, for example tetrachloro-p-benzoquinone or 2,3-dichloro-5,6-dicyano-p-benzoquinone, or anthraquinones, for exanple phenanthrene-9,10-quinone. The reaction is carried out in an inert, optionally highboiling, solvent, such as an ether, for example diphenyl ether, if necessary under pressure, in a closed vessel and/or under an inert gas, for exanple nitrogen.

The compounds of the formula X to be used as starting materials can be produced according to the afore-described processes.

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

If the group R2 contains free carboxy, this can be converted according to esterification methods known per se into correspondingly esterified carboxy, for exanple by reacting optionally reactive modified carboxy or a salt thereof by alcoholysis with a desired alcohol, for exanple a reactive derivative thereof or an olefin derived therefrem, or by alkylation with diazo-lower alkane.

Suitable reactive functional carboxy derivatives are, for exanple, anhydrides, there being used as anhydrides especially mixed anhydrides, for exanple these with inorganic acids, such as hydrohalic acids, for exanple hydrochloric acid, or hydrazoic or hydrocyanic acids, or with organic carboxylic acids, such as lower alkanoic acids, for exanple acetic acid.

Reactive derivatives of an alcohol are, for exanple, carboxylic, phosphorous, sulphurous or carbonic acid esters, for exanple lower alkanecarboxylic acid esters, tri-lower alkylphosphite, di-lower alkylsulphite or pyroearbonate, or mineral or sulphonic acid esters, for exanple chloride, bromide or sulphuric acid esters, henzenesulphonic,' toluenesulphonic or methanesulphonic acid esters, of the alcohol concerned.

The esterification of free carboxy is carried out in the presence of a condensing agent. There come into consideration as agents that split off water by catalysis in the esterification with alcohols, for exanple acids, for example protonic acids, such as hydrochloric, hydrobromic, sulphuric, phosphoric, boric, henzenesulphonic and/or toluenesulphonic acid or Lewis acids, such as boron trifiuoride etherate. Customary water-binding condensing agents are, for exanple, carbodiimides substituted by hydrocarbon radicals, for exanple B,B*diethylcarbodiimide, N,N-dic yclohexylcarbodiimide or N-ethyl-N ‘ - (3-dimethylaminopropyl' -carbodiimide. Condensing agents for the esterification with reactive esters are, for exanple, basic condensing agents, such as inorganic bases, for exanple alkali metal or alkaline 50885 earth metal hydroxides or carbonates, sueh as sodium, potassium or calcium hydroxide or carbonate, or organic nitrogen bases, for example tertiary organic amines, such as triethylamine or pyridine. The esterification is advantageously carried out with the alcohol in excess. It is preferably carried out in an anhydrous medium, if necessary in the presence of an inert solvent, such as in halogenated hydrocarbons, for exanple chloroform or chlorobenzene, or in ethers, for exanple tetrahydrofuran or dioxan.

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

Furthermore, free carboxy or reactive functional carboxy derivatives can be converted into a desired amidated form by solvolysis with anssonia or a primary or secondary amine, it being possible also for hydroxylamines or hydrazines to ba used, the solvolysis being carried out in customary manner with dehydration, optionally in the presence of a condensing agent. There are used as condensing agents preferably bases, for exanple inorganic bases, such as alkali metal hydroxides, for exasple scdium or potassium hydroxide, organic nitrogen bases, such as tert.-amines, for exanple pyridine, tributylamine or N-dimethylaniline, or tetrahalosilanes, such as tetrachlorosilane.

Further, compounds of the formula I obtainable according to the invention in which R2 contains esterified carboxy as substituent, can be transesterified in customary manner, for exanple by reaction with a corresponding alcohol or a metal salt thereof, such as an alkali metal salt, for exasple 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 alcoholates, for example potassium hydroxide, sodium amide or sodium methanolate, or a strong acid, such aa a mineral acid, for example sulphuric acid, phosphoric acid or hydrochloric acid, or such as an organic sulphonic acid, for example an aromatic sulphonic acid, such as p-toluenesulphonic acid.

Esterified carboxy can furthermore be converted 10 into the free carboxy group according to known processes, for example by hydrolysis in the presence of a catalyst. There came into consideration as catalysts preferably bases, for example alkali metal hydroxides, such as sodium or potassium hydroxide. Esterified carboxy may furthermore be converted into carboxy in customary manner, for example by solvolysis, optionally in the presence of a catalyst, for example an acidic or basic agent, or into amidated carboxy by ammonolysis or aminolysis with ammonia or with a primary or secondary amine. There are used as bases, for example alkali metal hydroxides, such as sodium or potassium hydroxides, and as acids, for example mineral acids, such as sulphuric acid, phosphoric acid or hydrochloric acid. Likewise, compounds of the formula X obtainable according to the invention in which the group Rg contains an amidated carboxy substituent can be transformed according to methods known per se that split the amide bond and thus convert the carbamoyl into free carboxy. This operation is carried out in the presence of a catalyst, for example a base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, for example sodium, potassium or calcium hydroxide or carbonate, or an acid, such as a mineral acid, for example hydrochloric acid, sulphuric acid or phosphoric acid. if the group Rg of the formula I contains an esterified carboxy group, this can be converted into an amidated carboxy group, for example by customary solvolysis, advantageously by an axcess of ammonia, or an amine containing at least one hydrogen atom, optionally in the presence of a catalyst. There are used as catalysts, for example acids, such as mineral acids, for example hydrochloric, sulphuric or phosphoric acid, or bases, such as alkali metal hydroxides, for example sodium or potassium hydroxide.

If the group of the formula 1 contains as substituent amidated carboxy, this can be converted into esterified carboxy, for example by customary solvolysis with an alcohol in the presence of a catalyst. The catalysts used are, for example, acidic catalysts, such as mineral acids, for example phosphoric acid, hydrochloric acid or sulphuric acid.

If the substituent Rj of the formula I is substituted by lower alkylthio, this can be oxidised in customary manner to corresponding lower alkanesulphinyl or lower alkanesulphonyl. There come into consideration as suitable oxidising agents for the oxidation to the sulphoxide stage, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulphuric acid, organic peracids, such as suitable percarboxylic or persulphonic acids, for example peril onaic, peracetic, trifluoroperacetic, perbenzoic or ptoluenepersulphonic acid, or mixtures of hydrogen peroxide and acids, for example a mixture of hydrogen peroxide with acetic aeid.

Frequently, the oxidation is carried out in the presence of suitable catalysts, and there should be mentioned as catalysts suitable acids, such as optionally substituted carboxylic acids, for example acetic or' trifluoroacetic acid, or transition metal oxides, such as oxides of elements of sub-group VII, for example vanadium, molybdenum or tungsten oxide. The oxidation is carried out under mild conditions, for example at temperatures of arTro-*1'’n,t~*1 y -50° to approximately +1OO°C.

The oxidation to the sulphone stage ean also be carried out in corresponding manner, with dinitrogen tetroxide as catalyst in the presence of oxygen at low tenperatures, as can also the direct oxidation of the lower alkylthio to lower alkanesulphonyl, except that usually the oxidising agent is used in excess.

Conpounds of the formula I in which R1 represents an aromatic radical substituted by lower alkylsulphinyl or lower alkylsulpbonyl can be reduced according to methods known per se to the corresponding lower alkylthio conpounds, and, starting from lower alkanesulphonyl derivatives, also to lower alkanesulphinyl. A suitable reducing agent is, for exanple, catalytically activated hydrogen, there being used noble metals or oxides, such as palladium, platinum or rhodium or their oxides, optionally supported on a suitable carrier, such as active carbon or -barium sulphate. There also come into consideration reducing metal cations, such as tin(III lead(II1, copper(I>, manganese(I11, titanium(II1, vanadiumdll, molybdenum(III) or tungsten(III 1 conpounds, hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, hydrides, such as complex metal hydrides, for exanple lithiumaluminium hydride, sodium borohydride and tributyl tin hydride, phosphorus conpounds, such as phosphorus halides, for exanple phosphorus trichloride, phosphorus trihromide, phosphorus pentachloride or phosphorus oxychloride, phosphines, such as triphenylphosphine, or phosphorus pentasulphidepyridine, or sulphur conpounds, such as mercaptans, thio acids, such as thiophosphoric acids or dithiocarboxylie acids, dithionite or sulphur/oxygen complexes, such as an iodine/pyridine/sulphur dioxide complex.

Resulting salts can be converted into free compounds in a manner known per se, for exanple by treating with an acidic reagent, such as a mineral acid, or a base, for example an alkali hydroxide solution.

Depending on the choice of starting materials and methods, the new compounds may be in the form of one of the possible isomers or mixtures thereof, for exanpie, depending on the number of asymmetrical carbon atcns, as pure optical isomers, such as antipodes, or as mixtures of isomers, such as racemates, mixtures of diastereoisomers or mixtures of racemates.

Resulting mixtures of diastereoiscmers and mixtures of racemates can be separated on the basis of the physicochemical differences of the constituents, in known manner, into the pure isomers, diastereoiscmers or racemates, for exanpie by chromatography and/or fractional crystallisation.

Resulting racemates can furthermore be resolved into the optical antipodes by known methods, for exanpie by recrystallisation from an optically active solvent, by means of microorganisms or by reacting an acidic end product with an optically active base that forms salts with the racanic acid, and separating the salts obtained in this manner, for exanpie bn the basis of their different solubilities, into the diastereoiscmers, from which the antipodes can be liberated by the action of suitable agents. Advantageously, the more active of the two antipodes is isolated.

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

Owing to the close relationship between the new compounds in free form and in the form of their salts, there axe herein to be understood by the free compounds cr their salts accordingly and appropriately optionally also the corresponding salts or free eonpounds respectively.

The invention relates also to these embodiments of the process according to which eonpounds obtainable as intermediates at any stage of the process are used as starting materials and the rranai ni ng steps are parri out, or a starting material is used in the form of a salt or especially is formed under the reaction conditions .

In the process of the present invention, there are preferably used as starting materials those that result in compounds described at the beginning as being especially valuable. The invention relates also to novel starting materials and processes for their manufacture.

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 as well as for topical administration to warm-blooded animals, that contain the pharmacological active aubstance alone or together with a pharmaceutically acceptable carrier. The dosage of the active substance depends on the species of warm-blooded animal, the age, and the individual condition, and on the method of administration. Normally, where administration is oral and the warm-blooded animal weighs approximately 75 kg, an app-rmrima-ta daily dosage of 30 to 300 mg, advantageously divided into several egual portions, is estimated.

The new pharmaceutical preparations contain, for exatqple, from approximately 10 X to approximately 80 %, preferably from approximately 20 % to approximately €0 %, of the active substance. Pharmaceutical preparations according to the invention for enteral or parenteral administration are, for exasqple, those in dosage unit forms, such as dragees, tablets, capsules or suppositories, or also ampoules. These are produced in a manner known Tier se. for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes. Thus, pharmaceutical preparations for oral administration can be obtained by combining the active substance with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granulate to form tablets S0985 or dragee cores, if desired or necessary after the addition of suitable adjuncts.

Suitable carriers are especially fillers, such as sugar, for example lactose, saccharose·, mannitol or sorbitol, cellulose preparations and/or calcium phos5 phates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as 3tareh pastes using, for example, com, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow-regulating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesiisn or calcium stearate, and/or polyethyleneglycol. Dragee cores are provided with suitable, optionally gastric juice-resistant, coatings, there being used, inter alia, concentrated sugar solutions, which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethyleneglycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures, or, to produce gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulosephthalate or hydroxypropylmethylcellulosephthalate.

Colouring matter or pigments may be added to the tablets or dragee coatings, for example for identification purposes or for indicating different doses of active substance.

Other pharmaceutical preparations for oral administration are dry-filled capsules made of gelatin, and soft sealed capsules consisting of gelatin and a plasticiser, such as glycerin or sorbitol. The dry-filled capsules may contain the active substance in the form of a granulate, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethyleneglycols, it likewise being possible for stabilisers to be added.

There cent into consideration as rectally administrable pharmaceutical preparations, for example suppositories consisting of a combination of the active substance with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethyleneglycols or higher alkanols. It is also possible to use gelatin rectal capsules that contain a combination of the active substance with a base, there coming into consideration as base substances, for exasple liquid triglycerides, poly15 ethyleneglycols or paraffin hydrocarbons.

Especially suitable forms for parenteral administration are aqueous solutions of an active substance in water-soluble form, for exasple a water-soluble salt, or suspensions of the active substance, such as corres20 ponding oily injection suspensions, suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for exasple ethyloleate or triglycerides, being used, or aqueous injection suspensions that contain viscosity-increasing substances, for exasple sodium carboxymethylcellulose, sorbitol and/or dextran and optionally also stabilisers.

For topical administration, there come into consideration especially creams, ointments, pastes, foams, tinctures and solutions that contain from approximately 0.5 to approximately 20 % of the active substance.

Creams are oil-in-water emulsions that consist of store than 50 % of water. As oily base there are used especially fatty alcohols, for exasple lauryl, cetyl or stearyl alcohol, fatty acids, for exasple palmjtic or stearic acid, liquid-to-solid waxes, for example isopropylmyristate, wool wax or beeswax, and/or hydrocarbons, for exanple11 Vaseline (petrolatum) or paraffin oil. There come into consideration as emulsifiers surface-active substances with predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, for exasple fatty acid esters of polyalcohols or ethylene oxide also polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, for exanple sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are usually used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, inter alia, agents that reduce the drying-out of creams, for exanple polyalcohols, sueh as glycerin, sorbitol, propyleneglycol and/or polyethyleneglycol, and also preservatives, odoriferous substances, etc., (Vaseline and Tween are Trade Marks).

Ointments are water-in-oil emulsions that contain up to 70 %, but preferably from approximately 20 % to approximately 50 %, water or aqueous phases. There come into consideration as fatty phase especially hydrocarbons, for exanple Vaseline, paraffin oil and/or hard paraffins, which, to improve the water-binding capacity, preferably contain suitable hydroxy conpounds, such as-fatty alcohols or esters thereof, for exanple cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate. Additives to the aqueous phase are, inter alia, moisture-retaining agents, such as polyalcohols, for exanple glycerin, propyleneglycol, sorbitol and/or polyethyleneglycol, and preservatives, odoriferous substances etc. (Span is a Trade Mark).

Fatty ointments are anhydrous and contain as base especially hydrocarbons, for example paraffin? Vaseline*1 and/or liquid paraffins, also natural or partially synthetic fat, for exasple, coconut fatty acid triglyceride, or preferably hardened oils, for exasple hydrogenated peanut oil or castor oil, also fatty acid partial esters of glycerin, for example glycerin mono- and di-stearates, as well as, for example, the fatty alcohols that increase the ability to absorb water, the emulsifiers and/or the additives, mentioned in connection with the ointments.

Pastes are creams and ointments with secretionabsorbing pewder constituents, such as metal oxides, for example titanium oxide or zine oxide, and also talc and/or aluminium silicates which serve to bind any moisture or secretions present.

Poams are dispensed from pressure containers and are liquid oil-in-water emulsions in aerosol foxm, halogenated hydrocarbons, such as chlorofluoro-lower alkanes, for example dichlorodifluorcmethane and dichlorotetrafluoroethane, being used as propellants. As oil phase there are used, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropylmyristate, and/or other waxes. As emulsifiers there are used, inter alia, mixtures of emulsifiers with predominantly hydrophilic properties, such as polyoxyethylene-sorbitan-fatty acid esters (Tweens', and emulsifiers with predominantly lipophilic properties, such as sorbitan fatty acid esters μ V (Spans'. In addition there are the customary additives, such as preservatives etc.

Tinctures and solutions usually have an aqueous ethanolic base, to which there are added, inter alia, polyalcohols, for exasple glycerin, glycols and/or polyethyleneglycol, as moisture-retaining agents for reducing evaporation, and fat-restoring substances, such as fatty acid esters with low polyethyleneglycols, that is to say lipophilic substances soluble in aqueous mixture as a replacement for the fatty substances removed from the skin by the ethanol, and, if necessary, other adjuncts and additives.

The manufacture of the topically administrable pharmaceutical preparations is carried out in a manner known per se. for exanple by dissolving or suspending the active substance in the base material or in a portion thereof, if necessary. When processing the active sub10 stance in the form of a solution, this is usually dissolved in one of the two phases before emulsification; when processing in tbe form of a suspension, it is usually mixed with a portion of the base after emulsification and then added to the rest of the formulation.

The present invention relates also to the use of conpounds of the formula I and the salts of such compounds with 3alt-forming properties preferably for the treatment of inf lammati'ons, especially inflammatory disorders of the rheumatic type, especially chronic arthritis.

The following Examples illustrate the above-described invention but are not intended in any way to limit the scope thereof. Temperatures are in degrees Centigrade.

There is no consistent characterisation in the 25 literature of the linking points in the pyrimido-indole ring system, forming the basis of the compounds of the formula I.

Thus, the older literature sources characterise the linking points in the ring system by [3,4-a], whereas recently the characterisation [i,6-a] has been used.

From considerations of principle, the following nomenclature is used hereinafter for the above ring structure: pyrimidcf1,6-alindole.

Example 1s 7-(aethoxy-1-(g-chlorophanyl)-3,4-dihydro7 pyrimido[l,6-a]indole-5-acetic acid ethyl eater hydrochloride 165 g (0.4 mol) of 2-[(o—chlarobenzoyl-amino)—ethyl]5-aethoxy-indole-3-acetic acid ethyl ester are boiled under reflux for 3 hours in 825 ml of phosphorus trichloride and excess phosphorus trichloride is subsequently distilled off at a bath temperature of 60° under a slight vacuum.

The residue is dissolved in 1500 ml of methylene chloride, extracted by stirring with 2000 ml of ice-water and io rendered alkaline by adding 500 ml of concentrated ammonia and, after brief stirring, the methylene chloride phase is separated off. The methylene chloride phase is washed neutral with water, dried over Na^SO^ and the methylene chloride is distilled off. The residue (136.7 g) is dissolved in 120 ml of aeetone and 500 ml of ether, and 100 ml of an approximately 4 normal hydrogen chloride solution in ether are added to the solution. While so doing, the hydrochloride of 7-methoxy-1-(p-chlorophenyl3,4-dihydro-pyrimido[l,6-a]indole-acetie acid ethyl ester crystallises out.

^CS2-COOC2Hg HCl The latter is filtered with suction and washed with acetone/ether 1:10 yielding yellowish crystals having a melting point of 204-208° and, after recrystallisation fro· methanol/acetone, a melting point of 205-208°.

The starting material ean be manufactured as follows: a) 131 g (0.45 mol) of 3-benzyl-6-aethoxy-tetrahydro-i-carboline are dissolved at 40°, while stirring, in 1300 ml of acetonitrile, and, in the eourse of' 10 minutes, 94 g (0.55 mol) of bensyl bromide are added. After a short time, the benzyl aimwnlum derivative begins to crystallise out. Stirring is continued at roam temperature for approximately 15 hours, the mixture is then cooled in an ice bath, and the crystals are filtered with suction: sup. 150-151°. b) 464 g (1 mol) of the resulting 5Γ, N-dibenzyl-6methoxy-tetrahydro-y-carboliminium bromide are dissolved, while heating to 65°, in 4250 ml of methanol, and, in the course of 5 minutes and while stirring, a solution of 196 g (4 mol) of sodium cyanide in 500 ml of water is added. The solution is boiled under reflux for 3 hours.

On cooling, 2-{dibenzylamino-ethyl)-3-cyano-mathyl-5methoxy-indole crystallises, after seeding, to yield colourless crystals having a melting point of 102-104°. c) 220 g (0.537 mol) of the nitrile produced in b) are dissolved in 300 ml of absolute ethanol and the solution is saturated, at -5°, with dry hydrogen chloride. The solution is then stirred for 5¾ days at 20°. The separated crystals are allowed to settle, the supernatant solution is decanted, the sediment is dissolved in 2000 ml of ice-water and the solution is stirred for apprcrri aately 3 hours at 20°. While cooling with ice, it is then rendered alkaline with concentrated ammonia solution and extracted by stirring with 1500 ml of toluene/ies-water.

The separated toluene phase is washed with water, dried over sodium sulphate aad filtered over 1000 g of aluminium oxide (Act. Grade 3) and subsequently washed with toluene. After distilling off the toluene, a light brown oil remains which is subjected to hydrogenation as described in d) without further purification. d) 181.3 g of the 2-dibenzylamino-5-methoxy-indole3-aeetie acid ethyl ester obtained in c) are dissolved in 1500 ml of absolute alcohol and hydrogenated at 20-35° under normal pressure with the addition of 18 g of pall adi tas^c—carbon (5 %). When 12500 ml of Sj have been absorbed a further 18 g of catalyst are added and hydrogenation is continued until the absorption of ceases at a total of 17300 al. After filtering off the catalyst and subsequently washing with methylene chloride, the solution is concentrated to dryness by evaporation and the residue is dissolved in 250 ml of ether. After seeding, 2-aminoethyl-5-methoxy-indole-3-acetic acid ethyl ester crystallises to form colourless crystals having a melting point of 79-80°. e) 61.7 g (0.223 sol) of the 2-aminoethyl-5msthoxy-indole-3-acetie acid ethyl ester produced in d) are dissolved in 600 al of methylene chloride and the solution is covered with a layer of 150 ml of 2H sodium hydroxide solution. A solution of 43 g (0.245 mol} of p-chlorobenzoyl chloride is added, at 0-5°, in the course of 2¾ hours, while stirring vigorously, and extraction by stirring is then carried out for a further hour. The methylene chloride phase is then separated off, washed with water, dried over MgSO^ and concentrated to dryness by evaporation. The residue crystallises on being taken up in ether, to form colourless crystals of 2-[(p-chlorobenzoyl-aaino)-ethyl]-5-mathoxy-indole-3-aeetic acid ethyl ester having a melting point of 136-138°.

Exasple 2: 1 -Phenyl-3,4-dihydro-pyrimido[i. 6-a]indole-5acetic acid ethyl ester. g (0.154 mol) of 2-(benzoylamino-ethyl)-indole3-acetie acid ethyl ester are boiled under reflux for 3 hours in 250 ml of phosphorus oxychloride. Excess phosphorus oxychloride is then distilled off at 60° in vacuo and the residue is stirred with 1000 ml of ice-water. The agueous solution is clarified by filtration over Hyflo, rendered alkaline with concentrated ammonia and extracted with 500 nil of ether. The ether phase is dried over sodium sulphate and concentrated to dryness.

The residue is dissolved in 200 ml of acetone, and 25 ml of an approximately 4 normal hydrogen chloride solution in ether are added. After seeding, the hydrochloride of I* 5 * * * * 10 1-phenyl-3,4-dihydro-pyrimido[l, 6-a]indole-5-acetic acid ethyl ester crystallises to form yellowish crystals having a melting point of 172-175°, which can be recrystallis’ed from 1ST hydrochloric acid (melting point 187-1S90). The base liberated from the salt melts at 83-84° after recrystallisation from ether.

The 2-{benzoylamino-ethyl)-indole-3-acetic acid ethyl ester having a melting point of 162-163° which is used as starting material can be manufactured analogously to Exasple 1 a) - e).

Example 3: 7-fluoro-l-(g-methyl thio-phenyl-3,4-dihydropyriaido[l,6-a]indole-5-acetic acid ethyl ester having a melting point of 119-120° is obtained, in a manner analogous to that described in Example 2, from 2-[(p-methyl30 thio-benzoyl-amino)-ethyl ]-5-f luoro-indole-acetic acid ethyl ester having a melting point of -,57-1580.

Example 4: 6, S-dimethyl-7 -phenyl-3,4-dihydro-pyriaido[l,6-a]iadole-5-aeetie acid ethyl ester having a melting point of 142-743° is obtained, in an analogous manner, from 2-ben2oyl-aiainoethyl-4(5-diffisthyl"iad0le-3-acetie acid ethyl ester having a melting point of 183-184°.

Exanple 5: 1-(3-sulphaaoyl—4-chloro-phsnyl)-3,4-dihydropyrimido[l,6-a]indole-5-acetic acid ethyl ester having a melting point of 227-228° is obtained, ia an analogous manner, from 2-[(3-sulpbamoyl-4-chlorobenzoyl-amino)ethyl]-indole-3=acetic acid ethyl ester having a melting point of 212-213°.

Exanple 8: 7-(2,6-diehlorophenyl)-3,4-dihydro-pyrimido[l,6-a]indole-5-acetie acid ethyl ester having a melting point of 92-93° (hydrochloride m.p. 138-142°) is obtained, ia an analogous manner, from 2-(2,6-dichlorobensoyl-aminoethyl)* iadole-3-acetic acid ethyl ester having a melting point of 125-126°.

Exanple 7; 1-(2-picolinyl)-3,4—dihydro-pyrimido[l,6-a]indole5-acetic acid ethyl ester having a melting point of 113-174° (hydrochloride m.p. 192-204°) is obtained, ia aa analogous manner, from 2«(2-pieolinoyl-amineethyl)indole-3-acetic acid ethyl ester having a melting point of 117-118°.

Example 8: The hydrochloride of 1-(2-thienyl)-3,4-dihydropyrimido[l,6-a]indale-5-aeetic acid ethyl ester having a melting point of 153-157° is obtained, in an analogous manner, from 2-(2-thienylamino-ethyl)-indole-3-aeetie acid ethyl ester having a melting point of 140-141°.

Example 9: 7-aathoxy-1-(p-chlorophenyl)-3,4-dihydropyrimido[l,6-a]indole-5-acetic acid 117.2 g {0.27 mol) of 7-methoxy-l-(p-chlorophenyl)3,4-dihydro-pyriaido(i ,6-a]indole-5-acetic acid ethyl ester hydrochloride are introduced, while stirring, into a solution of 550 g of potassium hydroxide in 200 ml of water and 1500 ml of methanol. The mixture is stirred for 10 hours at roan temperature, the'methanol is distilled off in vacuo, the residue is dissolved-in-t500· ml of icewater, and 700 ml of concentrated hydrochloric acid are added to the solution while cooling with ice. The separated hydrochloride is filtered with suction and recrystallised from 2300 ml of 50 % ethanol to yield 7-methoxy-1 -(p-chlorophenyl) -3,4-dihydro-pyriaido[1,6-a]indole-5-acetic acid hydrochloride in the form of yellowish crystals having a melting point of 225-228° (with decomposition).

Example 10: The hydrochloride of 1-phenyl-3,4-dihydro-pyrimido[1,6-a]iadole-5-aeetic acid having a melting point of 235-240° (with decomposition} is obtained in an analogous manner from the corresponding ethyl ester. 50S85 Example 11: The hydrochloride of 7-fluoro-1-(g-methylthiophenyl )-3, 4-dihydro-pyrimido[l ,6-a]indole-5-aeetic acid having a melting point of 220-222° (with decomposition) is obtained in an analogous manner from the corresponding ethyl ester.

Exanple 12: The hydrochloride of 7-fluoro-1-(p-methylsulphinylphenyl)-3,4-dihydro-pyriaido[l,6-a]indole-5-acetic aeid having a melting point of 208-210° (with deooaposition) is obtained in an analogous manner from the corresponding ethyl estar.

Example 13: The hydrochloride of 6,8-dimethy1-1-phenyl-3,4dihydro-ovrimidoi1,6-a]indole-5-acetic acid having a melting point of 212-220° (with decomposition) is obtained in an analogous manner from the corresponding ethyl ester. The corresponding hemihydrate has a melting point of above 210°. Example 14: The hydrochloride of 1-{3-eulphamayl-4-chlorophenyl)=3,4-dihydro-pyriaido[l,6-a]indole-5-acetic acid having a malting point of 216-220° (with decomposition) is obtained in an analogous manner from the corresponding ethyl ester.

Exasple 15: The hydrochloride of 1-(2,6-dichlorophenyl)-3,4dihydro-pyrimido[l,6-a]indole-5-acetic acid having a melting point of 270-277° (with decomposition) is obtained in an analogous manner from the corresponding ethyl ester. 5098S Exasple 16: The hydrochloride of 1-(2-thienyl)-3,4-dihydropyrimido [1 ,6-a]indole-5-*cetic acid having a melting point of 230-235° (with decomposition) is obtained in an analogous manner from the corresponding ethyl ester. 1-(2-thienyl)-3,4-dihydro-pyrimido[1.6-a]indole-5-acetic acid crystallises at pB 6-7 from the aqueous solution of the hydrochloride, in the form of an internal salt having a melting point of 187-189°.

Exasple 17: 1-phenyl-3,4-dihydro-pyrimido[i,6-a]indole5-acetie acid amide g (0.003 mol) of 1-phenyl-3,4-dihydro-pyrimido[1,6-a]indole-5-acetonitrile is heated at 100° for 30 minutes in 10 g of polyphosphoric acid. The reaction mixture is dissolved in 100 ml of water, the solution is rendered alkaline, while cooling with ice, by adding concentrated asraonia and the reaction product is extracted with methylene chloride. The methylene chloride phase is washed neutral with water, dried over Na2SO4 and the solution is concentrated to dryness. The solid 1-phenyl3, 4-dihydro-pyrimido[1,6-a]indole-5-aeetie acid amide remaining as residue is recrystallised frcsi methanol to yield colourless crystals having a melting point of 239-240°. The corresponding hydrochloride has a melting point of 253-260° (with decomposition).

The starting material can be manufactured as follows: a) 38 g (0.1 mol) of 2-(dibenzylamino-ethyl)-indole3-acetonitrile are introduced into 300 g of polyphosphoric acid and the mixture is heated at 100°, while stirring, for approximately 60 minutes- The mixture is poured onto 1 kg of ice, rendered alkaline by adding concentrated ammonia and extracted with ether. After washing and drying the ether phase and concentrating it by evaporation, 2-(dibenzyl amino—ethyl)-indole-3-acetamide is obtained as a syrup which can be crystallised from a little ether; a.p. 135-136°. b) 120 g (0.3 mol) of 2-(dibenzylamino-ethyl)indole-3-aeetamida are hydrogenated at 30-35° under normal pressure, with the addition of 12 g of 5 % palladium-oncarbon, in 1.2 litres of methanol. When 14.4 litres of hydrogen have been absorbed, hydrogenation is discontinued, the catalyst is filtered off and the solution is concentrated to dryness in vacuo. The residue is «crystallised from 100 ml of ethanol with the addition of 250 ml of ether. The resulting 2-aminoethyl-indole-3-acetamide has a melting point of 156-157°. e) 17.5 ml (0.15 mol) of benzoyl chloride are added, while stirring thoroughly and cooling to approximately 5°,.to 21.7 g (0.1 mol) of 2-aminoethy1indole-3-acetamide in a mixture of 200 ml of ether and 100 ml of water, and 100 ml of 2H NaOH are gradually added dropwise. The reaction is complete after approximately 1 hour. Stirring is continued for 1 hour at 0-5° and the separated 2-(henzoylamino-ethyl)-indole-3-aeetamide having a melting point of 223-225° is filtered with suction. d) 1.6 g (0.005 mol) of 2-(benzoylamino-ethyl)indole-3-acetamids is heated under reflux for 2 hours in 16 ml of phosphorus oxychloride. Excess phosphorus oxychloride is distilled off, the oily residue is taken up ia water and by-products of the reaction are removed by extracting with ether. Concentrated ammonia is added to the aqueous phase, while cooling, and extraction with ether is carried out. After washing and drying the ether phase and concentrating it by evaporation, 1-phenyl-3,450985 dihydro-pyrimido[i, 5-a]indole-5-acetorxitrile is obtained as a yellowish oil which, by dissolving in methanol and adding ethereal hydrochloric acid, can be converted into a crystalline hydrochloride having a melting point of 195-205°.

Exaaple 13: The hydrochloride of i-(3-sulphaa»yl-4-chlorophenyl )-3 ,4-dihydro-pyrimido[l,6-a]indole-5-acetamide having a melting point of 249-257° (with decomposition) is obtained, in a manner analogous to that described in Exaaple 17, from i-(3-sulphamoyl-4-chloro-phenyl)-3,4dihydro-pyriaiido[l,6—a]indole-5—acetonitrile having a melting point of 280-285°.

Exaaple 19: g (0.03 mol) of 1-(p-methylthio-phenyl)-3,4dihydro-pyrimido[i,6-a]indole-5-acetic acid ethyl ester are dissolved in 120 ml of glacial acetic acid, and 4 ml of 30 % hydrogen peroxide are added. The mixture is left to stand for approximately 20 hours at room teaperature, is poured onto 1 litre of ice-water, rendered alkaline with concentrated ammonia and extracted with ethyl acetate. The ethyl acetate phase is washed, dried and concentrated by evaporation. The resulting i-(p-methylsulphoxy-phenyl)3.4- dihydro-pyriaido[l,6-a]indole-5-acetic acid ethyl ester crystallises from ether to yield yellowish crystals having a melting point of 150-151°.

Exaaple 20: Xn a manner analogous to that described in Exaaple 1 the hydrochloride of 7-fluoro-1-(p-methylthio-pbenyl)3.4- dihydro-pyriaiido[l,6-a]indole-3-acetic acid ethyl ester 50986 having a malting point of 2"Ό° (with decomposition) is obtained starting from 2-[(g-methylthie-phenyl-amino)ethyl]-5-fluoro-indole-5-acetie acid ethyl ester and, starting from 2-[(p-chloramethylthio-phenyl-amino)ethyl]-5-fluoro-indole-3-acetic acid ethyl ester, there is obtained the hydrochloride of 7-fluoro-·’-(p-chloromethylthio-phenyl )-3,4-dihydro-pyrimido[l, 6-a] indole-5-acetie acid ethyl ester having a melting point of 198-202°.

Example 21: The hydrochloride of 7-fluoro-7-(p-methylsulphoxyphenyl)-3,4-dihydro-pyrimido[l,6-a]indoIe-5-acetic acid ethyl ester having a melting point of 26^-264° is obtained, in a manner analogous to that described in Example i9, starting from 7-fluoro-1-{p-methylthiophenyl )-3,4-dihydro-pyrimido[i,6-a]indole-5-acetic acid ethyl ester hydrochloride.

Exanple 22: 7-fluoro-1-(p-methylthio-phenyl)-pyrimido[l,6-a]indole-5-acetic acid having a melting point of 213-220° (with decomposition) is obtained, in a manner analogous to that described in Example 9, by hydrolysing 7-fluorol-(p-methylthio«-phenyl)-pyrimido[l,6-a]indole-5-acetic acid ethyl ester.

Exanple 23: 7-fluoro-1-(p-methylthio-phenyl)-pyrimido[1,6-a]indole-5-acetic acid ethyl ester g of 7-fluoro-1-(p-methylthio-phenyl)-3,4dihydro-pyrimido[l,6-a]indole-5-acetie acid ethyl ester are heated under reflux, while stirring, in 20 ml of diphenyl ether with 0.5 g of palladium-on-carbon (10 %).

After 2 hours, a further 0.5 g of palladium-on-carbon is added and the mixture is heated for a further 3 hours. After filtering off the catalyst, the reaction mixture ia concentrated In vacuo, the residue is taken up ia a little ethyl acetate and chrmatographed over silica gel.

Using hexane/ethyl acetate (9:1) fractions are obtained which, after concentration by evaporation and recrystallisation from ether, yield 7-fluoro-l-(p-methylthio-phenyl)pyriaido[l,6-a]indole-5-acetic acid ethyl ester having a melting point of 120-122°. io CHgS ’ . CH,-CCCC,H, z 2 23 I II II *v‘V'xι II /•yV* X I z’x4> The following are obtained in an analogous manner: 1-phenyl-pyrimido[l,6-ajindole-5-acetic acid ethyl ester having a melting point of 59-62° and 7.-methoxy-1-(g-chlorophenyl)-pyriaddo[l ,6-a]indole5-acetic acid ethyl ester having a melting point of 130-131*.

Example 24: 1.0 g (0.003 mol) of 1-phenyl-3,4-difaydropyrimido[l,6-a]indole-5-acetonitrile is stirred for hours at 0° in 50 ml of absolute ethanol and 50 ml of ethanol saturated with hydrogen chloride. The solvent is 5098S then distilled off under reduced pressure. The remaining, crude hydrochloride of 1-phenyl-3,4-dihydro-pyrimido[1,6-a]indole-5-acetiminoethyl ester is suspended in '0 ol of water and heated at 40° for 15 minutes while stirring. After cooling, 1-phenyl-3.4-dihydro-pyrimido[1,6-a]indole5-acetic acid ethyl ester hydrochloride crystallises and, after recrystallisation from 15 hydrochloric acid, yields crystals having a malting point of 187-189°.

Exanple 25: 3.84 g (0.01 mol) of 7-fluoro-i-(p-methylsulphoxyphenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid ethyl eater are heated under reflux for 2 hours, while stirring, in 500 ml of ethyl acetate with 40 g of deactivated Raney nickel. The catalyst is then filtered off and the filtrate is concentrated hy evaporation under reduced pressure. The residue yields, after recrystallisation from ether. 7-fluoro-1-(p-ffiethylthio-phenyl)-3,4dihydro-pyrimido[i,6-ajindole-5-acetic acid ethyl ester having a melting point of 119-120°.

Exasple 26: Tablets each containing 25 mg of active substance, for exasple 7-fluoro-1-(p-mathylthio-phenyl)-3,4-dihydropyrimido[l,6-a]indole-5»aeetic acid or a salt thereof, for exanple the hydrochloride, can be manufactured in the following manner: Constituents (for 1000 tablets): active substance 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.

Manufacture: All the solid ingredients are first forced through a sieve having a mesh width of 0.6 mn. Then the active substance, lactose, talc, magnesium stearate and half of 5 the starch are mixed. Ihe 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 »00 ml of water. The resulting starch paste is added to the main portion and the mixture is granulated, if necessary with lo the addition of water. The granulate is dried overnight at 35°, forced through a sieve having a mesh width of 1.2 mm and pressed to form tablets of approximately 6 an diameter having concave faces on both sides.

In an analogous manner, it is also possible to manufacture tablets each containing 25 mg of one of the conpounds of the formula I mentioned in Examples 1 to 19, it being possible for the compounds to be also in the form of acid addition salts, such as hydrochlorides, and for compounds in which Rg is 1 -carboxymethyl to be also in the form of salts and bases, such as sodium, potassium or zinc salts.

Example 27: Tablets for chewing, each containing 30 mg of active substance, for example 7-fluoro-1-(p-methylthio25 phenyl)-3,4-dihydro-pyrimido[l,6-a]indole-5-acetic acid or a salt thereof, for example the hydrochloride, can be manufactured, for example in the following manner: Composition (for 1000 tablets); active substance mann-i tnl lactose talc glycine stearic acid saccharine % gelatine solution .0 g 267.0 g 179.5 g 20.0 g 12.5 g 10.0 g 1.0 g q.s.

Manufacture: All the solid ingredients are first forced through a sieve ba^-ing a mesh width of 0.25 ma. The mannitol and the lactose are mixed and granulated with the addition of the gelatine solution, the mixture is forced through a sieve having a mesh width of 2 mm, dried at 50° and again forced through a sieve having a mesh width of 1.7 mm.

The active substance, glycine and saccharine are carefully mixed, the mannitol, the lactose granulate, the stearic acid and the talc are added, and the whole is thoroughly mixed and pressed to form tablets of approximately 100 mm diameter having concave faces on both sides and a break groove on the upper side.

In an analogous manner it is also possible to manufacture tablets for chewing,each containing 30 mg of one of the compounds of the formula I mentioned in Examples 1 to 19, it being possible for the eonpounds to be also in the form of acid addition salts, such as hydrochlorides, and for compounds in which R^ is 1earbcsrymsthyl to he also in the form of salts with bases, such as sodium, potassium or zinc salts.

Example 28: Tablets each containing 100 mg of active substance, for exasple 7-fluoro-1-(g-aethyIthio-phenyl,-3,4-dihydropyrimido[l,6-a]indole-5-aeetie acid or a salt thereof, for exasple tbe hydrochloride, can be manufactured in the following manner: Composition (for 1000 tablets): active substance _ 100.0 g lactose 248.5 g com starch 17.5 g polyethylene glycol 6000 5.0 g talc 15.0 g magnesium stearate 4.0 g demineralised water q.s.

Manufacture: The solid ingredients are first forced through a sieve having a mesh width of 0.6 ns. Then the active substance, lactose, talc, magnesium stearate and half of the starch are intimately mixed. The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting paste is added to the pulverulent substances, and the whole is mixed and granulated, if necessary with the addition of water. The granulate is dried overnight at 35°, forced through a sieve having a mesh width of 1.2 mm and pressed to form tablets of approximately 10 mm diameter having concave faces on both sides and a break groove on the upper side.

Xn an analogous manner, it is also possible to manufacture tablets each containing 100 mg of a conpound of the formula X according to Exasples 1 to 25, it being possible for compounds to be also ia the form of acid addition salts, such as hydrochlorides, and for conpounds in which Rg ia 1-earboxymethyl to be also in the form of salts with bases, such as sodium, potassium or zinc salts

Claims

CLAIMS 1. ,2-phenylene optionally mono-substituted in the 4position in relation to the bonded nitrogen atom by lower alkoxy having up to and including 4 carbon atoms, or in the 4-position by halogen having an atomic number 1,2-phenylene optionally substituted by lower alkyl having up to and including 4 carbon items, by lower alkoxy having up to and including 4 carbon atoms, and/or by halogen having up to and including an atomic number of 35, and alk is 1,2-ethylene, and their salts. 1-carboxy-lower alkyl, Ph represents optionally substituted 1,

1. H,S’-bridged carboxylic acid amidines of the general formula

2. -phenylene, 3. -thia- or 3-aza-alkyleneaminocarbonyl, Rg represents hydrogen or lower alkyl. Ph represents J,2-phenylene optionally substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, and alk represents lower alkylene separating the methine group frcm the im-in»? group by from 1 to 3 carbon atoms or lower alkenylene separating the methine group from the imino group by 2 carbon atoms, and their salts.

3. Conpounds of the formula I according to claim 1 in which R 1 represents phenyl optionally substituted by lower alkyl, lower alkoxy, lower alkylthio, halolower alkylthio, lower alkanesulphinyl, halo-lower alkanesulphinyl, lower alkanesulphonyl, halo-lower alkanesulphonyl, sulphamoyl, N-mono- or N,N-di-lower alkylsulphamoyl and/or halogen, or represents pyrrolyl, furyl, thienyl, thiazolyl, pyridyl or pyrimidyl each optionally substituted by lower alkyl, lower alkoxy and/ or halogen, Rg represents a group of the formula - 3-thia- or 3-aza-alkylene, Rg is hydrogen or lower alkyl. Ph is 1,2-phenylene optionally substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromathyl, and alk is lower alkylene separating the methine group from the imino group by from 1 to 3 carbon atoms or lower alkenylene separating the mc-t-Tn’na group from the imino group by 2 carbon atoms, and their salts.

4. Compounds of the formula I according to claim 1 in which R 1 represents phenyl optionally substituted by lower alkyl having up to and including 4 carbon atoms, by lower alkoxy having up to and including 4 carbon atoms, by halolower alkylthio having up to and including 4 carbon atoms, by lower alkylthio having up to and including 4 carbon atoms, by halo-lower alkanesulphinyl having up to and including 4 carbon atoms, by lower alkanesulphinyl having up to and including 4 carbon atoms, by halo-lower alkanesulphonyl, by lower alkanesulphonyl having up to and including 4 carbon atoms, by sulphamoyl, by ST-mono- or N,N-di-lower alkanesulphamoyl each having up to and including 4 carbon atoms in the alkyl radical, and/or by halogen having an atomic number of up to and including 35, or represents pyridyl or thienyl each optionally substituted by lower alkyl having up to and including 4 carbon atoms, by lower alkoxy having up to and including 4 carbon atoms, and/or by halogen having an atomic number of up to and including 35, Rg represents a group of the formula -CH(R 3 J-Rj in which Rj represents carboxy, phenyl- or pyridyl-lower alkoxycarbonyl, optionally substituted by lower alkyl having up to and including 4 carbon atoms, by lower alkoxy having up to and including 4 carbon atoms, and/or by halogen, lower alkoxycarbonyl, mono- or di-hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, 27hydroxy- or B-amino-carbamoyl, N-mono- or H,B-di-lower alkoxycarbamoyl, or carbamoyl, Rg is hydrogen or lower alkyl having up to and including 4 carbon atoms. Ph is 5. -5-acetic acid, or a salt thereof. 5 for the manufacture of compounds of the formula X in which Rj represents amidated 1-carboxymethyl and Ph, R^ and alk have the above meanings, characterised by the addition of water and splitting off a proton in compounds of the formula G in which R g represents optionally substituted lower alkyl or phenyl and X g represents a radical of the formula «Ν-OH or »N-£JSN1 ; or for the manufacture of conpounds of the formula X in 15 which Rj represents esterified or amidated 1-carboxylower alkyl, alk represents vinylene and R^ and Ph have the above meanings, characterised in that compounds of the formula Ph--/ alk (I), in which alk represents ethylene are dehydrogenated with the splitting off of hydrogen and simultaneous formation of an additional bond, and, if desired, a canpound obtainable according to the 5 invention is converted into a different compound of the formula I, or a free canpound of the formula I obtainable according to the invention is converted into a salt, or a salt obtainable according to the process is converted into the free conpound of the formula I or into a different 5 in which Z g represents optionally functionally modified hydroxy or mercapto, or amino, or a salt thereof, is cyclised ; or in a compound of the formula 5 io. 7-itethoxy-1-(p-ehlorophenyl1-3,4-dihydrori ,6-a]indole-5-acetic acid or a salt thereof. 5 lower alkyl having up to and including 4 carbon atoms, or in the 4-position by halogen having an atomic number of up to and including 35, and alk is 1,2-ethylene or vinylene, and their salts.

5. Compounds of the formula I according to claim 1 in which R 1 represents phenyl optionally substituted by halogen, lower alkylthio, lower alkanesulphinyl, lower 5098S alkanesulphonyli halo-lower alkylthio and/or sulphamoyl, or pyridyl or thienyl, & 2 represents a group of the formula in which R^ represents carboxy, lower alkoxyearbonyl or carbamoyl, Ph represents 1,2-phenylene optionally substituted by lower alkoxy, lower alkyl and/or halogen, and alk is 1,2-ethylene or vinylene, and their salts. 5 in which R 7 represents an aromatic radical, Rj represents optionally, esterified or amidated

6. Compounds of the formula Σ according to claim i in which R 1 represents phenyl optionally substituted by halogen having an atomic number of up to and including 35, by lower alkylthio having up to and including 4 carbon atoms, by lower alkanesulphinyl having up to and including 4 carbon atoms, by halo-lower alkylthio having up to and including 4 carbon atoms,and/or by sulphamoyl, or pyridyl, or thienyl, R 2 represents a group of the formula -CEj-Rj ia which R^ represents carboxy, lower alkoxyearbonyl having up to and including 5 carbon atoms, or carbamoyl. Ph represents 1,2-phenylene optionally substituted by lower alkoxy having up to and including 4 carbon atoms, by lower alkyl having up to and including 4 earbon atoms, and/or by halogen having an atomic number of up to and including 35, and alk is 1,2-ethylene or vinylene, and their salts.

7. Compounds of the formula Σ according to claim 1 in which R^ represents phenyl optionally substituted in the p-pos ition by halo-lower alkylthio having up to and including 4 carbon atoms, by lower alkylthio having up to and including 4 carbon atoms, by lower alkanesulphinyl having up to and including 4 carbon atoms, or by halogen having an atomic number of up to and including 35, or in the 3-position by sulphamoyl and, in addition, in the 4position by halogen having an atomic number of up to and including 35, or pyridyl or thienyl, R 2 represents a group of the formula -CHj-R^ in which R 2 represents carboxy, lower alkoxycarbonyl having up to and including 5 carbon atoms, or carbamoyl. Ph represents 1,2-phenylene optionally substituted in the 4-position in relation to the bonded nitrogen atom by lower alkoxy having up to and including 4 carbon atoms, in the 3- and 5-position by

8. Ccnpounds of the formula I according to claim 1 10 in which S 1 represents phenyl optionally substituted in the p-position by lower alkylthio having up to and including 4 carbon atoms, by lower alkanesulphinyl having up to and including 4 carbon atoms, or hy halogen having an atomic number of up to and including 35,

9. Compounds of the formula X according to claim 1 in which R 1 represents phenyl optionally substituted in the p-position by lower alkylthio having up to and

10. Salt. 10 in which represents a group of the formula -CH(R 3 )-Rj and in which R^ represents hydrogen or lower alkyl and Rj -represents functionally modified carboxy different from R j, or a group of the formula -C(=o)-N^3®, in which B®is the anion of a mineral acid, or represents methyl optionally oxidised to the formyl stage, or in salts thereof, R^ is converted by solvolysis or oxidation into the group Rj; or 10 and alk represents an aliphatic hydrocarbon radical separating the imino group froa the aethine group by from 1 to 3 carbon atoms, and their salts.

11. 7-Fluoro-l-Methylthio-phenyl)- 3,4-dihydropyrimido[l,6-a]indole-5-acetic acid or a salt thereof.

12. 7-S’luoro-1-(p-Miiethylthiophenyli-3,4-dihydropyrimido10 [1,6-a]indole-5-acetic acid ethyl ester or a salt thereof.

13. Compounds of formula I according to claim 1 substantially as described with reference to any of Examples 1 to 25.

14. Pharmaceutical preparations containing a compound of the formula I according to any one of claims 1 to 13 15. Of a salt or, especially, is formed under the reaction conditions .

15. Pharmaceutical preparations according to claim 14 substantially as described with reference to any of Examples 26 15 in free form or in the form of a pharmaceutically acceptable salt together with customary pharmaceutical adjuncts and carriers . 15 Rj represents lower alkoxycarbony lmethyl, Ph represents 15 *2. Compounds of the formula X. according to claim 1 in which R 1 represents phenyl optionally substituted by lower alkyl, by lower alkoxy, by optionally halogencontaining lower alkyl thio, lower alkanesulphinyl or lower alkanesulphony1, by sulphamoyl optionally mono2o or di-substituted by lower alkyl, and/or by halogen, or represents 5- or 6-membered monocyclic heteroaryl optionally containing lower alkyl, lower alkoxy and/or halogen and having as hetero atom nitrogen, oxygen or sulphur, or nitrogen and, in addition, sulphur or oxygen,

16. · Craroounds of the formula I according to any one of claims 1 to 13 for use in a method for the therapeutic treatment of the human or animal body.

17. Antiphlogistic and/cr analgesic catpositians containing canpainds 25 af the formula I according to any one of claims 1 to 13.

18. Use of compounds of the formula 1 according to any one of claims 1 to 13 for the manufacture of pharmaceutical preparations.

19. Process for the manufacture of eonpounds of the 30 formula (I), in which R^ represents an aromatic radical, R 2 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 aethine group by from 1 to 3 carbon atoms, and their salts, characterised in that from compounds of the general formula H in which Z^ represents optionally functionally modified hydroxy or mercapto, or from salts thereof, H-Z^ is split off with the introduction of an additional bond; or compounds qf the formula (V) 5098B in which Rj represents optionally esterified or amidated carboxy, or salts thereof, are isomerised; or a compound of the general formula Ph7 \lk I k R, = ONE ° 20. Claimed in any of claims 19 to 21.

20. Process according to claim 19, wherein compounds obtainable as intermediates at any stage of the process are used as starting materials and the remaining steps are carried out, or a starting material is used in the form 20 to 28. 20 of up to and including 35, and alk is 1,2-ethylene, and their salts.

21. Process according to claim 19 substantially as described with reference to any of Examples 1 to 25.

22. A compound of formula I when produced by a process

23. l-Phenyl-3,4-dihydro-pyrimido-[l,6-a]indole-5acetic acid, or a salt thereof.

24. 7-Fluoro-l- {js-methylsulphinylphenyl)-3,4-dihydropyriraido[l,6-a]indole-5-acetic acid, or a salt thereof.

25. 25. l-(2-Thienyl)-3,4-dihydro-pyrimido[l,6-a]-indole 25 including 4 carbon atoms, by lower alkanesulphinyl having up to and including 4 carbon atoms, or by halogen having up to and including an atomic number of 35, R? represents carboxymethyl, Ph represents 1,2-phenylene optionally substituted in the p-position to the nitrogen atom by lower alkoxy having up to and including 4 carbon atoms or by halogen having up to and including an atomic number of 35 „ and alk represents 1,2-ethylene, and their salts. 25 Rj represents 1-carboxy-lower alkyl of the formula -CBiR-jl-Rj, in which Rj represents carboxy, lower alkoxycarbonyl optionally substituted by lower alkyl-, lower alkoxy- or halogen-containing phenyl or pyridyl, by hydroxy or hy lower alkoxy, or represents carbamoyl optionally substituted once by hydroxy or amino, once off twice by lower alkyl or hydroxy-lower alkyl, or twiee by 4- to 7-membered lower alkylene or 3-oxa-,

26. 7-Fluoro-l-(D-methylsulphOxyphenyl)-3,4-dihydropyrimido[l,6-a]indole-5-acetic acid ethyl ester, or a salt thereof. 30

27. 7-Fluoro-l-(g-methylthio-phenyl)-pyriniido-[l,6-a] indole-5-acetic acid ethyl ester, or a salt thereof.

28. 7-Fluoro-l-(p-methylthio-phenyl)-pyrimido-[1,6-a) indole-5-acetic acid, or a salt thereof.