IE54156B1 - N-substituted-2-pyridylindoles - Google Patents

Abstract

Die Erfindung betrifft Thromboxan-Synthetase hemmende Verbindungen der Formel worin R1 Wasserstoff oder Niederalkyl bedeutet, Ar für unsubstituisrtes oder durch Niederalkyl, Carboxy, Niederalkoxycarbonyl oder Carbamoyl substituiertes Pyridyl steht, R2 und R3 unabhängig voneinander Wasserstoff, Niederalkyl, Halogen, Trifluormethy!, Hydroxy, Nlederalkoxy, Carboxyniederalkyl, Niederafkoxycarbonyl-niederalkyl, Carboxy, Niederalkoxycarbonyl oder Nlederalkyl-(thio, sulfinyl oder sulfonyl) bedeutet, oder R2 und R3 zusammen, an benachbarten Kohlenstoffatomen, für Nlederalkylendioxy stehen; A für Alkylen mit 1 bis 12 Kohlenstoffatomen, Alkenylen mit 2 bis 12 Kohlenstoffatomen, Alkynylen mit 2 bis 12 Kohlenstoffatomen, Niederalkylen-phenylen-niederafkylen, Nisderatkylen-phenylen, Phenylen-niederalkylen, Phenylen, eine direkte Bindung, Niederalkylen-(thio oder oxy)-niederalkylen, (Thio oder Oxy)-phenylen, Niederalkylen-(thio oder oxy)-phenylen, Phenylen-(thio oder oxy)-niederalkylen oder Phenylen-niederalkenylen steht, B Carboxy, Niederalkoxycarbonyl, Carbamoyl, Mono- oder Di-niederalkyl-carbamoyl, Hydroxymethyl, Hydroxycarbamoyl, 5-Tetrazolyl oder Formyl bedeutet; ihre N-Oxide; und ihre Salze, insbesondere ihre therapeutisch verwendbaren Salze. Sie können z.B. durch Ringschluß von Verbindungen der Formel erhalten werden.

Description

United States Patent 3,468,894 disclosed the 1-unsubstituted 3-methy1-2-(3- ot 4-pyridyl)-indoles as diuretic agents. 2-(2Pyridyl)-indole-3-(acetic, propionic) acids are reported e.g., in Pharm. Bull.ii, 16 (1956) and Chemical Abstracts 64, 19540d (1966) respectively. Various optionally substituted 2-(3-pyridyl)-indole-3acetic acids have been described as chemical intermediates in Bull. Soc. Chim. France 1966, 771-2 and Bull. Soc. Chim. France 1969, 4154-9. The preparation of l-cyanoethyL-2-(2~pyridyl)-indole is reported in Fharmazie 23 (10),557-60 (1968).

Surprisingly it was found, that N-(or l)-substituted-2-pyridylindoles of formula 1 represent a novel class of outstanding potent and highly specific thromboxane synthetase inhibitors.

The foregoing attributes render the N-substituted-2-pyridyl indoles of this invention particularly useful when administered, alone or in combination, to mammals, e.g. for the treatment or prevention of diseases responsive to the inhibition of thromboxane synthetase, comprising cardiovascular disorders such as thrombosis, athero sclerosis,coronary spasm, arrhythmias, cerebral ischaemic attacks, migraine and other vascular headaches, myocardial infarction, angina pectoris, hypertension; respiratory disorders, such as asthma and apnea; and inflammatory disorders. Inhibition of thromboxane synthetase also has been noted to decrease metastasis in certain classes of tumors, and the compounds of this invention may be useful for the treatment of certain carcinomas. 415« This invention concerns therefore 1-substituted 2-pyridyl indoles of formula I V._.A I II II • · · ,A'Y\r R3 .

CHj-A-B (I) wherein R^ represents hydrogen or lower alkyl; Ar represents pyridyl unsubstituted or substituted by lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl; an<^ ^3 independently represent hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carboxy, lower alkoxycarhonyl, or lower alkyl-(thio, sulfinyl or sulfonyl), or 1&2 uad R3 together on adjacent carbon atoms represent lower alkylenedioxy; A represents alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, alkynylene of 2 to 12 carbon atoms, lower alkylenephenylene lower alkylene, lower alkylenephenylene, phenylene lower alkylene, phenylene, a direct bond, lower alkylene-(thio or oxy)-lower alkylene, (thio- or oxy)-phenylene, lower alkylene-(thio- or oxy)-phenylene, phenylene-(thio or oxy)lower alkylene or phenylene lower alkenylene; B represents carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lover alkylcarbamoyl, hydroxymethyl, hydroxycarbamoyl, 5-tetrazolyl or formyl; the N-oxides thereof; and salts, especially pharmaceutically acceptable salts thereof, process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application.

Preferred embodiments of this invention relate to compounds of formula I wherein R^ represents hydrogen or lower alkyl; Ar represents 2-, 3- or 4-pyridyl optionally substituted by lower alkyl; R^ is hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, :1156 lower alkoxy, lower alkylthio, carboxy lower alkyl or lower alkoxycarbonyl lower alkyl; R^ is hydrogen; or R^ and R^ together on adjacent carbon atoms represent lower alkylenedioxy; A represents alkylene of 1 to 12 carbon atoms, phenylene, lower(alkylenephenylene, alkylene-thio-phenylene or alkylene-oxy-phenylene) of 7 to 10 carbon atoms, or a direct bond; B represents carboxy, lower alkoxycarbonyl, carbamoyl, hydroxycarbamoyl, 5-tetrazolyl or hydroxymethyl; the Hoxides thereof; and salts, especially pharmaceutically accepcable salts thereof.

LO Further preferred are said compounds of formula I wherein is attached at the 5-position of the indole nucleus.

Particularly preferred are said compounds of formula I wherein £ represents carboxy, lower alkoxycarbonyl, carbamoyl, 5-tetrazolyl or hydroxycarbamoyl.

X5 Greatly preferred are the compounds of formula I wherein A represents alkylene of 3 to 10 carbon atoms, phenylene, lower alkylenethio-phenylene or lower alkylene-oxy-phenylene of 7 to 10 carbon atoms each.

Very useful are the compounds of formula I wherein A represents alkylene of 1 to 12 carbon atoms or phenylene.

Particularly useful are compounds of formula II \\ XEi « ·ιι i.m I II 11 R<>/V\y R3 I C H, jia 2m COR.

(XX) 54155 ’5 wherein Rj. represents hydrogen or lower alkyl; R^ and Rj represent independently hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkylthio or lower alkoxy; or Rj and Rj together on adjacent carbon atoms represent methylenedioxy; Pyr represents 2-, 3- or 4-pyridyl; m represents an integer from 1 to 13; R^ represents hydroxy, lower alkoxy or ainino; and salts, especially pharmaceutically acceptable salts thereof.

Preferred are the compounds of formula II wherein Rj represents hydrogen.

Particularly useful are also compounds of formula III n R.C-C H- — 6 p 2p -H- U (I Vy\ (Ill) c a, 2n COR. 'yr wherein n represents an integer from 3 to 10; p represents an integer from 0 to 4; Pyr represents 2-, 3- or 4-pyridyl; Rs and Rg independently represent hydroxy or lower alkoxy;and, salts, especially pharmaceutically acceptable salts thereof.

Preferred are compounds of formula III wherein n is 4 to 8, p is 1 to 4; Pyr is 3- or 4-pyridyl; R_ and Rg represent hydroxy.

Also valuable are compounds of formula IV _ 55156 '6 R2.

X· · ' ' X 11 1 „>/V\ yr C H, ,1 2q X I f\ • · I 11 •k · V I COR, (IV) wherein R^ and R^ independently represent hydrogen, lower alkyl, halogen, lower alkoxy, lower alkylthio or hydroxy; or "Ί ^3 together on adjacent carbon atoms represent methylenedioxy; X represents oxygen, sulfur or a direct bond; q represents an integer from 1 to 4; R? represents hydroxy or lower alkoxy; Pyr represents 2-, 3- or 4-pyridyl, and salts, especially pharmaceutically acceptable salts thereof.

Preferred are the compounds of formula IV wherein X is a direct bond, 10 Also preferred are the compounds of formula IV wherein q is an integer from 2 to 4 and X is oxygen or sulfur.

The general definitions used herein have the following meanings with in the scope of the present invention.

An alkylene representing C^-C^ ^kylene, may have a straight chain 15 or branched chain, and is preferably propylene, butylene, pentylene, hexylene, or heptylene, said radicals being unsubstituted or substituted by one or more lower alkyl groups, with the proviso that the total number of carbon atoms equals no more than 12.

The term alkenylene representing ^2^12 alkeny1ene groups, may have a straight or branched chain, and is preferably propenylene, 1- or 2- butenylene, 1- or 2-pentenylene, 1-, 2- or 3-hexenylene, 1-, 2-, 3- or 4-heptenylene, said groups being unsubstituted or substituted by one or more lower alkyl groups, with the proviso that the total number of carbon atoms equals no more than 12.

The term alkynylene representing ^ky^lene, may have a straight or branched chain, and is preferably propynylene, 1- or 2-butynylene, 1- or 2-pentynylene, 1-, 2- or 3-hexynylene, 1-, 2-, 3- or 4-heptynylene, said radicals being unsubstituted or substituted by one or more lower alkyl groups with the proviso that the total number of carbon atoms equals no more than 12.

The term phenylene represents L.2-, 1,3- and preferably 1,4-phenylene.

The term pyridyl represents 2-, 3- and 4-pyridyl, preferably 3pyridyl.

The term lower when referred to above and hereinafter in connection with organic groups, radicals or compounds respectively defines such as with up to and including 7, preferably up to and including 4 and advantageously one, two or three carbon atoms.

A lower alkylenephenylene group, a phenylene lower alkylene group, a lower alkylenephenylene lower alkylene group, a lower alkylene(thio or oxy)-phenylene group, a phenylene-(thio or oxy)-lower alkylene group, or a phenylene lower alkenylene group preferably contains 1 to 4 carbon atoms and advantageously one or two carbon atoms in each alkylene or alkenylene portion. The lower alkylene and alkenylene portions may be straight chain or branched.

A lower alkylene-(thio or oxy)-lower alkylene group is straight chain or branched and may contain a total of 2 to 12 carbon atoms, 34156 preferably 2 to 8 carbon atoms.

A lower alkyl group preferably contains 1-4 carbon atoms and represents for example ethyl, propyl, butyl or advantageously methyl.

A lower alkylenedioxy group represents preferably ethylenedioxy 5 and methylene-dioxy.

A lower alkoxy group preferably contains 1-4 carbon atoms and represents for example, ethoxy, propoxy or advantageously methoxy.

A lower alkyl-(thio, sulfinyl or sulfonyl) group represents advantageously methylthio, methylsulfinyl or methylsulfonyl respectively.

A lower alkoxycarbonyl group preferably contains 1-4 carbon atoms in the alkoxy portion and represents for example: methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or advantageously ethoxycarbonyl.

A mono(lower alkyl)-carbamoyl group preferably contains 1-4 carbon atoms in the alkyl portion and is for example N-methylcarbamoyl, N-propylcarbamoyl, or advantageously N-ethylcarbamoyl. A di(lower alkyl)-carbamoyl group preferably contains 1-4 carbon atoms in each lower alkyl portion and represents for example N,Ν-dimethylcarbamoyl, N-eethyl-N-ethylcarbamoyl and advantageously N,N-diethylcarbamoyl.

Halogen is preferably fluorine and chlorine, hut may also represent bromine or iodine.

Salts are preferably pharmaceutically acceptable salts, e.g. metal or anmonium salts of said compounds of formula I having a free carboxy group, more particularly alkali or alkaline earth metal salts, e.g., the sodium, potassium, magnesium or calcium salt; or advantageously easily crystallizing ammonium salts derived from ammonia or organic amines, such as mono-, di- or tri-lower (alkyl, cycloalkyl or hydroxyalkyl)-amines, lower alkylenediamines or (hydroxy-lower-alkyl or aryl-lower alkyl)-alkylanmonium bases, e.g., methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris-(hydroxymethyl)-aminomethane or benzyl-trimethylasmoniuffi hydroxide. Said compounds of formula I form acid addition salts, which are preferably such of pharmaceutically acceptable inorganic or organic acids, such as of strong mineral acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic,acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, maleic, fumaric, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid, or ascorbic acid.

The compounds of this invention exhibit valuable pharmacological properties, e.g. cardiovascular effects, by selectively decreasing thromboxane levels through selective inhibition of thromboxane synthetase in 1«- The compounds are thus useful for treating diseases responsive to thromboxane synthetase inhibition in mammals, primarily cardiovascular disorders such as thrombosis, atherosclerosis, coronary spasm, cerebral ischaemic attacks, migraine and other vascular headaches, myocardial infarction, angina pectoris, and hypertension.

These effects are demonstrable in in vitro tests or in vivo animal tests using advantageously mammals, e.g. guinea pigs, mice, rats, cats, dogs, or monkeys. Said compounds can be administered to them enterally or parenterally, advantageously orally, or subcutaneously, intravenously or intraperitoneally, for example, within gelatin capsules, or in the form of starchy suspensions or aqueous i - 54158 IQ solutions respectively. The applied dosage may range between about 0.01 to 100 mg/kg/day, preferably between about 0.05 and 50 mg/kg/ day, advantageously between about 0.1 and 25 mg/kg/day.

The in vitro inhibition of the thromboxane synthetase enzyme can be demonstrated, analogous to the method of Sun, Biochem. Biophys.

Res. Comm. 74, 1432 (1977); the testing procedure is as follows: C-Arachidonic acid is incubated with an enzyme mixture preparation consisting of solubilized and partially purified prostaglandin cyclo-oxygenase from sheep seminal vesicles and a crude microsomal preparation of thromboxane synthetase from lysed human platelets.

The test compound (dissolved'in buffer, or if necessary, in a small amount of ethanol) is added to the incubation medium. At the end of Che incubation period (30 minutes), Prostaglandin (PGE2) is reduced to a mixture of Prostaglandin and (PGF2 α+β) hy addition of sodium borohydride. The radioactive products and excess substrate are extracted into ethyl acetate; the extract is evaporated to dryness; the residue is dissolved in acetone, spotted on thinlayer plates and chromatographed in the solvent system toluene: acetone: glacial acetic acid (100 volumes: 100 volumes: 3 volumes). οθ The radioactive zones are located; those corresponding to Thromboxane B^ (TxBj) and PGF2 "+β are transferred to liquid scintillation vials and counted. The ratio of counts for TxB2/PGF2 α+β is calculated for each concentration of test compound and values are determined graphically as the concentration of test compound at which the ratio of TxB^/JG^ α+β is reduced to 50% of the control value.

The in-vitro effect on prostaglandin cyclooxygenase is measured by a modification of the method of Takeguchi et al. described in Biochemistry 10, 2372 (1971); the testing procedure is as follows: Lyophilized sheep seminal vesicle microsomes are utilized as the prostaglandin-synthesizing enzyme preparation. The conversion of 5415S C-arachidonic acid to PGE^ is measured. Test compounds (dissolved in buffer, or if necessary, in a small amount of ethanol) are added to the incubation mixture. The prostaglandins are extracted and separated by thin-layer chromatography; the plates are scanned, the radioactive zones corresponding to FCE^ are transferred to liquid scintillation vials and counted for radioactivity. ΙΟ^θ values for inhibition are determined graphically as the concentration of test compound causing a 50Z reduction in the amount of PGE., synthesized.

The in-vitro effect on prostacyclin (PGIj) synthetase is measured analogous to the method of Sun et al., Prostaglandins 14, 1055 (1977). The testing procedure is as follows: .....

C-Arachidomc acid is incubated with an enzyme mixture consisting of solubilized and partially purified prostaglandin cyclo-oxygenase from sheep seminal vesicles and crude PGI,, synthetase in the form of a microsomal fraction of bovine aorta.

Test compound (dissolved in buffer, or if necessary, in a small amount of ethanol) is placed in the incubation medium. The reaction mixture is incubated in 100 tiM Tris HCl (pH 7.5) for 30 minutes at 37°C, acidified to pH 3 and extracted into ethyl acetate. The extract is evaporated to dryness, the residue is dissolved in acetone, spotted on thin-layer plates and chromatographed in a solvent system described by Sun et el. The radioactive zones are located with a scanner; those corresponding to 6-keto-PGF^"(a stable end product of prostacyclin biotransformation) and PGE2 are transferred to liquid scintillation vials and counted. The ratio of counts for 6-keto-PGF^»/ PGE2 is calculated for each concentration of test compounds used.

ICgQ values for inhibition are determined graphically as the concentration of test compound at which the ratio of 6-keto-PGF^"/PGE2 is reduced co 50% of the control value.

S415& The inhibition of the synthesis and the reduction of plasma levels of thromboxane is determined in vivo on administration to rats in the following manner (as adapted from the procedures described by Tai et al. in Anal. Biochem. 87:343, 1978 and by Salmon in Erosta5 glandins 15:383, 1978): Rats are dosed with vehicle or test drug and injected intravenously with ionophore A23187 (0.5 mg/kg) two hours later. Blood is collected for analysis 2 minutes after the ionophore injection. A single aliquot of each plasma sample is assayed for thromboxane Bj and Ιθ another aliquot for 6-keto-EGFjO, the stable metabolites of thromboxane Aj and prostacyclin (EGIj) respectively, by radioimmunoassay.

Compounds of the formula 1 are very potent and selective, thromboxane synthetase inhibitors. At and above the effective dose levels for thromboxane synthetase inhibition neither the beneficial prostacyclin synthetase enzyme system nor the prostaglandin cyclooxygenase enzyme system is significantly inhibited. Surprisingly, the prostacyclin levels are significantly increased.

Illustrative of the invention, the ICjQ for l-(7-earboxyheptyl)-3methyl-2-(3~pyridyl)-indole is 1.2X10®M for thromboxane synthetase -,(, inhibition whereas the ΙΟ^θ for both inhibition of prostacyclin synthetase and cyclooxygenase is several orders of magnitude higher, i.e. about 1X10 Si.

Furthermore the ΙΟ^θ for thromboxane synthetase inhibition is e.g.

X 10'Si for l-(5-carboxypentyl)-5-(2-carboxyethyl)-3-mechyl-2-(325 pyridyl)-indole, 5 X 10 Si for l-(4-carboxybenzyl)-3-methyl-2-(3-9 pyridyl)-indole, 1 X 10 M for l-(5-carboxypentyl)-5-chloro-3-methyl 2- (3-pyridyl)-indole, 1 I 10 71 for l-(5-carbamoylpentyl)-5-chloro3- methyl-2-(3-pyridyl)-indole, 2.6 x 10-Sl for l-[2-(4-carboxyphenoxy)-ethyl]-3-methyl-2-(3-pyridyl)-indole and 5.8 x 10- M for 1-[2-(4-carboxypheny1thio)-ethyl]-3-methy1-2-(3-pyridy1)-indole hydrochloride. l-(7-Carboxyheptyl-3-methyl-2-(3-pyridyl)-indole and l-(5-carboxypentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole, as representative compounds of the invention, decrease the plasma concentration of thromboxane B^ by over SOZ in the rat at an oral dose as low as 0.10 mg/kg; a surprising increase in the plasma level of prostacyclin is observed at this or a higher dose thereof.

The aforementioned advantageous properties render the compounds oi this invention of great value as specific therapeutic agents for mammals including man.

The inhibition of variously induced platelet aggregation and thrombocytopenia by compounds of this invention, e.g. l-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole,is indicative of the utility in thromboembolism. Experimentally, prolongation of bleeding time in the rat is indicative of a beneficial antithrombotic effect, e.g. l-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole, when administered orally to rats at a dose of about 30 mg/kg.

Indicative of the beneficial effect in respiratory disorders is tbe fact, that the compounds of this invention afford protection against sudden death due to arachidonic acid induced pulmonary obstruction. Thus, for example, l-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)- indole protects against sudden death when administered orally to mice at a dose of 100 mg/kg.

In addition to the pharmaceutically acceptable salts cited above, any prodrug derivatives thereof, e.g., pharmaceutically acceptable esters and amides of the carboxylic acids of this invention that may be convertible by solvolysis or under physiological conditions to the 415 6 said carboxylic acids, are embraced within this invention.

Said esters are preferably e.g., the lower alkyl esters unsubstituted or suitably substituted such as the pivaloyloxymethyl, 2-diethylaminoethyl, hornyloxycarbonylmethyl, α-carboxyethyl or suitably esterified «-carboxyethyl esters which are prepared by methods well known to the art.

Said amides are preferably e.g. simple primary and secondary amides and amides derived from the amino acids or derivatives thereof, such as the amides derived from alanine or phenylalanine.

The compounds of this invention are prepared according to conventional methods, advantageously by 1) condensing a compound of the formula V I II II RXZV\r R3 1 X (V) wherein X is hydrogen, alkaline metal or tri-lower alkyl silyl, R^, R^, Rj and Ar have meaning as defined above, with a reactive functional derivative of a compound of the formula VI hqch2-a-b (VI) wherein A und B have meaning as defined above, or 2) ring-closing a compound of formula VII 5415S V. "λ 1 ll „ „ „ ·_ «-Η - Ν « C - Αχ κΛ 1 3 CH2-A-B (VII) «herein Ar, Rp Rp R^, A and B have meaning as defined above, or 3) cyclizing a compound of the formula VIII R2.

V/V, • · o >/\-C—Ar (VIII) R3 I CH2-A-B «herein Ar, Rp Rp Ry A and B have meaning as defined above; 4) in a compound of the formula Ia \\ /R1 • ·«*· I II II .VA *3 I CH2-A-C (la) wherein A, Ar, Rp R2 and R^ have meaning as defined above and C is a group differing from B and convertible into B, converting said group C into B, optionally by extending the chain A within its definition, or ) decarboxylating a compound of the formula IX \\ /θ0Η I II II (IX) *3 I CH2-A-B in which A, Ar, R^, R^ and R^ have meaning as defined above, and, if desired or necessary, temporarily protecting in each of these processes an interfering reactive group, and, if desired, converting Γ) any resulting compound of formula 1 into another compound of che invention, and/or, if desired, converting a resulting free compound into a salt or a resulting salt into che free compound or into another salt, and, if required, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and, if required, resolving a racemate obtained into the optical antipodes.

Ihe condensation according to process 1) is preferably carried out under basic conditions, e.g. with a basic alkali metal salt or a quaternary ammonium salt such as tetrabutyl ammonium hydroxide.

For example more specifically compounds of formula 7, wherein X is hydrogen, are converted preferably in situ, to reactive organometallic intermediates with a reactive metallizing agent, preferably about one molar equivalent of e.g. a strong alkali metal base, such as lithium diisopropylamide, sodium hydride, potassium t-butoxide,in an inert solvent such as dimethylformamide or tetra20 hydrofuran,at a temperature range between -50’ to +75’.preferably between -25° and +50°. Condensation of the resulting reactive organo metallic compound of formula 7 with a reactive functional derivative of a compound of formula 71 proceeds at a temperature range from about -25° to +50°C,preferably at a temperature range of 0° to 30°C.

In the case where B represents carboxy, carbamoyl, hydroxycarbamoyl, or mono lower alkylcarbamoyl, additional, e.g. one molar equivalent, of metallizing agent is required.

For example starting materials of formula V wherein X is hydrogen are either known to the art (e.g. U.S. Patent 3,468,894; J. Chem.

Soc. 1955, 2865; Bull. Soc. Chim. France 1969, 4154) or are prepared analogously from the corresponding optionally substituted phenylhydrazines and ketones of the formula ArCOCHjRj in the presence of a condensing agent, e.g. ethanolic hydrogen chloride or polyphosphoric acid by the well-known Fischer indole synthesis. 0 The starting materials .of formula VI or formula Via hereinafter are known or if new, are prepared according to conventional methods, e.g. che methods illustrated in US patent 4,256,757, British patent Application 2,016,452A or as described in the Examples herein.

More specifically, the compounds of formula I are advantageously pre15 pared according to process 1) as follows: Condensing preferably under basic conditions a compound of the formula V \\ A I II II R R3 I (V) X wherein X is hydrogen, R^ represents hydrogen or lower alkyl; 20 Ar represents pyridyl or pyridyl substituted by lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl; Rj and R^ represent hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carboxy or lower alkoxycarbonyl; 115 6 with a reactive functional derivative of a compound of the formula Via H0CH2 -A-B' (Via) wherein A represents alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, alkynylene of 2 to 12 carbon atoms, lower alkylenephenylene lower alkylene, lower alkylenephenylene, phenylene lower alkylene, phenylene or a direct bond; and B' represents carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkylcarbamoyl, hydroxymethyl, etherified hydroxymethyl, halomethyl, trialkoxymethyl or cyano; and in a resulting compound of formula lb ( II tl ,XZY'\.

R3 1 CH2-A-B' (lb) 1ΰ wherein B1 differs from B, converting said group B* into B, optionally by extending the chain A within its definition, and, if desired, converting any resulting compound of formula I into another compound of this invention.

The conversion of an initial product in uhich B' differs from B and the conversion of the resulting product into another compound of this invention are performed hy chemical methodology known to the art.

The ring-closure of the starting material of formula VII according 20 to process 2) is carried out by the well-known Fischer indole synthesis [as described in Heterocyclic Compounds, Indoles Fart I edited by W.J. Houlihan pp. 232-317] thermally or preferably in the presence of an acid condensing agent, advantageously a hydrogen halide, e.g. ethanolic hydrogen chloride, or polyphosphoric acid, optionally in an inert solvent preferably at a temperature of about 50-100"C.

The hydrazone starting materials of formula VII are either isolated or are preferably prepared in situ by the condensation of a ketone of the formula ArCOCH^Rj, wherein Ar and have the meaning given above, with a substituted hydrazine of the formula X rXz\-nh, ® j I 2 CHj-A-B wherein the symbols A, B, R^ and Rj have meaning given above, advantageously in the presence of an acid catalyst.

The starting hydrazines of formula X are in turn preferably prepared by e.g. nitrosation of the correspondingly substituted anilines of formula XI , \hch,-a-b 2 (XI) wherein the symbols A, B, Rj and Rj have meaning as previously 15 defined, and subsequent reduction of the R-nitroso derivatives, e.g. with zinc in acetic acid or by other methods well-known to the art.

If said intermediates contain interfering reactive groups, e.g. hydroxy or amino groups, such may advantageously be temporarily protected at any stage with easily removable blocking groups, e.g. >115 6 in the form of esters or amides respectively, by methods well known to the art.

The cyclization according to process 3) is carried out under conditions of the Madelung indole synthesis as described in Hetero5 cyclic Compounds, Indoles Fart I, edited by U.J. Houlihan, pp. 385396. Tbe intramolecular cyclization is preferably carried out in the presence of a strong base, e.g. sodium ethoxide, sodium amide or potassium t-butoxide .advantageously at elevated temperature e.g. ca. 300* heat or in an inert high boiling solvent such as tetrahydro10 naphthalene.

The starting materials of formula VIII are prepared by acylation of the substituted anilines of formula XI above with a compound of the formula ArCOOH or a reactive functional derivative thereof.

The decarboxylation according to process 5) is carried out in a conventional manner, e.g. with heat in an inert high boiling solvent or in the presence of a strong acid, e.g. a mineral acid such as hydrochloric acid.

The starting 3-carboxy-substituted indoles are prepared according to conventional methods. For example, compounds of formula IX, wherein the substituent at the 3-position is carboxy and wherein one of ^3 represents 5-hydroxy, may he prepared according to the Nenitzescu synthesis as described in Heterocyclic Compounds,Indoles Bart I, page 413, e.g. by condensing p-benzoquinone with a lower alkyl p-pyridyl-g-CCH^-A-B-substituted amino)-acrylate, such as lower alkyl 0-(3-pyridyl-p-(5~ethoxycarbonyl pentylamino)-acrylate, and hydrolyzing the resulting lower alkyl ester of the corresponding substituted 5-hydroxy-2-(3-pyridyl)indole-3-carboxylic acid (a compound of formula I wherein R^ is lower alkoxycarbonyl). 1 j 5 6 The conversion of s compound of formula la according to a process 4) wherein C differs from 8 into a compound of formula I, and the optional conversion of resulting product of formula I into another compound of this invention are performed by chemical methodology known to the art, and/or e.g. as described herein.

Convertible group C preferably represents trialkoxymethyl, esterified hydroxymethyl, etherified hydroxymethyl, halomethyl, cyano, 2oxazolinyl, dihydro-2-oxazolinyl, lower alkanoyloxymethy1, acetyl, methyl, carboxycarbonyl, trihaloacetyl, di(lower)alkoxymethyl, IQ alkylenedioxymethyl, vinyl, alkynyl, esterified carboxy, amidated carboxy.

The starting materials of formula Ia are prepared according to processes 1 to 3 and/or as described herein, using conventional chemical methodology well knoun to the art.

Certain terms used in the foregoing processes have the meanings as defined below: Reactive functional derivatives of alcohols of formula VI or Via are e.g. such esterified by a strong inorganic or organic acid above all a hydrohalie acid, e.g. hydrochloric, hydrobromic or hydriodic acid, an aliphatic or aromatic sulfonic acid, e.g. methanesulfonic acid, p-toluenesulfonic acid, and are prepared by methods known in the art.

Trialkoxymethyl represents preferably tri(lower alkoxy)-methyl, particularly triethoxy- or trimethoxymethyl.

Etherified hydroxymethyl· represents preferably tertiary lower alkyloxymethyl, lower alkoxyalkoxymethyl such as methoxymethoxymethyl, 2-oxa- or 2-thiacycloaikoxymethyl particularly 2-tetrahydropyranyloxymethyl.

Esterified hydroxy-methyl represents preferably lower alkanoyloxy methyl, advantageously acetoxymethyl.

Halomethyl represents especially chloromethyl but may also be bromomethyl or iodomethyl.

An alkali metal represents preferably lithium but may also be potassium or sodium.

Intermediates of formula Ia or lb wherein C or B' is halomethyl may be reacted preferably with an alkali metal cyanide such as potassium cyanide in a conventional manner to yield the compounds of formula Ia or lb wherein the chain is extended by 1 carbon atom and C or B* is cyano. These in turn are converted to compounds of formula I wherein B is carboxy, alkoxycarbonyl or carbamoyl using methods known to the art.

Thus, the compounds of formula Ia or lb wherein C or Br represents cyano (nitriles) are converted to compounds of formula I wherein B is carboxy by hydrolysis with inorganic acids, e.g. a hydrohalic acid such as hydrochloric acid or sulfuric acid in aqueous solution, or advantageously by hydrolysis with aqueous alkali metal hydroxide e.g. potassium hydroxide at reflux temperature.

The conversion of said nitriles to compounds of formula I wherein B represents lower alkoxycarbonyl is advantageously carried out by treatment first with a lower alkanol, e.g. anhydrous ethanol, in the presence of a strong acid, e.g. hydrochloric acid preferably at reflux temperature, followed by careful hydrolysis with water.

Furthermore, the conversion of the said nitriles to compounds of formula 1 wherein B represents carbamoyl is preferably carried out by treatment with an alkali metal hydroxide, e.g. dilute sodium hydroxide, and hydrogen peroxide, preferably at room temperature.

Furthermore, the intermediates of formula Ia or lb wherein C or B' is halomethyl, such as chloromethyl, are converted to compounds of formula X, wherein B is carboxy and the chain length is extended by two carbons, by first treating with e.g. a di-(lower) alkyl malonate, such as diethyl malonate, in the presence of a base, such as potassium carbonate or sodium ethoxide, in a solvent such as dimethylformamide, preferably at a temperature range from 50 to 100°. The resulting substituted di(lower)alkyl malonate is hydrolyzed, advantageously with an aqueous base, such as dilute sodium hydroxide, to the corresponding malonic acid which is decarboxylated under standard conditions, e.g. by heating in xylene solution, to give a compound of formula I wherein B is carboxy. Substitution of the di-(lower)alkyl malonate with a lower alkyl cyanoacetate yields the corresponding compounds of formula Ia or lb wherein C or B' is cyano.

Compounds of the invention, wherein A represents straight chain or branched alkenylene with a terminal double bond, may also be prepared from intermediates of formula Ia or lb wherein C or B' is halomethyl. For instance, said intermediates are first treated with e.g. a lower alkyl ester of an a-(aryl- or alkyl thio)acetic acid such as ethyl a-(phenylthio)-acetate, in the presence of a strong base such as sodium hydride. Subsequent oxidation of the resulting o-arylthio or α-alkylthio substituted ester to the a-arylsulfin>l ! 24 or α-alkylsulfinyl ester with e.g. sodium periodate, followed hy heatinduced elimination, by e.g. refluxing in xylene, yields a compound of general formula 1 (an a,β-unsaturated ester) wherein A represents alkenylene and B represents e.g. lower alkoxycarbonyl, and the chain length has been extended by two carbon atoms. The same transformation is also carried out using e.g. ethyl a-(phenylseleno)acetate as described in J. Am. Chem. Soc. 95, 6137(1973). Similarly, the compounds of formula la wherein C represents halomethyl may first he converted to the corresponding carboxaldehydes vith e.g. dimethylsulfoxide in the presence of triethylamine and silver tetrafluoroborate, or with chromium trioxide and pyridine in methylene chloride. Subsequent Hittig condensation e.g. with trimethylphosphonoacetate or ethyl (triphenylphosphoranylidene)-acetate also yields the above-cited α,β—unsaturated esters.

Compounds of formula I wherein B is lower alkoxycarbonyl may be amidized with ammonia, mono- or di-(lower) alkylamines e.g. methylamine, dimethylamine in an inert solvent, e.g. a lower alkanol, such as butanol, optionally at elevated temperatures to yield compounds of formula I wherein B represents unsubstituted, mono- or di(lower) alkylcarbamoyl.

Compounds of formula 1 wherein A represents straight chain or branched alkenylene with a terminal double bond, e.g. α,β-unsaturated esters, may also be prepared from the corresponding α,βsaturated compounds by treatment with e.g. phenylselenyl chloride in the presence of a strong base according to the procedure described in J.Am. Chem. Soc. 95, 6137 (1973).

Conversion of compounds of formula 1 or lb wherein B or B' respectively is lower alkoxycarbonyl; cyano; unsubstituted, monoor di-(loweralkyl) carbamoyl to compounds of formula I wherein B represents carboxy is advantageously carried out by hydrolysis with 415 6 '25 inorganic acids such as hydrohaiic or sulfuric acid or with aqueous alkalies, preferably alkali metal hydroxides such as lithium or sodium hydroxide.

Compounds of formula I wherein B represents carboxy or lower alkoxy5 carbonyl may be reduced-with simple or complex light metal hydrides such as lithium aluminum hydride, alane or diborane to compounds of formula 1 wherein B is hydroxymethyl. Said alcohols are also obtained by appropriate solvolysis of compounds of formula Ia wherein C is halomethyl by treatment with e.g. an alkali metal hy10 droxide as lithium or sodium hydroxide.

Said alcohols may in turn be transformed to the compounds of formula 1 wherein B is carboxy with conventional oxidizing agents, advantageously with pyridinum dichromate in dimethylformamide at room temperature.

Free carboxylic acids may be esterified with lower alkanols such as ethanol in the presence of a strong acid, e.g. sulfuric acid, advantageously at elevated temperature or with diazo (lower) alkanes, e.g. diazomethane in a solvent such as ethyl ether, advantageously at room temperature, to give the corresponding esters, namely com20 pounds of formula I wherein B is lower alkoxycarbonyl.

Furthermore, the free carboxylic acids may be converted via treatment of a reactive intermediate thereof, e.g. an acyl halide such as the acid chloride, or a mixed anhydride, e.g. such derived from a lower alkyl halocarbonate such as ethyl chloroformate, with ammonia, mono- or di-(lower) alkylamines, in an inert solvent such as methylene chloride, preferably in the presence of a basic catalyst such as pyridine, to compounds of formula I wherein B represents unsubstituted, mono or di-(lower)-alkylcarbamoyl. 415 6 Compounds o'f formula I wherein B represents mono(lower)-alkylcarbamoyl are converted to compounds of formula I wherein B is diilower) alkyl-carbamoyl by treatment of the former with a strong base e.g. sodium hydride followed by an alkylating agent, e.g. a lower alkyl halide in an inert solvent, e.g. dimethylformamide.

Furthermore compounds of formula I wherein A represents a straight chain or branched alkynylene or alkenylene may be converted by catalytic hydrogenation, advantageously under neutral conditions e.g. with palladium catalyst at atmospheric pressure in an inert solvent, e.g. ethanol, to compounds of formula I wherein A represents straight chain or branched alkylene.

The carboxaldehydes, the compounds of formula I wherein B represents formyl, may be prepared by oxidizing compounds of formula la wherein C represents respectively hydroxymethyl or halomethyl with e.g. dimethyl sulfoxide and a catalyst, such as a mixture of triethylamine and silver tetrafluoroborate, or with chromium trioxide and pyridine or other oxidizing agents known in the act.

Said carboxaldehydes are converted to Che corresponding acetals, the compounds of formula Ia wherein C represents di(lower)alkoxy20 methyl, or alkylenedioxymethyl e.g. a dimethylacetal, by acidcatalyzed condensation wich an alcohol, e.g. methanol.

Compounds of formula I wherein B represents carboxy may be converted by the well-known Arndt-Eistert synthesis to compounds of formula I wherein B represents carboxy and the chain has been 25 extended by 1 carbon atom. More particularly, a reactive functional derivative of the starting carboxylic acid, e.g. the acid chloride, is treated with diazomethane in e.g. diethyl ether to yield a compound of formula Ia wherein C represents diazoacetyl. Rearrangement with e.g. silver oxide yields said carboxylic acid of formula I wherein the chain has been extended by 1 carbon atom.. 415 6 A specific embodiment of process 4) is for Che preparation of compounds of formula I wherein B represents carboxy and comprises converting in a compound of the formula Ia in vhich C represents a group convertible into a carboxyl group, the group C into carboxy, r} optionally by extending Che chain A within its definition.

Groups convertible into a carboxy group are, for example, esterified carboxy groups, carboxy groups in form of their anhydrides, including corresponding groupe of asymetrical and inner anhydrides, amidated carboxy groups, cyano, amidino groups, including cyclic Ιθ amidino group such as 5-tetrazolyl, iminoether groups, including cyclic iminoether groups, e.g., 2-oxazolinyl or dihydro-2-oxazolinyl groups substituted by lower alkyl, and also methyl, hydroxymethyl, etherified hydroxymethyl, lower alkanoyloxymethyl, trialkoxymechyl, acetyl, trihaloacetyl, halomethyl, carboxycarbonyl (COCOOH), formyl (CHO), di(lower)alkoxymethyl, alkylenedioxymethyl, vinyl, ethynyl or diazoacetyl.

Simultaneously with conversion of C into the carboxy group, the chain A can be extended within its definition.

Esterified carboxy groups are preferably in form of the lower alkyl esters, e.g. the methyl, ethyl, n- or i-(propyl or butyl) esters; substituted lower alkyl esters e.g. the CJ-amino, LJ-mono- or dimethylamino, β-carboxy or e-carbethoxy-(ethyl, propyl or butyl) esters; aryl(lower)alkyl esters, e.g. benzyl, (methyl-, methoxy-, chloro-)substituted benzyl, and pyridylmethyl esters; lower alkanoyl25 oxy-(lower)alkyl esters, e.g. pivaloyloxymethyl esters; 3-phthalidyl and (methyl-, methoxy-, chloro-)substituted 3-phthalidyl esters, derived from the corresponding 3-hydroxyphthalides, (hydroxy-, lower alkanoyloxy-, lower alkoxy-) substituted lower alkoxymethyl esters e.g. ^-(hydroxy-, acetyloxy-, methoxy-) ethoxymethyl esters; bicycloalkyloxy-carbonyl-(lower) alkyl esters, e.g. those derived 4 1 5 S from bicyclic monoterpenoid alcohols, such as unsubstituted or lower alkyl substituted bicyclo (2,2,l]heptyloxycarbonyl-(lower)alkyl esters, advantageously bornyloxyearbonylmethyl esters; halo substituted lower alkyl esters, e.g. trichloroethyl or iodoethyl esters.

Amidated carboxy groups are preferably carboxy groups in form of their unsubscituted amides; N-mono or di-louer alkylamides, e.g. mono- or di-methylamides; tertiary amides derived from e.g. pyrrolidine, piperidine or morpholine; a-(carbo loweralkoxy)- or carboxysubstituted lower alkylamides, e.g. mono N-(carboethoxymethyl)10 amides, and mono N-(carboxymethyl)-amides; «-(carbo loweralkoxy)- or carboxy-substituted aryl(lower) alkylamides, e.g. (carboethoxy or carboxy) substituted phenethylamides; amino(lower)-alkylamides, e.g. (5-aminoethylamides and β-(carbobenzyloxy-amino)-ethylamides.

The conversion into the carboxy group is accomplished by methods which are known per se, and as described herein and in the Examples, e.g., by solvolysis such as hydrolysis or acidolysis as previously described, or hy reduction (esterified carboxy groups). For example, a trichloroethyl or 2-iodoethyl ester may be converted into the carboxylic acid by reduction, e.g. with zinc and a carboxylic acid in the presence of water. Benzyl esters or nitrobenzyl esters may be converted into che carboxy group by catalytic hydrogenation, the latter also with chemical reducing agents, e.g., sodium dithionite or with zinc and a carboxylic acid. Xn addition, tert-butyl esters may also be cleaved with trifluoroacetic acid. During the reduction of the group C, an alkenylene or alkynylene chain A may be converted into the corresponding alkylene chain.

Furthermore, compounds of formula Ia wherein C represents acetyl may be oxidatively cleaved to the corresponding compounds of formula I wherein B represents carboxy by conversion first to a compound of formula Ia wherein C represents trihaloacetyl, e.g. tribromo or ;> 4 1 5 C triiodoacetyl, by treataent e.g. with sodium hypobromite followed by cleavage with e.g. an aqueous base, such as sodium hydroxide.

The starting materials of formula la wherein C represents acetyl are in turn prepared from compounds of formula Ia wherein C represents halomethyl by treatment with an alkyl ester of acetoacetic acid, e.g. ethyl acetoacetate, in the presence of a base, e-.g. sodium hydride, followed by hydrolysis with a strong base, e.g., aqueous sodium hydroxide.

Said compounds are also prepared by condensing a compound of formula Ia wherein C is cyano with e.g. a Grignard or other organometallic reagent, e.g. methyl magnesium bromide under standard conditions.

Compounds of formula la wherein C represents carboxycarbonyl (COCOOH) are converted thermally or by oxidation to compounds of formula I wherein B represents carboxy by beating at elevated temperature e.g., at about 200 degrees, in the presence of glass powder, or by treating e.g., with hydrogen peroxide in the presence of a basic agent, e.g. sodium hydroxide.

The starting materials Of formula la wherein C represents COCOOH are prepared by e.g. condensation of a compound of formula la wherein C represents halomethyl with e.g. 2-ethoxy-carbony1-1,3dithiane, and subsequent oxidative hydrolysis, e.g. with N-bromosuccinimide in aqueous acetone followed by treatment with dilute aqueous sodium hydroxide.

Compounds of formula Ia wherein C represents formyl, di(lower)alkoxymethyl or alkylenedioxymethyl (formyl protected in the form of an acetal), e.g. the dimethyl acetal, are oxidized with e.g. silver nitrate, pyridinium dichromate or ozone to the corresponding compound of formula I wherein B represents carboxy. 4 15 6 Compounds of formula Ia wherein C represents vinyl may be converted to compounds of formula 1 wherein B represents carboxy hy first ozonolysis to compounds of formula I wherein B represents formyl, which are in turn oxidized to compounds of formula I wherein B re5 presents carboxy.

Compounds of formula Ia wherein C represents vinyl may also be treated with nickel carbonyl and carbon monoxide -under high pressure conditions to give compounds of formula I wherein B represents carboxy and the chain A contains a double bond adjacent to the carboxyl ιθ group.

Compounds of formula la wherein C represents ethynyl may be treated with a strong base, e.g. butyl lithium followed by condensation vith carbon dioxide or condensation with a lower alkyl haloformate, e.g. ethyl chloroformate followed hy hydrolysis to give compounds of formula I wherein B represents carboxy and the chain A contains a triple bond adjacent to the carboxyl group.

Compounds of formula Xa wherein C represents halomethyl may be converted to a corresponding organometallic intermediate, e.g. a cuprous or magnesium derivative, under conditions well known to the art.

Condensation of e.g. the resulting organomagnesium (Grignard) reagent e.g. a compound of formula Xa wherein C is transformed co e.g. CHjMgCl, with carbon dioxide yields a compound of formula I wherein B represents carboxy and the chain has been extended by 1 carbon atom.

Condensation of said Grignard reagent with e.g. a lower alkyl haloacetate or e.g. ethyl bromoacetate and subsequent hydrolysis yields a compound of formula I wherein B represents carboxy and wherein the chain has been extended by 2 carbon atoms. ' 4 1 5 S •7 J Said Grignard reagent may be condensed in Che presence of a cuprous halide, e.g. cuprous chloride,uith an α,β-unsaturated acid, e.g. propiolic or acrylic acid to yield a compound of formula I wherein B represents carboxy and wherein the chain has been extended by 3 carbon atoms.

Furthermore, compounds of formula Ia wherein C represents halomethyl may be condensed with e.g. the 3-lithio derivative of propiolic acid (prepared wich e.g. lithium diisopropylamide) to yield a compound of formula I wherein A contains a terminal alkynylene, B represents carboxy and the chain length has been extended by 3 carbon atoms.

Compounds of formula 1 wherein A represents lower alkylene or a direct bond and B represents hydroxymethyl, or reactive functional derivatives thereof, may be condensed with a lower alkanol (or thiol), or a phenol (or thiophenol) appropriately substituted by B, preferably in the presence of a strong base, to give compounds of formula I wherein A represents lower aIkylene-(thio or oxy)-phenylene, or lower alkylene-(thio cr oxy)-lower alkylene.

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert co the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures preferably at the boiling point of the solvents used, and at atmospheric or super-atmospheric pressure. The preferred solvents, catalysts and reaction conditions are set forth in the appended illustrative Examples. ,115 6 The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.

Mainly those starting materials should be used in said reactions, that lead co the formation of those compounds indicated above as being especially useful.

Depending on the choice of starting materials and methods, the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, depending on the presence of a double bond and the number of asymmetrical carbon atoms, as pure optical isomers, such as antipodes, or as mixtures of optical isomers such as racemates, mixtures of diastereoisomers, mixtures of racemates or mixtures of geometrical isomers. The aforesaid possible isomers or mixtures thereof are within the purview of this invention; certain particular isomers may be preferred.

Any resulting mixtures of diastereoisomers, mixtures of racemates and geometric isomers can be separated on the basis of the physicochemical differences of the constituents, in known manner, into the pure isomers, diastereoisomers, racemates, or geometric isomers, for example by chromatography and/or fractional crystallisation.

Any resulting racemates can be resolved into the optical antipodes by known methods, for example by e.g. reacting an acidic end product with an optically active base that forms salts with che racemic 4 13 G -t -7 acid, and separating the salts obtained in this manner, for example by fractional crystallization, into the diastereoisomeric salts from vhich the optically active carboxylic acid antipodes can he liberated on acidification. The basic racemic products can likewise r, be resolved into the optical antipodes, e.g. by separation of the diastereoisomeric salts thereof, with an optically active acid, and liberating the optically active basic compound by treatment with a standard base. Racemic products of the invention can thus be resolved into their optical antipodes, e.g., by the fractional crystallisation 111 of d- or l-(tartrates, mandelates, camphorsulfonates) or of d- or l-( Finally the compounds of the invention are either obtained in the free form, or as a salt thereof. Any resulting base can be converted into a corresponding acid addition salt,preferably with the use of a therapeutically useful acid or anion exchange preparation, or resulting salts can be converted into the corresponding free bases, for example, with the use of a stronger base, such as a metal or ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchange preparation. A compound of formula I wherein B represents carboxy can thus also be converted into the corresponding metal or ammonium salts. These or other salts, for example, the picrates, can also be used for purification of the bases obtained; tbe bases are converted into salts, the salts are separated and the bases are liberated from the salts.

In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, Ιθ provided such is possible or appropriate under the circumstances.

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

The pharmaceutical compositions according to the invention are those 5 suitable for enteral, such as oral or rectal, and parenteral administration to mammals, including man, for the treatment or prevention of diseases responsive to inhibition of thromboxane synthetase, comprising an effective amount of a pharmacologically active compound of formula I, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture vith excipients or carriers suitable for either enteral or parenteral application.

I', Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g. magnesium 2o aluminiim silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions are pre2'> ferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.

In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional 415 6 mixing, granulating or coating methods, respectively, and contain about 0.1 to 75Z, preferably about 1 Co 50Z, of the active ingredient. A unit dosage for a mammal of about 50 to 70 kg may contain between about 10 to 100 mg of the active ingredient.

The following Example·. are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade, and all parts wherever given are parts by weight. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and 100 mmHg.

I 541 Example 1: Dimethylformamide (1640 ml) is charged into a 76 litre glass kettle along with 430 g of potassium t-butoxide. This solution is stirred under nitrogen and cooled to -8*. A solution of 682 g of 3-methyl-2-(3-pyridyl)-indole in 3280 ml of dimethylformamide is added over 0.75 hour while the temperature is maintained below 0*. After 2 hours of stirring at "10’, 1640 ml of a solution of 780 g of methyl 8-bromooctanoate in dimethylformamide is added over 1 hour. Reaction temperature is maintained below 0*. After 2 hours stirring, the reaction mixture is allowed to warm to room temperature overnight. The rust-coloured mixture is then cooled to about 5' and treated with 19700 ml of ice-water. The temperature rises to 25’. After 0.5 hour stirring, the mixture is extracted with 2 x 8000 ml of ether.

The extracts are dried over magnesium sulfate and concentrated in vacuo to'give the l-(7-methoxycarbonylheptyl)-3-methyl-2-(3-pyridyl)-indole as aa oil; 1293 g of this oil is treated with 6530 ml of IN sodium hydroxide and warmed over steam to 90* for 2.5 hours. After cooling to room temperature, the solution is washed with 3 x 3000 ml of ether. The aqueous layer is cooled to 10° and acidified 2G to pH 3.5 with 3400 ml of 2N hydrochloric acid. The heavy suspension which results is extracted with 4 x 4000 ml of methylene chloride.

The combined extracts are washed once uith 4000 ml of water and dried over magnesium sulfate. After filtration and evaporation of solvent in vacuo at 60°, the residue is triturated with ether (2000 ml) and dried to give l-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole, m.p. 113-115°. Recrystallization from ethanol raises the melting point to 114-116°.

The starting 3-methyl-2-(3-pyridyl)-indole is prepared essentially as described in D.S. patent 3,468,894.

Methyl 8-bromooctanoate is prepared from azelaic acid essentially as described in D.S. patent 3,852,419, or by direct esterification of 8-bromooctanoic acid as follows: Methanol (4700 ml), 8-bromooctanoic acid (912 g) and sulfuric acid (912 ml) are charged into a suitable reactor and the mixture is heated at reflux temperature for 5 hours and is then stirred at ambient temperature overnight. The solvent is removed at reduced (3 mm Hg) pressure and the oily residue is dissolved in ether (4000 ml). The solution is washed with water (3 x 2000 ml), saturated sodium hydrogencarbonate solution (1000 ml) and saturated aqueous sodium chloride solution (1000 ml). The ether portion is dried over magnesium sulfate and filtered. Evaporation of solvent followed by distillation of the crude oil gives methyl 8-bromooctanoate, b.p. 73-76*/O.O5 mm Hg, np23 . 1.4614.

Example 2: To a suspension obtained by diluting 4.8 g of a 50 Z sodium hydride suspension in mineral oil with 40 ml of dimethylformamide under nitrogen, there is added dropwise a solution of 13.5 g of 3-methyl-2-(3-pyridyl)-indole in 80 ml of dimethylformanide. After addition is completed, the greenish yellow mixture is stirred at room temperature for about 1 hour. Ethyl bromoacetate (11.2 ml, 0.10 mole) is added dropwise to the reaction mixture which is cooled to 0-5* and stirred at room temperature for 4 hours.

The reaction mixture is poured into 1000 ml of ice-water and is extracted with 3 x 300 ml of ether. The ether layer is extracted with 3 x 300 ml of IN hydrochloric acid. The acidic extract is adjusted to pH 9-10 with concentrated anmonium hydroxide and extracted with 3 x 250 ml of ether. The combined ether extracts are dried over magnesium sulfate, filtered, and concentrated under vacuum to give l-ethoxyearbonylmethyl-3-methyl-2-(3-pyridyl)-indole as an nil.

This oil is heated at reflux for 4 hours in 500 ml of IN hydrochloric acid. After standing at room temperature overnight a yellow solid is collected and dried at 60-80*C/30 mm Hg for 12 hours. . :15« Recrystallization from ethanol gives l-earboxymethyl-3-methyl-2(3-pyridyl)-indole hydrochloride, m.p. 204-207*.

If the free amino acid is desired, it may be obtained by adjusting the pH of the hydrolysis medium to 3.5.

Examples 3-6: Utilizing the procedures of Examples χ antj 2, the following compounds of formula II in which R^'-CH^, R^' and R^' »H, and R^» OH are prepared: Example Starting EsterCmH2m Pyr , Recrystallization solvent 3 Br(CHj)jCOOEt (ch2)s 3-pyridyl 113-4 acetonitrile 111 4 Br (CHJ, COOMe (ch2)6 3-pyridyl 106-7.5 acetonitrile 5 Br(CH,),COOMe 2 4(CH2>4 3-pyridyl 123-5 ethanol 6 Br(CHj)jCOOEt (ch2)5 4-pyridyl 186-8 acetonitrile The starting 2-(3- and 4-pyridyl)-indoles are prepared according to U.S. patent 3,468,894.

The starting ethyl or methyl ω-bromo esters are obtained commercially or are prepared from the commercially available ω-bromoacids as illustrated below for methyl 6-bromohexanoate. A solution of 6-bromohexanoic acid (10 g) in 50 ml of methanol to which is added 1.0 ml of concentrated sulfuric acid, is heated under reflux for 8 hours.

The methanol is distilled off, the residue is dissolved in ether.

The echer solution is washed free of acid with water, dried over sodium sulfate and evaporated to dryness. Distillation at 0.8 nm Hg gives methyl 6-bromohexanoate, b.p. 85-90’/0.8 ran Hg. l-(7-Carboxyheptyl)-3-methyl-2-(2-pyridyl)-indole is prepared analogous to the procedure of Example· 1 using as starting material the 3-methy 1-2-(2-pyridyl)-indole described in J. Chem. Soc. 1955, 2865. d 1 5 ί’< The corresponding compounds of formula II wherein R^' » hydrogen, Pyr 2-,3-, or 4-pyridyl and R^' fluoro, hydrogen or methyl, and R^' » hydrogen, are similarly prepared, using the procedures of Examples 1 and 2, from the prerequisite ω-bromo ester and the following known starting 2-(pyridyl)-indoles: the 2-(2-,3- and 4-pyridyl)-indoles described in Pharm. Bull. Japan £, 16 (1956); and 5-(fluoro and methyl)-2-(3-pyridyl)-indoles described in Bull. Soc. Chim. France 1969, 4154.

Examples 7 and 8: The following compounds of formula II in which R ’ - CH3; R3' - H; Pyr - 3-pyridyl; - (CH^ and - OH qre prepared using analogous procedures to those described in previous Examples.

Example Rj' M.P.’ Salt -C1 143-5 15 8 5-OCH3 175-8 HCl The compound of Example 7 is prepared as follows: To a suspension obtained by diluting 1.39 g of a 50 Z sodium hydride suspension in mineral oil with 30 ml of dimethylformamide, there is added under nitrogen at 0-5" dropwise while stirring a solution of 6.59 g of -chloro-3-methyl-2-(3-pyridyl)-indole (prepared as described in US patent 3,468,894) in 60 ml of dimethylformamide. After addition is complete the suspension is stirred at 0° for 1/2 hour. While maintaining the temperature at 0°, a solution of 6.06 g of methyl 6-bromohexanoate in 10 ml of dimethylformamide is added dropwise.

The reaction mixture is allowed to reach room temperature, stirred at room temperature for 5 hours and poured into 400 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 to give 130 (5-methoxycarbonylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole as an oil.

A solution of 3.2 g of the above ester in 30 ml of 3N sodium hydroxide is heated under reflux for 17 hours. After cooling, the resulting product is collected hy filtration, and dissolved in 50 ml of water. Acidification with 2N hydrochloric acid to pH 4-5 precipitates the product which is purified by suspending in ether to give l-(5-carboxypentyl)-5-chloro-3-methy1-2-(3-pyridyl)-indole, m.p. 143-5*.

Similarly prepared is l-(5-carboxypentyl)-5-methoxy-3-methyl-2(3-pyridyl)-indole, obtained as an oil. Treatment with ethanolic hydrochloric acid in ethanol and crystallization by addition of ethyl ether yields compound of Example S, namely l-(5-carboxypentyl)5-wethoxy-3-methyl-2-(3-pyridyl)-indoIe hydrochloride, m.p. 175-178*. l-(5-carboxypentyl)-5-hydroxy-3-methyl-2-(pyridyl)-indole is prepared as follows: A solution of 1.70 g of l-(5-carboxypentyl)-5jr, methoxy-3-methyl-2-(3-pyridyl)-indole in 85 ml of 48 Z hydrobromic acid is heated under reflux for 0.5 hour. The reaction mixture is evaporated to dryness, diluted with water and adjusted to pH 6 with diluted sodium hydroxide. The precipitate is collected and recrystal lized from acetone/ethyl ester, to yield l-(5-carboxypentyl)-520 hydroxy-3-methy 1-2-(3- pyridyl) -indole.

Examples 9 and 10: The following examples of formula III in which CpH-,p represents CH^CH^, and Pyr represents 3-pyridy I are prepared essentially according to the procedure of Example 2. Condensation of ethyl 3-methyl-2-(3-pyridyl)-indole-5-propionate with ethyl 6bromohexanoate and methyl 8-bromooctanoate respectively yields the esters of Example 9a and 10a. Hydrolysis with hydrochloric acid gives the corresponding diacids of Examples 9 and 10.

Example C H, n 2n M.P.* Recrystallization solvent 9a (CH ) oil OCH OH °C H 9 (αφ> 143-5 OH2 5 10a (CH2)5. oil OCH, OCH OH 3 10 (ch5; 128-30 OH 3 acetonitrile acetonitrile <1 1 5 Β l-Carboxyheptyl-3-methy1-2-(4-pyridyl)-indole-5-propionic acid is similarly prepared.

Tbe scarring indoles are prepared as follows: To a suspension of p-hydrazinohydrocinnamic acid [Manske and Kulka, J. Can. Res., 25B: 376 (1947), 4.50 g] in 50 ml of absolute ethanol under nitrogen at room temperature is added while stirring 10 ml of a saturated ethanolic hydrogen chloride solution. A solution results in approximately 5 minutes. To the red-orange solution is added 3-propionylpyridine (3.37 g, 0.025 mole), the reaction mixture is heated to V reflux and maintained at reflux for 18 hours. The resulting solution is cooled in an ice-water bath and the resulting yellow crystals of ethyl 3-methyl-2-(3-pyridyl)-indole-5-propionate hydrochloride are collected, m.p. 249-51°. The free base, ethyl 3-methyl-2-(3-pyridyl)indole-5-propionate is prepared by suspending the hydrochloride j5 salt in water, basifying with 3R sodium hydroxide and extracting with ether.

Similarly prepared is ethyl 3-methyl-2-(4-pyridyl)-indole-5propionate hydrochloride, m.p. greater than 275°, and che corresponding free base.

Hearing a suspension of 7.5 g of echyl 3-methyl-2-(3-pyridyl)indole-5-propionate hydrochloride in 450 ml of 2N hydrochloric acid ac reflux Cemperature for 2 hours, cooling and colleceing the resulting solid gives 3-methyl-2-(3-pyridyl)-indole-5-propionic acid hydrochloride, m.p. 290°. Similar hydrolysis of echyl 3-methyl-2-(425 pyridyl)-indole-5-propionate hydrochloride yields 3-methy1-2-(4-pyridyl)-indole-5-propionic acid hydrochloride, melting above 305°.

Example 11: a) A solution of l-(4-cyanobenzyl)-3-methyl-2-(3-pyridyl)-indole (5.8 g) in 100 ml of a 1:1 mixture of 20 2 aqueous hydrochloric acid and glacial acetic acid is heated at reflux for 20 hours. After :> 3 ί ί> 6 cooling, the solution is poured into ice-water (100 ml) and the pH is adjusted to 4.5-5 with saturated aqueous sodium bicarbonate solution. The resulting precipitate is extracted with ethyl acetate, the extract is washed with water and evaporated to dryness to give l-(4-carboxyhenzyl)-3-methyl-2-(3-pyridyl)-indole, m.p. 273-275*.

The starting nitrile is prepared as follows: To a suspension of 2.9 g (0.06 mole) of 50 % sodium hydride in mineral oil in 40 ml of dimethylformamide under nitrogen at 0-5* is added dropwise over 20 minutes a solution of 10.4 g (0.05 'mole) of 3-methyl-2-(3-pyridyl)10 indole in 60 ml of dimethylformamide. The reaction mixture is stirred for 0.5 hour at 0-5’ followed by dropwise addition of 9.8 g (0.05 mole) of p-cyanobenzyl bromide in 50 ml of dimethylformamide. After stirring at 0-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture is poured into ice-water (600 ml). The result'r‘ ing solid is collected, dried, washed with petroleum ether and xedissolved in ether (500 ml). The ether solution is first washed with water, then with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfide, treated with charcoal and filtered. Evaporation of the ether solution to dryness yields a yellow solid.

This product is slurried in hot cyclohexane and collected by filtration to give l-(4-cyanobenzyl)-3-methyl-2-(3-pyridyl)-indole, m.p. 127-129°. b) Similarly prepared is l-(4-carboxybenzyl)-5-chloro-3-methyl-2-(3pyridyl)-indole hydrochloride, m.p. 217-220°.

Example 12: a) To a suspension of 0.49 g of lithium aluminium hydride in 50 ml of anhydrous tetrahydrofuran under nitrogen is added dropwise at room temperature a solution of 3.92 g of l-(5-methoxy-carbonylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole in 30 ml of anhydrous tetrahydrofuran. After addition is complete the suspension is stirred for 1 hour at room temperature and 50 ml of a saturated aqueous ammonium chloride solution is added. The reaction mixture 415 6 is allowed to stand at room temperature overnight and the organic layer is separated. The aqueous layer is filtered to remove 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 concentrated in vacuo. The crude product is purified by trituration with hexane/ether and dissolved in ethanol. Ethanolic hydrochloric acid is added to acidity and the solution diluted with anhydrous ether to crystallize the product. l-(6-Hydroxyhexyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole hydro10 chloride hemihydrate, m.p. 115-118*, is obtained. b) Similarly prepared is l-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)indole as an oil; NMR (CDClj)’ <$3.50 (t,2H), 3.98 (t,2H).

Example 13; To a suspension of 1.52 g of l-(5-carboxypentyl)-5-chloro3-methyl-2-(3-pyridyl)-indole in 50 ml of toluene under nitrogen is added dropwise at room temperature 0.31 ml of thionyl chloride. The resulting mixture is heated under reflux for 1 hour. An additional 0.10 ml portion of thionyl chloride is added and the solution is stirred at room temperature overnight. The resulting suspension is evaporated to dryness to give crude l-(5-chlorocarbonylpentyl)-52'! chloro-3-methyl-2-(3-pyridyl)-indole which is used directly without further purification.

A suspension of 0.86 g of the above l-(5-chlorocarbonylpentyl)-5chloro-3-methyl-2-(3-pyridyl)-indole in 20 ml of concentrated ammonium hydroxide is stirred at room temperature overnight. Filtra25 tion of the suspension and slurrying of the resulting solid in ethyl ether yields l-(5-carbamoylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole, m.p. 137-140*.

Example 14: To a suspension of 2.9 g (0.06 mole) of 50 % sodium hydride in mineral oil in 40 ml of dimethylformamide under nitrogen at 0-5’ is added dropwise over 20 minutes a solution of 10.4 g of : ί 5 c. 4 3-methy1-2-(3-pyridyl)-indole in 60 ol of dimethylformamide. The mixture is stirred for 0.5 hour at 0-5° followed by the dropwise addition of 17.6 g (0.06 mole) of l-tetrahydropyranyloxy-8-bromooctane in 50 ml of dimethylformamide. After stirring at 0-10* for 1 hour and at room temperature for 0.5 hour, the reaction, mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried over magnesiumsulfate and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting solution is kept at roam temperature for H> 0.5 hour, washed with ether, basified with aqueous 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness to give l-(8-hydroxyoctyl)-2(3-pyridyl)-3-methylindole.

Example 15; A solution of 4 g of l-(7-methoxycarbonylheptyl)-315 methyl-2-(3-pyridyl)-indole in 40 ml of n-butanol is Saturated with methylamine and heated on a steam bath in a pressure bottle for 3 days. The reaction mixture is evaporated to dryness and the product is crystallized from ethyl ester to yield the l-[7-(N-methylcarbamoyl)-heptyl]-3-methyl-2-(3-pyridyl)-indole.

Example 16; Preparation of 10,000 tablets each containing 10 mg of the active ingredient of Example 1: Formula; l-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole 100 g Lactose 1,157 g Corn starch 75 g Polyethylene glycol 6,000 75 g Talcum powder 75 g Magnesium stearate 18 g Purified water q.s.

Procedure: All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearace and half of che starch are mixed in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 150 ml of water. The paste fonned is added to the powders which are granulated, if necessary, with an additional amount of water.

The granulate is dried overnight at 35*, broken on a screen with 1.2 nm openings and compressed into tablets with 6.4 mm diameter, uppers bisected.

Example 17; Preparation of 10,000 capsules each containing 25 mg of the active ingredient of Example 11a: Formula: l-(4-carboxybenzyl)-3-methyl-2-(3-pyridyl)-indole Lactose Talcum powder 250 g 1,650 g 100 g Procedure: All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the talcum, then with che lactose until homogenous.

No. 3 capsules are filled with 200 mg, using a capsule filling machine.

Similarly prepared are Cablets and capsules comprising about 10100 mg of other compounds of the invention, e.g. of l-(5-carboxypentyl)-5-(chloro, fluoro, methoxy or methyl)-3-methyl-2-(3-pyridyl)indole, l-(5-carboxypentyl)-5,6-dichloro-3-m«thyl-2-(3-pyridyl)indole, or any ocher compound given in the Examples therein.

Example 18: A solution of 50 mg of l-(5-carbamoylpentyl)-5-chloro-3methyl-2-(3-pyridyl)-indole in 1 ml of 6N hydrochloric acid is heated at reflux temperature for 3 hours. On cooling the hydrochloride salt precipitates. The suspension is concentrated to dryness and the residue basified with saturated aqueous sodium hydrogencarbonate solution. This solution is washed with ether and neutralized to pH 6-7 with 2N hydrochloric acid. The crude free acid, 1-(5-carboxyr pentyl)-5-chloro-3-methyl-2-(3-pyridyl)-indole, m.p. 137-141°, is obtained.

Example 19: To a mixture of 4.17 g of 3-methyl-2-(3-pyridyl)-indole, 0.64 g of tetra-tr-butyl ammonium bromide and 1.02 g powdered potassium hydroxide in 500 ml of acetonitrile, while stirring at room in temperature under nitrogen, is added 5.06 g of ethyl p-(2-bromoethoxy)benzoate [for preparation see U.S. Patent 2,790,825 (1957)]. The suspension is stirred for five days. After filtration to remove potassium bromide, the filtrate is concentrated to an oil which is dissolved in ethyl acetate and extracted with 3N hydrochloric acid.

• The acid layer is separated and treated with 3H sodium hydroxide.

This suspension is extracted with ethyl acetate (3 x 100 ml) and the organic extract is separated, dried over magnesium sulfate and concentrated to give as an oil l-[2-(4-ethoxycarbonylphenoxy)-ethyl]-2(3-pyridyl) -3-methyUndo le.

., Example 20: A mixture of 4.7 g of l-[2-(4-ethoxycarbonylphenoxy)ethyl]-2-(3-pyridyl)-3-methylindole in 2H hydrochloric acid (220 ml) is heated under reflux for 6 hours. After cooling the solution is made basic with 3N sodium hydroxide and extracted with ethyl acetate. The basic solution is filtered and acidified to pH 6-7 with 5N hydrochloric acid. The solid is collected, dried and recrystallized from acetone to give l-[2-(4-carboxyphenoxy)-ethyl]-2-(3-pyridyl)-3— methylindole, m.p. 190-193°.

Example 21: A solution of 5.9 g of p-mercaptobenzoic acid ethyl ester (prepared according to J. Chem. Soc., 1963, 1947-1954) in 30 ml of dimethylformamide is added dropwise to a slurry of 1.55 g of 50 2 sodium hydride-mineral oil in 30 ml of dimethylformamide. This mixture ή? is stiTred at room temperature for 0.5 hour under nitrogen atmosphere. This solution is added dropwise to a solution of 9.78 g of l-(2-niethylsu! f<>nyloxyethyl)-2-(3-pyridyl)-3-methylindole in 60 ml of dimethylformamide at -10°. This mixture is stirred at room temperature overr.ignt and poured into 1000 ml of ice-water. This is extracted several times with ether (ca. 1000 ml total). The ether extract is washed with water (3 x 200 ml), dried over magnesium sulfate and evaporated in vacuo yielding l-[2-(4-ethoxycarbonylphenylthio)-ethyl}-2-(3-pyridyl)-3-methylindole as an oil; NHR (CDCl^) confirms the structure.

The starting material is prepared as follows: To 11.77 g of 1-(2erhoxvcarbonylmethyl)-2-(3-pyridyl)-3-methylindole in 400 ml of fry tetrahydrofuran at 0° is added 60 ml of a 1 M solution of lithium aluminium hydride in tetrahydrofuran. This is allowed co stir at room temperature for 1 hour, then cooled by an ice bath and quenched successively with 2.26 ml of water, 2.26 ml of a 15 7. sodium hydroxide solution, and 6.78 ml of water. The mixture is filtered, concentrated in vacuo, and the residue dissolved in ether, washed with a saturated sodium hydrogencarbonate solution, dried over magnesium sulfate and concentrated in vacuo. There is obtained the semi-solid l-(2-hycroxyethyl)-2-(3-pvridyl)-3-methylindole which is Used directly in the next step.

Methanesulfonyl chloride (2.70 ml) is added dropwise to a solution of 7.5 g l-(2-hydroxyethyl)-2-(3-pyridyl)-3-methylindole and 10.34 ml of triethylamine in 150 ml of methylene chloride at -10°. This mixture is stirred at room temperature for 0.5 hour and poured into 600 r.·.; of ice-water. The resulting slurry is extracted with metl’/Iene chloride, the extract is washed with saturated sodium hydrogencarbonate solution, dried over magnesium sulfate and evaporated in vacuo. There is obtained l-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-3methviindole which is used directly in the above reaction.

Example 22: A mixture of 6.39 g of l-[2-(4-ethoxycarbonylphenylthio)~ ethyl]-2-(3-pyridyl)-3-methylindole in 260 ml of 2N hydrochloric acid is heated at reflux temperature for 6 hours. After cooling the pH is adjusted to 6-7 with saturated sodium hydrogencarbonate, (ca. 500 ml). About 200 ml of ether is added and the mixture is stirred for 0.5 hour. A solid is collected, first washed with water, then ether, and then dissolved in 100 ml hot absolute ethanol. The solution is filtered, and while still hot treated with 1.68 ml of 6.5 N ethanolic hydrogen chloride. The solution is cooled and diluted with ca. 100 ml ether. The resulting product is collected to yield l-[2-(4-carboxyphenylthio)-ethyl]-2-(3-pyridyl)-3-methylindole hydrochloride, m.p. 222-224’.

Example 23: A solution of lithium diisopropylamide (IDA) is prepared by adding n-butyl lithium (7.66 mmol, 1.6M in hexane) to a solution of diisopropylamine (7.6 mmol) in tetrahydrofuran (THF, 12 ml) at -20°. The LDA solution is cooled to -78’ and l-(5-methoxycarbonylpentyl)-2-(3-pyridyl)-3-methylindole (2.48 g) in THF (24 ml) is added dropwise over 5 minutes. The mixture is stirred at -78’ for 20 minutes, followed by addition of phenylselenyl chloride (1.5 g) in THF (12 ml). After 5 minutes the cooling bath is removed and the mixture allowed to warm to O’. Saturated aqueous sodium bicarbonate (60 ml) is added, followed by ether extraction (3 x 50 ml). The combined organic phases are washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Concentration in vacuo gives the crude l-(5-methoxycarbonyl-5-phenylselenyl-2-(3-pyridyl)-3-methylindole as a yellow oil. The crude selenide is dissolved in dichloromethane (40 ml) and 30 % hydrogen peroxide (1.8 g, 16 nmol) in water (1.8 ml) is added dropwise. An exotherm reaction begins after the addition of ca. 10 Z of the hydrogen peroxide. The temperature rises to 30° by completion of the addition. Stirring is continued for an additional minutes, then 5 Z aqueous sodium carbonate (40 ml) is added. The dichloromethane layer is separated. The aqueous phase is extracted 4 15 6 with dichloromethane (25 ml). The combined organic phases are washed with 5 Z aqueous sodium carbonate, water, saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Concentration in vacuo yields l-(5-methoxycarbonylpent-4-enyl)-2-(3-py5 ridyl)-3-methylindole as a light yellow oil. Further purification is achieved by flash chromatography (SiO^) using ethyl acetate : hexane (2:3) as the eluent. NMR (CDClj) «5.53 (d, IH), 6.65 (m, IH); IR (neat) 1720 cm"l· Example 24: To a solution of the α,β-unsaturated ester l-(5-methoxyjq carbonylpent-4-enyl)-2-(3-pyridyl)-3-methylindole (84 mg) in methanol (1 ml) is added IN aqueous lithium hydroxide (1 ml). The mixture is stirred at room temperature overnight, then evaporated to dryness in vacuo. The residue is dissolved in water (2 ml) and washed with diethyl ether (5 ml). The aqueous phase is acidified Ij to pH 6.6-7.0 and extracted with dichloromethane. The organic extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate, then concentrated in vacuo to a pale yellow oil which solidifies upon trituration with chloroform to give l-(5-carboxypent-4-enyl)-2-(3-pyridyl)-3-methylindole, m.p. 145-147°.

Example 25: To a solution of Collins Reagent prepared with chromium trioxide (5.6 g) and pyridine (8.86 g, 112 mmol) in dichloromethane (150 ml) at 0-5° under a nitrogen atmosphere is added all at once 1.8 g of l-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)-indole in ι dichloromethane (15 ml). The mixture is stirred for 25 minutes, then filtered through celite (Celite is a Reaistered Trade Mark), The filtrate is then passed thrcugh a silica gel column. The product is eluted frcm the silica gel with a 1:1 mixture of ethyl acetate :dichlorcnethane (500 ml). Concentration in vacuo yields the desired l-(5-farmylpentyl)-2-(3-pyridyl)-3-methylindole as a pale yellow oil; NMR (CDC13) S 9.7 (t, 1H); IR (neat) 2710, 1720 cm’1.

Example 26: Trimethyl phosphonoacetate (328 mg) is added dropwise to a solution of potassium tert-butoxide (220 rag) in THF (5 ml) of 0* under a nitrogen atmosphere. The solution is stirred at 0’ for 20 minutes, then cooled to -78". A solution of the l-(5-formylpentyl)-2(j (3-pyridyl)-3-methylindole (450 mg) in THF (5 ml) is added dropwise over 15 minutes. The mixture is kept at -78" for 15 minutes, then the cooling hath is removed. The mixture is stirred overnight at room temperature, then diluted with water (25 ml) and extracted with diethyl ether (3 x 25 ml). The combined extracts are washed with saturated aqueous sodium bicarbonate, then saturated aqueous sodium chloride solution, and dried over magnesium sulfate. Concentration in vacuo yields Che 1-(7-methoxycarbonylhept-6-enyl)-2-(3-pyridy1)-3methylindole as a pale yellow oil; IR (neat) 1735 cm~5.

Example 27: Hydrolysis of 50 mg of l-(7-methoxycarbonylhept-6-enyl)-2 (3-pyridyl)-3-methylindole according to the procedure ofExample. 24 yields l-(7-carboxyhept-6-enyl)-2-(3-pyridyl)-3-methylindole, m.p. 144-146" (recrystallized from dichloromethane/hexane).

Example 28: l-(7-Carboxyhept-6-enyl)-3-methyl-2-(3-pyridyl)-indole (10 mg) is dissolved in 1 ml of absolute ethanol with a catalytic amount of 10 I palladium ou charcoal and hydrogenated at 1 atmosphere pressure. After 3.5 hours, the catalyst is removed by filtration and washed with a few milliliters of ethanol. The combined filtrates are concentrated in vacuo to yield a colourless oil which crystallizes to give l-(7-carboxyheptyl)-3-methyl-225 (3-pyridyl)-indole of Example 1 (crude product has m.p. 110-113").

Example 29: l-(4-Cyanobutyl)-3-methyl-2-(3-pyridyl)-indole (578 mg) is heated at 185’ for 0.5 hour with 450 mg of powdered sodium hydroxide and 5 ml of ethylene glycol; there is obtained, after pouring the reaction solution into 50 ml water, washing with ether, and adjusting the pH to 6 with 2N hydrochloric acid, an oily solid which crystallises to give l-(4-carboxybutyl)-3-methyl-2-(3-pyridyl) indole of Example 5 (m.p. 127-129°)· The starting material is prepared as follows: A solution of 3-methyl-2-(3-pyridyl)-indole (2.09 g) in 12 ml of DMF is added to a suspension of 0.528 g of 50 2 sodium hydride-mineral oil in 6 ml of DMF at 0°. The mixture is stirred at 0° for 0.5 hour and is treated with a solution of 1.78 g of 5-bromovaleronitrile in 4 ml of DMF. This mixture is stirred at room temperature overnight and is poured into 125 ml of water. This is extracted with 2 x 50 ml of ether, the extract is washed with 3 x 20 ml of water and dried over magnesium sulfate to give l-(4-cyanobutyl)-3-methyl-2-(3~pyridyl)-indole as an oil.

Example 30: A mixture of 578 mg of l-(4-cyanobutyl)-3-methyl-2(3-pyridyl)-indole, 173 mg of sodium azide, 142 mg of amnonium chloride and 5 mg of lithium chloride in 2 ml of DMF is heated at 120* overnight. After cooling the mixture is filtered and the filtrate diluted with ca. 25 ml of water. After the pH is adjusted to 10-11 vith 3S sodium hydroxide, the solution is vashed with ether to remove unreacted nitrile. The aqueous phase is adjusted to pH 5-6 with 2H hydrochloric acid and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and concentrated in vacuo. The solid residue is slurried in petroleum ether and collected to give l-[4-(5-tetrazolyl)-butyI]-3-methyl-2(3-pyridyl)-indole, m.p. 177-179*.

Example 31: A solution of 3-methy1-2-(3-pyridyl)-indole (2.08 g) in 12 ml of DMF is added to a suspension of 0.528 g of 50 2 sodium hydride-mineral oil in 6 ml of DMF under nitrogen at 10-15°. After complete addition the mixture is stirred at room temperature for 0.5 hour and is Created with a solution of 2.39 g of ethyl 3(p-chloromethylphenyl)-2-methylacrylate in 5 ml of DMF dropwise.

The resulting mixture is stirred at room temperature overnight and poured in 100 ml of water. The resulting mixture is extracted with ? ethyl acetate (2 x 50 ml) and the organic layer is washed with 100 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to yield l-[p-(2-ethoxycarbonylpropen-l-yl)~ benzyl]-3-methyl-2-(3-pyridyl)-indole.

Hydrolysis with 2H aqueous hydrochloric acid yields l-[p-(2-carboxypropen-l-yl)-benzyl]-3-methyl-2-(3-pyridyl)-indole.

The starting material is prepared as follows: To a suspension of 10.0 g of a 50 2 sodium hydride in mineral oil in freshly distilled dimethoxyethane (DME, 350 ml) stirred under nitrogen at 10* is added 53.6 ml of triethyl 2-phosphonopriopionate in ca. 40 minutes. The mixture is stirred for 0.5 hour3 at 10° and for an additional 1.5 hours during which time the temperature is allowed to rise to room temperature. This solution is transferred under nitrogen by cannula to a 500 ml addition funnel and ia added dropwise to a solution of terephthalaldehyde (33.53 g) in dry DME (475 ml) over a period of hour at 22-34*. After addition is complete the reaction mixture is stirred mechanically at room temperature for 2 hours, poured into 1000 ml of water and extracted with 4 x 500 ml of ether. The ether extract is washed vith a saturated sodium chloride solution (700 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil which partially crystallizes on standing. This crude mixture is purified by suspending in petroleum ether and ethyl acetate (93:7). The filtrate, after removal of unreacted dialdehyde, is concentrated in vacuo to give a mixture which is further purified by high pressure liquid chromatography (using petroleum ether/ethyl acetate 93:7). There is obtained pure ethyl 4-£ormyl-amethylcinnamate. A solution of the aldehyde (34.80 g) in 820 ml of absolute ethanol is treated with 12.11 g of granular sodium borohydride at room temperature under nitrogen. The resulting mixture is stirred at room temperature for 3 hours (or until all borohydride has dissolved) and then concentrated to ca. 200 ml volume, diluted with 400 ml of water, and extracted with 3 x 200 ml of ether. The echer extract is washed with 100 ml of water and saturated aqueous sodium chloride solution (100 ml), is dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo to give ethyl 3(p-hydroxymethylphenyl)-2-methylacrylate. To a solution of this product in 350 ml of methylene chloride is added at room temperature 11.53 ml of thionyl chloride dropwise over 25 minutes. The clear, colourless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated sodium bicarbonate, 100 ml of water, and 100 ml of saturated aqueous sodium chloride solution.

The organic layer after drying and removal of solvent yields ethyl 3-(p-chloromethylphenyl)-2-methylacrylate, used without further purification.

Example 32: l-(5-Formylpentyl)-3-methyl-2-(3-pyridyl)-indole (127 mg) is dissolved in DMF (0.66 ml) and pyridinium dichromate (298 mg) added all at once. The mixture is stirred overnight at room temperature, then diluted with etherzethyl acetate (25 ml, 4:1) and filtered. The solid is washed with hot chloroform and the combined filtrates concentrated in vacuo to yield a dark brown gum which is slurried in ether:ethyl acetate (4:1) and extracted with 0.1 N aqueous sodium hydroxide (2 ml). The aqueous extract is acidified to pH 5.5-6.0 and extracted with chloroform. The chloroform extract is dried and concentrated in vacuo yielding a yellow oil; thin layer chromatography ( TLC); (SiO^, ethyl acetate:hexane 1:1) indicates the presence of the desired acid. Further purification by chromatography on silica gel using ethyl acetate: hexane (1:1) as the eluent yields the desired l-(5-carboxypentyl)-3-methyl-2(3-pyridyl)-indole of Example 3.

Example 33: Bromine (0.344 ml) is added to a solution of 692 mg of sodium hydroxide in 4 ml of water with ice bath cooling. The result30 iug solution is added to 400 mg of l-(5-oxohexyl)-3-wethyl-2(3-pyridyl)-indole and this mixture is stirred for 2 hours at room temperature. The mixture is washed with ether. The aqueous solution 41 5 6 is filtered and acidified to pH 5-6 with 2N hydrochloric acid. A crude white solid is collected which melts in the range of 108-120’.

TLC (silica gel; methylene chloride/methanol 9:1) separation gives l-(4-carboxybutyl)-3-methyl-2-(3-pyridyl)-indole of Example 5.

The starting material is prepared as follows: l-(4-cyanobutyl)-3methyl-2-(3-pyridyl)-indole (1.5 g) in 15 ml of ether is added to a solution of 0.0103 mole of methyl magnesium bromide in 15 ml of ether , and this mixture is heated at reflux temperature for 3 hours. After cooling, 10 ml of 6N hydrochloric acid is added dropwise and this mixture refluxed for several hours. The reaction mixture is washed with ether, and basified to p.H. 10-11 with 3N sodium hydroxide. Ether extraction and evaporation of the solvent yields the l-(5-oxohexyl)-3-methyl-2-(3-pyridyl)-indole; IR 1720 cm*^.

NMR (CDClj) ί 2.0.

IExample 34: l-(7-carboxyheptyl)-5-chloro-3-methyl-2-(3-pyridyl)indole hydrochloride (421 mg) dissolved in 7 ml of tetrahydrofuran is warmed and treated with 202 mg (0.278 ml) of triethylamine. This solution is added dropwise to a solution of 108 mg (0.096 ml) of ethyl chloroformate in 1 ml of tetrahydrofuran which is cooled to 0-5°. The reaction mixture is stirred 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 (40 mg) in 10 ml of methanol. This mixture is stirred 0.5 hour and concentrated in vacuo. The residue is treated with 25 ml of ether-methanol (10:1) and filtered. The filtrate is evaporated in vacuo leaving a thick oil which is dissolved in acetone and treated with 6.5 N ethanolic hydrogen chloride to give 1-(7hydroxycarbamoyl-heptyl-5-chlaro-)-3-methyl-2-(3-pyridyl)-indole hydro chloride, m.p. 170-173°.

Example 35: Ethanolic hydrogen chloride (7.1 N, 0.14 ml) is added to 236 mg of N-phenyl-N-(5-meehoxycarbonylpentyl)-hydrazine in 2 ml 415 6 of absolute ethanol followed by 135 mg of 3-propionylpyridine. The mixture is heated at reflux temperature overnight. Additional ethanolic hydrogen chloride (0.62 ml) is added and heating is continued for an additional 24 hours. After cooling the mixture is filtered and the filtrate evaporated in vacuo. The residue is stirred in 10 ml of water and basified to pH 10-11 with 1 N sodium hydroxide; this mixture is extracted with ether. The extract after washing with water and drying over magnesium sulfate gives on evaporation of solvent an oil which is identified as l-(5-ethoxycarbony lpentyl)-3-methyl-2-(3-pyridyl)-indole.· This ester is hydrolyzed with 10 ml of 2N hydrochloric acid at reflux temperature followed by adjustment of the pH to ca. 6 with saturated sodium bicarbonate and extraction with ether. Work-up of the organic extract gives l-(5-carboxypentyl)-3-methyl-2-(3-pyridyl)indole of Example 3 (crude m.p. 111-113*.

The starting material is prepared as follows: Aniline (2.79 g, 2.73 ml), 6.27 g of methyl 6-hromohexanoate and 12.24 g (0.09 mole) of sodium acetate trihydrate are heated at 80-100* overnight in 15 ml of absolute ethanol. 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 sulfate and evaporated in vacuo to give N-(5-methoxycarbonylpentyl)-aniline.

A solution of 1.4 g of sodium nitrite in 5 ml of water is added dropwise at 0-10* to a mixture of 4.42 g of N-(5-methoxycarbonylpentyl)-aniline, 2.9 ml of concentrated hydrochloric acid, and ice as needed to maintain the desired temperature. The mixture is then allowed to stir at ambient temperature for 1 hour and is then extracted with ether. The extract is washed with water, dried over magnesium sulfate, and evaporated in vacuo to give N-nitroso-N-(5methoxycarbonylpentyl)-aniline as an oil. 515 6 The above N-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 an exothermic reaction to 33*, che mixture is stirred at room temperature for 2 hours. After filtration to remove zinc, the fil5 trate is washed with ether and basified to pH 10-11 with 40 Z sodium hydroxide and extracted with ether. The extract is dried over magnesium sulfate and evaporated in vacuo to give a crude oil.

After flash chromatography through silica gel with hexane-acetic acid (5:1), N-phenyl-N-(5-methoxycarbonylpentyl)-hydrazine of about I.q 80 Z purity is obtained, which is used directly in the Fischer cyclization described above.

Example 36: 1-[7,7-(bis-methoxycarbonyl)-heptyl]-3~methy1-2-(3pyridyl)-indole (273 mg) is dissolved in methanol (0.5 ml) and 1 N aqueous lithium hydroxide (1.95 ml) added. The mixture is stirred Y5 at room temperature for 1 hour, then refluxed for 2.5 hours. The clear solution, is concentrated to dryness, the residue dissolved in water and the pH adjusted to 6-6.2. A yellow gumsy solid precipitates which is extracted into chloroform. Concentration of the chloroform, which is dried over magnesium sulfate, yields crude l-[7,7-(bis20 carboxy)-heptyl]-3-methyl-2-(3-pyridyl)-indole; NMR (CDClj) £10.60 (2H).

A sample of the crude dicarboxylic acid (28 mg) is heated with p-xylene (3 ml) containing 0.1 N hydrochloric acid (0.1 ml) for 0.5 hour. The clear solution is allowed to cool to room temperature.

A gum precipitates and is extracted into aqueous sodium hydroxide.

The aqueous phase is separated, and after adjustment of the pH to 6-6.2, extracted with ethyl acetate:ether (8:2). The organic phase is dried over magnesium sulfate and concentrated to give a colourless oil which solidifies on standing to yield l-(7-carboxyhepty1)-330 wethyl-2-(3-pyridyl)-indole, identical by NMR and TLC to the compound of Example 1. 415 6 The starting material is prepared as follows: Thionyl chloride (0.36 ml) is combined with l-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)-indole (1.37 g) at 0*. The mixture is then stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate is added and the mixture is extracted with dichloromethane. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Concentration in vacuo yields the crude chloride as an oil. Purification by silica gel chromatography (methylene chloride/ethyl acetate 19:1) gives 1-(6chlorohexyl)-3-methyl-2-(3-pyridyl)-indole as a light yellow oil; NMR (CDC13) 43.30 (t, 2H), 3.92 (t, 2H).

The l-(6-chlorohexyl)-3-methyl-2-(3-pyridyl)-indole (0.5 g) is combined with dimethyl malonate (792 mg), potassium carbonate (790 mg) and dimethylformamide (11.6 ml) and the mixture heated at 80-90° for 18 hours under nitrogen. The mixture is poured into ice-water (80 ml), acidified with IN hydrochloric acid and washed uith ether. The aqueous layer is adjusted to pH 6 and extracted with ether which is then dried over magnesium sulfate and concentrated to yield a yellow oil. Purification by preparative TLC (chloroformethyl ester 9:1) gives l-[7,7-(bis-methoxycarbonyl)-heptyl]-3methyl-2-(3-pyridyl)-indole; NMR (CDC13) £3.32 (t, 1Η), 3.78 (s, 6Η), 4.03 (t, 2H): IR (neat) 1750 cm-1.

Example 37: l-(6-chlorohexyl)-3-methyl-2-(3-pyridyl)-indole (165 mg) in dry THF (2 ml) is added dropwise to magnesium turnings (12 mg) in dry THF (2 ml) under a nitrogen atmosphere. A crystal of iodine is added during the addition to initiate the reaction. The mixture is refluxed for 4hours after the addition is completed, then cooled to 0°, and dry carbon dioxide gas bubbled into the flask with stirring for 15 minutes. The cloudy mixture is poured into 5 ml IN sodium hydroxide and extracted with ether. The aqueous phase is adjusted to pH 6-6.2 and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated in vacuo yielding e white solid, crude m.p. 106-107*, being l-(6-carboxyhexyl)-3-methyl-2-(3-pyridyl)-indole, identical by TLC and NMR to the compound of Example 4.

Example 38; l-(Frop-2-ynyl)-3-methyl-2-(3-pyridyl)-indole (90 mg) is dissolved in THF (2 ml) under a nitrogen atmosphere and the resulting solution cooled to -78°. A solution of n-butyl lithium (0.024 ml, 1.6M in hexane) is added dropwise via syringe over 1 minute. After stirring at -78° for an additional 10 minutes the orange coloured mixture is quenched with methyl chloroformate (0.031 ml) and allowed to warm to room temperature. The mixture is then poured into saturated aqueous sodium chloride solution and extracted with ether. The extract is washed with water and dried over magnesium sulfate. Concentration in vacuo yields an oil which is purified by preparative TLC using (1:1) ethyl acetate:hexane as the developing solvent. The l-(3-methoxycarbonyl-prop-2-ynyl)-3methyl-2-(3-pyridyl)-indole is isolated as an oil; NMR (CDCl^) 53.73 (a, 3H), 4.83 (s, 2H); IR (CHClj) 1715, 2245 cm1.

The starting material is prepared as follows: Sodium hydride (50 Z mineral oil dispersion, 53 mg) is washed with petroleum ether under nitrogen. The washed sodium hydride is suspended in dry DMF (2 ml) and 3-methyl-2-(3-pyridyl)-indole (208 mg) in DMF (2 ml) added dropwise. The mixture is stirred an additional 30 minutes followed by the dropwise addition of propargyl bromide (220 mg). The mixture is stirred for an additional 2 hours, poured into ice-water, acidi25 fied with IN hydrochloric acid and extracted with ether. The aqueous phase is made basic with sodium bicarbonate and extracted with ether. The ether extract is washed with water, saturated aqueous sodium chloride solution and dried over magnesium sulfate.. Concentration in vacuo yields l-(prop-2-ynyl)-3-methyl-2-(3-pyridyl)-indolej NMR (CDCip 2120 cm1; m.p. 104-105° after purification with silica gel flash chromatography using ethyl acetate:hexane (1:1).

Example 39: Treatment of 33 mg of l-(3-methoxycarbonylprop-2-ynyl)3-methyl-2-(3-pyridyl)-indole in I ml of methanol with 0.3 ml of IN lithium hydroxide ac room temperature yields l-(3-carboxyprop-2ynyl)-3-methyl-2-(3-pyridyl)-indole; IR 1720 cm"l.

Example 40: Preparation by methods analogous to those described in the previous Examples of additional compounds of formula II wherein Rl' ^3 ‘ Pyr ^'Pyridyl and R^ " OH.

Compound V VCmH2m Salt m.p· 4Q/1 5-C1 H (ch2)7 HCl 173-176° 40/2 5-0CH3 H ^5 HBr 188-189° 40/3 5-C1 6-C1 (ch2)5 HCl 178-80° 40/4 5-Γ H (¾ HCl 216-219° 40/5 5-CH3 H ?! HCl 185-8* 40/6 5-CH3 H (CH2)7 - 124-125° 40/7 H H(CH?10 - 100-102° 40/8 40/9 5-O-CH2-O-6 5-OH H(CH2>5 (ch2)5 168-170° 40/10 5-SCH3 H (ch2)5 - 135-7° The starting N-unsubstituted indoles are known. The new starting material for compound 4Q/10, 5-methylthio-3-mechyl-2-(3-pyridyl)-indole, has m.p. of 160-162°.

The compound of Example 40/9 is prepared by hydrogenolysis of 1-(5carboxypentyl)-5-benzyloxy-3-methyl-2-(3-pyridyl)-indole, m.p. 176178°. The starting 5-benzyloxy-3-methyl-2-(3-pyridyl)-indole has the m.p. 164-166°. 415 f60 Example 41: Preparation by methods analogous to those described in the previous Examples of additional compounds of formula I wherein R^ » CHj, Ax » 3-pyridyl, and B - COOH Example *2 *3 A B 41/1 H H c=c-(ch2)3 COOH 41/2 H H ch2s(ch2)2 COOH 41/3 H H (ch2)20(ch2)2 COOH 41/4 H H (ch2)20(ch2)3 COOH The alkylating starting materials for compounds 41/4 are prepared as described in J. Org. Chem. 41/2, 41/3 and 34, 2955 (1969) U.S. Patent 3,984,459 and Chem. Abstr. 83, 166177b respectively.

Effect on thromboxane synthetase from human platelets The method is carried out according to the description given above, i.e. the in vitro inhibition of the thromboxane synthetase enzyme is demonstrated analogous to the method of Sun, Biochem. Biophys. Res. Comm. 74, 1432 (19 Results: Compound of Example No. 1 2 9 7 13 )77).

ICS0 UM) Tromboxane Synthetase 0.003 0.012 1.800 0.008 0.007 0.021 0.069 0.050 3.400 0.001 0.260 0.013

Claims (56)

Claims

1. A compound of the general formula I (I) 3 ώΗ 2 -Α-Β wherein represents hydrogen or lower alkyl; Ar represents pyridyl unsubstituted or substituted by lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl; R 2 and R 3 independently represent hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carboxy, lower alkoxycarbonyl,‘or lower alkyl-(thio, sulfinyl or sulfonyl), or R 2 and Rj together on adjacent carbon atoms represent lower alkylenedioxy; A represents alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, alkynylene of 2 to 12 carbon atoms, lower alkylenephenylene lower alkylene, lower alkylenephenylene, phenylene lower alkylene, phenylene, a direct bond, lower alkylene-(thio or oxy)-lower alkylene, (thio or·oxy)-phenylene, lower alkylene-(thio or oxy)-phenylene, phenylene-(thio or oxy>lower alkylene or phenylene lower alkenylene; B represents carboxy, lower alkoxycarbonyl, carbamoyl, mono- or dilower alkylcarbamoyl, hydroxymethyl, hydroxycarbamoyl, 5tetrazolyl or formyl; and the N-oxides thereof.

2. A compound of the formula I shown in claim 1, wherein R^ represents hydrogen or lower alkyl; Ar represents pyridyl unsubstituted or substituted by lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl; R 2 and Rj independently represent hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carboxy or lower alkoxycarbonyl, A represents alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, alkynylene of 2 to 12 carbon atoms, lower alkylenephenylene lower alkylene, lower aIkylenephenylene, phenylene lower alkylene, phenylene, a direct bond, B represents carboxy, lower alkoxycarbonyl, 5 carbamoyl, mono- or di-lower aIkylcarbamoyl or hydroxymethyl- and the N-oxides thereof.

3. A compound of the formula I shown in claim 1, wherein represents hydrogen or lower alkyl; Ar represents 2-, 3- or 4-pyridyl optionally substituted by lower alkyl; 10 K-2 lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, lower alkylthio, carboxy lower alkyl or lower alkoxycarbonyl lower alkyl; Rj is hydrogen; or R 2 and Rj together on adjacent carbon atoms represent lower alkylenedioxy; A represents alkylene of 1 to 12 carbon 15 atoms, phenylene, lower(alkylenephenylene, alkylene-thiophenylene or alkylene-oxy-phenylene) of 7 to 10 carbon atoms, or a direct bond; B represents carboxy, lower alkoxycarbonyl, carbamoyl, hydroxycarbamoyl, 5-tetrazolyl or hydroxymethyl; and the N-oxides thereof. 20 4. A compound of the formula I shown in claim 1, wherein

4.R^ represents hydrogen or lower alkyl; Ar represents 2-, 3- or 4-pyridyl optionally substituted by lower alkyl; R 2 is hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, carboxy lower alkyl or lower alkoxy25 carbonyl lower alkyl; R-j is hydrogen; A represents alkylene of 1 to 12 carbon atoms, phenylene, lower aIkylenephenylene of 7 to 10 carbon atoms or a direct bond; B represents carboxy, lower alkoxycarbonyl, carbamoyl or hydroxymethyl; and the N-oxides thereof. 54 ί s6

5. A compound of the formula II wherein R^' represents hydrogen or lower alkyl; R^' and Rj' represent, independently hydrogen, lower alkyl, halo• gen, trifluoromethyl, hydroxy, lower alkylthio or lower alkoxy; or R^ 1 and R^' together on adjacent carbon atoms represent methylenedioxy; Pyr represents 2-, 3- or 4pyridyl; m represents an. integer from 1 to 13; represents hydroxy, lower alkoxy or amino. 10 6. A compound of the formula II shown in claim 5, wherein

6.R * represents hydrogen or lower alkyl, R 2 ' is hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy or lower alkoxy, R^' represents hydrogen, Pyr is 2-, 3- or 4pyridyl, m represents an integer from 1 to 13, and R^ 15 represents hydroxy, lower alkoxy or amino.

7. A compound of the formula III wherein n represents an integer from 3 to 10; p represents an integer from 0 to 4; Pyr represents 2-, 3- or 4-pyridyl; 20 Rj and Rg independently represent hydroxy or lower alkoxy.

8. A compound of the formula IV (IV) £or 7 wherein R 2 ' and *3' independently represent hydrogen, lower alkyl, halogen, lower alkoxy, lower alkylthio or hydroxy; or R 2 ' and R^' together on adjacent carbon atoms represent methylenedioxy; X represents oxygen, sulfur or a direct bond; g represents an integer from 1 to 4; R 7 represents hydroxy or lower alkoxy; and Pyr represents 2-, 3- or 4pyridyl.

9.LO 9- A compound of the formula I shown in claim 1, wherein R 1 = CH 3 r Ar = 3-pyridy 1, R 2 and R 3 * Η, B = COOH, and A is selected from the group consisting of CsC-(CH 2 ) 3 , CH 2 S-(CH 2 ) 2 , (CH 2 ) 2 O(CH 2 ) 2 and (CH 2 ) 2 O(CH 2 ) 3

10. A compound of the formula II shown in claim 5, wherein 15 R l' = CH 3 , R 2 ' and R 3 ' = H, R^ = OH and the other symbols have the following meanings: C H, oi zin Pyr (CH 2 ) 5 3-pyridyl (CH 2 ) 6 3-pyridyl (ch 2 ) 4 3-pyridyl 20 (CH 2 ) s 4-pyridyl.

11. A compound of the formula II shown in claim 5, wherein R l' = CHj, Pyr = 3-pyridyl, = OH and the other symbols have the following meanings: 5 4 15 6 Compound R 2* *3 ' C m H 2m 1 5-C1 H (ch 2 ) 7 2 5-OCH 3 H (ch 2 ) 5 3 5-C1 6-C1 (CH ? )ς 4 5-F H (0Η ? ) ς 5 5-CH 3 H ( ch 2) 5 6 5-CH 3 H (ch 2 ) ? 7 H H (ch 2 ) 10 8 5-0—CHj—0- -6 (CH,),. 9 5-OH H (θΗ-,)ς 10 5-SCHj H (ch 2 ) 5 ·

12. 1-(7-Methoxycarbonylheptyl)-3-methyl-2-(3-pyridyl) indole.

13. 1-(7-Carboxyheptyl)-3-methyl-2-(3-pyridyl)-indole. 15

14. 1-Ethoxycarbonylmethy1-3-methy1-2-(3-pyridyl)-indole.

15. 1-Carboxymethy1-3-methy1-2-(3-pyridyl)-indole.

16. 1-(5-Carboxypentyl)-5-chlorc-3- me thy1-2-(3-pyridyl)indole.

17. 1-(5-Carboxypentyl)-5~methoxy-3-methyl-2-(3-pyridyl)2o indole.

18. 1-(5-Ethoxycarbonylpentyl)-5-[2-^thoxycarbonyl)-ethyl]3-methyl-2-(3-pyridyl)-indole.

19. 1-(5-Carboxypentyl)-5-(2-carboxyethyl)-3-methyl-2(3-pyridyl)-indole. 5 4 1 ·> {: ·

20. 1-(7-Methoxycarbonylheptyl)-5-[(2-tethoxycarbonyl)ethy1]-3-methy1-2-(3-pyridyl)-indole.

21. 1-(7-Carboxyheptyl)-5-(2-carboxyethy1)-3-methy1-2-(3pyridyl)-indole. 5

22. 1-(4-Carboxybenzyl)-3-methy1-2-(3-pyridyl)-indole.

23. 1-(4-Carboxybenzyl)-5-chloro-3-roethy1-2-(3-pyridyl)indole.

24. 1-(6-Hydroxyhexyl)-5-chloro-3-methy1-2-(3-pyridyl)indole. 10

25. 1-(6-Hydroxyhexyl)-3-methy1-2-(3-pyridyl)-indole.

26. 1-(5-Carbamoylpentyl)-5-chloro-3-methy1-2-(3-pyridyl) · indole.

27. 1-(8-Hydroxyocty1)-3-methyl-2- (3-pyridyl)-indole.

28. 1-[7-(N-methylcarbamoyl)-heptyl]-3-methy1-2-(3-pyridyq yl)-indole.

29.9. 1-(2-(4-Ethoxycarbonylphenoxy)-ethy1]-3-methy1-2-(3pyridyl)-indole.

30. 1-[2-(4-Carboxyphenoxy)-ethyl]-3-methy1-2-(3-pyridyl) indole. 20

31. 1-[2-(4-Ethoxycarbonylphenylthio)-ethyl]-3-methy1-2(3-pyridyl)-indole.

32. 1-[2-(4-Carboxyphenylthio)-ethy l]-3-methy 1-2-(35 4 1 St 6/ pyridyl)-indole.

33. 1-(5-Methoxycarbonylpent-4-enyl)-3-methy1-2-(3-pyridyl)-indole.

34. 1-(5-Carboxypent-4-enyl,-3-methy1-2-(3-pyridyl)-indole. 5

35. 1-(5-Formylpentyl)-3-methy1-2-(3-pyridyl)-indole.

36. 1-(7-Methoxycarbonylhept-6-enyl)-3-methy1-2-(3-pyridyl)-indole.

37. 1-(7-Carboxyhept-6-enyl)-3-methy1-2-(3-pyridyl)-indole.

38. 1-[4-(5-Tetrazolyl)-butyl]-3-methyl-2-(3-pyridyl)I ο indole.

39. 1-[4-(2-Ethoxycarbonylpropen-l-yl,-benzyl]-3-methy12-(3-pyridyl-indole.

40. 1-(4-(2-Carboxypropen-l-yl)-benzyl]-3-methy1-2-(3pyr idy1)-indole.

41.IS 41. 1-(7-Hydroxycarbamoyl-heptyl,-3-methy1-2-(3-pyridyl)indole.

42. 1-(5-Ethoxycarbonylpentyl)-3-methy1-2-(3-pyridyl)indole.

43. 1-(3-MethoxycarbonyI-prop-2-ynyl)-3-methyl-2-(3-py20 ridyl)-indole.

44. 1-(3-Carboxyprop-2-ynyl)-3-methy1-2-(3-pyridyl)-indole. ρ. 41 5 C 6Β

45. A compound of formula I substantially as described with reference to any of the Examples .

46. A salt of a compound having a salt forming group, as claimed in any one of claims 1, 3, 5, 8, 9, 11, 23, 25 and 5 29- * 5 ·

47. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in arty one of claims 1, 3, 5, 8, 9, 11, 23, 25 and 29-45.

48. A salt of a compound having a salt forming group, as 10 claimed in any one of claims 2, 4, 5, 7, 10, 12-22, 24 and 26-28.

49.- A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in any one of claims 2, 4, 6, 7, 10, 12-22, 24 and 26-28.

50.. A pharmaceutical preparation comprising a compound claimed in any one of claims 1, 3, 5, 8, 9, 11, 23, 25, 29-45 and 46, in admixture or conjunction with a pharmaceutically suitable carrier.

51. A pharmaceutical preparation comprising a compound 20 claimed in any one of claims 2, 4, 6, 7, 10, 12-22, 24, 26-28 and 43, in admixture or conjunction with a pharmaceutically suitable carrier.

52.. Process for the manufacture of a compound of formula I claimed in claim 1, of an N-oxide and a salt thereof, 25 whioh consists in 1) condensing a compound of the formula V 5 4 15 6 wherein X is hydrogen, alkaline metal or tri-lower alkyl silyl, R^, R 2 , Rj and Ar have meanings given in claim 1, with a reactive functional derivative of a compound of the formula VI HOCH 2 - A - Β (VI) wherein A and B have meaning given in Claim 1, or 2. ) ring-closing a compound of formula VII wherein Ar, R^, Rj, Claim 1, or R l Ϊ- N » C - Ar (VII) h 2 -a-b Rj, A and B have meaning given in 3. ) cyclizing a compound of the formula VIII tt (VIII) Ί8 — $ — Ar CH 2 - A — B wherein Ar, R^, Rj, Rj, A and B have meaning given in Claim 1, or 4) in a compound of the formula Ia “tl X 1 (Ia) g^^Ar *3 < :h 2 -a-c β Λ 15 6 wherein A, Ar, R^, R 2 and R^ have meaning given in claim 1 and C is a group differing from B and convertible into B, converting said group C into B, optionally by extending the chain A within its definition, or r 5) decarboxylating a compound of the formula IX in which A, B, Ar, R^, Rj and Rj have meaning given in claim 1, and, if desired or necessary, temporarily protecting in each of these processes an interfering reactive group, 10 and, if desired, converting any resulting compound of formula I into another compound of the invention, and/or, if desired, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt, and, if required, resolving a mixture of 15 isomers or racemates obtained into the single isomers or racemates, and, if required, resolving a racemate obtained into the optical antipodes.

53. The process for the preparation of an end-product compound described in any one of Examples 1 to 11a, 12a 20 and 13 to 15.

54. The process for the preparation of an end-product compound described in any one of Examples lib, 12b and 18 to 41.

55. The end-product compounds prepared according to 25 claim 53.

56. The end-product compounds prepared according to either of claims 52 to 54.