IE57641B1 - Indole derivatives - Google Patents

Abstract

1. Indole derivatives of the general formula see diagramm : EP0144012,P18,F1 wherein Ind is an indol-3-yl radical which is substituted by a hydroxymethyl or COW group and which can additionally be monosubstituted or disubstituted by alkyl, O-alkyl, OH, F, Cl or Br, W is H, OH, Oalkyl, NH2 , NHalkyl or N(alkyl)2 , A is -(CH2 )n -, -CH2 -S-CH2 CH2 -, -CH2 -SO-CH2 CH2 -or-CH2 -SO2 -CH2 CH2 -, n is 2, 3, 4 or 5, the two radicals Y are each H or together are a C-C bond, one radical Z is Ar, the other radical Z is H and Ar is a phenyl group which is unsubstituted or is monosubstituted or disubstituted by O-alkyl and/or OH or is substituted by a methylenedioxy group, or Ar is a 2-thienyl or 3-thienyl group, in which formula each of the alkyl groups has 1 - 4 C atoms, wherein, however, when n is 2 or 3, the hydroxymethyl or COW group must be in the 4-, 5-, 6- or 7-position of the indol-3-yl radical, and also physiologically acceptable acid addition salts thereof.

Description

The invention relates to new indole derivatives of the general formula I wherein Ind is an indol-3-yl radical which is substituted by a hydroxymethyl or COU group and which can additionally be mono- or disubstituted by alkyl, 0-alkyl, OH, F, Cl or Br, U is H, OH, O-alkyl, NH2z NHalkyl or N(alkyl)2z A is -(CH2)n-, -CH2-*S-CH2 CH2-, -CH2-S0-CH2 CH2 " or -CH2-SO2"CH? CH2 ", n is 2, 3, 4 or 5, the two radicals Y are each H or together are a C-C bond, one radical Z is Ar, the other radical Z is H and Ar is a phenyl group which is unsubstituted or is monoor disubstituted by 0-alkyl and/or OH or is substituted by a methylenedioxy group, or Ar is a 2-thienyl or 3-thienyl group, in which formula each of the alkyl groups has 1 - 4 C atoms, u/herein, however, when n is 2 or 3, the hydroxymethyl or COW group must be in the 4-, 5-, 6- or 7-position of the indol-3-yl radical, and also physiologically acceptable acid addition salts thereof.

* Similar compounds are known from U.S. patent no. 3,639,414 and from Australian patent no. 36 833/68.

* $ The invention was based on the object of finding new compounds which can be used for the preparation of medi caments .

It has been found that the compounds of the formula I and their physiologically acceptable acid addi10 tion salts possess valuable pharmacological properties.

Thus they exhibit, in particular, an action on the central nervous system, above all a dopamine-stimulating presynaptic (neuroleptic) or postsynaptic (an t i-Pa r k i n s on i an) action.: In detail, the compounds of the formula I induce contralateral turning behaviour in hemiparkinson rats (detectable by the method of Ungerstedt et al., Brain Res. 24 (1970), 485-493) and inhibit the binding of tritiated dopamine-agonists and dopamineantagonists to striatal receptors (detectable by the method of Schwarcz et al., «I. Neurochemistry 34 (1980), 772-778 and Creese et al., European J. Pharmacol. 46 (1977), 377-381). In addition, the compounds inhibit the linguomandibular reflex in anaesthetised rats (detectable by a method based on the methods of Barnett et al., European J. Pharmacol. 21 (1973), 178-182 and of Ilhan et al., European J. Pharmacol. 33 (1975), 61-64). Analgaesic and hypotensive effects also occur; thus in conscious, catheter-carrying, naturally hypertensive rats (strain SHR/NIH-MO/CHB-EMD; for method see Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 104 (I960), 646-648), the directly measured blood pressure is lowered after intragastric administration of the compounds.

Compounds of the formula I and their physiologically acceptable acid addition salts can, therefore, be used as active compounds for medicaments and also as intermediate products for the preparation of other active compounds for medicaments.

The invention relates to the indole derivatives of the formula I and to their physiologically acceptable acid addition salts.

In the radicals Ind, W and Ar, alkyl is preferably methyl and also ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl. Ο-Alkyl is preferably methoxy, and also ethoxy, n-propoxy, isopropoxy, nbutoxy, isobutoxy, sec.-butoxy or tert.-butoxy.

The radical Ind is, in particular, a monosubstituted indol-3-yl radical. It is preferably substituted in the 5-position or 6-position or in the 4-position or 7-position. Substitution in the 1-position or 2-position is also possible. Preferred disubstituted indol-3-yl radicals are substituted in the 5,6-position; disubstitution is also possible in the 1,2-, 1,4-, 1,5-, 1,6-, 1,7-, 2,4-, 2,5-, 2,6-, 2,7-, 4,5-, 4,6-, 4,7-, 5,7- or 6,7position. In all these cases the substituents can be identical or different.

Specifically, the preferred substituents in the benzene ring of the radical Ind are hydroxymethyl, formyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methy Icarbamoy I, N-ethy Icarbamoyl, Ν,Ν-dimethyl15 carbamoyl and Ν,Ν-diethyIcarbamoyl; in the second place they are propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl> sec.-butoxycarbonyl and tert.-butoxycarbony I, N-propy Icarbamoy I, N-isopropylcarbamoyl, N-buty IcarbamoyI, N-isobutyIcarbamoyI, N-sec.20 buty I carbamoy I, N-tert.-butylcarbamoyl, N-methy l-N-ethyLcarbamoyl, Ν,Ν-dipropyIcarbamoyI, N-methy l-N-propylcarbamoyl, N-ethy l-N-propy Icarbamoyl and Ν,Ν-dibuty Icai— bamoyl and, additionally, methyl, ethyl, methoxy, ethoxy, OH, F, Cl and/or Br. Accordingly, some preferred mean25 ings of the radical Ind are 2-, 4-, 5-, 6- or 7-formylindol-3-yl, 2-, 4-, 5-, 6- or 7-carboxyindo l-3-yI, 2-, 4-, 5-, 6- or 7-methoxycarbonylindol-3-yI, 2-, 4-, 5-, 6- or 7-ethoxycarbonylindol-3-yl, 2-, 4-, 5-, 6- or 7carbamoyIindol-3-y1, 2-, 4-, 5-, 6- or 7-N-methyIcarbam30 oyI in do l-3-y I, 2-, 4-, 5-, 6- or 7-N-ethyIcarbamoy lindol3-yl, 2-, 4-, 5-, 6- or 7-N,N-dimethyIcarbamoyIindo 1-3yl, 2-, 4-, 5-, 6- or 7-N,N-diethyIcarbamoyI in dol-3-yI, 1-methyl-4-, -5-, -6- or -7-hydroxymethyI in do l-3-y1, 1methyl-4-, -5-, -6- or -7-f ormyl indol*73-yl, 1-met hy 1-4-, -5-, -6- or -7-carboxyindo l-3-yL, 1-methyl-4-, -5-, -6or -7-carbamoylindol-3-yl, 2-methyl-4-, -5-, -6- or -7hydroxymethy I indo l-3-y 1, 2-methyl-4-, -5-, -6- or -7formy I in do l-3-y I, 2-methyl-4-, 5-, -6- or -7-carboxy6 indol-3-yl, 2-mjet h y 1-4-, -5-, -6- or -7-carbamoylindol3-y .l, 5-methoxy-4-, -6- or -7-methoxycarbony lindol-3-y I, 5-methoxy-4-, -6- or -7-ethoxycarbonylindol-3-yl, 5methoxy-4-, -6- or -7-carboxyindol-3-yl, 5-methoxy-4-, -6- or -7-carbamoyI in do l-3-y I, 5-fluoro-4-, -6- or -7carboxyindo l-3-y I, 5-chloro-4-, -6- or -7-carboxyindo1-3yl, 7-chloro-4-, -5- or -6-carboxyin dol-3-yI, 5-bromo-4-, « -6- or -7-carboxyindol-3-y I, 5-hydroxy-4-, -6- or -7methoxycarbonyIindol-3-y1, 5-hydroxy-4-, r6- or -7- « ethoxycarbonylindol-3-yl, 5-hydroxy-4-, -6- or -7-carboxyindol-3-yl, 5-hydroxy-4-, -6- or -7-carbamoy I indol-3-yI. - hydroxy-2-, -4-, -6- or -7-hydroxymethy1indol-3-yl, 6- hydroxy-4-, -5- or -7-carboxyindol-3-yl, 6-hydroxy-2-, -4-, -.5- or -7-hydroxymethylindol-3-yl.

The parameter n is preferably 4 and the radical A is preferably -(CHg^" or -CH2-S-CH2CH2" and also preferably -2)2-, -(CH2>3- or -(CH2>5-.

The radical Ar is preferably unsubstituted phenyl. If Ar is a substituted phenyl group, the latter is preferably monosubstituted. It can, however, also be disubstituted, and the substituents can be identical or different. Preferred substituents on the phenyl group are methoxy and OH. Specifically, Ar is preferably phenyl, 0-, m- or p-methoxyphenyL, o-, m- or p-hydroxy25 phenyl and also 0-, m- or p-ethoxyphenyI, 2,3-, 2,4-, ί 2,5-, 2,6-, 3,4- or 3,5-dimethoxypheny I, 3-hydroxy-4methoxyphenyI, 3-methoxy-4-hydroxyphenyI, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyI, 2,3- or 3,4I methylenedioxyphenyI, 2-thienyl or 3-thienyl.

Accordingly, the invention relates especially to the compounds of the formula I in which at least one of the said radicals has one of the meanings indicated above, particularly the preferred meanings indicated above. Some preferred groups of compounds can be expressed by means of the following partial formulae Ia to Ik, which correspond to the formula I and in which the radicals and parameters not designated in detail have the meaning indicated in formula I, but in which: in Ia Ind is hydroxymethylindol-3-yI, formylindol-340 yl, carboxyindol-3-yl, methoxycarbonylindol-3-yI, ethoxycarbonylindol-3-yI, carbamoylindol-3-yl, In lb 5 » in I c in Id in Ie in If in Ig in lh in Ii in I j 35 in Ik ethoxycarbonylmethoxyindol-3-yI or carboxymethoxyindol-3-yl, the substituents being preferably in the 5-position and/or 6-position; Ind is 4-, 5-, 6- or 7*-h yd r oxymet hy I in do l-3-y I , -, 6- or 7-formyIindol-3-yI, 5-, 6- or 7-carboxyindol-3-yl, 5-, 6- or 7-methoxycarbonyI in do 1-3ylz 5-, 6- or 7-ethoxycarbonyIindol-3-yI, 5-, 6or 7-carbamoy I indo l-3-yI, 5-methoxy-6-ethoxycarbonyIindol-3-yI or 5-methoxy-6-carboxyindol3-yl; A is -2)n- or -CH2-S-CH2CH2-; A is -(CH2>4"/ the two radicals Y are together a C-C bond; Ar is phenyl, hydroxyphenyl or methoxyphenyl; Ar is in the 4-position and is phenyl; Ind is 4-, 5-, 6- or 7-hydroxymethylindol-3-yI, -, 6- or 7-formylindol-3-yI, 5-, 6- or 7-carboxyindol-3-yl, 5-, 6- or 7-methoxycarbonyI in do 1-3yl, 5-, 6- or 7-ethoxycarbonyIindol-3-yI, 5-, 6or7-carbamoylindol-3-yl, 5-methoxy-6-ethoxycarbonyIindol-3-yI or 5-methoxy-6-carboxyindol3-yl, A is —2)n— or -CH2-S-CH2CH2- and Ar is phenyl, hydroxyphenyl or methoxyphenyl; Ind is 4-, 5-, 6- or 7-hydroxymethyIindol-3-yI, -, 6- or 7-formy I in dol-3-y I, 5-, 6- or 7-carboxyindol-3-yl, 5-, 6- or 7-methoxycarbonyI in do 1-3yl, 5-, 6- or 7-ethoxycarbonylindol-3-yl, 5-, 6or 7-carbamoy lindol-3-yI, 5-methoxy-6-ethoxycarbonyI in dol-3-yI or 5-methoxy-6-carboxyindol3-yl, A is -2)4- or -CH2-S-CH2CH2- and Ar is phenyl, m-hydroxyphenyl or p-hydroxyphenyI; Ind is carboxyindo l-3-yI or carbamoy I indo l-3-y I, A is -(CH2)4- or -CH2-S-CH2CH2- and Ar is phenyl, m-hydroxyphenyl or p-hydroxypheny I;.

Ind is 5-carboxyindol-3-yl or 5-carbamoylindol3-ylz A is -2>4- ο γ *—C H2 — S — C H2 C H2— and the two radicals Y together are a C-C bond and Ar is in the 4-position and is phenyl.

The compounds of the formula I can contain one or more asymmetric carbon atoms. They can, therefore, exist as racemates andz if several asymmetric carbon atoms are present, also as mixtures of several racemates, as well as in different optically active forms.

The invention also relates to a process for the preparation of the compounds of the formula I and of their physiologically acceptable acid addition salts. The process comprises reacting a compound of the general formula II Ind-A-X1 II wherein X1 is X or NH2 and X is Cl, Br, I, OH or a reactive, functionally modified OH group, and Ind and A have the meanings indicated above, with a compound of the general formula III x2-ch2ch2-cyz-cyz-ch2-x3 III wherein X and X can be identical or different and, if X' is NH2, are each X and otherwise are together NH and Y and Z have the meanings indicated above, or reacting a ccnpound which otherwise corresponds to the formula I, but which contains one or more reducible group(s) and/ or one or more additional C-C and/or C-N bond(s) instead of one or more hydrogen atoms, with a reducing agent, or reacting a ccnpound which otherwise corresponds to the formula I, but which contains one or more solvolysable group(s) instead of one or more hydrogen atoms, with a solvolytic agent, or, in order to prepare a thioether of the formula I wherein A is -CHg-S-CHgCHg-/ reacting a compound of the general formula IV Ind-CH2N(R>2 IV wherein R is alkyl having 1-4 C atoms or both radicals R together are also ~(CH2)p or -CH2CH2OCH2CH2** and p is 4 or 5 and Ind has the meaning indicated above, with a thiol of the creneral formula V wherein Y and Z have the meanings indicated above, or with one of its salts, or, in order to prepa re a conpound of the formula I wherein both radicals Y together are a C-C bond, reacting a compound of the general formula VI VI wherein one radical E is X, CN or NHjz the other radical E is H and Ind, A, Z and X have the meanings indicated, with an agent which splits off HE, and/or in a compound of the formula I, if appropriate, oxidising a thioether group to give an SO group or SO2 to give an SOj group with the formation of an group, or oxidising an SO group and/or cleaving an alkoxy group OH group, and/or converting a CCW group into another COW group by oxidation, reduction, esterification, amidation or solvolysis, and/or reducing a COW group to give a hydroxymethyl group, and/or oxidising a hydroxymethyl group to give a CHO or COOH group, and/or converting a resulting base of the formula I, by treatment with an acid, into one of its physiologically acceptable acid addition salts.

The preparation of the compounds of the formula I is effected in other respects by methods which are in themselves known, such 4s are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; or Organic Reactions, John Wiley S Sons, Inc., New York), specifically under reaction conditions such as are known and suitable for the reactions mentioned. In these reactions it is also possible to make use of variants which are in themselves known but not mentioned here in detail.

The starting materials for the claimed process can, if desired, also be forme.d in situ, in such a way that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the formula I. ή In the indole derivatives of the formula II, X1 is preferably X; accordingly, in the compounds of the 2 3 formula III, X and X together are preferably NH.

The radical X is preferably Cl or Br; it can, however, also be I, OH or a reactive, functionally modified OH group, especially a I ky I suIfony loxy having 1-6 C atoms (for example methanesu I fonyIoxy) or ary I su I fonyIoxy having 6-10 C atoms (for example benzenesulfonyIoxy, ptoluenesuIfonyIoxy, 1-naphtha I enesu I fony Ioxy or 2-naphthalenesulf on yloxy). /13 I Accordingly, the indole derivatives of the formula I are obtainable, in particular, by reacting compounds of the formula Ind-A-Cl or Ind-A-Br with piperidine or tetrahydropyridine derivatives of the formula III wherein and X-3 together are an NH group (designated below as Ilia).

The compounds of the formulae II and especially III are in part known; the compounds of the formulae II and III which are not known can readily be prepared analogously to the known compounds. Compounds of the formula II (A = -CHg-S-CHjCHg") can be prepared, for example, from Mannich bases of the formula IV and thiols of the formula HS-CHgCHg-X1, for example HS-CHgCHjOH.

The sulfoxides and sulfones of the formula II (A = —CHg—S0—CHgCHg— or —CHg—SOg—CHgCHg—) are accessible by oxidising the thioethers (II, A = -CHj-S-CHgCHg-) . Primary alcohols of the formula Ind-A-OH can be obtained, for example, by reducing the corresponding carboxylic acids or their esters. Treatment with thionyl chloride, hydrogen bromide, phosphorus tribromide or similar halogen compounds gives the corresponding halides of the formula Ind-A-Hal. The corresponding sulfonyloxy compounds can be obtained from the alcohols Ind-A-OH by reaction with the corresponding sulfonyl chlorides.

The iodine compounds of the formula Ind-A-I can be obtained, for example, by the action of potassium iodide on the appropriate p-toluenesulfonic acid esters. The amines of the formula Ind-A-NHg can be prepared, for example, from the halides by means of potassium phthalimide or by reducing the corresponding nitriles.

The piperidine derivatives Ilia are, for the most part, known (cf. German Offen legungsschrift 2,060,816) and can be obtained, for example, by reacting 3-piperidone or 4-piperidone with organometallic compounds of the formula Μ-Ar (wherein M is an Li atom or MgHal), subsequently hydrolysing the product to give the corresponding 3-Ar-3-hydroxypiperidines or 4-Ar-4-hydroxypiperidines and, if desired, subsequently dehydrating the latter to give 3-Ar-3,4-dehydropiperidines or 4-Ar-3,4-dehydropiperidines. Compounds of the formula III (X? and X^ being X in each case) can be prepared, for example, by reducing diesters of the formula alkyLOOC-CHj-CYZ-CYZCOOalkyt to give diols of the formula' HO-CHgCHg-CYZ-CYZCHjOH (III, X = X = OH) and, if appropriate, subsequently reacting the latter with SOClg or PBrj.

The reaction of the compounds II and III takes 10 place in accordance with methods such as are known from the literature for the alkylation of amines. The components can be melted with one another in the absence of a solvent, if appropriate in a sealed tube or in an autoclave. It is also possible, however, to react the com15 pounds in the presence of an inert solvent. Examples of suitable solvents are hydrocarbons, such as benzene, toluene or xylene; ketones, such as acetone or butanone; alcohols, such as methanol, ethanol, isopropanol or nbutanol; ethers, such as tetrahydrofuran (THF) or dioxane; amides, such as dimethylformamide (DMF) or N-methylpyrrolidone; nitriles, such as acetonitrile, and also, if appropriate, mixtures of these solvents with one another or mixtures with water. It can be advantageous to add an acid-binding agent, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably the potassium, sodium or calcium salt, or to add an organic base, such as triethylamine, dimethylaniline, pyridine or quinoline, or an excess of the amine component Ind-A-NHg or of the piperidine derivative of the formula Ilia. Depending on the conditions employed, the reaction time is between a few minutes and 14 days, while the reaction temperature is between about 0 and 150°, normally between 20 and 130°.

It is also possible to obtain a compound of the formula I by treating a precursor containing one or more reducible group(s) and/or one or more additional C-C and/ or C-N bond(s) instead of hydrogen atoms with a reducing . i* agent, preferably at temperatures between -80 and +250° and in the presence of at least one inert solvent.

Reducible groups (replaceable by hydrogen) are, in particular, oxygen in a carbonyl group, hydroxyl, ary Isutfonyloxy (for example p-toluenesuIfony loxy), Nbenzenesulfony I, N-benzyl or 0-benzyl.

In principle, it is possible to convert compounds containing only one of the groups or additional bonds listed above, or compounds containing two or more of the groups or additional bonds listed above, adjacent to one another, to a compound of the formula I by reduction; COW groups present in the starting compound can be reduced at the same time. For this purpose it is preferable to use nascent hydrogen or complex metal hydrides, and also the UoIff-Kishner method of reduction.

The most preferred starting reduction correspond to the formula Ind'-L-β wherein Ind' is an indol-3-yl radical which hydroxymethyl or COM group and tion, be monosubstituted or disubstituted by alkyl, 0-alkyl, OH, F, Cl, Br and/or 0-benzyl and/or can be substituted in the 1-position by an arylsulfonyl group or a benzyl group, L is A or a chain which corresponds to the radical A but in which one or more "CH2- group(s) have been replaced by -CO- and/or one or more hydrogen atoms have been replaced by OH groups, Q i s materials for the VII VII is substituted by a which can. in addione radical Z' z the other radical Z' is Η, An" is an anion of a strong acid and Ar* is a phenyl group which is unsubstituted or is monosubstituted or disubstituted by 0-alkyl, OH and/or 05 benzyl or is substituted by a methylenedioxy group, but wherein it is not possible at the same time for Ind* /~\xF to be Ind, L to be A, Q to be -\ Z and Ar' to Y Z be Ar.

In the compounds of the formula VII, L is prefer10 ably -CO-(CH2>n_2-CO- Cspecifica I ly -COCO-, -COCHjCO-, -C0-(CH2)2-C0- or -C0-(CH2)3-C0-3, -CCH2>n„1-C0Cspecifica Ily -CH2C0-, -CH2CH2~CO", -(CH2>3"CO- or -2>4-co-i, -ch2-s-ch2-co-, -ch2-so-ch2-co- or -CH2"SO2-CH2-CO- and also, for example, -CO-CH2CH2~, -ch2-co-ch2-, -co-cch2>3-, -ch2-co-ch2ch2-, -ch2ch2-co-ch2-, -co-(ch2)4-, -ch2-co-2>3-, -ch2ch2-co-ch2ch2- or -2)3-co-ch2-.

Compounds of the formula VII can be prepared, for example, by reacting 4-Ar '-1,2,3,6-tet r ahydropy ri diri e or 4-Ar’-pyridine with a compound of the formula VIII Ind'-L-X1 VIII wherein Ar’, Ind', L and X have the meanings indicated above, under the conditions indicated above for the reaction of II with III.

If the reducing agent used is nascent hydrogen, the latter can be produced, for example, by treating metals with weak acids or with bases. Thus it is possible, for example, to use a mixture of zinc and an alkali metal hydroxide solution or of iron and acetic acid It is also possible to use sodium or another alkali metal in an alcohol, such as ethanol, isopropanol, butanol, amyl alcohol or isoamyl alcohol or phenol. It is also possible to use an aluminium/nicke I alloy in an aqueous alkaline solution, if appropriate with the addition of ethanol. Sodium amalgam or aluminium amalgam in an aqueous alcoholic or aqueous solution are also suitable for the production of the nascent hydrogen. The reaction can also be carried out in a heterogeneous phase, preferably using an aqueous phase and a benzene or toluene phase.

Complex metal hydrides, such as LiAlH^, NaBH^, diisobutylaluminium hydride or NaAI(OCH2CH2OCH3)2H2 and diborane can also be employed with particular advantage as the reducing agent, if desired with the addition of catalysts, such as BF3, ALCI3 or LiBr. Solvents suitable for this reaction are, in particular, ethers, such as diethyl ether, di-n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane, and also hydrocarbons, such as benzene. Alcohols, such as methanol or ethanol, and also water and aqueous alcohols are primarily suitable as solvent for reduction with NaBH^. Reduction by these methods is preferably carried out at temperatures between -80 and +150°, in particular between about 0 and about 100°.

CO groups in acid amides or vinylogous acid amides (For example those of the formula VII wherein L is a -(CH„) .-C0-, L n-1 -Ch^-S-CI^-CO- or -CO-(CH2)n group) can be reduced to give CH2 groups particularly advantageously by means of LiAlH^ in THF at temperatures between about 0 and 66°. In the course of this it is possible to split off by simultaneous reduction arylsulfonyl protective groups present in the 1-position of the indole ring and/or to reduce COW 30 groups present on the indo le ring, for example to reduce COOalkyl, COOH or CHO g roups to give CH2OH groups.

A reduction pf the pyridinium salts of the formula VII (wherein Q is an d An is preferably Cl, Br or CH3SO3) to give compounds of the formula I can be effected, for example, by means of NaBH^ in water, methanol or ethanol or in mixtures of these solvents, if desired with the addition of a base, such as NaOH, at temperatures between about 0 and 80°.

N-Benzyl groups can be split off by reduction by means of sodium in liquid ammonia.

It is also possible to reduce one or more carbonyl groups to CHj groups by the Wo Iff-Kishner method, for example by treatment with anhydrous hydrazine in absolute ethanol under pressure at temperatures between about 150 and 250°. Sodium alcoholate is advantageously used as a catalyst. The reduction can also be varied in accordance with the Huang-Ninlon method, by carrying out the reaction with hydrazine hydrate in a high-boiling, water miscible solvent, such as diethylene glycol or triethylene glycol, in the presence of an alkali, such as sodium hydroxide. As a rule, the reaction mixture is boiled for about 3-4 hours. The water is then removed by distillation, and the resulting hydrazone is decomposed at temperatures up to about 200°. The Wo Iff-Kishner reduction can also be carried out at room temperature in dimethyl sulfoxide using hydrazine.

Compounds which in other respects correspond to the formula I, but contain one or more solvolysable group(s) instead of one or more H atoms, can be solvolysed, in particular hydrolysed, to give the compounds of the formula I.

The starting materials for the solvolysis can be obtained, for example, by reacting Ilia with compounds which correspond to the formula II (X1 = X), but contain one or more solvolysable group(s) instead of one or more H atoms. Thus it is possible, in particular, to hydrolyse, for example in an acid medium, or, better, in a neutral or alkaline medium and at temperatures between 0 and 200°, 4-, 5-, 6- or 7-cyanoin dole derivatives to give the corresponding 4-, 5-, 6- or 7-carbamoy I indole derivatives or to hydrolyse 4-, 5-, 6- or 7-carboxyindole derivatives of the formula I or 1-acylindole derivatives (corresponding to the formula I, but containing, in the 1-position of the Ind radical, an acyl group, preferably an alkanoyl, alkylsulfonyl or arylsulfonyl group having in each case up to 10 C atoms, such as methanesulfony I, benzenesu IfonyI or p-toluenesulfonyl) to give the corresponding indole derivatives which are unsubstituted in the 1-position of the indole ring.

The basic catalysts used are preferably sodium hydroxide or carbonate, potassium hydroxide or carbonate ' or calcium hydroxide or ammonia. The selected solvent is preferably water; lower, alcohols, such as methanol or * ethanol; ethers, such as THF or dioxane; sulfones, such as tetramethylene sulfone; or mixtures thereof, preferably mixtures containing water. Hydrolysis can also be carried out merely by treatment with water alone, particularly at the boil.

Indole derivatives of the formula I (A = -CH2"S-CH2CH2-) can also be obtained by reacting Mannich bases of the formula IV with thiols of the formula V (or salts thereof).

Some of the starting materials of the formulae IV and V are known; those of the starting materials which are not known can readily be prepared analogously to the known compounds. Thus the Mannich bases of the formula IV can be obtained, for example, from indoles of the formula Ind-H, formaldehyde and amines of the formula HN(R)2, and the thiols of the formula V can be obtained from the bases of the formula Ilia and thiol derivatives 1 of the formula HS-CH2CH2~X (it being also possible to protect the HS group intermediately).

A Specifically, the reaction of IV with V is carried out in the presence or absence of an inert sol** vent at temperatures between about -20 and 250°, prefer- * ably between 60 and 150°. Examples of suitable solvents are hydrocarbons, such as benzene, toluene, xylenes or mesitylene; tertiary bases, such as triethylamine; pyridine or picolines; alcohols, such as methanol, ethanol or butanol; glycols and glycol ethers, such as ethylene glycol, diethylene glycol or 2-methoxyethanol; ketones, such as acetone; ethers, such as THF or dioxane; amides, such as DMF; or sulfoxides, such as dimethyl sulfoxide. Mixtures of these solvents are also suitable. The thiols of the formula V are preferably first converted into the corresponding mercaptides, preferably into the corres5 ponding sodium or potassium mercaptides by reaction with sodium hydroxide or ethylate or potassium hydroxide or ethylate.

Compounds of the formula I are also obtained by eliminating HE from compounds of the formula VI, with the formation of a double bond. Depending on the definition of E, this can be, for example, an elimination of hydrogen halide, water (dehydration), a carboxylic acid or another acid, ammonia or HCN. The starting materials of the formula VI can be obtained, for example, by reacting II (χ1 = X) with a compound of the formula IX wherein E and Z have the meanings indicated.

If one of the radicals E is Hal, this substituent can be eliminated readily under basic reaction conditions.

The following bases can be used: alkali metal hydroxides, alkali metal carbonates, alcoholates, such as, for example, potassium tert.-buty late, or amines, such as, for example, dimethylani line, pyridine, collidine or quinoline; examples of solvents used are benzene, tolu25 ene, cyclohexane, THF or tert.-butanol. The amines used as bases can also be employed in an excess as solvents.

If one of the radicals E is an OH group, it is preferable to use acids, such as acetic acid or hydrochloric acid or mixtures of both, as dehydrating agents. It can be advantageous to add a solvent (for example water or ethanol). Elimination of acyl, a Iky Isu If on y I and alkoxysulfonyloxy or amino radicals can be carried out under similar conditions. A gentle elimination of sulfonic acid radicals, for example those of mesylates or tosyl20 ates, is effected by boiling in DMF or dimethyl sulfoxide with alkali metal carbonates, for example Li2C03z or with potassium acetate. Ammonia can be eliminated merely by heating the salts of the corresponding amino compounds (in particular the 4-amino derivatives). HCN can be eliminated similarly from compounds of the formula VI (one group E is CN) by heating. The elimination of HE from VI is ' generally effected at temperatures between 0 and about 250°, preferably between 50 and 200°. χ It is also possible, if desired, to convert a compound of the formula I into another compound of the formula I by methods which are in themselves known.

Thus, in a thioether of the formula I (A « -CHg-S-CHgCHj"), the thioether group can be oxidised to give an SO group or an SOg group, or, in a sulfoxide of the formula I (A = -CHg-SO-CHgCHg-), the SO group can be oxidised to give an SO2 group. If it is desired to obtain the sulfoxide, oxidation is carried out with, for example, hydrogen peroxide, per-acids, such as inch loroperbenzoi c acid, Cr(VI) compounds, such as chromic acid, KMnO^, 1-chlorobenztriazo le, Ce(IV) compounds, such as (NH^^CelNOj)^ aromatic diazonium salts containing negative substituents, such as o-nitrophenyldiazonium or p-nitropheny ldiazonium chloride, or electrolytically, under relatively mild conditions and at relatively low temperatures (about -80 to +100°). If, on the other hand, it is desired to obtain the sulfones (from the thioethers or the sulfoxides), the same oxidis9 ing agents are used under more vigorous conditions and/or in excess and, as a rule, at higher temperatures. The customary inert solvents can be present or absent in these reactions. Examples of suitable inert solvents are water, aqueous mineral acids, aqueous alkali metal hydroxide solutions, lower alcohols, such as methanol or ethanol, esters, such as ethyl acetate, ketones, such as acetone, lower carboxylic acids, such as acetic acid, nitriles, such as acetonitrile, hydrocarbons, such as benzene, or chlorinated hydrocarbons, such as chloroform ' a* or CCI4. A preferred oxidising agent is 30% aqueous hydrogen peroxide. If it is used in the calculated amount in solvents such as acetic acid, acetone, methanol, ethanol or aqueous sodium hydroxide solution at tempera5 tures between -20 and 100°, this oxidising agent gives the sulfoxides, while in excess, at higher temperatures, preferably in acetic acid or in a mixture of acetic acid and acetic anhydride, it gives the sulfones.

Ethers of the formula I in which the radicals Ind 10 and/or Ar are monosubstituted or disubstituted by 0-alkyl can be split, whereupon the corresponding hydroxy derivatives are formed. For example, the ethers can be split by treatment with the dimethyl su Ifide/boron tribromide complex, for example in toluene, ethers, such as THF, or dimethyl sulfoxide, or by fusing with hydrohalides of pyridine or aniline, preferably pyridine hydrochloride, at about 150-250°, Or by treatment v/ith diisobutylaluminium hydride in toluene at about 0-110°.

COW groups can also be converted into other COW groups by methods which are in themselves known. Thus it is possible to oxidise aldehyde groups to give carboxyl groups, for example by means of Mn02 in an inert solvent, such as methylene dichloride. On the other hand, carboxyl groups can be reduced, for example by means of diisobutylaluminium hydride in toluene. Carboxyl groups can be esterified, for example by treatment with alcohols in the presence of an acid catalyst, or by reaction.with diazoalkanes. Converting the carboxylic acids into their chlorides, for example by means of SOCl2, and subsequently reacting the product with NHj or amines results in the corresponding carboxamides, which can also be obtained by treating the carboxylic acid esters with ammonia or amines. Solvolysis of the esters or amides, preferably hydrolysis under the conditions indicated above, results in the carboxylic acids; in particular, carboxylic acids can be obtained from the carbamoyl compounds by treating the tatter with NaOH or KOH in aqueous glycols or glycol ethers, for example diethylene glycol monomethyl or monoethyl ether, preferably at temperatures between about 50 and about 200°.

Reduction of COW groups, in particular formyl, a Ikoxycarbonyl or carboxyl groups, can also result in hydroxymethyl groups. It is preferable to use a complex hydride, such as LiAlH^; aldehydes and esters can also be reduced by means of other reducing agents out of those listed above. It is preferable to carry out the reaction under the conditions indicated above. Conversely, hydroxymethyl groups can be oxidised to give formyl or carboxyl groups, for example by means of Mn(>2 or CrOg or derivatives thereof.

The resulting base of the formula I can be converted into the appropriate acid addition salt by means of an acid. Acids which afford physiologically accept15 able salts are suitable for this reaction. Thus it is possible to use inorganic acids, for example sulfuric acid, hydrogen halide acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, nitric acid or sulfamic acid, and also organic acids, specifically aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicot inic acid, methanesulfonic or ethanesulfonic acid, ethanedisuIfonic acid, 2-hydroxy30 ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemonosuIfonic and naphthaLenedisulfonic acids and laurylsulfuric acid.

The free bases of the formula I can, if desired, be liberated from their salts by treatment with strong bases, such as sodium hydroxide or carbonate or potassium hydroxide or carbonate.

The invention also relates to the use of the compounds of the formula I and their physiologically acceptable salts for the preparation of pharmaceutical formula23 tions, especially by a non-chemical route. In this connection, they can be brought into a suitable dosage form, together with at least one excipient or auxiliary and, if appropriate, in combination with one or more further active compound(s).

The invention also relates to agents, especially pharmaceutical formulations, containing at least one compound of the formula I and/or one of its physiologically acceptable salts. These formulations can be employed as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral administration or for topical application and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc or petroleum jelly. Tablets, coated tablets, capsules, syrups, elixirs, drops or suppositories, in particular, are used for enteral administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants are used for parenteral administration, while ointments, creams or po.wders are used for topical application. The new compounds can also be lyophilised, and the resulting lyophilisates can be used, for example, for the preparation of injection formulations.

The formulations indicated can be sterilised and/ or can contain auxiliaries, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavouring substances and/or aroma substances. If desired, they can also contain one or more further active compounds, for example one or more vitamins.

The invention also relates to the use of the compounds of the formula I and their physiologically acceptable salts in the therapeutic treatment of the human or animal body and in combating diseases, in particular Parkinson's disease, extrapyrami da I disorders in neuroleptic therapy, depressions and/or psychoses and side effects in the treatment of hypertension (for example by means of pt-methyIdopa). The compounds can also be used in endocrinology and gynaecology, for example for the therapy of acromegalia, hypogonadism, secondary amenorrhoea, premenstrual syndrome, undesirable puerperal lactation and generally as a prolactin inhibitor, and also for the therapy of cerebral disorders (for example migraine), particularly in geriatrics, in a manner similar to that of certain ergot a Ika loids,and also for lowering the blood pressure.

In this respect, the substances according to the invention are, as a rule, administered analogously to J 5 known, commercially available formulations (for example bromocriptin or dihydroergocornin), preferably in dosages between about 0.2 and 500 mg, in particular between 0.2 and 50 mg, per dosage unit. The daily dosage is preferably between about 0.001 and 10 mg/kg of body weight.

The low dosages (about 0.2 to 1 mg per dosage unit; about 0.001 to 0.005 mg/kg of body weight) are particularly suitable in this respect for use as migraine agents; for the other indications dosages between 10 and 50 mg per dosage unit are preferred. The particular dose for each ?.'> specific patient depends, however, on a very wide variety of factors, for example on the effectiveness of the particular compound employed, on age, body weight, general state of health, sex, diet, periods and means of adminis-! tration, the rate of excretion, the combination of medicaments and the severity of the particular disease to which the therapy relates. Oral administration is preferred.

In the examples below, customary working up means as follows: if necessary, water is added, the mixture is extracted with methylene dichloride, the phases are separated, the organic phase is dried over sodium sulfate and filtered and evaporated and the residue is purified by chromatography over silica gel and/or by crystallisation. Temperatures are quoted in °C.

Example 1 A solution of 28.4 g of methyl 3-(4-chloro-2thiabuty l>-indole-5-carboxylate Cor 32.8 g of methyl 3(4-bromo-2-thiabutyl)-indole-5-carboxylate; obtainable by reacting methyl gramine-5-carboxylate with 2-mercapto ethanol to give methy I 3-(4-hydroxy-2-thiabutyI)-indole5-carboxylate and subsequently reacting the latter with SOCI2 or PBrj3 and 16 g of 4-pheny1-1,2,3,6-tetrahydropyridine in 100 ml of acetonitrile is stirred for 12 hours at 20° and is worked up in the customary manner to give methyl 3-C4- (4-pheny 1-1,2,3,6-tetrahydropyridyl>-2-thiabuty 13-indo le-5-carboxylate (P); hydrochloride, m.p. 202-203°.

The following are obtained analogously from the corresponding starting materials of the formulae II and III; 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-5hydroxymethylindole, m.p. 178°, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl320 4-hydroxymethytindole, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl35- hydroxymethyIindo le, m.p. 118-120°, 3-C4-(4-phen y1-1,2,3,6-tet rahydropyr idyD-2-thiabutylD6- hydroxymethylindole, m.p. 142-143°, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyI>-2-th i abuty137- hydroxymethyl indole, 3- C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyll4- methoxycarbonylindole, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyL330 6-methoxycarbonylindole, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyll7-methoxycarbonylindole, 3- C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl34- ethoxycarbonylindole, 3-C4-(4-pheny1-1,2,3,6-tetrahydropyridyl)-2-thiabutyl35- ethoxycarbonylindole, 3-C4-(4-phen y1-1,2,3,6-tetrahydropyridyl)-2-thiabutyl36- ethoxycarbony lindole, m.p. 127-129° and 3-C4-(4-pheny l-1,2,3,6-tetrahydropyridyl)-2-thiabutyll" 7-ethoxycarbonylindole.

Exainple 2 A mixture of 2.64 g of methyl 3-(4-amino-2-thiabuty l)-indole-5-carboxylate ^obtainable by reacting methyl 3-(4-bromo-2-thiabutyI)-indole-5-carboxylate with potassium phthalimide and subsequent hydrolysis! and 2.15 g of 1,5-dichloro-3-phenyl-2-pentene (obtainable by reducing diethyl 3-phenyl-2-pentene-1,5-dioate with LiAlH^ and subsequently reacting the product with S0Cl2> in 40 ml of acetone and 40 ml of water is boiled for 24 hours and worked up in the customary manner. This gives P, hydrochloride, m.p. 202-203°.

Example 3 A suspension of 41.6 g of methyl 3-C4-(4-phenyl1.2.3.6- tetrahydropyridy1)-1,4-dioxobutyl!-indo le-5carboxylate Cm.p. 218°; obtainable from 4-(5-methoxycarbonyl-3-indole)-4-oxobutyric acid and 4-pheny 1-1,2,3,6tetrahydropyridine! in 3 litres of hot absolute THF is added dropwise, with stirring, to a suspension of 23.4 g of LiAlH^ in 1,100 ml of absolute THF, the mixture is boiled for 1 hour and cooled and the product is decomposed with water and sodium hydroxide solution and worked up in the customary manner. This gives 3-C4-(4-phenyl1.2.3.6- tetrahydropyridyl)-butyl!-5-hydroxymethylindole, m.p. 178°.

From the corresponding dioxo esters, for example: methyl 3-C4-(4-pheny1-1,2,3,6-tet rahydropyr i dy D-ί,4dioxobutyll-in dole-4-carboxylate, m.p. 228°, methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-1,4dioxobutyll-indole-6-carboxylate, m.p. 237°. and methyl 3-C4-(4-pheny 1-1,2,3,6-tet rahydropyri dyI)-1,4dioxobutyll-indo le-7-carboxylate, m.p. 208°, the following can be obtained analogously: 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl!-4hydroxymethylindole, m.p. 183-184°, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl!-6hydroxymethylindole, m.p. 179° and a? 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-7hydroxymethy lindole, m.p. 178°.

The following is obtained analogously from 3-C4oxo-4-(4-phen yl-1z2z3z6-tetrahydropyri dy I)-buty 13-in do le2-carboxylic acid by means of LiALH^ in THF: -C4-(4-phenyl-1,2,3,6-tet rahyd ropyridyl)-butyL3-indole2- carboxylic acid, m.p. 206-208°.

Example 4 g of NaBH^ in 20 ml of water is added, with stirring, to a solution of 4.51 g of 1-C4-(5-carboxy-3indo lyI)-buty13-4-phenylpyridinium bromide Eobtainable from 3-(4-bromobutyU-indole-5-carboxylic acid and 4phenyIpyridine] in 50 ml of 1N NaOH, and stirring is continued for a further 3 hours at 60°. Working up in the customary manner gives 3-E4-(4-phenyl-1,2,3,6-tetrahydropyridy l)-buty 13-in do le-5-carboxy I ic acid, m.p. 284-285°. Example 5 A mixture of 35.5 g of 3-E4-(4-pheny1-1 ,2,3,6tetrahydropyridy l)-butyU-5-cyanoindole Em.p. 167°; obtainable from the corresponding 5-formyl compound via the oxime3, 27.1 g of NaOH, 520 ml of water and 420 ml of diethylene glycol monoethyl ether is stirred for 3 hours at a bath temperature of 140°. The mixture is cooled and worked up in the customary manner to give 3-C4-(4phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-indole-5-carboxamide, m.p. 200-205°.

The following are obtained analogously by hydrolysing the corresponding nitriles: 3- C2-(4-pheny1-1,2,3,6-tetrahydropyridyl)-ethyl3-indole5-carboxamide, 3-C3-(4-pheny1-1,2,3,6-tetrahydropyridyl )-propy 13-indol e5- carboxami de, 3- C4-(4-pheny1-1,2,3,6-tetrahydropyridyI)-buty13-in do I e4- c arboxami de, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-indole6- carboxamide, m.p. 226°, 3-C4-(4-pheny 1-1,2,3,6-tetrahydropyridyI)-buty 13-indole7- carboxamide, m.p. 203°, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-5methoxyindole-6-carboxamide, 3-C4-(4-pheny1-1,2,3,6-tetrahydropyridyl)-butyl3-5hydroxyindole-6-carboxamide, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-7chloro in dole-4-carboxamide, 3-C4-(4-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)buty 13-indole-5-carboxamide, 3-C4-(4-p-hydroxypheny 1-1,2,3,6-tetrahydropyridyDbuty l3-indole-5-carboxami de, * 3-C5-(4-phenyl-1,2,3,6-tet rahydropyridyI)-penty13-indo Ie5-carboxami de, 3-C4-(3-pheny1-1,2,3,6-tetrahyd ropyridy1)-buty13-indole5-carboxamide, 3-C4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl3indoIe-5-carboxamide, 3-C4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyI3indo le-6-carboxamide, 3-£4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl3indo I e-5-carbox ami de, 3-£4-(3-p-hydr oxy pheny 1-1,2,3,6-tetrahydropyridyl)-butyl3indole-6-carboxamide, 3-£4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl3indo I e-4-carboxamide, 3-£4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl3indo Ie-5-carboxamide, 3-£4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl3indo I e-6-carboxamide, 3-£4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl3indo I e-7-carboxamide, 3-£4-(4-pheny1-1,2,3,6-tetrahydropyridyl)-2-thiabutyl35-methoxyindole-6-carboxamide, 3-£4-(4-phen y 1-1,2,3,6-tetrahydropyridyI)-2-th iabuty 135-hydroxyindole-6-carboxamide, 3-£4-<4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl37-chloroin do I e-4-carbox ami de, 3-£4-(4-m-hydroxypheny1-1,2,3,6-tetrahydropyridyl)-2-thiabuty 13-in dole-5-carboxamide, 3- C4-(4-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2thiabutyl3-indole-5-carboxamide, 3-C4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2thiabutyl3-indole-5-carboxamide, I 3-C4- (3-m-hydroxyphen y1-1,2,3,6-tet rahydropyridy1)-2t h i abuty13-indole-6-ca rboxami de, 3-C4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2thiabutyl3-indole-5-carboxamide, 3-C4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2thiabuty13-indole-6-carboxami de, 3-E4-(4-phenyIpi peri din o)-buty 13-indole-5-carboxami de, 3-E4-(4-phenyIpi peri di no)-buty13-indole-6-carboxamide, 3-C4-(4-m-hydroxyphenylpiperi dino)-butyl3-indole-5carboxamide, 3-E4-(4-m-hydroxyphenyIpiperi dino)-buty13-indo Le-6c a rboxami de, 3-E4-(4-p-hydroxyphenyIpiperidino)-butyI3-indole-5carboxamide, 3-E4-(4-p-hydroxypheny Ipi peri dino)-buty13-in dole-6carboxami de, 3-E4-(3-m-hydroxyphenylpiperidino)-butyl3-indole-5carboxamide, 3-E4-(3-m-hyd roxyphenyIpi per idino)-buty13-indole-6carboxami de, 3-E4-(3-p-hydroxyphenylpiperidino)-butyl3-indole-5carboxami de, 3-E4-(3-p-hydroxyphenyIpiperidino)-butyI3-indole-6carboxamide, 3-E4-(4-phenylpiperidino)-2-thiabutyl3-indole-5-carboxamide, 3-E4-(4-phenylpiperidino)-2-thi abutyl3-indole-6-carboxi amide, 3-C4-(4-m-hydroxyphenylpiperidino)-2-thiabutyl3-indole5- ca rboxami de, 3-E4-(4-m-hydroxyphenylpiperidino)-2-thiabutyl3-indole6- carboxamide, 3-E4-(4-p-hydroxyphenylpiperidino)-2-thiabutyl3-indole5-carboxami de, 3-C4-(4-p-hydroxyphenylpiperidino>-2-thiabutyl3-indole6-ca rboxam i de, 3-C4-(3-m-hydroxyphenylpiperidino)-2-thiabutyl3-indole5- carboxamide, 3-C4-(3-m-hydroxyphenyLpiperidino)-2-thiabutyl]-indoLe6- carboxamide, 3-E4-(3-p-hydroxyphenylpiperidino)-2-thiabutyl3-indole5- carboxamide and 3-C4-(3-p-hydroxyphenylpiperidino)-2-thiabutyl]-indol e6- carboxamide.

Example 6 The reaction is carried out as described in Example 5, but the mixture is boiled for 16 hours and, after working up in the customary manner, gives 3-C4-(4phen y1-1,2,3,6-tet rahydropyri dyI)-buty13-in dole-5-carboxylic acid, m.p. 284-285°.

The following are obtained analogously by hydrolysing the corresponding nitriles: 3-C2-(4-phenyl-1,2,3,6-tetrahydropyri dy I)-ethy13-indo I e5-carboxylic acid, 3-C3-(4-phenyl-1,2,3,6-tetrahydropyridyl)-propyl3-indole5- carboxylic acid, 3- C4-(4-phen y1-1,2,3,6-tet rahydropyr i dyl)-butyl3-indole4- carboxylic acid, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-indole6- carboxylic acid, m.p. 268°, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-indole7- carboxyI ic acid, m.p. 262-265°> 3-C4-(4-phen y1-1,2,3,6-tetrahydropy ridyl)-butyl3-5methoxyindole-6-carboxylic acid, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-5hydroxyindole-6-carboxylic acid, 3-C4-(4-pheny1-1,2,3,6-tetrahydropyri dy I)-buty 13-7chloroindole-4-carboxy I ic acid, m.p. 263-266° 3-C4-(4-0-methoxyphenyl-1,2,3,6-tetrahydropyridy l>-buty 13indole-5-carboxylic acid, 3-C4-(4-m-methoxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl3indoLe-5-carboxylic acid, ·/ 30 3-C4-(4-p-methoxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl3 indole-5-carboxylic acid, 3-C4-(4-o-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyL3 in do le-5-carboxy I ic acid, 3-C4-(4-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyL3 indo le-5-carboxy lic acid, 3-C4-(4-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyL3 jndo le-5-carboxy Iic acid, 3-C4-(4-C3-methoxy-4-hydroxypheriy U7I,2,3,6-tetrahydropyridyU-butyU-indole-5-carboxy lie acid, 3-C4-(4-(3,4-dimethoxyphenyl)-1z2,3,6-tetrahydropyridyl)buty13-in dole-5-carboxy I ic acid, 3-C4-(4-(3,4-methyIenedioxypheny1)-1,2,3,6-tetrahydropyridyl) -butyl3-indole-5-carboxylic acid, 3-C4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-butyl3indo le-5-carboxy I ic acid, 3-C4-(4-(3-thienyl)-1,2,3,6-tetrahydropyridyl)-butylJindo le-5-carboxy I ic acid, 3-C5-(4-phenyl-1,2,3,6-tetrahydropyridyl)-pentyl3-indole5-carboxylic acid, 3-C4-(3-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-indole5-carboxylic acid, 3-C4-C3-p-methoxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl3 in do I e-5-carboxy I ic acid, 3-C4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl3 in do le-5-carboxy I ic acid, 3-C4-(3-m-hyd roxypheny 1-1,2,3,6-tetrahydropyridyl)-butyl3 in do I e-6-carboxy I ic acid, 3-C4-(3-p-hydroxypheny1-1,2,3,6-tet rahydropyridyI)-buty13 indole-5-carboxylic acid, 3-C4-(3-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl3indo le-6-carboxyIic acid, 3-C4-(4-phenylpiperidino)-butyl3-indole-5-carboxylic acid 3-E4-(4-phenylpiperidino)-butyl3-indole-6-carboxylic acid 3-E4-(4-m-hydroxyphenylpiperidino)-butyl3-indole-5carboxylic acid, 3-E4-(4-m-hydroxyphenylpiperidino)-butyl3-indo le-6carboxylid acid. 3-E4-(4-p-hydroxyphenylpiperidin o)-but yl3-indole-5carboxy I i c acid, 3-E4-(4-p-hydroxyphenylpiperidino)-butyl3-indole-6carboxylicacid, 3-E4-(3-m-hydroxyphenylpi peridino)-buty13-in dole-5carboxylic acid, 3-E4-(3--hydroxyphenylpi peri dino)-buty13-in dole-6carboxylic acid, 3-E4-(3-p-hydroxyphenylpiperidino)-butyl3-indole-5carboxylic acid, 3-E4-(3-p-hydroxyphenylpi peridino)-buty13-indole-6carboxylic acid, 3-E4-(4-phenylpiperi dino)-buty13-7-chloroin dole-4-carboxy.lic acid and 3- C4-(3-m-hydroxyphenylpiperidino)-buty13-7-chloroin dole" 4- carboxylic acid.

Example 7 4.68 g of methyl 1-benzenesulfonyl-3-E4-(4phenyl-1,2,3,6-tetrahydropyri dyI)-butyl3-indole-5-carboxylate Eobtainable from methyl 1-benzenesulfonyl-3-(4chlorobutyl)-indole-5-carboxylate and 4-pheny1-1,2,3,6tetrahydropyridine3 are boiled with 1 g of KOH in 7 ml of water and 14 ml of ethanol for 16 hours, and the mixture is concentrated and worked up in the customary manner to give 3-E4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3indo le-5-carboxyIic acid, m.p. 284-285°.

Example 8 2.76 g of Na are dissolved in 180 ml of ethanol, 21.9 g of 1 -(2-mePcaptoethyI)-4-pheny1-1,2,3,6-tetrahydropyridine Eobtainable by reacting 4-pheny1-1,2,3,6tetrahydropyridine with thioglycolic acid to give 1-(2mercaptoacetyl)-4-phenyl-1,2,3,6-tetrahydropyridine and reducing the latter with L1AIH43 and 23.2 g of methyl gramine-5-carboxylate are added, the mixture is boiled for 16 hours and evaporated, and the residue is worked up in the customary manner to give P, hydrochloride, m.p. 202-203°.

The following are obtained analogously from the corresponding starting materials of the formulae IV and V: methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyll-5-methoxyindole-6-carboxylate, ethyl 3-C4-(4-pheny 1-1,2,3,6-tetrahydropyridyI)-2-thia, butyll-5-methoxyindole-6-carboxylate, hydrochloride, m.p. 169-173°, v methyl 3-C4-(4-pheny 1-1,2,3,6-tetrahydropyridyI>-2-thiabutyll-5-hydroxyindole-6-ca rboxylate, ethyl 3-C4-<4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabuty 11-5-hydroxyin do I e-6-carboxylate and methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyll-7-chloroindo le-4-carboxylate.

Example 9 4.05 g of 1-methyl-3-C4-(4-hydroxy-4-pheny1-1piperidyl)-buty ll-indole-5-carboxamide ^obtainable by reacting 1-methyl-3-(4-bromobutyl>- in dole-5-ca rbox amide with 4-piperidone, followed by reaction with C^HjLi and hydrolysis! are heated at 50° with 40 ml of hydrochloric acid for 2 hours, and the mixture is worked up in the customary manner to give 1-methy l-3-C4-(4-pheny 1-1,2,3,6tetrahydropyridyl)-butyl!-indole-5-carboxamide.

Example 10 ml of 30% HjOg are added to a boiling solution of 4.06 g of P" in 50 ml of ethanol, and the mixture is then boiled for 3 hours. After a further 4 ml of the oxidising agent have been added, the mixture is boiled « for a further 9 hours and is cooled and worked up in the customary manner to give methyl 3-C4-(4-pheny 1-1,2,3,630 tetrahydropyridyl)-2-thiabutyll-indole-5-carboxylate-Sox i de.

Example 11 ml of 30% Η2θ2 are ac*ded to a solution of 4.06 g of P in 20 ml of acetic acid, and the mixture is boiled for 90 minutes. Working up in the customary manner gives methyl 3-C4-(4-pheny 1-1,2,3,6-tetrahydropyridyl)-2-thiabutyll-indole-5-carboxylate-S,S-dioxide.

Example 12 A mixture of 4.04 g of 3-C4-(4-p-methoxyphenyl1,2,3,6-tetrahydropyridyl)-butyl3-indole-5-carboxylic acid and 3.5 g*of pyridine hydrochloride is stirred for 3 hours at 160°. Working up in the customary manner gives 3-C4-(4-p-hydroxyphenyl-1,2,3,6-tet rahydropyr idyI)buty ll-indole-5-carboxylic acid.

Example 13 g of 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)buty ll-5-hydroxymethyIindole are dissolved in 1.6 litres of THF, and 300 ml of ether are added. 55 g of MnOg are added with stirring. The mixture is stirred for 16 hours at 20°, a further 100 g of MnOj are added in portions, and stirring is continued for a further 100 hours at 20°. Filtration and working up in the customary manner gives 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyll-5-formylindole,m.p.131°.

The following are obtained analogously by oxidising the corresponding hydroxymethylindoles: 3-C4-(4-pheny1-1,2,3,6-tetrahydropyridyL)-buty 11-2-formylindole, m.p. 129-130°, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyll-4-formylindole, 3-C4-(4-pheny1-1,2,3,6-tet rahydropyri dy L)-butyll-6-formy l~ indole, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyll-7-formylin do le, 3- C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyll4- formyI in do Ie, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyll5- formylindole, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyll5-formylindole and 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyll7-formylindole.

Example 14 3.9 g of 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyll-6-hydroxymethyI in dole are dissolved in 50 ml of methylene dichloride, 9 g of Mn02 are added to the solution, the mixture is stirred for 60 hours at 40° and the insoluble components are filtered off. Working up the filtrate in the customary manner gives 3-E4-(4-phenyI 1,2,3,6-tetrahydropyridyl)-butyl3-indole-6-carboxylic acid, m.p. 268°.

Example 15 3.88 g of 3-E4-(4-pheny1-1,2,3,6-tetrahydropyridy l)-buty 13 —5—formy I indo le are dissolved in 80 ml of methylene dichloride, 9 g of Mn02 are added, and the suspension is stirred for 48 hours at 40°. Filtration and working up in the customary manner give 3-E4-(4phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-indole-5carboxylic acid, m.p. 284-285°.

Example 16 4.04 g of 3-E4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-buty13-indole-5-carboxyLic acid are suspended in 25 ml of toluene, and a 3-fold molar amount of a 20% strength solution of diisobutylaluminium hydride in toluene is added dropwise, under N2 and with stirring, the mixture is boiled for 2 hours and cooled and is decomposed with water, and the product is worked up in the customary manner to give 3-E4-(4-pheny 1-1,2,3,6-tetrahydropyridy l)-butyl3-5-formylindole, m.p. 131°.

Example 17 A solution of 4.04 g of 3-E4-(4-pheny 1-1,2,3,6tetrahydropy r i dy I)-but y 13-in do le-5-carboxy I i c acid in 40 ml of THF is added dropwise, with stirring and under N2, to a suspension of 0.76 g of lithium aluminium hydride in 30 ml of THF. The mixture is stirred for a further 2 hours at 20°, is decomposed with dilute sodium hydroxide solution and then with water and is filtered. The filtrate is worked up in the customary manner. This gives 3-E4-(4-pheny1-1,2,3,6-tetrahydro35 pyridy I)-buty 13-6-hydroxymethy I in do le, m.p. 178°.

Example 18 A solution of 4.18 g of methyl 3-E4-(4-pheny l1,2,3,6-tetrahydropyridyl)-butyl3-indole-5-carboxylate in ml of THF is added dropwise, with stirring and under N2, to a suspension of 0.57 g of lithium aluminium hydride in 20 ml of THF. The mixture is stirred for 1 hour at 20° and is decomposed with dilute sodium hydroxide solution and then with water and is filtered, and the filtrate is worked up in the customary manner to give 3C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-5-hydroxymethylindole, m.p. 178°.

The hydroxymethyl compounds mentioned in Example 3 and also 2-hydroxymethy 1-3-E4-(4-pheny1-1,2,3,6-tetrahydropyridyl)-butyl3-indole, m.p. 162-163.5° are obtained analogously from the corresponding esters.

Example 19 A solution of 3.88 g of 3-E4-(4-pheny1-1,2,3,6tetrahydropyridyl)-buty13-5-formyIindole in 40 ml of THF is added dropwise, under N2 and with stirring, to a suspension of 0.57 g of lithium aluminium hydride in 20 ml of THF. The mixture is stirred for a further hour at 20° and is decomposed with dilute sodium hydroxide solution and then with water and is filtered and worked up in the customary manner to give 3-E4-(4-phenyl-1,2,3,6tetrahydropyridyl)-butyl3-5-hydroxymethylindole, m.p. 178°.

Example 20 HCl is passed into a boiling solution of 4.04 g of 3-E4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3indo le-5-carboxy I ic acid in 50 ml of absolute ethanol for 2 hours. The mixture is boiled for a further hour and worked up in the customary manner to give ethyl 3-E4-(4phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-indole-5carboxylate. Rf 0.65 (silica gel; 8:2 CH2C l2/CHjOH).

The following are obtained analogously by esterification: methyl 3-E4- (4-pheny 1-1 ,2,3,6-t et rahyd ropyri dyI)-but y 13 J indole-5-carboxylate, methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3in do le-6-carboxylate, methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl35 in doLe-7-carboxy late, ethyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3indole-2-carboxylate, ethyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3indole-4-carboxylate, ethyl 3-C4-(4-pheny 1-1,2,3,6-tetrahydropyridyI)-buty13indo I e-6-carboxy late, ethyl 3-C4-(4-pheny1-1,2,3,6-tetrahydropyridyI)-buty137-carboxy late, methyl 3-C4-(4-phenyI-1,2,3,6-tet rahydropyridyI)-buty 1315 5-methoxyindole-6-carboxylate, ethyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl35-methoxyindole-6-carboxylate, methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl35-hydroxyin do Ie-6-carboxy late, ethyl 3-C4-(4-pheny1-1,2,3,6-tetrahydropyridyl)-buty 135-hydroxyindo I e-6-ca rboxylate, methyl 3-C4-(4-phenyI-1,2,3,6-tetrahydropyridy I)-buty 137-ch loroindole-4-carboxy late, hydrochloride, m.p. 219-221° ethyl 3-C4-(4-pheny1-1,2,3,6-tetrahydropyridyI)-buty1325 7-chloroindo Ie-4-carboxy late and butyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridy l)-butyl3indole-5-carboxylate.

Example 21 4.04 g of 3-C4-(4-pheny1-1,2,3,6-tetrahydropyrid30 y l>-buty 13-indo le-5-carboxy I ic acid are dissolved in 30 ml of chloroform, the solution is saturated uith HCl gas, 1.8 g of thionyl chloride are added dropwise and the mixture is boiled for 2 hours. After evaporation, 30 ml of toluene are added and the mixture is evaporated again.

The residue is dissolved in 20 ml of chloroform, this solution is added dropwise, with stirring, to a saturated solution of ammonia in 50 ml of chloroform, the mixture is stirred for 2 hours at 20° and is filtered, and the filtrate is concentrated. Working up in the customary manner gives 3-C4-(4-pheny1-1,2,3,6-tetrahydropyridyI)buty 13-in do le-5-carbox amide, m.p. 207-208°.

The following are obtained analogously from the acids by reacting the latter with SOCI2 and then with ammonia or the corresponding amines: 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyD-butyl3-indole2- ca rbox amide, 3- C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl3-indole2- carboxylic acid N-methy lamide and 3- C4-(4-phen yl-1,2,3,6-tetrahydropyridyl)-butyll-indole2- carboxylic acid Ν,Ν-dimet.hylamide. Rf 0.72 (silica gel, 8:2 CH2Cl2/CH30H).

Example 22 0.02 mol of concentrated ammonia (D = 0.9) is added dropwise at 20° to a solution of 4.18 g of methyl 3- C4-(4-pheny1-1,2,3,6-tetrahyd ropyridyI)-buty13-indo I e5-carboxylate in 30 ml of dimethylformamide. The mixture is stirred for a further hour at 20° and worked up in the customary manner to give 3-C4-(4-pheny1-1,2,3,6tetrahydropyridyl)-buty13-indole-5-carboxamide, m.p. 2Q7t 208°.

Example 23 A mixture of 37.3 g of 3-C4-(4-pheny1-1,2,3,6tetrahydropyridyl)-butyl3-5-carbamoylindole, 27.1 g of NaOH, 525 ml of water and 450 ml of diethylene glycol monoethyl ether is boiled with stirring for 16 hours.

The mixture is cooled, worked up in the customary manner and acidified to give 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyI>-buty13-indo le-5-carboxy I ic acid, m.p. 284-285°. Example 24 4.5 g of 3-C4-(4-pheny1-1,2,3,6-tetrahydropyridyl) -2 -thiabutyll -5 -methoxy-6- ethoxycarbon ylindole are boiled with 20 ml of water and 100 ml of 2N ethanolic KOH for 30 minutes> and the mixture is worked up in the customary manner to give 3-C4-(4-pheny1-1,2,3,6-tetrahydropyridyl)-2-thiabuty 13-5-methoxyindoIe-6-ca rboxyIi c acid, m.p. 168-171°.

The following are obtained analogously by saponifying the corresponding methyl or ethyl esters: 3-C4-(4-phenyl-1,2,3,6~tetrahydropyridyl)-2-thiabutyl3indo I e-4-carboxy I ic acid, 3-C4-(4-pheny I-1,2,3,6-tetrahydropyridy 1)-2-thiabuty 13• indo le-5-carboxy I ic acid, m.p. 184-189°, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl3i in do Ie-6-carboxyIic acid, 3-C4-(4-pheny1-1,2,3,6-tetrahydropyridyI)-2-th iabuty1310 indole-7-carboxylic acid, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl35-hydroxyindole-6-carboxylic acid, 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl37-chloroindo le-4-carboxylic acid, 3-C4-(4-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2thiabuty 13-in dole-5-carboxyIic acid, 3-C4-(4-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2thiabutyl3-indole-5-carboxylic acid, 3-C4-(3-m-hydroxypheny1-1,2,3,6-tetrahydropyridy 1)-220 thiabuty 13-in dole-5-carboxyIic acid, 3-C4-(3-m-hyd roxypheny1-1,2,3,6-t et rahyd ropyri dyI)-2thiabutyl3-indole-6-carboxylic·acid, 3-C4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2thiabutyl3-indole-5-carboxylic acid, 3-C4-(3-p-hydroxypheny1-1,2,3,6-tetrahydropyridyI)-2thiabutyl3-indole-6-carboxylic acid, 3-C4-(4-phenylpiperidino)-2-thiabutyl3-indole-5-carboxyv licacid, 3-C4-(4-phenylpiperidino)-2-thiabutyl3-indol e-6-carboxy 30 lie acid, 3-C4-(4-m-hydroxyphenyIpi peridino)-2-thiabutyl3-indole5- carboxylic acid, 3-C4-(4-m-hydroxyphenylpiperidino)-2-thiabutyl3-indole6- carboxylic acid, 3-L4-(4-p-hydroxyphenylpiperidino)-2-thiabutyl3-indole5- carboxylic acid, 3-C4-(4-p-hyd roxypheny Lpiperidino)-2-thiabutyl3-indole6- carboxylic acid, 3"C4-(3"n»-hydroxyphenylpiperid'ino)"2-thiabutyl3-indole5- carboxylic acid, 3-C4-(3-w· hyd roxypheny Ipi peri dino)-2-thi abuty 13- indo le6- carboxylic acid, 3-C4-(3-m"hydroxyphenylpiperidino)-2-thiabutyl3-7"chloroindo I e-4-carboxyIic acid, » 3-C4-C3-p-hydroxyphenyIpiperidino)-2-thiabutyl3-7-chloroindole-5-carboxylic acid and v 3-C4-(3-p-hydroxyphenyIpiperi dino)-2-thiabuty13-7-chloro10 indole-6-carboxyIic acid.

Example 25 In analogy to Example 1, the following are obtained from the corresponding starting materials of formula II and III: 3-/3-(4-pheny1-1,2,3,6-tetrahydropyridyl) -propy//-4-hydroxy15 methy1-indole , m.p. 164 - 168° 2-hydroxymethyl-3-/4-(4-pheny1-1,2,3,6-tetrahydropyridyl )bu tyl_/-5-me thoxy indole , m.p. 145 - 146° 2- hydroxymethy 1-3-/4-(4-phenyl-l,2,3,6-tetrahydropyridyl)buty//-6-methoxyindole. 2d lx amp L e 26 In analogy to Example 5, there are obtained from I lie corresponding oxo-carboxy1ic acids: -/2 - ( 4 - ph e n y 1 - 1,2,3,6 -1 e t r ah y d r opy r i d y 1 ) - e t hy // - i n d ο 1 e - v 6-carboxylic acid, m.p. 7240° 3-/3-( 4-pheny1-1,2,3,6-tetrahydropyridy1)-propy//-indole-4carboxylic acid, m.p. 268 - 271° 3- /4- (4-phenyl-l ,2,3,6-tetrahydropyridyl) -buty//-5-hydroxyindole-6-carboxylic acid 3-/4 - ( 4-pheny 1-1,2,3,6-tetrahydropyridyl) - bu ty_l/-6-hydroxyindole-5-carboxylic acid 3-/4-(4-pheny1-1,2,3,6-tetrahydropyridyl)-2-thiabuty//-5hydroxy-indole-6-carboxy1ic acid -/4-(4-phenyl-l,2,3,6-tetrahydropyridyl)-2-thi abuty//6-hydroxy-indoie-5-carboxylic acid. ’ 41> Example 27 In analogy to Example 8 there is obtained from l-(2~mercaptoethy1)-3-m-hydroxyphenyl-piperidine and 5-hydroxyt methy 1 -gramine: 3-/4-(3-m-hydroxypheny1-piper idino) -2-thiabuty 1/-5hydroxymethyl-indole.

Example 28 A solution of 1.5 g of diisobufylaluminiumhydride in 15 ml of toluene is added with cooling and stirring to a suspen10 sion of 3.9 g of 2-hydroxymethy 1-3-/4-(4-pheny1-1,2,3,6tetrahydropy ridyl)-buty_l/-6-methoxy - indole in 400 ml of toluene. The mixture is warmed to room temperature, refluxed for 3 hours with stirring, cooled and worked up in the usual manner. 2-Hydroxymethy1-3-/4-(4-pheny1 15 1,2 , 3,6-1 e t r ahydropy r i dy 1 )-bu tyl_/-6-hydroxy-indole is obtained .

From the corresponding 5-methoxy compound there is obtained analogously: 2-hydroxymethyl-3-/4-(4-phenyl-l,2,3,6-tetrahydropyridylΙΣΟ buty1/-5-hydroxy-indole . •7 The examples below relate to pharmaceutical formulations containing amines of the formula I or acid addition salts thereof: Example A: Tablets A mixture of 1 kg of 3-C4-(4-pheny1-1,2,3,6tet rahydropyridyL)-butyl]-indole-5-carboxamide, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the customary manner to give tablets, so that each tablet contains 10 mg of active compound.

Example B: Coated tablets Tablets are compressed analogously to Example A and are then coated in a customary manner with a coating composed of sucrose, potato starch, talc, tragacanth and colorant.

Example C: Capsules kg of 3-C4-(4-pheny1-1,2,3,6-tetrahydropyridyI) buty 13-indole-5-carboxyIic acid are filled into hard gelatine capsules in a customary manner, so that each capsule contains 20 mg of the active compound.

Example D: Ampoules A solution of 1 kg of 3-C4-(4-phenyl-1,2,3,6tetrahydropyridyl>"butyl3-5-methoxyindo Le-6-ca rboxylie acid hydrochloride in 60 litres of twice distilled water is filtered under sterile conditions and is filled into ampoules, which are lyophilised under sterile conditions and closed in a sterile manner. Each ampoule contains 10 mg of active compound.

Tablets, coated tablets, capsules and ampoules containing one or more of the other active compounds of the formula I and/or physiologically acceptable acid addition salts thereof can be obtained analogously.

Claims (11)

CLAIMS :

1. An indole derivative of the general formula I wherein Ind is an indol-3-yl radical which is substituted by a hydroxymethyl or COW group and which can additionally be mono- or disubstituted by alkyl, 0-alkyl, OH, F, Cl or Br, W is H, OH, 0-alkyl, NH 2 , NHalkyl or N(alkyl> 2 , A is -CCH 2 ) n -, -CH 2 -S-CH 2 CH 2 -, -CH 2 -S0-CH 2 CH 2 or -CH 2 -S0 2 -CH 2 CH 2 -, n is 2, 3, 4 or 5, the two radicals Y are each H or together are a C-C bond, one radical Z is Ar, the other radical Z is H and Ar is a phenyl group which is unsubstituted or is monoor disubstituted by 0-alkyl and/or OH or is substituted by a methylenedioxy group, or Ar is a 2-thienyl or 3-thienyl group, in which formula each of the alkyl groups has 1 - 4 C atoms, wherein, however, when n is 2 or 3, the hydroxymethyl or COW group must be in the 4-, 5-, 6- or 7-position of the indol-3-yl radical, or a physiologically acceptable acid addition salt thereof .

2.a) 3-C4-(4-Pheny1-1,2,3,6-tet rahyd ropyr i dyl>-butyljindole-5-carboxylic acid; or b) 3-C4-(4-Phenyl-1,2,3,6-tet rahyd ropyr i dyl)-butyl]indole-5-carboxamide.

3. A process for the preparation of an indole derivative of the general formula I according to Claim 1 ora physiologically acceptable acid addition salt thereof, which comprises reacting a compound of the general formula II Ind-A-X 1 II wherein X 1 is X or NH 2 and X is Cl, Br, I, OH or a reactive, functionally modi’* fied OH group, and Ind and A have the meanings indicated in Claim 1, with a compound of the general formula III X 2 -CH 2 CH 2 -CYZ-CYZ-CH 2 -X 3 III wherein 2 3 1 X and X can be identical or different and, if X 1 is NH 2 , are each X and otherwise are together NH and Y and Z have the meanings indicated in Claim 1, or reacting a ccmpound which otherwise corresponds to the formula I, but which contains one or more reducible group(s) and/ or one or more additional C-C and/or C-N bond(s) instead of one or more hydrogen atoms, with a reducing agent, or reacting a ccnpound which otherwise corresponds to the formula I, but which contains one or more solvolysable group(s) instead of one or more hydrogen atoms, with a solvolytic agent, or, in order to prepare a thioether of the formula I wherein A is -CH 2 -S-CH 2 CH 2 ~, reacting a compound of the general formula IV Ind-CH 2 N(R> 2 IV wherein R is alkyl having 1-4 C atoms or both radicals R together are also —CCH 2 > p — or -CHjjCH^CHgCHg” end p is 4 or 5 and V Ind has the meaning indicated in Claim 1, with a thiol of the general formula V HS-CH 2 CH 2 wherein Y and Z have the meanings indicated in Claim 1, or with one of its salts, or, in order to prepa re a compound of the formula I wherein both radicals Y together are a C-C bond, reacting a compound of Lhe general formula VI wherein one radical E is X, CN or NH2, the other radical E is H and Ind, A, Z and X have the meanings indicated, with an agent which splits off HE, and/or in a compound of the formula I, if appropriate, oxid15 give an SO group to give an S0 2 group with the formation of an or SO20 ising a thioether group to group, or oxidising an SO group and/or cleaving an alkoxy group OH group, and/or converting a COW group into another COW group by oxidation, reduction, esterification, amidation or so I vo ly s i s, an d/o r reducing a COW group to give a hydroxymethyl group, and/or oxidising a hydroxymethyl group to give a CHO or COOH group, and/or converting a resulting base of the formula I, by treatment with an acid, into one of its physiologically acceptable acid addition salts.

4. Ά process for the preparation of a pharmaceutical formulation, which comprises bringing a compound of ι the formula I according to Claim 1 and/or one of its physiologically acceptable acid addition salts into a 5. Suitable dosage form together with at least one solid, liquid or semiliquid carrier or auxiliary and, if appropriate, in combination with one or more further active compounds.

5. A pharmaceutical formulation containing at least 10 one compound of the general formula I according tp Claim 1 and/or one of its physiologically acceptable acid addition salts in association with a pharmaceutically acceptable carrier or diluent therefor.

6. A compound of the general formula I according tp 15 Claim 1 for use in combating diseases.

7. The use of a compound of the general formula 1 according to Claim 1 for the manufacture of a pharmaceutical formulation. .1 4T

8. An indole derivative of the general fonnula I given and defined in claim 1 or a physiologically acceptable acid addition salt thereof, substantially as hereinbefore described with particular reference to Examples 1-28 of the accompanying Examples.

9. A process for the preparation of an indole derivative of the general formula I given and defined in claim 1 or a physiologically acceptable acid addition salt thereof, substantially as hereinbefore described with particular reference to Examples 1-28 of the accompanying Examples.

10. An indole derivative of the general formula I given and defined in claim 1 or a physiologically acceptable acid addition salt thereof, whenever prepared by a process claimed in claim 3 or 9.

11. A pharmaceutical formulation according to claim 5, substantially as hereinbefore described with particular reference to Examples A-D of the accompanying Examples.