NO159929B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE N-SUBSTITUTED 2-PYRIDYL INDOLES. - Google Patents

Description

According to US patent 3,468,894, 1-unsubstituted 3-methyl-2-(3- or 4-pyridyl)-indoles are known as diuretic agents. 2-(2-pyridyl)-indole-3-(acetic and propionic) acids are mentioned, e.g. in Pharm. Bull. 4 1° (1956) or in Chem. Abstracts 64., 1 9540d (1 966). Various optionally substituted 2-(3-pyridyl)-indole-3-acetic acids are discussed as chemical intermediates in Bull. Soc. Chim. France 1 966, 771 -2 and Bull. Soc. Chim. France 1969, 41 54-9. The preparation of 1-cyanoethyl-2-(2-pyridyl)-indoles is discussed in Pharmazie 23 (10) 557-60 (1968).

It has now surprisingly been found that N- (or 1)-substituted 2-pyridylindoles of formula I are a new class of highly effective and highly specific thromboxane synthetase inhibitors.

The above-mentioned properties contribute to the fact that the N-substituted 2-pyridylindoles according to the invention are particularly useful when administered alone or in combination to mammals, e.g. for the treatment or prevention of diseases that respond to inhibition of Thromboxane synthetase. These diseases include cardiovascular disorders such as thrombosis, atherosclerosis, coronary spasm, arrhythmias, cerebral seizures, migraine and other vascular headaches, myocardial infarction, angina pectoris, hypertension, breathing disorders such as asthma and apnea, and inflammatory diseases. It had also been established that the inhibition of thromboxane synthetase reduces metastasis in certain tumor classes. The compounds according to the invention can therefore be useful in the treatment of certain types of cancer.

The invention therefore relates to an analogous process for the production of new therapeutically active 1-substituted 2-pyrridyl indoles of the general formula I

wherein R 1 means (C 1 -C 4 )alkyl,

Pyr means 3- or 4-pyridyl,

R 2 and R 3 independently mean hydrogen, (C 1 -C 4 )-alkyl, halogen, hydroxy, (C 1 -C 4 )-alkoxy, carboxyl-C 1 -C 4 -alkyl, (C 1 -C 4 )-alkyloxycarbonyl-(C 1 -C 4 ) -alkyl or C-^-C4-alkyl-(thio),

A means alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, alkynylene of 2 to 4 carbon atoms, phenylene, a direct bond, C1-C4-alkylene-(thio or oxy)-phenylene or phenyl-(C1-C4 ) -alkenylene, B means carboxy, (C1-C4)-alkoxycarbonyl, carbamoyl, mono- or di-(C1-C4)-alkylcarbamoyl, hydroxymethyl, hydroxycarbamoyl, 5-tetrazolyl or formyl, or pharmaceutically acceptable salts of these compounds .

The general definitions used here have the following meanings within the scope of the invention.

An alkylene residue means alkylene with 1 to 12 carbon atoms, which may be straight or branched, and preferably means propylene, butylene, pentylene, hexylene or heptylene, the said residues being unsubstituted or substituted with one or more lower alkyl groups, with the precaution that the sum of the carbon atoms are not more than 12.

The term alkenylene means an alkenylene radical with 2 to 12 carbon atoms which radicals can be linear or branched and preferably means propenylene, 1- or 2-butenylene, 1- or 2-pentenylene, 1-2- or 3-hexenylene, 1-, 2-, 3- or 4-heptenylene. The mentioned residues are unsubstituted or substituted with 1 or more lower alkyl groups with the precaution that the sum of the carbon atoms does not exceed 12.

The term alkynyl denotes an alkynyl radical of 2 to 4 carbon atoms which is linear or branched and preferably means propynyl.

The term phenylene means 1,2-, 1,3-<p>g preferably 1,--4.-phenylene.

The term pyridyl means 3-pyridyl.

The expression "lower" defines in the above and the following mentioned organic groups, residues or compounds, such with a maximum of 7, preferably i, especially 1, 2 or 3 carbon atoms.

A (C1~C4)-alkyl group means e.g. ethyl, propyl or butyl, especially methyl.

A (C1~C4)-Alkoxy group is e.g. ethoxy, propoxy or especially methoxy.

A (C₁-C₁)-Alkoxycarbonyl group means e.g. methoxycarbonyl, propoxycarbonyl or isopropoxycarbonyl, especially ethoxycarbonyl. A mono-(C 1 -C 2 )-alkyl-carbamoyl group is e.g. N-methylcarbamoyl, N-propylcarbamoyl or especially N-ethylcarbamoyl. A di-(C-^-C^ )-alkyl-carbamoyl group means e.g. N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl and especially N,N-diethylcarbamoyl.

Halogen is preferably fluorine or chlorine, but can also be bromine or iodine.

Salts are preferably therapeutically usable salts, e.g. metal or ammonium salts of said compounds of formula I, which have free carboxy, especially alkali metal or alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, primarily easily crystallising ammonium salts. These are derived from ammonia or organic amines, e.g. mono-, di- or tri-lower (alkyl, cycloalkyl or hydroxyalkyl) amines, lower alkylene diamines or (hydroxy lower alkyl or aryl lower alkyl) lower alkyl ammonium bases, e.g. methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris-(hydroxymethyl)aminomethane or benzyltrimethylammonium hydroxide. The aforementioned compounds of formula I form acid addition salts. These are preferably prepared with acids which give therapeutically usable acid addition salts. Acids which give therapeutically useful acid addition salts are, for example, strong mineral acids, such as halogenated acids, e.g. hydrogen chloride or hydrogen b.rajmiti, sulphur-

acid, phosphoric acid, nitric acid or perchloric acid, or organic acids such as aliphatic or aromatic carboxylic or sulphonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, maleic acid, fumaric acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenAoic acid, salicylic acid, 4- aminosalicylic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanil or cyclohexyl sulfamic acid, or ascorbic acid.

The compounds according to the invention show valuable pharmacological properties, e.g. cardiovascular effects, as it selectively inhibits thromboxane elimination in mammals. This inhibition is achieved by selective reduction of the thromboxane synthetase mirror. The compounds are therefore useful in the treatment of diseases responsive to thromboxane synthetase inhibition in mammals. Such diseases are primarily cardiovascular disorders, as well as thrombosis, arterio-sclerosis, coronary spasm, cerebral ischemic attacks, migraine and other vascular headaches, myocardial infarction; angina pectoris and hypertension.

These effects can be demonstrated using in vitro experiments or in vivo animal experiments, preferably on mammals,

eg, guinea pigs, mice, rats, cats, dogs or monkeys. The compounds mentioned can be administered enterally or parenterally, preferably orally, or subcutaneously intravenously or intraperitoneally, e.g. by means of gels that are encapsulated, or in the form of starch-containing suspensions, or by ordinary solutions. The dose used may range from about 0.01 to 100 mg/kg/day, preferably about 0.05 to 50 mg/kg/day, especially about 0.1 to 25 mg/kg/day.

The in vitro inhibition of the thromboxane synthetase enzyme can be demonstrated analogously to the method of Sun. Biochem. Biophys., Res. Comm. 74, 1432 (1977). The test procedure is carried out as follows: 14 C-arachidonic acid is incubated with an enzyme mixture preparation, consisting of solubilized and partially purified prostaglandin cyclooxygenase from sheep seminal vesicles and from a crude microsome preparation of thromboxane synthetase from lysed human platelets. The test compound (dissolved in a buffer, or if necessary in a little ethanol) is added to the incubation medium. At the end of the incubation period (30 minutes), prostaglandin E2 (PGE2) is reduced by the addition of sodium borohydride to a mixture of prostaglandin F2<* and F^B (PGF£ (a + S)). The radioactive products and excess substrate are extracted with acetic acid ethyl ester qg the extract is evaporated to dryness. The residue is dissolved in acetone, applied dropwise to thin-layer plates and chromatographed with a solvent system of toluene: acetone : glacial acetic acid /~ 1 QO: 1 00: 3 (volume_}_7. The radioactive zones are located. The zones of thromboxane B2 ( TxB£) and PGFg a + 6 are transferred into liquid scintillation tubes and counted. The quotient of the numerical value of TXB2/PGF2 01 + 8 is calculated for each concentration of the test compound and the IC^Q value is determined graphically. This value is the concentration of the test compound in which the quotient of TxB^/PGF^ a+B is reduced to 50% of the control value.

The in vitro action on prostaglandin cyclooxygenase is measured according to a modification of the method of Tagecuchi et al, which is discussed in Biochemistry 10, 2372 (1971). The test procedure is as follows: Lyophilized sheep seminal vesicle microsomes are used as a prostaglandin-synthesizing enzyme preparation. The conversion of 14 C-arachidonic acid into PGE2 is measured. The test compounds (dissolved in a buffer, or if necessary in a little ethanol) are added to the incubation mixture. The prostaglandin is extracted and separated by thin-layer chromatography. The plates are examined for radioactive zones corresponding to PGEg, transferred into small scintillation tubes for liquids, and their radioactivity is counted. The IC Q value of the inhibition is determined graphically. This value means the concentration of the test compound which reduces the amount of synthesized PGE2 by around 50%.

The in-vitro effect on prostacyclin (PGI2) synthetase is measured analogously to the method by Sun et al. Prostaglandin 14, 1 <w>55» (1 977). The test procedure is as follows:

14. C-arachinonic acid is incubated with enzyme mixture, consisting of solubilized and partially purified prostaglandin-nyclo-oxygenase from sheep seminal vesicle and crude PGIg synthetase in the form of a microscopic fraction of bovine aortas.

The test compound (dissolved in a buffer or if necessary in a little ethanol) is added to the incubation medium. The reaction mixture is incubated in 100 mmol tris HC1 (pH 7.5) for 30 minutes at 37°C, acidified to pH 3, and extracted with acetic acid ethyl ester. The extract is evaporated to dryness, the residue is dissolved in acetone, applied to thin-layer plates, chromatographed with one of Sun et al. referred to as a solvent system. The radioactive zones are located with a detector. Those of 6-keto-PGF et

a (a stable end product of prostacyclin biotransformation) and PGE2 corresponding zones are transferred into small liquid scintillation tubes and counted. The quotient of the numerical values of 6-keto-PGF 2 a /PGE 2 is calculated for each concentration of the test compound used. The IC^Q value of he mair.gen is determined graphically - This value is the concentration of the sample value where the quotient of 6-keto-PGF'^ a/PGE2 is reduced to 50' %■ of cowtrol -value.

The inhibition of the synthesis and the reduction of the troiboxane plasma level is determined in vivo by the administration of the test compound to rats (analogous to those of Tai et al. in Annual Biochem. 87, 34-3, 1978, and by Salmon in prostaglandin 1 5 383 , 1978 mentioned procedure is as follows: Rats are treated with the test substance or the carrier material, and 2 hours later Inofor A 23187 (0.5 mg/kg) is injected intravenously. Two minutes after the Ionofor administration the animals are taken for analysis blood. In a specific single amount of plasma sample, thromboxane Bg is determined, and from additional single amounts, 6-keto-PGF.j a, stable metabolites of thromboxane A^, or prostacyclin (PG^) are determined by radioimmunoassay.

The compounds of formula I are very effective and selective thromboxane synthetase inhibitors. At effective dose levels and higher, neither the beneficial prostacyclin synthetase nor the porstaglandin cyclooxygenase enzyme system is significantly inhibited. Surprisingly, the prosta cycle is further increased in spe il et.

The IC^Q value for a compound according to the invention e.g. for 1 -(7-carboxyheptyl)-3-methyl-2 - (3-pyridyl)-indole, amounts to 1.2 x 10" mol for thromboxane synthetase inhibition, while for inhibition of prostacyclin synthetase and prostacyclin cyclo- oxygenase, the IC^Q value is each several powers higher, namely about 1 x 10"^ mol* 1 -(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole and 1 -(5-carboxy -pentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole as representative compounds according to the invention reduce the plasma level of thromboxane B2 in rats, at an oral dose as low as 0.10 mg/kg, with more than 50%. At this or higher oral doses, a surprising increase in the prostacyclin plasma response is determined.

Because of the above beneficial properties, the compounds of the invention are very valuable to mammals including humans as specific therapeutic agents.

The inhibition of the various produced aggregations of blood platelets and thrombocytopenia is induced by means of the compound according to the invention, e.g. using 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole, shows its usefulness in thromboembolism. Experimentally, prolongation of the soaking time in the rat is considered to be a sign of the beneficial anti-thrombotic effect. Thus, e.g. 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole this effect when administered orally to rats at a dose of approximately 30 mg/kg.

Against the beneficial effect in respiratory disorders is shown by the fact that the compound according to the invention protects against sudden death, which occurs due to the lung obstruction caused by arachindonic acid. Thus, e.g. 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole mice against sudden death by oral administration of a dose of 100 mg/kg.

The compounds according to the invention are prepared in a manner known per se, as the analog method according to the invention is characterized by

a) a compound of formula V in which X is hydrogen, alkali metal or tri-lower alkylsilyl, Rlf R2, R3 and Pyr have the indicated meaning, is condensed with a reactive functional derivative of a compound of formula VI

in which A and B have the above meaning, or

b) a compound of formula VII

wherein Pyr, ~ Rlt R2, R3, A and B have the above meaning,

ring closed or

c) a compound of formula VIII

wherein Pyr, R 1 , R 2 , R 3 , A and B have the indicated meaning, are cyclized, or

d) in a compound of formula Ia

wherein A, Pyr, R 1 , R 2 and R 3 have the above meaning, and C is

a different from a group B transferable group to the group B, the group C is converted to B, possibly during the extension of the chain A Within its definition,

and if desired or necessary, an interfering reactive group is protected in all of these processes transiently, and if desired, a formed compound of formula I is converted into another compound according to the invention, and/or if desired, a formed free compound is transferred to a salt or a formed salt to the free compound or to another salt.

Condensation according to method a) is preferably carried out under basic conditions, e.g. with a basic alkali metal salt or a quaternary ammonium salt, e.g. tetrabutylammonium hydroxide. Thus, e.g. especially compound of formula V, wherein X is hydrogen, preferably in situ, with a reactive metallizing agent to reactive organometallic intermediates. One preferably works at approximately 1 molar equivalent, e.g. of a strong alkali metal base, such as lithium diisopropylamide, sodium hydride or potassium tert-butoxide, in an inert solvent,

e.g. dimethylformamide, or tetrahydrofuran, in a temperature range between -50°C to +75°C, preferably -25° and +50°C.

The condensation of the formed reactive organometallic compound of formula V with a reactive functional derivative of a compound of formula VI is carried out in a temperature range between approximately -25° to +50°C, preferably at a temperature between 0° and 30°C. When B means carboxy, carbamoyl, hydroxycarbamoyl, or mono-lower alkyl-carbamoyl, one additionally uses, e.g. 1 mole equivalent of a metal is an intermediate.

For example, the starting substances with formula V, in which X means hydrogen, are either known (e.g. US patent 3 4.68 894, J. Chem. Soc. 1 955, 2865 Bull, Soc. Chim. France 1969 4154), or are prepared analogously, starting from corresponding optionally substituted phenylhydrazines and ketones of the formula ArCOCH^R^ in the presence of condensation agents such as e.g. ethanolic hydrogen chloride, or polyphosphoric acid according to the well-known indole synthesis according to Fischer.

Starting substances with formula VI or those discussed further below with formula Via are known, or if new, they can be prepared according to methods known per se, e.g. as discussed in US patent 4,256,757 or in British patent application 2,016,452A or as discussed here in the examples.

The compounds of formula I are preferably prepared according to method a) in that a compound of formula

V

in which X means hydrogen, R., means hydrogen or lower alkyl, Ar means pyridyl optionally substituted with lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl, each of the symbols R^ and Rp means hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, carboxy-lower alkyl , lower alkoxycarbonyl -lower alkyl, carboxy or lower alkoxycarbonyl, is condensed with a reactive functional derivative of a compound of formula Via

wherein A means alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, alkynylene of 2 to 12 carbon atoms, lower alkylene-phenyl lower alkyl one, lower alkylene-phenylene. phenylene lower alkylene, phenyl or a direct bond, and B<1 >means carboxy, lower alkoxycarbonyl, carbamoyl mono- or di- lower alkyl carbamoyl, hydroxymethyl, etherified hydroxymethyl, halomethyl, trialkyloxymethyl or cyano, preferably under basic conditions, and is converted into a compound of formula Ib

in which B' differs from B, the residue B' is optionally converted during extension of the chain A within its definition, to the group B, and if desired, a formed compound of formula I is transferred to another compound according to the invention.

The conversion of the precursor in which B' differs from B, and transfer of a formed product to another compound according to the invention is carried out according to chemical methods known per se.

The cyclization of starting substances of formula VII according to process variant b)> is carried out according to the well-known indole synthesis according to Fischer ]_ as discussed in "Hetero-cyclic Compounds, Indoles Part I", published by W.J. Houlihan, pages 232-317.7" thermally or preferably in the presence of an acidic condensing agent. One works in the presence of preferably halogen hydrogens, e.g. ethanolic hydrogen chloride or polyphosphoric acid, optionally in an inert solvent, at temperatures between approximately 50 and 100°C.

Hydrazone starting materials of formula VII are prepared either in isolation or preferably in situ by condensation of a ketone of formula ArCOCH^R^, in which Ar and R-j have the above meaning, with a substituted hydrazine of formula y.

wherein A, B, Rp and R^ have the above meaning, preferably in the presence of an acidic catalyst. The hydrazine starting materials of formula X are in turn preferably prepared, e.g. by nitrosation of correspondingly substituted anilines of formula XI

in which the symbols A and B, R2 and R^ have the above meaning, and subsequent reaction of the N-nitroso derivatives, e.g. with zinc in acetic acid or by other per se known methods.

When the mentioned intermediates contain disturbingly reactive groups, e.g. hydroxy or amino groups, such can preferably be temporarily protected in each step by easily removable protective groups, e.g.

in the form of esters, resp. amides according to well-known methods.

The cyclization according to method alternative c) is carried out under conditions of the indole synthesis according to Madelung as discussed in "Heterocyclic Compounds Indoles Part

I", editor W.J. Houlihan, pages 385-396. The intramolecular cyclization is preferably carried out in the presence of a strong base,

e.g. sodium ethoxide, sodium amide or potassium tert-butoxide, preferably at elevated temperature, e.g. about 30o°C, or in an inert high-boiling solvent, e.g. tetra-hydronaphthalene in.

The starting substances of formula VIII are obtained by acylation of substituted anilines of the above-mentioned formula XI with a compound of formula ArCOOH, or one of its reactive functional variants.

The conversion of a compound of formula Ia according to process alternative cl), wherein C is different from B,

to a compound of formula I, and the possible conversion of a formed product of formula I to another compound according to the invention, is carried out according to per se known chemical methods and/or as discussed here.

Transformable groups C are preferably tri-hydroxymethyl, esterified hydroxymethyl, etherified hydroxymethyl, halomethyl, cyan, 2-oxazolinyl, dihydro-2-oxazolinyl, lower alkanoyloxymethyl, acetyl, methyl, carboxycarbonyl, trihaloacetyl, di-lower hydroxymethyl, alkylenedioxymethyl, vinyl, alkynyl, esterified carboxy and amidated carboxy.

The starting materials with formula Ia are prepared according to process alternatives a to c, or as described

here using per se chemical methods. The individual definitions in the previously mentioned methods have the following meanings.

In a reactive functional derivative of an alcohol of formula VI or Via, the hydroxy group, e.g. esterified with a strong inorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydroiodic acid, an aliphatic or aromatic sulphonic acid, e.g. methanesulfonic or p-toluenesulfonic acid. These compounds are produced in a manner known per se.

Trialkoxymethyl preferably means tri(lower oxy)methyl, especially triethoxy or trimethoxymethyl.

Ethered hydroxymethyl preferably means tertiary lower alkoxymethyl, lower alkoxy- alkoxymethyl, e.g. methoxy-methoxymethyl, 2-oxa-r or 2-thiacycloalkoxymethyl, especially 2-tetrahydropyranyloxymethyl.

Esterified hydroxymethyl preferably means lower alkanoyloxymethyl, preferably halomethyl, especially chloromethyl but also bromomethyl or iodomethyl.

An alkali metal preferably means lithium, but it can also be potassium or sodium.

The intermediate product of formula Ia or Ib, in which C or B' means halomethyl, can preferably be reacted in a manner known per se with an alkali metal cyanide, e.g. potassium cyanide. This results in a compound of formula Ia or Ib, in which the chain is extended by a carbon atom, and C or B' means cyan. These, in turn, can be transferred according to methods known per se in connection with formula I, in which B means carboxy, alkoxycarbonyl or carbamoyl.

Thus, compounds of formula Ia or Ib in which C or B<1> means cyan (nitriles) can be converted to compounds of formula I, in which B means carboxy by hydrolysis with inorganic acids, e.g. with hydrohalic acids such as hydrochloric acid or sulfuric acid in aqueous solution, or preferably with hydrolysis with aqueous alkali metal hydroxides, e.g. potassium hydroxide at reflux temperature.

The conversion of the aforementioned nitriles to compounds of formula I, in which B means lower alkoxycarbonyl, is preferably carried out by treatment with a lower alkanol, e.g. anhydrous ethanol, in the presence of a strong acid, e.g. hydrochloric acid, preferably under reflux, and subsequent various hydrolysis with water.

The transfer of the aforementioned nitriles in connection with formula I, in which B means carbamoyl, is preferably carried out again by treatment with an alkali metal hydroxide, e.g. dilute sodium hydroxide, and hydrogen peroxide, preferably at room temperature.

Intermediates of formula Ia or Ib in which C or B' means halomethyl, e.g. chloromethyl, can be converted into a compound of formula I, in which B means carboxy, and the chain is extended by two carbon atoms, primarily by treatment, e.g. with a di-lower alkyl malonate e.g. diethyl malonate, in the presence of a base, e.g. potassium carbonate or sodium methoxide, in a solvent such as dimethylformamide, preferably at a temperature between 50 and 100°C,

to substituted di-lower alkyl malonates. These are then hydrolysed with an aqueous base, e.g. dilute sodium hydroxide solution to the corresponding malonic acid, which is decarboxylated under standard conditions, e.g. by heating in xylene solution to the compounds of formula I, where B is carboxy. If you replace malonic acid di-lower alkyl ester with a cyanoacetic acid lower alkyl ester, you get the corresponding compounds of formula Ia or Ib, in which C or B' means cyano.

The compounds according to the invention in which A means a linear or branched alkenylene residue with a terminal double bond, can also be prepared from the intermediates of formula Ia or Ib, in which C resp. B' means halomethyl. Thus, e.g. these intermediates are first treated with a lower alkyl ester of a ct-(aryl or alkyl)-thioacetic acid, e.g. et-(phenyl-thio)-acetic acid ethyl ester, in the presence of a strong base, e.g. sodium hydride. The subsequent oxidation of the formed α-arylthio or α-alkylthio substituted ester to the α-arylsulfinyl - or α-alkylsulfinyl ester"', e.g. sodium periodate, and then by heat-triggered elimination, e.g. on heating with xylene gives a compound of the general formula I (an α,3-unsaturated ester), in which Å means alkenylene and B means e.g. lower alkoxycarbonyl. Kjeåem is simultaneously extended by 2 carbon atoms. Legs together transformation is also carried out during application, of e.g. et-(phenylseleno)-acetic acid ethyl ester, so>m omatlt in J. Am Chem. Soc. 95 6137 (1 973). The compounds of formula Ia in which C means halomethyl can also first be converted into the corresponding carboxyaldehydes, e.g. with dimethylsulfoxide in the presence of triethylamine and silver tetrafluoroborate, or with chromium trioxide and pyridine in methylene chloride, The subsequent Wittig condensation, e.g. with trimethyl f csf oioacetate or (triphenylphosphoranylidene)-acetic acid ethyl ester gives the above-mentioned an α,3-unsaturated ester.

Compounds of formula I, in which B means lower alkoxycarbonyl can be amidated with ammonia, mono- or di-lower alkylamines, e.g. methylamine or dimethylamine, in an inert solvent, e.g. lower alkanol, such as butanol, optionally at elevated temperatures to compounds of formula I, in which B means unsubstituted carbamoyl, mono- or di-lower alkyl-carbamoyl.

Compounds of formula I, wherein A is a linear or branched alkene yl moiety with a terminal double bond, e.g. et,8-unsaturated esters can also be obtained from the corresponding ct,3-saturated esters by treatment with e.g. phenylselenyl chloride in the presence of a strong base, according to the method described in J. Am. Chem. Soc. 95, 6137 (1973).

The conversion of compounds of formula I resp. Ib, in which B or B' means lower alkoxycarbonyl, cyan, unsubstituted mono- or dilower alkylcarbamoyl, in connection with formula I, in which B means carboxy, is preferably carried out by hydrolysis with inorganic acids, e.g. with hydrohalic acid. or sulfuric acid, or with aqueous alkalis, preferably with alkali metal hydroxides, e.g. lithium or sodium hydroxide.

Compound of formula I, in which B is carboxy or lower alkoxycarbonyl can be reduced with simple or complex light metal hydrides, e.g. with lithium aluminum hydride, alane or diborane, to compound of formula I, wherein B is hydroxymethyl. The alcohols can also be obtained by means of suitable solvolysis of intermediates of formula Ia, in which C means halomethyl, by treatment, e.g. with an alkali metal hydroxide, e.g. lithium or sodium hydroxide.

The above-mentioned alcohols can, in turn, be converted into the compound of formula I, in which B means carboxy, with usual oxidizing agents, preferably with pyridine dichromate in dimethylformamide at room temperature.

Free carboxylic acid can be esterified with lower alkanols, e.g. ethanol in the presence of a strong acid, e.g. sulfuric acid, preferably at elevated temperatures, or with diazo-lower alkanes, e.g. diazomethane in a solvent,

e.g. ethyl ether, preferably at room temperature, to the corresponding esters, namely those compounds of formula I, in which B means lower alkoxycarbonyl.

Furthermore, they can free carboxylic acids by treating their reactive intermediates, e.g. an acrylic halide such as an acid chloride or mixed anhydride, e.g. one derived from a halocarbonic acid lower alkyl ester, e.g. Chloroformic acid ethyl ester is, with ammonia, mono- or dilave alkylamines, in an inert solvent, e.g. methyl enchloride, preferably in the presence of a basic catalyst, e.g. pyridine, to compound of formula I, wherein B is unsubstituted carbamoyl, mono- or di-(lower alkyl)-carbamoyl.

Compound of formula I, wherein B is mono-lower alkyl-carbamoyl, can be introduced into compound of formula I, wherein B is di-lower alkyl-carbamoyl by treatment with a strong base, e.g. sodium hydride, and then with an alkylating agent, e.g. a lower alkyl halide in an inert solvent, e.g. dimethylformamide.

Furthermore, compound of formula I, in which A means a linear or branched alkenylene or alkenylene residue can be converted by catalytic hydrogenation, preferably under neutral conditions, e.g. with a p.alladium catalyst, at atmospheric pressure, in an inert solvent, e.g. ethanol, to the compounds of formula I, in which A means straight or branched alkylene.

The carboxaldehydes, namely the compounds of formula I, in which B means formyl, can be prepared by oxidation of compounds of formula Ia, in which C means hydroxymethyl, resp. halomethyl, with e.g. dimethyl sulfoxide and a catalyst, e.g. a mixture of triethylamine and silver tetrafluoride, orally or with chromium trioxide and pyridine or with other suitable oxidizing agents known per se. The mentioned carboxyaldehydes can be converted into corresponding acetals, i.e. compound of formula Ia, in which C means de-(lower aryloxy)methyl or alkylenedioxymethyl, e.g. dimethyl acetal, by acid-catalyzed condensation with an alcohol, e.g. methanol.

Compound with formula I, in which B means carboxy, can be converted by the well-known Arndt-Eistert synthesis into compound with formula I, in which B means carboxy and the chain contains one more carbon atom. In particular, a reactive functional derivative of the carboxylic acid used as starting material is treated, e.g. acid chlorides with diazomethane,

e.g. in diethyl ether, obtaining a compound of formula Ia, in which C means diazoacetyl. The conversion with e.g. silver oxide gives said carboxylic acids of formula I, in which the chain A contains one more carbon atom.

A special embodiment of process alternative d) relates to the preparation of a compound of formula I, in which B means carboxy. It consists in that in a compound of formula Ia in which C means a residue that can be transferred to a carboxy group, the group C is transferred to the carboxy group, optionally while extending the chain A within the framework of its definition.

Transferable residues in a carboxy group are e.g. esterified carboxy groups anhydridized carboxy groups including corresponding groups of asymmetric and internal anhydrides, amidated carboxy groups, cyan, amidino groups, including cyclic amidino groups such as 5-tetrazolyl, the imino ether group, including cyclic imino ether groups, such as e.g. with lower alkyl-substituted 2-oxazolinyl or dihydro-2-oxazolinyl groups, further methyl, hydroxymethyl, etherified hydroxymethyl loweralkanoyloxymethyl, trialkoxymethyl, acetyl, trihaloacetyl, haloiqethyl, carboxycarbonyl (C0C00H), formyl (CHO) di-laveral oxymethyl, alkylenedioxymethyl, vinyl,

ethynyl or diazoacetyl. During the conversion to the carboxy group, the chain A can be simultaneously extended within the framework of its definition.

Esterified carboxy groups are preferably in the form of their lower alkyl esters, e.g. methyl, ethyl, n- or iso-(propyl or butyl) esters. Furthermore in the form of substituted lower alkyl esters, e.g. cj-amino, w-mono- or dimethylamino-, a-carboxy or a-carbethoxy (ethyl, propyl or butyl) esters. Further esters are aryl-lower alkyl esters, e.g. benzyl-, (methyl, methoxy-, chloro)-substituted benzyl or pyridyl methyl ester, lower alkanoyloxy-lower alkyl esters, e.g. pivaloyloxy methyl ester, 3-phthalidyl- and methyl, methoxy or chlorine-substituted 3-phthalidyl ester which is derived from corresponding 3-hydroxy-phthalic acid esters (hydroxy, lower alkanoyloxy, lower alkoxy)-substituted lower alkoxy methyl ester, e.g. 8~(hydroxy, acetyloxy, methoxy)-ethoxymethyl ester, bicycloalkoxycarbonyl-lower alkyl ester, e.g. such, of bicyclic monoterphenoidal alcohols, e.g. unsubstituted or with lower alkyl substituted bicyclo [_ 2, 2, 1_7heptyloxycarbonyl lower alkyl ester, preferably bornyloxycarbonyl methyl ester, halogen substituted lower alkyl ester, e.g. trichloroethyl or iodoethyl ester.

Amidated carboxy groups are preferably carboxy groups in the form of their unsubstituted amides, N-mono- or di-lower alkyl amides, e.g. mono- or dimethyl amides, tertiary amides, such as are derived from pyrrolidine, piperidine or morpholine with α-carbon lower alkyl oxy or carboxy-substituted lower alkyl amides, e.g. mono-N-(carboethoxymethyl)-amides, and mono-N-(carboxymethyl)-amides, α-carbolower alkyl oxy- or carboxy-substituted aryl lower alkyl amides, e.g. (carboethoxy or carboxy) substituted phenylethyl amides, amino-lower alkyl amides, e.g. -aminoethyl amides, and 8-(carbobenzyloxy-amino)-ethyl amides.

The transfer to the carboxy group is carried out according to methods known per se, as indicated here or in the examples, e.g. solvolytic, such as hydrolytic or acidolytic or reductive (esterified carboxy groups). Thus, e.g. trichloroethyl or 2-iodoethyl ester by reduction, e.g. with zinc and a carboxylic acid in the presence of water to the carboxylic acid. The benzyl ester or nitrobenzyl esters can be converted by catalytic hydrogenation, the latter also with chemical reducing agents, e.g. sodium dithionite or with zinc and a carboxylic acid, to the carboxyl group. Furthermore, e.g. tert,-butyl ester is also split, e.g. with trifluoroacetic acid.

In the reduction of the group C, an alkenylene or alkynylene chain A can be converted into the corresponding alkylene chain

Furthermore, compounds of formula Ia, in which C means acetyl, can be oxidatively cleaved to the corresponding compounds of formula I, in which B means carboxy. First, the starting material is converted into a compound Ia, in which C means trihaloacetyl, e.g. tribromo- or triiodoacetyl, e.g. by treatment with sodium hypobromide and then split, e.g. with an aqueous base, e.g. sodium hydroxide.

Starting substances of formula Ia, in which C means acetyl, can be prepared starting from compound Ia, in which C means halomethyl by treatment with an acetoacetic acid lower alkyl ester, e.g. acetoacetic acid ethyl ester, in the presence of a base, e.g. sodium hydride with subsequent hydrolysis with a strong base, e.g. with aqueous sodium hydroxide.

The aforementioned compounds can also be prepared by condensation of compound of formula Ia, in which C means cyan, with e.g. a Grignard or other organometallic reagent,

e.g. methylmagnesium bromide under the standard conditions.

Starting substances of formula Ia, in which C means carboxycarbonyl (C0C00H), are transferred by thermal treatment or by oxidation to the compounds of formula I, in which B means carboxy. Starting materials are thereby heated to an elevated temperature, e.g. approximately 200°C, in the presence of glass powder or e.g. treated with hydrogen peroxide in the presence of a basic agent, e.g. sodium hydroxide.

The starting substances • with formula Ia, in which C means C0C00H, can e.g. is obtained by condensation of a compound of formula Ia, in which C means halomethyl, with e.g. 2-ethoxycarbonyl-1,3-dithiane, and subsequent oxidative hydrolysis,

e.g. with N-bromosuccinimide in aqueous acetone, and then by treatment with dilute aqueous sodium hydroxide.

Compounds of formula Ia, in which C means formyl, di-lower alkyloxymethyl or alkylenedioxymethyl (formyl protected in the form of an acetal), e.g. dimethyl acetate is oxidized, e.g. with silver nitrate, pyridinium dicarbamate or azone to compound of formula I, wherein B is carboxy.

Compound of formula Ia, in which C means vinyl, is converted to the compounds of formula I, in which B means carboxy, first by ozonolysis, to compound of formula I, in which B means formyl. These are then oxidized to the compounds of formula I, in which B means carboxy.

Starting materials of formula Ia, in which C means vinyl, can also be treated with nickel carbonyl and carbon monoxide under high pressure, obtaining the compounds of formula I, in which B means carboxy, and the chain A next to the carboxy group contains a double bond.

Compounds of formula Ia, in which C is ethenyl can be treated with a strong base, e.g. butyllithium, then condensed with carbon dioxide or a halogen-formic acid lower alkyl ester, e.g. chloroformic acid ethyl ester, then hydrolyzed. A compound with formula I is obtained, in which B means carboxy and the chain A contains a three bond in a position adjacent to the carboxy group.

Compound of formula Ia, in which C means halomethyl, can be converted in the corresponding organometallic intermediates, e.g. copper or magnesium derivatives according to methods known per se.

Condensation, e.g. of a formed organic magnesium (Grignard) reagent, e.g. with a compound of formula Ia, in which C e.g. is converted to CH^MgCl, with carbon dioxide, gives a compound of formula I, in which B means carboxy, and the chain is extended by a carbon atom.

The condensation of said Grignard reagent with e.g. a haloacetic acid lower alkyl ester, e.g. bromoacetic acid ethyl ester and subsequent hydrolysis, gives a compound of formula I, in which B means carboxy and the chain is extended by 2 carbon atoms.

The aforementioned Grignard reagents can, in the presence of a copper I halide, e.g. copper I chloride is condensed with an α,3-unsaturated acid or an ester, e.g. with propiolic acid or acrylic acid, obtaining a compound of formula I, in which B means carboxy, and the chain is extended by 3 carbon atoms.

Furthermore, the compound of formula Ia, in which C means halomethyl, can be condensed, e.g. with 3-lithio derivatives of propiolic acid (produced in situ, e.g. with lithium diisopropylamide), obtaining a compound of formula I, in which A means a terminal alkenylene, B means carboxy and the chain length is extended by 3 carbon atoms.

Compound of formula I, wherein A is lower alkylene or a direct bond, and B is hydroxymethyl, which reactive functional derivative may be condensed with lower alkanol, (or thiol), or a phenol (or thiophenol), (which is suitably substituted with B ), preferably in the presence of a strong base. A compound of formula I is obtained, in which A means lower alkylene-(thio or oxy)-phenylene, phenylene-(thio or oxy)-lower alkylene or lower alkylene-(thio or oxy)-lower alkylene.

The above-mentioned reactions are carried out according to methods known per se in the presence or absence of a diluent, preferably in such that are inert towards the reagents and dissolve them, catalysts, condensation or other above-mentioned agents, and/or in an inert atmosphere under

cooling at room temperature or elevated temperatures, preferably at the medium boiling point of the solution used at normal or elevated pressure. The preferred solvents, catalysts and reaction conditions are indicated in the examples.

Finally, the compounds according to the invention can be obtained in free form or as salts. A formed free base can be transferred into corresponding acid addition salts, preferably with acids, which give therapeutically useful acid addition salts or with anion exchangers. Formed salts can be transferred into the corresponding free bases, e.g. by treatment with a stronger base, such as a metal hydroxide or ammonium hydroxide, or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchanger. A compound of formula I, in which B means carboxy, can also be transferred to corresponding metal or ammonium salts. These or other salts e.g.

e.g. the picrates can also be used in the purification of the formed free bases. The bases are transferred in their salts, the salts are separated, and the bases are released from the salts.

Due to the narrow relationship between the new compounds in free form and in the form of their salts, in the foregoing and the following, free compounds and salts also possibly mean the corresponding salts resp. free connection.

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

The invention will be explained in more detail with the help of some examples. Temperatures are stated in degrees Celsius, and the indications or parts relate to parts by weight. When nothing else is specified, evaporation of solvents is carried out under reduced pressure, e.g. between about 15 and 100 mg/Hg.

Example 1

164.0 ml of dimethylformamide and 4-30 g of potassium tert, -butyoxide are filled into a 76 liter glass jar. The solution is stirred under nitrogen and cooled to -8°C. A solution of 682 g of 3-methyl-2-(3-pyridyl)-indole in 3280 ml of dimethylformamide is added over the course of 0.75 hours, the temperature being kept below 0°C. The mixture is stirred for 2 hours at -10°C, and over the course of 1 hour 1640 ul of a solution of 780 g of 8-bromooctanoic acid methyl ester in dimethylformamide is added. The reaction temperature is kept below 0°C. The reaction mixture is stirred for 2 hours and allowed to warm to room temperature overnight. The rust-colored mixture is then cooled to about 5°C, and treated with 19,700 ml of ice water. The temperature rises to 25°C. The mixture is stirred for 1/2 hour, and extra

washed with 2 x 8000 ml of ether. The extract is dried over magnesium sulfate and evaporated in vacuo. 1-(7-Methoxycarbonyl-heptyl)-3-methyl-2-(3-pyridyl)-indole is obtained as an oil. 1293 g of this oil is treated with 6530 ml of 1-normal sodium hydroxide solution and the mixture is heated in a steam bath for 2 1/2 hours at 90°C. The solution is cooled to room temperature

turn, and wash with 3 x 3000 ml of ether. The aqueous layer is cooled to 10°C and adjusted with 34-00 ml of 2-normal hydrochloric acid to a pH value of 3.5. The formed heavy emulsion is extracted with 4 x 4000 ml of methylene chloride. The combined extracts are washed once with 4000 ml of water and dried over magnesium sulfate. Filter and evaporate the solvent at 6o°C, triturate the residue with 2000 ml of ether and dry the product. One obtains 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole, of m.p. 113-115°C. One is recrystallization from ethanol, the melting point rises to 11 4--11 6°C.

3-methyl-2-(3-pyridyl-indole starting materials are essentially prepared according to US patent 3 4-68 894..

The 8-bromooctanoic acid methyl ester is prepared from azelaic acid essentially according to US patent 3 852 41 9, or by direct esterification of 8-bromooctanoic acid, as follows:

A mixture of methanol (4700 ml), 8-bromooctanoic acid (912 g) and sulfuric acid (912 ml) is boiled in a suitable reaction vessel for 5 hours under reflux, stirred overnight at room temperature. The solvent is evaporated under reduced pressure (3 mm Hg) and the oily residue is dissolved in ether (4000 ml). The solution is washed with water (3 x 2000 ml), saturated aqueous sodium bicarbonate solution (1000 ml) and saturated aqueous sodium chloride solution. The ether layer is dried over magnesium sulfate and filtered. After evaporation of the solvent and distillation of the crude oil, 8-bromooctanoic acid methyl ester is obtained which boils at 73-76°C/0.05 mm Hg. n<jp> = 1.4614.

Example 2

A solution of 13.5 g of 3-methyl-2-(3- pyridyl)-indole in 80 ml of dimethylformamide. After completion of the addition, the greenish-yellow mixture is stirred at room temperature for approximately 1 hour. The reaction mixture is mixed dropwise while cooling to 0-5°C with bromoacetic acid ethyl ester (11.2 ml, 0.10 mol) and stirred for 4 hours at room temperature.

The reaction mixture is poured into 1000 ml of ice water and extracted with 3 x 300 ml of ether. The ether layer is extracted with 3 x 300 ml of 1-normal hydrochloric acid. The acidic extract is adjusted with conc. ammonium hydroxide at a pH value of 9-10, and extracted with 3 x 250 ml of ether. The combined ether extracts are dried over magnesium sulphate, filtered and evaporated under reduced pressure. 1-Ethoxycarbonylmethyl-3-methyl-2-(3-pyridyl)-indole is obtained as an oil.

The previously mentioned oil is boiled in 500 ml of 1-normal hydrochloric acid for 4 hours under reflux. After standing overnight, a yellow, solid material separates, dried for 1.2 hours at 60-80°C/30 mmHg. After recrystallization from ethanol, 1-carboxymethyl-3-methyl-2-(3-pyridyl)-indole hydrochloride is obtained, m.p. 204-207°C.

If a free amino acid is desired, this can be obtained by setting the pH value of the hydrolysis medium to 3.5

Example 3-6

Analogously to the method according to examples 1 and 2, the compounds of formula I are also prepared, in which R^ = CH^, R2 and R^ = H, and b = COOfl:

The 2-(3- and 4-pyridyl)-indoles used as starting materials are prepared according to US patent 3 4-68 894.

The ethyl or methyl bromoester used as starting material is commercially available and produces commercially available bromoacids such as . below is shown for the 6-bromohexanoic acid methyl ester. A solution of 6-bromohexanoic acid (10 g) in 50 ml of methanol is mixed with 1.0 ml of conc. sulfuric acid and boil for 8 hours under reflux. The ethanol is evaporated and the residue is dissolved in ether. The ether solution is freed by washing with water for acid, dried over sodium sulphate and evaporated to dryness. The distillation at 0.8 mm Hg gives 6-bromohexanoic acid methyl ester, which boils at 85-90°C/0.8 mmHg.

1-(7-carboxyheptyl)-3"methyl-2-(2-pyridyl)-indole is prepared analogously to example 1. The 3-methyl-2-(2-pyridyl)-indole used as starting material is described in J. Chem Soc .1 955 2865.

Example 7-10

The following compounds of formula I, in which R 1 = CH 2 , R 3 = hydrogen, Pyr = 3-pyridyl, CH 2 A = (CH 2 ) 5 and B = COOH are prepared analogously to the methods described in the previous example.

The compounds according to example 7 are prepared

as follows: After stirring in a nitrogen atmosphere at 0-5°C, a solution of 6 .59 g of 5-chloro-3-methyl-3-(3-pyridyl)-indole (prepared according to US patent 3 4.68 894.) in 60 ml of dimethylformamide. After completion of the addition, the suspension is stirred for 1/2 hour at 0°C, and then mixed dropwise while cooling at 0°C with a solution of 6.06 g of 6-bromohexanoic acid methyl ester in 10 ml of dimethylformamide. The reaction mixture is allowed to warm to room temperature, stirred for 5 hours at room temperature and poured into 4.00 ml of ice water. The resulting mixture is extracted with ethyl acetate (3 x 300 ml). The extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. 1-(5-Methoxycarbonyl-p<!iotyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole is obtained as an oil.

A solution of 3.2 g of the latter compound in 30 ml of 3-normal sodium hydroxide solution is boiled for 17 hours under reflux. After cooling from raf, the product formed is filtered off and dissolved in 50 ml of water. After acidification with 2:^normal hydrochloric acid.: to a pH value of 4-5, the product precipitates. It is purified by suspension in ether. 1-(5-carboxypentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole is obtained, m.p. U3-U5°C.

Similarly, 1-(5-carboxypentyl)-5-methoxy-3"methyl-2-(3-pyridyl)-indole is produced as an oil. After treatment with ethanolic hydrochloric acid in ethanol and crystallization with the addition of ethyl ether , the compounds according to example 8 are obtained, namely 1-(5-carboxypentyl)-5-methoxy-3-methyl-2-(3-pyridyl)-indole hydrochloride, which melts at 1 75-1 78°C.

1-(5-carboxypentyl)-5-hydroxy-3-methyl-2-(3-pyridyl)-indole is prepared as follows: A solution of 1.70

g 1 -(5-carboxypentyl)-5-methoxy-3-methyl-2-(3-pyridyl)-indole in 85 ml of 4-8% hydrogen bromide is boiled for 30 minutes under reflux. The reaction mixture is evaporated to dryness, diluted with water, and the pH value is adjusted with dilute sodium hydroxide solution to 6. The precipitate is filtered off with suction and recrystallized from acetone/ethyl acetate. 1-(5-carboxy-pentyl)-5-hydroxy-3-methyl-2-(3-pyridyl)-indole is obtained.

Example 11

a) A solution of 1-(4-cyanobenzyl)-3-methyl-2-(3-pyridyl)-indole (5.8 g) in 100 ml of a 1:1 mixture of 20%

aqueous hydrochloric acid and glacial acetic acid are boiled for 20 hours under reflux. After cooling, the solution is poured into ice water (100 ml), and the pH value is adjusted with saturated aqueous sodium hydrogen carbonate solution to 4.5-5. The precipitate formed is extracted with acetic acid ethyl ester, the extract is washed with water and evaporated to dryness. 1-(4-carboxybenzyl)-3-methyl-2-(3-pyridyl)-indole is obtained, m.p. 273-275°C.

The nitrile used as starting material is prepared as follows: A suspension of 2.9 g (0.06 mol) of 50%-lg sodium hydride in mineral oil in 40 ml of dimethylformamide is mixed dropwise under nitrogen at 0-5°C over the course of 20 minutes, with a solution of 10.4 g (0.05 mol) of 3-methyl-2-(3-pyridyl)-indole in 60 ml of dimethylformamide. The reaction mixture is stirred for 1/2 hour at 0-5°C, and is then mixed dropwise with 9.8 g (0.05 mol) of p-cyano-benzyl bromide in 50 ml of dimethylformamide. The mixture is stirred for 1 hour at 0-10<0>C, then 30 minutes at room temperature and poured into ice water (600 ml). The solid material formed is collected, dried, washed with petroleum ether and redissolved in ether (500 ml). The ether solution is first washed with water then with saturated sodium bicarbonate solution, dried over magnesium sulfate and treated with activated carbon and filtered. After evaporation of the ether solution to dryness, a yellow, solid material is obtained. This product is slurried in hot cyclohexane and filtered off. 1-(4-cyanobenzyl)-3-methyl-2-(3-pyridyl)-indole is obtained, m.p. 127-129°C. b) Analogously, 1-(4-carboxybenzyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole hydrochloride is obtained, m.p. 217-220°C.

Example 12

a) A suspension of 0.4-9 g of lithium aluminum hydride in 50 ml of anhydrous tetrahydrofuran is mixed dropwise in a nitrogen -

atmosphere at room temperature with a solution of 3.92 g of 1-(5-methoxycarbonylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole in 30 ml of anhydrous tetrahydrofuran. After completion of addition, stir. the suspension for 1 hour at room temperature, and mixed with 50 ml of saturated aqueous ammonium chloride solution. The reaction mixture is allowed to stand overnight at room temperature, and the organic layer is separated.

The aqueous layer is filtered to remove the salts and extracted with ethyl acetate (2 x 50 mL). The combined organic layers are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The crude product is purified by trituration with hexane/ether and dissolved in ethanol. The solution is acidified with ethanolic hydrogen chloride, the solution is diluted with anhydrous ether to precipitate the crystalline product. The formed 1-(6-hydroxyhexyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole hydrochloride hemihydrate melts at 115-118°G. b) Analogously, 1-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)-indole is obtained, as an oil.

NMR (CDCl 3 ) δ 3.50 (t, 2H), 3.98 (t, 2H).

Example 13

A suspension of 1.52 g of 1-(5-carboxypentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole in 50 ml of toluene is mixed dropwise at room temperature under nitrogen with 0.31 ml of thionyl chloride. The resulting mixture is boiled for 1 hour under reflux, is additionally mixed with 0.10 g of thionyl chloride and this solution is stirred overnight at room temperature. It

The resulting suspension is evaporated to dryness. The crude 1-(5-chlorocarbonylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole is obtained, which is used directly without further purification.

A suspension of 0.86 of the above 1-(5-chlorocarbonylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole in 20 ml of conc. ammonium hydroxide and stirred overnight at room temperature. Filtration of the suspension and slurry of the solid material formed in ether gives 1-(5-carbamoylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole, m.p. 137-U0°C.

Example 1 4

A suspension of 2.9 g (0.06 mol) of 50% sodium hydride in mineral oil, in 4-0 ml of dimethylformamide is mixed dropwise under nitrogen at 0-5°C with a solution of 10.4 g 3- methyl-2-(3-pyridyl)-indole in 60 ml of dimethylformamide during 20 minutes. The mixture is stirred at 0-5°C for 30 minutes and then mixed dropwise with 17.6 g (0.06 mol) of 1-tetrahydro-pyramyloxy-8-bromooctane in 50 ml of dimethylformamide. The mixture is stirred for 1 hour at 0-10°C and 30 minutes at room temperature, poured into ice water and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 100 ml of 3-normal hydrochloric acid, the resulting solution is kept for 30 minutes at room temperature, washed with ether, made basic with aqueous 3-normal sodium hydroxide solution, and extracted with methylene chloride. The methyl enclof id solution is evaporated to dryness. 1-(8-hydroxyoctyl)-2-(3-pyridyl)-3-methylindole is obtained.

Example 15

A solution of 4 g of 1-(7-methoxycarbonylheptyl)-3-methyl-2-(3-pyridyl)-indole in 4-0 ml of n-butanone is saturated with methylamine and heated in a pressure vessel for 3 days on a steam bath. The reaction mixture is evaporated to dryness, and the product is recrystallized from acetic acid ethyl ester. 1-[7-(N-methyl-carbamoyl)-heptyl-7-3-methyl-2-(3-pyridyl)-indole is obtained.

Example 16

A solution of 50 mg of 1-(5-carbamoylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole in 1 ml of 6-normal hydrochloric acid is boiled for 3 hours under reflux. After cooling, the hydrochloride salt precipitates. The suspension is evaporated to dryness and the residue made basic with saturated aqueous sodium hydrogen carbonate solution. This solution is washed with ether and adjusted with 2-normal hydrochloric acid to a pH value of 6-7. The crude free acid is obtained, namely 1-(5-carboxypentyl)-5-chloro-3-)methyl-2-(3-pyridyl)-indole, m.p. 137-U1°C

Example 17

A mixture of 4.17 g of 3-methyl-2-(3-pyridyl)-indole, 0.64 g of tetra-n-butyl-ammonium bromide and 1.02 g of powdered potassium hydroxide in 500 ml of acetonitrile is mixed with stirring at room temperature under nitrogen with 5.06 g of p-(2-bromomethoxy)-benzoic acid (prepared according to US Patent 2,790,825 (1957)). The suspension is stirred for 5 days. The potassium bromide from raf is extracted, the filtrate is concentrated in an oil. This is dissolved in acetic acid ethyl ester and extracted with 3-normal hydrochloric acid. The acid layer is separated and treated with 3-normal sodium hydroxide solution. The resulting suspension is extracted with ethyl acetate (3 x 100 ml) and the organic extract is separated. This is dried over magnesium sulfate and concentrated. 1-(2-(4-Ethoxycarbonylphenoxy)-ethyl-7-2-(3-pyridyl)-3-methyl-indole is obtained as an oil.

Example 18

A mixture of (.7 g of 1-^~2-(4-ethoxycarbonylphenoxy)-ethyl7-2-(3-pyridyl)-3-methylindole in 2-normal hydrochloric acid 220 ml is boiled for 6 hours under reflux. After cooling, the solution is made basic with 3-normal sodium hydroxide solution, and extracted with acetic acid ethyl ester. The basic solution is filtered and adjusted with 5-normal hydrochloric acid to a pH value of 6-7. The solid material is separated, dried and recrystallized from acetone. You get 2-( 4-carboxyphenoxy)-ethyl 7-2-(3-pyridyl)-3-methylindole, mp 190-193°C.

Example 19

A solution of 5.9 g of p-mercapto-benzoic acid ethyl ester (prepared according to J. Chem. Soc, 1963, 1 94.7-1954) in 30 ml of dimethylformamide is added dropwise to a slurry of 1.55 g of 50%-lg sodium hydride -mineral oil in 30 ml of dimethylformamide. This mixture is stirred under nitrogen at room temperature for 30 minutes. This solution is added dropwise to a solution of 9.78 g of 1-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-3-methylindole in 60 ml of dimethylformamide at -10°C. This mixture is stirred at room temperature overnight, and poured into 1000 ml of ice water. The mixture is extracted several times with ether (total approximately 1000 ml).

The ether extract is washed with water (3 x 200 ml), dried over magnesium sulphate and evaporated in vacuo. 1-/-2-(4-Ethoxycarbonyl-phenylthio)-ethyl/-2-(3-pyridyl)-3-methyl-indole is obtained as an oil. NMR (CDCl3) confirms the structure.

The starting material is prepared as follows: 11.77 g of 1-(2-ethoxycarbonyl-ethyl)-2-(3-pyridyl)-3-methylindole are mixed in 4-00 ml of dry tetrahydrofuran at 0°C with 60 ml of 1-molar .in solution of lithium aluminum hydride in tetrahydrofuran. The reaction mixture is stirred for 1 hour at room temperature, then cooled in an ice bath and partitioned sequentially with 2.26 ml of water, 2.26 ml of a 15% sodium hydroxide solution and with 6.78 ml of water. The mixture is filtered and concentrated in vacuo. The residue is dissolved in ether, washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The semi-solid 1-(2-hydroxyethyl)-2-(3-pyridyl)-3-methyl-indole is obtained, processed directly in the next step.

Methanesulfonyl chloride (2.70 ml) is added dropwise at -10°C to a solution of 7.5 g of 1-(2-hydroxyethyl)-2-(3-pyridyl)-3-methylindole and 10.34 ml of triethylamine in 150 ml of methyl enchloride. The mixture is stirred at room temperature for 30 minutes and poured into 600 ml of ice water. The resulting slurry is extracted with methylene chloride, the extract is washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated in vacuo. 1-(2-methylsulfonyloxy-ethyl)-2-(3-pyridyl)-3-methylindole is obtained, which is used directly in the above reaction:-

Example 20

A mixture of 6.39 g of 1-f2-(4-ethoxycarbonyl-phenylthio)-ethyl7-2-(3-pyridyl)-3-methylindole in 260 ml of 2-normal hydrochloric acid is refluxed for 6 hours. After cooling, the pH value is adjusted to 6-7 with saturated sodium hydrogen carbonate solution (approximately 500 ml). The mixture is mixed with 200 ml of ether and stirred for 10 minutes. The solid material is separated, washed first with water, then with ether, and dissolved in 100 ml abs. methanol. The solution is filtered and the still warm solution is treated with 1.68 ml of 6.5-normal ethanolic hydrogen chloride. The solution is cooled and diluted with approximately 100 ml of ether. The product formed is separated. One obtains 1 - £~ 2-N-carboxyphenylthio)-ethyl7-2-(3-pyridyl)-3-methyl-indole hydrochloride, m.p. 222-224°C.

Example 21

A solution of lithium diisopropylamide (LDA) is prepared by adding n-butyl lithium (7.66 mmol, 1.6 mol in hexane) to a solution of diisopropylamine (7.6 mmol) in tetrahydrofuran (THF 12 ml) at -20 °C. The LDA solution is cooled to -78°C and mixed dropwise with 1-(5-methoxycarbonyl-pentyl)-2-(3-pyridyl)-3-methyl-indole (2.4-8 g) in THF ( 24 ml) within 5 minutes. The mixture is stirred for 20 minutes at -78°C and then mixed with phenylselenyl chloride (1.5 g) in THF (12 ml). After 5 minutes, the cooling bath is removed and the mixture is allowed to warm to 0°C. Saturated aqueous sodium bicarbonate solution (60 ml) is added and then extracted with ether (3 x 50 ml). The combined organic extracts are washed with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Concentration in vacuo gives the crude 1-(5-methoxycarbonyl-5-phenyl-selenyl-2-(3-pyridyl)-3-methylindole as a yellow oil. The crude selenide is dissolved in dichloromethane (40 mL) and mixed dropwise with 30% hydrogen peroxide (1.8 g, 16 mmol) in water (1.8 ml). After the addition of about 10% of hydrogen peroxide, an exothermic ■ reaction begins. Until the additions are complete, the temperature rises to 30°C. The mixture about -stir for a further 30 minutes, and then mix with 5% x g aqueous sodium carbonate solution (40 ml). The dichloromethane layer is separated. The aqueous phase is extracted with dichloromethane (25 ml). The combined organic phases are washed with 5% x g aqueous sodium carbonate , water, saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Concentration in vacuo affords 1-(5-methoxycarbonyl-pent-4-enyl)-2-(3-pyridyl)-3-methyl-indole as a pale yellow oil. A further purification carried out by short-path chromatography (silica gel) with ethyl acetate-hexane (2:3) as eluent NMR (COCl^) 6 5 , 53 (d, 1H), 6.65 (m, 1H), TR (floating) 1720 cm"<1>.

Example 22

A solution of ct, Ø-unsaturated ester, namely of 1 - (5-methoxycarbonylpent-4-enyl )-2-(3-pyridyl )-3-methylindole is (84 mg) in methanol (1 ml) is mixed with 1 -normal aqueous lithium hydroxide solution (1 ml). The mixture is stirred overnight at room temperature and evaporated to dryness. The residue is dissolved in water (2 ml) and washed with diethyl ether (5 ml). The aqueous phase is acidified to a pH value of 6.6-7.0 and extracted with dichloromethane. The organic extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. A pale yellow oil is obtained which becomes solid after trituration with chloroform. 1-(5-Carboxypeht-4-enyl)-2-(3-pyridyl)-3-methylindole is obtained, m.p. 145-U7°C.

Example 23

A solution of Collins reagent prepared under nitrogen at 0-5°C of chromium trioxide (5.6 mg) and pyridine (8.86 g, 112 mmol) in dichloromethane (150 mL) is mixed at once with 1, 8 g of 1-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)-indole in dichloromethane (15 ml). The mixture is stirred for 25 minutes and filtered through Celite. The filtrate is then applied to a silica gel column and eluted with a 1:1 mixture of ethyl acetate-dichloromethane (500 ml). Concentration in vacuo gives 1-(5-formylpentyl)-2-(3-pyridyl)-3-methylindole as pale yellow oil. NMR (CDCl 3 ) 6 9.7 (t, 1H), IR (liquid) 271 0, 1720 cm"<1>.

Example 24

Trimethylphosphonoacetate (328 mg) is added dropwise under nitrogen to a solution of potassium tert.-butoxide (220 mg) in THF (5 ml) at 0°C. The solution is stirred for 20 minutes at 0°C, then cooled to -78°C, and mixed dropwise with a solution of 1-(5-formyl-pentyl)-2-(3-pyridyl)-3-methylindole (450 mg) in THF (5 mL). The mixture is held for 15 minutes at -78°C and the cooling stops. The mixture is stirred overnight at room temperature, diluted with water (25 ml) and extracted with diethyl ether (3 x 25 ml). The combined extracts are washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation in vacuo, 1-(7-methoxycarbonylheptyl-6-enyl)-2-(3-pyridyl)-3-methyl indole is obtained as pale yellow oil. IR (liquid) 1735 cm"<1>.

Example 25

Hydrolysis of 50 mg of 1-(7-methoxycarbonylhept-6-enyl)-2-(3-pyridyl)-3-methylindole according to the method according to example 24 gives 1-(7-carboxyhept-6-enyl)-2-( 3-pyridyl)-3-methylindole. Sm.p. 144-146 oC (recrystallized from dichloromethane-hexane).

Example 26

1-(7-carboxyhept-6-enyl)-2-3-pyridyl)-3-methyl-indole (10 mg) is hydrogenated in 1 ml abs. ethanol with a catalytic amount of 10% palladium-on-charcoal at a pressure of 1 atmosphere. After 3 1/2 hours the catalyst is filtered and washed with some

ml of ethanol. The combined organic extracts are evaporated in vacuo. A colorless oil is obtained which then crystallizes. 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole is obtained according to example 1. The crude product melts at 110-113°C.

Example 27

1_(^-cyanobutyl)-3-methyl-2-(3-pyridyl)-indole (578 mg) is heated at 185°C for 30 minutes with ^50 mg of powdered sodium hydroxide, and 5 ml of ethyl englycol. The mixture is poured into 5 ml of water, washed with ether, the pH value is adjusted with 2-normal hydrochloric acid to 6. The oil formed crystallizes out. One obtains 1-(4-carboxybutyl)-3-methyl-2-(3-pyridyl)-indole according to example 5. (m.p. 127-129°C).

Starting materials are prepared as follows: A solution of 3-methyl-2-(3-pyridyl)-indole (2.09 g) in 12 ml DMF is added to a suspension of 50% sodium hydride mineral oil in 6 ml DMF at 0°C. The mixture is stirred for 30 minutes at 0°C and treated with a solution of 1.78 g of 5-bromovalerotritrile in 4 nil of DMF. The mixture is stirred overnight at room temperature, poured into 125 ml of water and extracted with 2 x 50 ml of ether. The extract is washed with 3 x 20 ml of water and dried over magnesium sulphate. 1-(4-cyanobutyl)-3-methyl-2-(3-pyridyl)-indole is obtained as an oil.

Example 28

A mixture of 578 mg of 1-(4-cyanobutyl)-3-methyl-2-(3-pyridyl)-indole, 173 mg of sodium azide, 14-2 mg of ammonium chloride and 5 mg of lithium chloride in 2 ml of DMF is heated overnight at 120 °C. After cooling, the mixture is filtered and the filtrate is diluted with approximately 25 ml of water. The pH is adjusted with 3-normal sodium hydroxide solution to 10-11, and the solution is washed to remove unreacted nitrile with ether. The pH value of the aqueous phase is adjusted with 2-normal hydrochloric acid to 5-6, and extracted with ether. The ether extract is washed with water, dried over magnesium sulphate and evaporated in vacuo. The solid residue is suspended in petroleum ether and separated. One obtains 1-fu-(5-tetrazolyl)-butyl7-3-methyl-2-(3-pyridyl)-indole. Sm.p. 177-179°C.

Example 29

A solution of 3-methyl-2-(3-pyridyl)-indole (2.08 g) in 12 ml DMF is placed under nitrogen at 10-15°C to a suspension of 0.528 g 50 µg sodium hydride mineral oil in 6 ml DMF. After completion of the addition, the mixture is stirred at room temperature for 30 minutes and mixed dropwise with 2.3:9 g of 3-(p-chloromethyl-phenyl7-2-methyl-acrylic acid ethyl ester in 5 ml of DMF. The resulting mixture is stirred overnight at room temperature and poured into 100 ml of water. The resulting mixture is extracted with ethyl acetate (2 x 50 ml). The organic layer is washed with 100 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. You get "\- £~p-(2- ethoxycarbonylpropen-1-yl)-benzyl 7-3-methyl-2-(3-pyridyl)-indole.

Hydrolysis with 2-normal aqueous hydrochloric acid

gives 1-β-(2-carboxypropen-1-yl)-benzyl-7-3-methyl-2-(3-pyridyl)-indole.

Starting materials are prepared as follows: A suspension of 10.0 g of a 50% strength sodium hydride in mineral oil in freshly distilled dimethoxyethane (DME, 350 ml) is stirred under nitrogen at 10°C and mixed during about 4-0 minutes with tri-ethyl-2-phosphonopropionate. The mixture is stirred for 30 minutes at 10°C. While stirring for a further 1 1/2 hours, the temperature is allowed to rise to room temperature. This solution is brought under nitrogen with a needle in a 500 ml dropping funnel, and added dropwise to a solution of terephthalaldehyde (33.53 g)

in dry DME (475 ml) during 1 hour at 22-34°C. After completion of the addition, the reaction mixture is mechanically stirred for 2 hours at room temperature, poured into 100 ml of water and extracted with 4 x 500 ml of ether. The ether extract is washed with saturated aqueous sodium chloride solution (700 ml), dried over magnesium sulphate, filtered and concentrated in vacuo. You get a yellow oil which partially crystallizes after standing. The crude mixture is purified by suspension in petroleum ether-ethyl acetate (93:7). The filtrate is concentrated in vacuo after unreacted dialdehyde has been removed. A mixture is obtained which is further purified at high pressure by liquid chromatography (using petroleum ether/acetic acid ethyl ester 93:7). The pure 4-formyl-α-methylcinnamic acid ethyl ester is obtained. A solution of the aldehyde (34.80 g) in 820 ml abs. ethanol is treated with 12.11 g of granulated sodium borohydride at room temperature under nitrogen. The resulting mixture is stirred for 3 hours at room temperature (or until the borohydride is dissolved), concentrated to a volume of approximately 200 ml, diluted with 400 ml of water and extracted 3 x 200 ml of ether. The ether extract is washed with 100 ml of water and saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and the filtrate is concentrated in vacuo.

3-(p-Hydroxymethylphenyl)-2-methylacrylic acid ethyl ester is obtained. To a solution of this product in 350 ml of methylene chloride, 11.53 ml of thionyl chloride are added dropwise over 25 minutes at room temperature. The clear, colorless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated aqueous sodium bicarbonate solution, 100 ml of water and 100 ml of saturated aqueous sodium chloride solution. The organic layer is dried and evaporated. 3-(p-chloromethyl-phenyl)-2-methyl-acrylic acid ethyl ester is obtained, which is used without further purification.

Example 30

1-(5-Formylpentyl)-3-methyl-2-(3-pyridyl)-indole (127 mg) is dissolved in DMF (0.66 mL) and mixed at once with pyridinium dichromate (298 mg). The mixture is stirred overnight at room temperature, then diluted with a mixture of ether and ethyl acetate (25 ml, 4=1) and filtered. The solid material is washed with hot chloroform and the combined filtrates are concentrated in vacuo. A dark brown gummy material is obtained which is slurried with ether:acetic ester (4:1) and extracted with 0.1 normal aqueous sodium hydroxide solution (2 ml). The aqueous extract is adjusted to a pH value of 5.5-6.0 and extracted with chloroform. The chloroform extract is dried and concentrated in vacuo. You get a yellow oil. Thin layer chromatography (silica gel, acetic acid ethyl ester:hexane 1:1) shows the presence of the desired acid. Further chromatography on silica gel using ethyl acetate:hexane (1:1) as eluent gives the desired 1-(5-carboxypentyl)-3-methyl-2-(3-pyridyl)-indole according to Example 3.

Example 31

Under ice bath cooling, bromine (0.344 ml) is added to a solution of 692 mg of sodium hydroxide in 4 ml of water. The resulting solution is added to 400 mg of 1-(5-oxohexyl)-3-methyl-2-(3-pyridyl)-indole and the mixture is stirred for 2 hours at room temperature. The mixture is washed with ether. The aqueous solution is filtered and adjusted with 2-normal hydrochloric acid to a pH value of 5-6. A white, solid crude product is separated which melts in a range of 108-120°C. Separation by thin-layer chromatography (silica gel, methylene chloride-methanol 9:1) gives 1-(4-carboxybutyl)~3-methyl-2-(3-pyridyl)-indole according to example 5.

Starting materials are prepared as follows: 1-(4-cyanobutyl)-3-methyl-2-(3-pyridyl)-indole (1.5 g) in 15 ml of ether is added to a solution of 0.0103 ml of methylmagnesium bromide in 15 ml of ether . The mixture is boiled for 3 hours under reflux. After cooling, 6-normal hydrochloric acid is added dropwise to 100 ml and the mixture is heated under reflux for several hours. The reaction mixture is washed with ether and adjusted to pH 10-11 with 3-normal sodium hydroxide solution. After extraction with ether and evaporation of the solvent, 1-(5-oxohexyl)-3-methyl-2-(3-pyridyl)-indole is obtained. IR 1720 cm"<1>, NMR (CDCl 3 ) 62.0.

Example . 3 2

1-(7-carboxyheptyl)-5-chloro_3-methyl-2-(3-pyridyl)-indole hydrochloride (4-21 mg) dissolved in 7 ml of tetrahydrofuran is heated and treated with 202 mg (0.278 ml) of triethylamine. This solution is added dropwise to a solution of 108 mg (0.096 ml) ethyl chloroformate in 1 ml tetrahydrofuran and cooled to 0-5°C. The reaction mixture is stirred for 1 hour at this temperature, and filtered to remove triethylamine hydrochloride. The filtrate is treated with a solution of hydroxylamine hydrochloride (69 mg) and sodium hydroxide

(4.0 mg) in 10 ml of methanol. This mixture is stirred for 0.5 hours and concentrated in vacuo. The residue is treated with 25 ml of ether-methanol (10:1) and filtered. The filtrate is evaporated in vacuo. A thick oil is obtained which is dissolved in acetone and treated with 6.5 normal ethanolic hydrogen chloride. One obtains 1-(7-hydroxycarbamoyl-heptyl)-3-methyl-2-(3-pyridyl)-indole hydrochloride, m.p. 170-173°C.

Example 33

Ethanolic hydrogen chloride (7.1-normal, 0.14-ml) is added to 236 mg of N-phenyl-N-(5-methoxycarbonylpentyl)-hydrazine in 2 ml of abs. ethanol and then mixed with 135 mg of 3-propionyl-pyridine. The mixture is boiled overnight under reflux. It is then mixed with further ethanolic hydrogen chloride (0.62 ml) and heated for a further 24 hours under reflux. After cooling, the mixture is filtered and the filtrate is evaporated in vacuo. The residue is stirred in 10 ml of water, and adjusted with 1-normal sodium hydroxide solution at pH value 10-11. This mixture is extracted with ether. The extract is washed with water, dried over magnesium sulphate and evaporated. An oil is obtained which is 1-(5-ethoxycarbonylpentyl)-3-methyl-2-(3-pyridyl)-indole.

This ester is hydrolysed with 10 ml of 2-normal hydrochloric acid under reflux. then the pH is adjusted with saturated aqueous sodium bicarbonate solution to about 6, and extracted with ether. The processing of the organic extract yields 1-(5-carboxypentyl)-3-methyl-2-(3-pyridyl)-indole according to example 3 (the crude product's m.p. 111-113°C).

The starting material is prepared as follows: Aniline (2.79 g, 2.73 ml) 6.27 g 6-bromohexanoic acid methyl ester and 12.24 g (0.09 mol) sodium acetate trihydrate are heated in 15 ml abs. ethanol overnight at 80-100°C. After cooling, the mixture is poured into 75 ml of ice water and extracted with ether. The organic extract is washed with water, dried over magnesium sulphate and evaporated in vacuo. N-(5-methoxycarbonylpentyl)-aniline is obtained.

A solution of 1.4 g of sodium nitrite in 5 ml of water is added dropwise at 0-10°C to a mixture of 4.42 g of N-(5-methoxycarbonyl-pentyl)-aniline, 2.9 ml of conc. hydrochloric acid and ice (which is necessary for cooling to said temperature). The mixture is then stirred for 1 hour at room temperature and extracted with ether. The extract is washed with water, dried over magnesium sulphate and evaporated in vacuo. N-nitroso-N-(5-methoxycarbonylpentyl)-aniline is obtained as an oil.

The above-mentioned nitroso derivative (3.6 g) in 4 ml of glacial acetic acid is added dropwise to 3.94 g of zinc powder in 6 ml of water. After the exothermic reaction to 35°C, the mixture is stirred for 2 hours at room temperature. The zinc from raf is filtered off, the filtrate is washed with ether, adjusted with . 4-0% Lg sodium hydroxide solution, pH value of 10-11, and extracted with ether. The extract is dried over magnesium sulfate and evaporated in vacuo. You get a crude oil. After a short path chromatography on silica gel with hexane-acetic acid (5:1), N-phenyl-N-(5-methoxycarbonylpentyl)-hydrazine of approximately 80% purity is obtained. This product is used directly in the above-mentioned Fischer cyclization.

Example 34

1-(7,7-(bis-methoxycarbonyl)-heptyl7-3-methyl-2-(3-pyridyl)-indole (273 mg) is dissolved in methanol (0.5 ml) and mixed with 1-normal aqueous lithium hydroxide solution (1.95 mL). The mixture is stirred for 1 hour at room temperature, and then boiled for 2 1/2 hours under reflux. The clear solution is evaporated to dryness, the residue is dissolved in water and the pH value is adjusted to 6-6.2. A yellow gummy solid material is formed, which is extracted in chloroform. The extract is dried over magnesium sulfate and evaporated. The crude 1 - £~ 1,7-(bis-carboxy)-heptyl_7-3-methyl-2-(3-pyridyl)-indole is obtained. NMR (CDCl 3 ) δ 10.60 (2H).

A sample of the crude dicarboxylic acid (28 mg) is heated for 30 minutes in p-xylene (3 ml) containing 0.1-N hydrochloric acid (0.1 ml). You let it. clear solution cool to room temperature. A gummy material precipitates which is extracted in sodium hydroxide. The aqueous phase is separated, its pH value is adjusted to 6-6.2, and extracted with ethyl acetate:ether (8:2). The organic phase is dried over magnesium sulfate and evaporated. You get a colorless oil that becomes solid after standing. 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole is obtained, which according to its NMR and TCL values is identical to the compound from example 1.

The starting material can be presented as follows: At 0°C, thionyl chloride (0.36 ml) is added to 1-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)-indole (1.37 g) and the mixture is stirred for 1 hour at room temperature. The mixture is then mixed with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation in a vacuum, the crude chloride is obtained as an oil. Purification by means of silica gel chromatography (methylene chloride/acetic acid ethyl ester is 19*1) gives 1-(6-chlorohexyl)-3-methyl-2-(3-pyridyl)-indole as a pale yellow oil. NMR (CDCl₂) δ 3.30 (t, 2H) 3.92 (t, 2H).

2-(6-Chlorohexyl)-3-methyl-2-(3-pyridyl)-indole (0.5 g) is added to a mixture of dimethyl malonate (792 mg), potassium carbonate (790 g) and dimethylformamide (11.6 ml) and heated under nitrogen for 18 hours at 80-90°C. The mixture is poured into ice water (80 ml), acidified with 1-normal hydrochloric acid and washed with ether. The aqueous layer is adjusted to pH 6 and extracted with ether. The extract is dried over magnesium sulfate and evaporated to a yellow oil. Purification by preparative thin-layer chromatography (chloroform-ethyl acetate 9:1) gives 1 - £~7,7-(bis-methoxycarbonyl)-heptyl-7-3-methyl-2-(3-pyridyl)-indole. NMR (CDCl 3 ) δ 3.32 (t, 1H), 3.78 (s, 6H), 4.03 (t, 2H), IR (liquid) 1750 cm"<1>.

Example 35

1-(6-chlorohexyl)-3-methyl-2-(3-pyridyl)-indole (165 mg) in dry THF (2 ml) is added dropwise to magnesium shavings (12 mg) in dry THF (2 ml) under nitrogen. To start the reaction, an iodine crystal is added during addition. After completion of mixing, the mixture is boiled for 4 hours under reflux, and cooled to 0°C. While stirring, dry carbon dioxide gas is introduced into the reaction vessel for 15 minutes. The cloudy mixture is poured into 5 ml of 1-normal sodium hydroxide solution and extracted with ether. The aqueous phase is adjusted to a pH value of 6-6.2 and extracted with acetic acid ethyl ester. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The crude product melts at 106-107°C. The product is 1-(6-carboxyhexyl)-3-methyl-2-(3-pyridyl)-indole, whose TLC and NMR values are identical to the compound according to example 4-

Example 36

1-(prop-2-ynyl)-3-methyl-2-(3-pyridyl)-indole (90 mg) is dissolved under nitrogen in THF (2 ml) and the resulting solution is cooled to -78°C. A solution of n-butyl lithium (0.024 mL, 1.6 mol hexane) is added dropwise over 1 minute. The orange colored mixture is stirred for a further 10 minutes at -78°C, then mixed with chloroformic acid methyl ester (0.031 ml). The mixture is allowed to warm to reading temperature, poured into saturated aqueous sodium chloride solution and extracted with ether. The extract is washed with water and dried over magnesium sulfate. Evaporation in vacuum yields an oil, which is purified by preparative thin-layer chromatography. A 1:1 mixture of acetic acid ethyl ester:hexane is used as eluent. 1-(3-methoxy-carbonyl-prop-2-ynyl)-3-methyl-2-(3-pyridyl)-indole is isolated as an oil. NMR (CDCl 3 ) δ 3.73 (s, 3H), 4.83 (s, 2H), IR (CHCl 3 ) 1715, 2245 cm -1 .

The starting material is prepared as follows: Sodium hydride (50% lg mineralol j e-dispersion, 53 mg) is washed under nitrogen with petroleum ether. The washed sodium hydride is suspended in dry DMF (2 ml) and mixed dropwise with 3-methyl-2-(3-pyridyl)-indole (208 mg) in DMF (2 ml). The mixture is stirred for a further 30 minutes and then propargyl bromide is added dropwise. The reaction mixture is stirred for a further two hours, poured into ice water, acidified with 1-N hydrochloric acid, extracted with ether. The aqueous phase is made basic ■with sodium bicarbonate and extracted with ether. The ether extract is washed with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. Evaporation in vacuo gives 1-(prop-2-ynyl)-3-methyl-2-(3-pyridyl)-indole, NMR (CDCl 3 ) S 2.20 (s, 4H), 4.70 (d, 2H, J = 3Hz), IR (liquid) 3200, 2120 cm-<1>. Sm.p. 104-105°C after purification by short path chromatography using a 1:1 mixture of acetic acid ethyl ester rhexane.

Example 37

The treatment of 33 mg of 1-(3-methoxycarbonylprop-2-ynyl)-3-methyl-2-(3-pyridyl)-indole in 1 ml of methanol with 0.3 ml of 1 normal lithium hydroxide solution at room temperature gives 1-(3-carboxyprop -2-ynyl)-3-methyl-2-(3-pyridyl)-indole. IR 1720 cm-<1>.

Example 38

Analogously to the method mentioned in the preceding examples, the following compounds of formula I are also prepared, in which Ri = CH3, Pyr = 3-pyridyl and B = COOH.

The N-unsubstituted indoles used as starting materials are known. The new starting materials for compound 38/10, namely 5-methylthio-3-methyl-2-(3-pyridyl)-indole melt at 160-162°C. The compound 38/9 is prepared by hydrogenolysis of 1-(5-carboxypentyl)-5-benzoyloxy-3-methyl-2-(3-pyridyl)-indole, melting point 176-178°C. The starting material used 5-benzyloxy-3 -methyl-2-(3-pyridyl)-indole melts at 164-166°C.

Effect on thromboxane synthetase of human platelets

The method is carried out as stated above. This in vitro inhibition of thromboxane synthetase enzyme has been shown analogously in Methode von Sun, Biochem. Biophys. Res. Comm. 74, 1432 (1977).

Results;

Claims (3)

1. Analogous process for the preparation of new therapeutically active N-substituted 2-pyridylindoles of the general formula I wherein R 1 means (C 1 -C 2 )-alkyl, Pyr means 3- or 4-pyridyl, R 2 and R 3 independently mean hydrogen, (C 1 -C 4 )-alkyl, halogen, hydroxy, (C 2 -C 4 )- alkoxy, carboxy-C 3 -C 4 -alkyl, (C 1 -C 4 )- alkoxycarbonyl-(C 1 -C4)-alkyl or C1-C4-alkyl-(thio), A means alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, alkynylene of 2 to 4 carbon atoms, phenylene, a direct bond, (C1-C4)-alkylene-(thio or oxy)-phenylene or phenylene-C^- C 4 -alkenylene, B means carboxy" (C 1 -C 4 )-alkoxycarbonyl, carbamoyl, mono- or di-(C 1 -C 4 )alkylcarbamoyl, hydroxymethyl, hydroxycarbamoyl, 5-tetrazolyl or formyl, or pharmaceutically acceptable salts of these compounds, characterized in that a) a compound of formula V wherein X is hydrogen, alkali metal or tri-lower alkylsilyl, Rj, R2, R3 and Pyr have the indicated meaning, is condensed with a reactive functional derivative of a compound of formula IV wherein A and B have the above meanings, or b) a compound of formula VII in which Pyr, R-^, R2, R3, A and B have the above-mentioned meaning, are ring-closed or c) a compound of formula VIII wherein Pyr, R^, R2, R3, A and B have the indicated meaning, is cyclized, or d) in a compound of formula Ia in which A, Pyr, R^, Rg and R3 have the above-mentioned meaning, and C is a group different from a group B, transferable group to the group B, the group C is converted to B, optionally during extension of the chain A within its definition, and if desired or necessary, an interfering reactive group is protected in all these methods transiently, and if desired, a formed compound of formula I is converted into another compound according to the invention, and/or, if desired, a free compound formed is transferred to a pharmaceutical acceptable salt or a formed salt to the free compound or to another pharmaceutically acceptable salt. 2. Process according to claim 1 for the production of 1-(7-carboxy-syheptyl)-3-methyl-2-(3-pyridyl)-indole or a salt thereof, characterized in that corresponding starting materials are used. 3. Process according to claim 1 for the production of 1-(5-carboxy-sypentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole or a salt thereof, characterized in that corresponding starting materials are used.