DK169104B1 - Analogous Process for Preparation of N-Substituted 2-Pyridylindoles or Salts thereof - Google Patents

Description

DK 169104 B1

The present invention relates to an analogous process for the preparation of novel N-substituted 2-pyridyl indoles of the general formula

R3 CH2-A-B

Wherein Rx is low alkyl, Ar is pyridyl, R 2 and R 3 are each independently hydrogen, halogen, carboxylavalkyl or lower alkoxycarbonyllavalkyl, A is alkylene having 1-12 C atoms, phenylene, a direct bond or low alkylene (thio or oxy) -phenylene, B means carboxy, lower alkoxycarbonyl, carbamoyl or hydroxymethyl, or salts thereof.

From the specification of U.S. Patent No. 3,468,894, it is known to use 1-unsubstituted 3-methyl-2- (3- or 4-pyridyl) -20 indoles as diuretic agents. Furthermore, 2- (2-pyridyl) -indole-3- (acetic and propionic) acids are described in e.g. Pharm. Bull. 4, 16 (1956) or Chemical Abstracts 64, 1954d (1966). In addition, optionally substituted 2- (3-pyridyl) -indole-3-acetic acids are described as chemical intermediates in Bull.

Soc. Chim. France 1966. 771-772, and Bull. Soc. Chim. France 1969. 4154-4159. Furthermore, the preparation of 1-cyanethyl-2- (2-pyridyl) indole is described in Pharmazie 23 (10) 557-560 (1968).

Surprisingly, it has been found that the N-substituted 2-pyridyl indoles of the above Formula I constitute a novel class of highly effective and highly specific thromboxane synthetase inhibitors.

The above mentioned properties cause the N-substituted 2-pyridylindoles in question to be particularly useful for administration alone or in combination with mammals, e.g. for the treatment or prevention of diseases related to the inhibition of thromboxane synthetase. These diseases include cardiovascular disorders such as thrombosis, atherosclerosis, coronary artery disease, arrhythmias, cerebral ischemic attacks, migraine and other vascular headaches, myocardial infarction, angina pectoris, hypertension, respiratory disorders such as asthma and apnea and asthma. It has also shown. itself; that the inhibition of the thromboxane synthase decreases metastasis in certain tumor classes. Therefore, the compounds of this invention may be useful in the treatment of certain types of cancer.

Preferred are compounds of the above Formula 15 I wherein R 2 is bonded to the indole nucleus at the 5-position.

Compounds of formula I wherein A is alkylene having 3-10 carbon atoms, phenylene, lower alkylene-thio-phenylene or lower alkylene-oxy-phenylene, each having 7-10 carbon atoms, are particularly preferred.

In addition, the compounds of formula I wherein A is alkylene of 1-12 carbon atoms or phenylene are important.

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

An alkylene group having 1-12 carbon atoms may be straight or branched and is preferably propyl, butyl, pentylene, hexylene or heptylene, said groups being unsubstituted or substituted by one or more lower alkyl groups, the sum of the carbon atoms being no more than 12.

Phenylene means 1,2-, 1,3- or preferably 1,4-phenylene.

3 DK 169104 B1

Pyridyl means 2-, 3- or 4-pyridyl, especially 3-pyridyl.

The term "low" used in connection with the organic groups, residues, or compounds listed above and hereinafter means those having at most 7, preferably 4, especially 1, 2 or 3 carbon atoms.

A lower alkylene (thio or oxy) phenylene group contains in the alkylene group preferably 1-4, especially 1 or 2 carbon atoms.

The lower alkylene group may be straight or branched.

A lower alkyl group preferably contains from 1 to 4 carbon atoms and means e.g. ethyl, propyl or butyl, especially methyl.

A lower alkoxy group preferably contains 1-4 carbon atoms and is e.g. ethoxy, propoxy or especially methoxy.

A lower alkoxycarbonyl group preferably contains 1-4 carbon atoms in the alkoxy moiety and means e.g. methoxycarbonyl or isopropoxycarbonyl, especially ethoxycarbonyl.

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

Salts are preferably therapeutically useful salts, e.g. metal salts or ammonium salts of the compounds of formula I which contain free carboxy, especially alkali metal or alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, primarily light crystallizing ammonium salts. These are derived from ammonia or organic amines, e.g. mono-, di- or tri-low (alkyl, cycloalkyl or hydroxyalkyl) amines, low alkylene diamines or (hydroxy-low alkyl or aryl-low alkyl) -lavalkylammonium bases such as methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) aminomethane or benzyl trimethylammonium hydroxide. The compounds of formula I mentioned form acid acid salts. These are preferably prepared with such acids which lead to therapeutically useful acid addition salts. Acids which provide therapeutically useful acid addition salts are e.g.

5 strong mineral acids such as hydrogen halide acids, e.g. hydrochloric or hydrobromic, sulfuric, phosphoric, nitric or perchloric, or organic acids such as aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, maleic acid, fumaric acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxy acid -salicylic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulphanilic acid or cyclohexylsulfamic acid, or ascorbic acid.

The compounds of the invention have valuable pharmacological properties, e.g. cardiovascular effects, in that they selectively inhibit mammalian thromboxane formation. This inhibition results from selective reduction of the thromboxane synthetase concentration. Therefore, the compounds are useful in the treatment of diseases which respond to thromboxane synthetase inhibition in mammals. Such diseases are primarily cardiovascular disorders such as thrombosis, arteriosclerosis, coronary cramps, cerebral ischemic attacks, migraine and other vascular headaches, myocardial infarction, angina pectoris and hypertension.

These effects can be detected by in vitro or in vivo animal studies, preferably with mammals, e.g. guinea pigs, mice, rats, cats, dogs or monkeys. Said compounds may be administered enterally or parenterally, preferably orally or subcutaneously, intravenously or intraperitoneally, e.g. by gelatin capsules or in the form of starchy suspensions or aqueous solutions. The dose used may be in the range of about 0.01 to 100 mg / kg / day, preferably approx. 0.05 to 50 mg / kg / day, in particular approx. 0.1 to 25 mg / kg / day.

The in vitro inhibition of the thromboxane synthetase enzyme can be detected analogously to the method of Sun, Biochem. Biophys., Res. Comm. 74, 1432 (1977). The test method is carried out as follows:

C-Arachidonic acid is incubated with an enzyme blend composition consisting of solubilized and partially purified sheep seminal vesicles prostaglandin cyclooxygenase and a human microplate thromboxane synthase preparation from lysed platelets. The test compound (dissolved in a buffer or, if necessary, in a little ethanol) is added to the incubation medium. At the end of the incubation period (30 minutes), prostaglandin E2 (PGE2) is reduced by the addition of sodium borohydride to a mixture of prostaglandin F2a and F2P.

[PGF2 (a + p)]. The radioactive products and excess substrate are extracted with ethyl acetate and the extract is evaporated to dryness. The residue is dissolved in acetone, added dropwise to thin-layer plates and chromatographed with a solvent system consisting of toluene: acetone: glacial acetic acid (100: 100: 3 (volume)]. The radioactive zones are located.

The zones of thromboxane B2 (TXB2) and PGF2a + 3 are transferred to scintillation tubes for liquids and counted. The quotient of the numerical values of TxB2 / PGF2a + 3 is calculated for each concentration of the test compound and the IC IC value is determined graphically. This value is the concentration of the test compound at which the quotient TxB2 / PGF2a + 3 is reduced to 50% of the control value.

The in vitro effect on prostaglandin cyclo oxygenase is determined by a modification of the method of Takeguchi et al., Described in Biochemistry 10, 2372 (1971). The test method is as follows: 6 DK 169104 B1

Lyophilized semen bladder microsomes are used as prostaglandin synthesizing enzyme preparation. Measurement of the conversion of β-arachidonic acid into PGE2 is performed. The test compounds (dissolved in a buffer or, if necessary, 5 in a little ethanol) are added to the incubation mixture regimen. The prostaglandins are extracted and separated by thin layer chromatography. The plates are examined, the radioactive zones corresponding to PGE2 are transferred to scintillation tubes for liquids and the radioactivity determined. The IC ^ value of inhibition 10 is determined graphically. This value means the concentration of the test compound which reduces the amount of the synthesized PGE2 by 50%.

The in vitro effect on prostacyclin (PGI2) synthetase is determined analogously to the method of Sun et al., Prostaglandins 14, 1055 (1977). The test method is as follows: 14 C-Arachidonic acid is incubated with an enzyme mixture consisting of solubilized and partially purified sheep semen bladder prostaglandin cyclooxygenase and of raw PG1 + synthase in the form of a bovine aortic microsomal fraction.

The test compound (dissolved in a buffer, or if necessary in a little ethanol) is added to the incubation mixture. The reaction mixture is incubated in 100 mM Tris * HCl (pH 7.5) for 30 minutes at 37 ° C, acidified to pH 3 and extracted with ethyl acetate. The extract is evaporated to dryness, the residue is dissolved in acetone and placed on thin-layer plates and chromatographed with one of Sun et al. described solvent system. The radioactive zones are located by means of a detector. The zones corresponding to 6-keto-PGF2a 30 (a stable end product of the prostacyclin biotransformation) and PGE2 are transferred to scintillation tubes for liquids and counted. The quotient for the numerical value of 6-keto-PGF 2 α / PGE 2 is calculated for each concentration of the test compound used. The ICsQ value for the inhibition is determined graphically. This value is the concentration of the test compound which reduces the quotient 6-keto-PGF1a / PGE2 to 50% of the control value.

Inhibition of the synthesis and decrease of thromboxane plasma concentration is determined in vivo by administration of the test compound to rats (analogous to that of Tai et al. In Annual. Biochem. 87, 343, 1978, and of Salmon 5 in Prostaglandins 15, 383, 1978, described as follows):

Rats are treated with the test compound or vehicle and 2 hours later intravenous injection of ionophore A 23187 (0.5 mg / kg) is made. Two minutes after the 10th ionophore injection, blood is drawn from the animals for analysis.

In a specific single amount of each plasma sample, thromboxane is determined and from other single amounts 6-keto-PGFβ, the stable metabolites of thromboxane A2 or prostacyclin (PGH₂) is determined by radioimmunoassay.

The compounds of formula I are highly effective and selective thromboxane synthetase inhibitors. At effective dose concentrations and above, there is no significant inhibition of neither the beneficial prostacyclin synthetase enzyme system nor the prostaglandin cyclooxygenase enzyme system. Surprisingly, a significant increase in prostacyclin concentration occurs.

The ICsQ value of one of the compounds of the present invention, e.g. for 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) indole is

_ O

1.2 x 10 moles for the thromboxane synthetase inhibition, while the 25 ICj-Q value for the inhibition of the prostacyclin synthetase and the prostaglandin cyclooxygenase in both cases, several 10's potencies are greater, viz. 1 x 10 'mol.

In addition, the IC Q value of the thromboxane synthetase inhibition is 2 x 10-8 moles for 1- (5-carboxypentyl) -5- (2-carboxyethyl) -1,8-3-methyl-2- (3-pyridyl) indole and 5 x 10 moles for 1- (4-carb-9-oxybenzyl) -3-methyl-2- (3-pyridyl) indole, 1 x 10 mole for 1- (5-carboxypentyl) -5-chloro -3-methyl-2- (3-pyridyl) indole and 1 x 10 mol for 1- (5-carbamoyl-pentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole, 2 , 6 x 10 8 moles for 1- [2- (4-carboxy-phenoxy) ethyl] -3-methyl-2- (3-pyridyl) indole and 5.8 x 10 8 mole for 1- [2- (4-carboxyphenylthio) ethyl] -3-methyl-2- (3-pyridyl) indole hydrochloride.

1- (7-Carboxyheptyl) -3-methyl-2- (3-pyridyl) indole and 1- (5-carboxypentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole are representative examples of the compounds of this invention, reducing the plasma concentration of thromboxane Έ> 2 in rats at a dose as low as 0.10mg / kg by more than 50%. At this or greater oral doses, a surprising increase in the plasma concentrations of prostacyclin is found.

Due to the advantageous properties set forth above, the compounds of this invention are extremely valuable as specific mammal and human therapeutic agents.

The inhibition of the variously induced platelet aggregation and thrombocytopenia by the compounds of the present invention, e.g. by means of 1- (7-carboxyheptyl) - 3 O-3-methyl-2- (3-pyridyl) indole, shows the utility of the compounds in thromboembolism. Experimentally, prolongation of bleeding time in rats is considered as evidence of beneficial antithrombotic effect. For example, 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) indole exhibits this effect

Λ C

by oral administration to rats at a dose of approx. 30 mg / kg.

With respect to the beneficial effects of respiratory disorders, it may be noted that the compounds of the present invention provide protection against sudden death occurring as a result of pulmonary obstruction caused by arachidonic acid. Thus, e.g. 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) -indole mice against sudden death by oral administration at a dose of 100 mg / kg.

DK169104 P9

The analogous process according to the invention is characterized in that one) condenses a compound of the formula 5 R2 ^ R1 ΓΓΤ (v) / ΛΑβ ^ Αγ

R3 I

X

Wherein X represents hydrogen, alkali metal or tri-lower alkyl silyl, and R 1f R 2, R 3 and Ar have the meanings given above, with a reactive functional derivative of a compound of formula 15 HO - CH 2 - A - B (VI) wherein A and B has the above meanings, or 2) cyclically terminates a compound of formula 20 r2 yv ™ 2-ri

L | J-N - N = C - ΛΤ (VXD

R3 CH2'A'B

wherein Ar, R 1, R 2, R 3, A and B have the above meanings, or 3) cyclizes a compound of formula

Vv-CHA

p i o (vm) 35 - C -Ar

R3 CH2 "A-B

Wherein Ar, R 1, R 2, R 3, A and B have the above meanings, or 4) in a compound of formula 5 R 1

TtjL (ia>.

λΛν / Ar

3 CH2 ~ A-C

Wherein A, Ar, R 2, R 2 and R 3 have the meanings given above and C means a group other than B and which can be converted to group B, group C transforms to group B, optionally extending the chain A within its definition, or 5) for the preparation of compounds of formula I wherein R 1 represents lower alkyl, Ar represents pyridyl, R 2 and R 3 each represent hydrogen, halogen, carboxylavalkyl or lower alkoxycarbonyl-lower alkyl, A means alkylene having 1-12 C atoms, phenylene or a direct bond, and B represents carboxy, lower alkoxycarbonyl, carbamoyl or hydroxymethyl, condenses a compound of formula V wherein X represents hydrogen and R 1, R 2, R 3 and Ar have the immediately above in the introduction to this variant, with a reactive functional derivative of a compound of the formula HO - CH 2 - A - B '(Via) 30 wherein A has the meaning given above in the introduction to this variant and B' means carboxy, low alkoxycarbonyl, approx rbamoyl, mono- or dilavalkyl-carbamoyl, hydroxymethyl, etherified hydroxymethyl, halo-methyl, trialkoxymethyl or cyan, and in a compound of formula 35 wherein P 'is different from B as defined above in the introduction to this variant, and R1 (R2, R3, A and Ar have the meanings given above in the introduction to this variant, converting group B 'to group B, optionally extending chain A within its definition, , if desired or if necessary, temporarily protect a disruptive reactive group in all of these processes, whereupon, if necessary, convert a prepared compound of formula I to another compound of formula 20 I and / or, if desired or if necessary, convert a prepared free compound to a salt or a prepared salt to the free compound or to another salt and / or, if desired, separates a formed mixture of isomers or racemates in the individual isomers or racemates 25 and / or, if desired, split racemates into the optical antipodes.

The 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, e.g. tetra-butyl ammonium hydroxide. Thus, e.g. in particular compounds of formula V wherein X represents hydrogen, preferably in situ with a reactive metallizing agent for reactive organometallic intermediates.

35 12 DK 169104 B1 0

It is preferable to use about 1 molar equivalent, e.g. of a strong alkaline metal base, such as lithium diisopropylamide, sodium hydride or potassium tert-butoxide, in an inert solvent, e.g. dimethylformamide 5 or tetrahydrofuran, in a temperature range from -50 to 75, preferably from -25 to 50 ° C.

The condensation of the formed reactive organometallic compound of formula V with a reactive functional derivative of a compound of formula VI is carried out in a temperature range of from ca. -25 to approx. 50, preferably from about 0 to about 30 ° C. When B is carboxy, carbamoyl, hydroxycarbamoyl or mono-lower alkyl-carbamoyl, further is used e.g. 1 mole equivalent of the metallizing agent.

The starting compounds of formula V wherein X represents hydrogen are either known, e.g. from the specification to U.S. Patent No. 3,468,894, J. Chem. Soc. 1955, 286¾ and

Bull. Soc. Chim. France 1969, 4154, or they are prepared analogously to the well-known indole synthesis of Fischer from similar, optionally substituted phenylhydrazines and ketones of the formula ArCOO ^ R ^ in the presence of condensing agents, e.g. ethanolic hydrochloric acid or polyphosphoric acid.

Starting compounds of formula VI or those hereinafter referred to as formula Via are known or novel compounds. In the latter case, they can be prepared in a manner known per se, e.g. as disclosed in the specification of U.S. Patent No. 4,256,757 or in the specification of GB Patent Application No. 2,016,452A, or as described in the following Examples.

r 35 0 13 DK 169104 B1

The cyclization of the starting compounds of formula VII according to process 2) is carried out thermally or preferably in the presence of an acidic condensing agent according to the well-known Fischer indole synthesis, e.g. as described 5 in Heterocyclic Compunds, Indoles Part I, published by W. J. Houlihan, pages 232-317. The reaction is preferably carried out in the presence of hydrogen halides, e.g. ethanolic hydrochloric acid, or polyphosphoric acid, optionally in an inert solvent, at temperatures between ca. 50 and 10 100 ° C.

The hydrazone starting compounds of formula VII are either isolated or preferably prepared in situ by condensation of a ketone of formula Ar-COCH 2 R 4, wherein Ar and R 2 have the meanings given above, with a substituted hydrazine of formula R2 ΪΧ 20 - NH 2

R I

3. CH 2 A-B

wherein A, B, R 2 and R 2 have the meanings given above, preferably in the presence of an acidic catalyst.

25

The hydrazine starting compounds of formula X are preferably prepared e.g. by nitrosating similarly substituted anilines of formula R2 30 (xi)

V'lrøCH ^ y ^ A-B

R3 wherein the symbols A, B, R2 and R3 have the above meanings and subsequent reduction of the N-nitroso derivative, e.g. with zinc in acetic acid or using another method known per se.

Preferably, when said intermediates contain nuisance-reactive groups such as hydroxy or amino groups, such groups may be temporarily protected in a well-known manner at any step by means of readily cleavable protecting groups, e.g. esters 5 or amides.

The cyclization according to process 3) is carried out under the conditions of the Madelung indole synthesis, e.g. as described in Heterocyclic Compounds, Indoles Part I, 10 published by W. J. Houlihan, pages 385-396. The intramolecular cyclization is preferably carried out in the presence of a strong base, e.g. sodium ethoxide, sodium amide or potassium tert-butoxide, advantageously at elevated temperature, e.g. ca. 300 ° Q or in an inert high boiling solvent, e.g. tetrahydronaphthalen.

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

The conversion of a compound of formula Ia according to method 4), wherein C is different from B, to a compound of formula I and the optional conversion of a prepared compound of formula I to another object compound is carried out using i and known chemical processes and / or as described herein.

Convertible groups C are preferably trialkoxymethyl, trifluorinated hydroxymethyl, etherified hydroxymethyl, halo-methyl, cyano, 2-oxazolinyl, dihydro-2-oxazolinyl, low-alkanoyloxymethyl, acetyl, methyl, carboxycarbonyl, tri-haloacetyl, di-loweralkoxymethyl, alkyl , vinyl, alkynyl, esterified carboxy and amidated carboxy.

0 15 DK 169104 B1

The starting compounds of formula Ia are prepared according to process Ij to 3) or as described herein using chemical methods known per se.

The individual definitions in the processes described above have the following meaning: In a reactive functional derivative of an alcohol of formula VI or Via, for example, the hydroxy group is esterified with a strong inorganic or organic acid, first of all with a hydrogen halide acid, f. eg. hydrogen chloride acid, hydrogen bromic acid or hydrogen iodide acid, an aliphatic or aromatic sulfonic acid, e.g. methanesulfonic acid or p-toluenesulfonic acid. These compounds are prepared in a manner known per se.

Trialkoxymethyl preferably means tri (lower alkoxy) methyl, especially triethoxy or trimethoxy methyl.

20

Preferably, pore ether hydroxymethyl means tertiary low-alkoxymethyl, lower alkoxy-alkoxymethyl, e.g. methoxy-methoxymethyl, 2-oxa or 2-thiacycloalkoxymethyl, especially 2-tetrahydropyranyloxymethyl.

25

Preferably, esterified hydroxymethyl means lower alkanoyl oxymethyl, advantageously halogen methyl, especially chloromethyl, but also bromomethyl or iodomethyl.

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

Intermediates of formula Ia or Ib, wherein C or B * is halogenomethyl, may preferably be reacted in a manner known per se, preferably with an alkali metal "cyanide, e.g. potassium cyanide. Thereby, compounds of formula Ia or Ib are obtained in which the chain is extended by a carbon atom and C or B * means cyano. These can again be converted into compounds of the formula I in a manner known per se in which B is carboxy, alkoxycarbonyl or carbamoyl.

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

15

The conversion of said nitriles to compounds of formula I wherein B is lower alkoxycarbonyl is preferably carried out by treatment with a lower alkanol, e.g. anhydrous ethanol, in the presence of a strong acid, e.g. hydrogen-2O chloride acid, preferably under reflux, with subsequent gentle hydrolysis with water.

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

Intermediates of formula Ia or Ib, wherein C or B '30 means halo methyl, e.g. chloromethyl may be converted to compounds of formula I wherein B is carboxy and the chain is extended by 2 carbon atoms, first by treatment e.g. with a dilavalkyl malonate, e.g. diethyl malonate, in the presence of a base / e.g. potassium carbonate or sodium ethoxide, in a solvent such as dimethylformamide, preferably at a temperature between 50 and 100 ° C to substituted di-lower alkyl malonates. These are then hydrolyzed with an aqueous base, e.g. dilute sodium hydroxide solution, to the corresponding malonic acid, which is decarboxylated under standard conditions, e.g. by heating in xylene solution, to the compound of formula I wherein B is carboxy. If instead of the malonic acid di-lower alkyl ester, a cyan acetic acid low alkyl ester is used, the corresponding compounds of formula Ia or Ib are obtained in which C or B 'means cyan.

10

Compounds of formula I wherein B is lower alkoxycarbonyl may be amidated with ammonia, mono- or dilavalkylamines, e.g. methylamine or dimethylamine, in an inert solvent, e.g. a lower alkanol such as butanol, optionally at elevated temperature, for compounds of formula I wherein B is carbamoyl.

The conversion of compounds of formula I or Ib wherein 20b or B 'means lower alkoxycarbonyl, cyano, unsubstituted mono- or dilavalkylcarbamoyl, into compounds of formula I wherein B represents carboxy is preferably carried out by hydrolysis with inorganic acids, e.g. with hydrogen halide acids or sulfuric acid, or with aqueous bases, preferably with alkali metal hydroxides, e.g. lithium or sodium hydroxide.

Compounds of formula I wherein B is carboxy or lower alkoxycarbonyl may be reduced by simple or complex light metal hydrides, e.g. with lithium aluminum hydride, alan or diborane, for compounds of formula I wherein B is hydroxymethyl. The alcohols may also be prepared by suitable solvolysis of intermediates of formula Ia, wherein C is halo methyl, by treatment e.g. with an alkali metal hydroxide, e.g. lithium or sodium hydroxide.

DK 169104 B1 0 18

The above-mentioned alcohols can again be converted to compounds of formula I wherein B is carboxy, with conventional oxidizing agents / preferably with pyridinium dichlorocate in dimethylformamide at room temperature.

5

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

10 ethyl ether, preferably at room temperature, to the corresponding esters, namely to such compounds of formula I wherein B is lower alkoxycarbonyl.

Furthermore, the free carboxylic acids can be converted by treating their reactive intermediates, e.g. an acrylic halide, such as an acid chloride, or a mixed anhydride, e.g. an anhydride derived from a halo-carbonic acid lower alkyl ester, e.g. chloromyric acid ethyl ester, with ammonia, mono or dilavalkylamines in an inert solvent, e.g. methylene chloride, preferably in the presence of a basic catalyst, e.g. pyridine, for the compounds of formula I wherein B is unsubstituted carbamoyl, mono- or di- (lower alkyl) carbamoyl.

25

Compounds of formula I wherein B is carboxy can, by the well-known Arndt-Eistert synthesis, be converted to compounds of formula I wherein B is carboxy and the chain contains an additional carbon atom. In particular, treatment of a reactive functional derivative of the starting carboxylic acid, e.g. the acid chloride, with diazomethane, e.g. in diethyl ether to form a compound of formula Ia wherein C is diazoacetyl. Conversion with e.g. silver oxide leads to the 35 carboxylic acids of formula I wherein the chain A contains an additional carbon atom.

0 19 DK 169104 B1

Groups that can be converted into a carboxy group are e.g. esterified carboxy groups, anhydrided carboxy groups, including corresponding groups of asymmetric and internal anhydrides, amidated carboxy groups, cyano, amidino groups, including cyclic amidino groups such as 5-tetrazolyl, imino ether groups, including cyclic imino ether groups such as e.g. substituted with lower alkyl 2-oxazolinyl or dihydro-2-oxazolinyl groups, further methyl, hydroxymethyl, etherified hydroxymethyl, lower alkanoyloxymethyl, trialkoxymethyl, acetyl, trihaloacetyl, halo methyl, carboxycarbonyl (COC00H), formyl (CHO , alkylenedioxymethyl, vinyl, ethynyl or diazoacetyl. At the time of conversion to the carboxy group, the chain A can simultaneously be extended within its definition.

15

Esterated carboxy groups are preferably in the form of lower alkyl esters, e.g. methyl, ethyl, n or iso (propyl or butyl) ester. Furthermore, they are in the form of substituted lower alkyl esters, e.g. ω-amino, ω-mono or 2Q is dimethylamino, α-carboxy or α-carbethoxy (ethyl, propyl or butyl) ester. Other esters are aryl-lower alkyl esters, e.g. benzyl, (methyl, methoxy, chloro) -substituted benzyl and pyridyl methyl esters, low alkanoyloxy-low alkyl esters, e.g. pivaloyloxymethyl ester, 3-phthalidyl and methyl, methoxy or chloro substituted 3-phthalidyl ester, derived from corresponding 3-hydroxy-phthalic acid esters, (hydroxy, low alkanoyloxy, low alkoxy) -substituted low alkoxy methyl esters, e.g. . β- (hydroxy, acetyloxy, methoxy) ethoxymethyl ester, bicycloalkoxycarbonyl-low alkyl esters, e.g. those derived from bicyclic monoterpenoid alcohols, e.g. unsubstituted or lower alkyl substituted bicyclo [2,2,1] heptyloxycarbonyl low alkyl esters, preferably boron yloxycarbonyl methyl ester, as well as halo-substituted lower alkyl esters, e.g. trichloroethyl or iodoethyl ester.

DK 169104 B1 0 20

Amidated carboxy groups are preferably carboxy groups in the form of unsubstituted amides, N-mono- or di-lower alkylamides, e.g. mono- or dimethylamides, tertiary amides derived, for example, from pyrrolidine, piperidine 5 or morpholine, with α-carbolavalkoxy or carboxy substituted lower alkylamides, e.g. mono-N- (carboethoxy-methyl) amides, and mono-N- (carboxymethyl) -amides, α-carbo-low alkoxy- or carboxy-substituted aryl-low-alkyl amides, e.g. (carboethoxy or carboxy) -substituted phenylethylamides, as well as amino-lower alkylamides, e.g. β-aminoethylamides and β- (carbobenzyloxyamino) ethylamides.

The conversion to the carboxy group is carried out in a manner known per se, e.g. as described herein or in the following examples, e.g. solvolytic, such as hydrolytic or acidolytic, or reductive (esterified carboxy groups). Thus, e.g. trichloroethyl or 2-iodo ethyl ester by reduction, e.g. with zinc and a carboxylic acid in the presence of water for the carboxylic acid. Benzyl esters or nitrobenzyl esters can be converted to the carboxy group by catalytic hydrogenation, in the latter case also by chemical reducing agents, e.g. sodium dithionite or with zinc and a carboxylic acid. Furthermore, e.g. tert-butyl esters are also cleaved e.g. with trifluoroacetic acid.

By the reduction of group C, an alkenylene or alkynylene chain A can be converted to the corresponding alkylene chain.

Further, compounds of formula Ia wherein C represents acetyl may be oxidatively cleaved to the corresponding compounds of formula I wherein B represents carboxy. First, the starting compound is converted to a compound of formula Ia wherein C is trihaloacetyl, e.g. tribromo or triiodoacetyl, e.g. by treatment with sodium hypobromite, after which cleavage, e.g. with an aqueous base, e.g. sodium hydroxide.

0 21 DK 169104 B1

Starting compounds of formula Ia in which C is acetyl can be prepared from compounds of formula Ia in which C is halo methyl by treatment with an acetacetic acid low alkyl ester, e.g. acetic acetic acid ethyl ester, in the vicinity of a base, e.g. sodium hydride, and subsequent hydrolysis with a strong base, e.g. with aqueous sodium hydroxide.

Said compounds may also be 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.

Starting compounds of formula Ia, wherein C is carb-oxycarbonyl (COC00H), are converted by thermal treatment or by oxidation to the compounds of formula I wherein B is carboxy. In this conversion, the starting compound is heated to an elevated temperature, e.g. ca. 200 ° C, in the presence of glass powder, or it is treated e.g.

20 with sodium hydrogen peroxide in the presence of a basic agent, e.g. sodium hydroxide.

The starting compounds of formula Ia in which C is COCOH may be prepared, for example, by condensing a compound of formula Ia in which C is halo methyl, e.g. 2-ethoxycarbonyl-1,3-dithian, and subsequent oxidative hydrolysis, e.g. with N-bromosuccinimide in aqueous acetone, and then by treatment with dilute aqueous sodium hydroxide solution.

30

Compounds of formula Ia, wherein C is formyl, di-low-alkoxymethyl, or alkylenedioxymethyl (formyl protected in the form of an acetal), e.g. dimethyl acetal, e.g. with silver nitrate, pyridinium dichromate or ozone to the compounds of formula I wherein B is carboxy.

22 DK 169104 B1 o

Compounds of formula Ia, wherein C is vinyl, are converted to the compounds of formula I wherein B represents carboxy, first performing ozonolysis to form the compounds of formula I, wherein B represents formyl, which is then oxidized to the compounds of formula I, in which

ISLAND

B means carboxy.

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

Compounds of formula Ia wherein C is ethynyl may be treated with a strong base, e.g. butyl lithium, then condensed with carbon dioxide or a halo formic acid low alkyl ester, e.g. chloromyric acid ethyl ester, and then hydrolyzed. In this way, compounds of formula I wherein B is carboxy are obtained and chain A contains a three to 20 double bond adjacent to the carboxy group.

Compounds of formula Ia wherein C is halo methyl may be converted to the corresponding organometallic intermediates, e.g. copper or magnesium derivatives, in a manner known per se.

For condensation e.g. of a manufactured organic magnesium (Grignard) reagent, e.g. with a compound of formula Ia wherein C is e.g. is converted to Cl 2 MgCl, with 30 carbon dioxide is obtained a compound of formula I wherein B is carboxy and the chain is extended by a carbon atom.

By condensing said Grignard reagent with e.g. a haloacetic acid low alkyl ester, e.g. bromoacetic acid ethyl ester, and subsequent hydrolysis is obtained a compound of formula I wherein B is carboxy and the chain is extended by 2 carbon atoms.

0 23 DK 169104 B1

Said Grignard reagent may be condensed in the presence of a copper I halide, e.g. copper I chloride, with an α, 3-unsaturated acid or an ester, e.g. with propiolic acid or acrylic acid to give a compound of formula I wherein B represents carboxy and the chain is extended by 3 carbon atoms.

Compounds of formula I wherein A represents low alkyl or a direct bond and B represents hydroxymethyl as a reactive functional derivative can be condensed with a low alkanol (or thiol), or a phenol (or thiophenol) (which is substituted with B in appropriate way), preferably in the presence of a strong base. Compounds of formula I are obtained in which A is lower alkylene (thio or oxy) phenylene, phenylene (thio or oxy) low alkylene or low alkylene (thio or oxy) low alkylene.

The above reactions are carried out in a manner known per se, in the presence or absence of diluents, preferably in those which are inert to the reagents and dissolve them, catalysts, condensing agents or other agents listed above, and / or in an inert atmosphere. , under cooling at room temperature 25 or at elevated temperature, preferably at the boiling point of the solvent used, at normal or elevated pressure. The preferred solvents, catalysts and reaction conditions are set forth in the following examples.

30

The process of the invention also encompasses such embodiments in which a starting material is formed under the reaction conditions or wherein an starting compound is used in the form of a salt or an optically pure antipode.

0. DK 169104 B1 24

In the process of the invention, such starting compounds are advantageously used which lead to the particularly valuable compounds described above.

Depending on the choice of starting compounds and methods, the novel compounds may be in the form of one of the possible isomers or mixtures thereof. For example, they can depending on the presence of a double bond and the number of asymmetric carbon atoms available as pure optical isomers, e.g. as antipodes, or as mixtures of optical isomers, e.g. such as racemates, mixtures of diastereomers, mixtures of racemates, or mixtures of geometric isomers. The above possible isomers and their mixtures are also encompassed by the invention. Many specific isomers may be preferred.

Produced mixtures of diastereomers, mixtures of racemates or geometric isomers can be separated into pure isomers, diastereomers, racemates or geometric isomers based on the physicochemical differences known per se in the known manner. by chromatography and / or fractional crystallization.

Furthermore, formed racemates can be separated into the optical anti-pods in a manner known per se, e.g. by reacting the acidic final product with an optically active base which forms salts with the racemic acid. These salts may e.g. by fractional crystallization, the diastereomeric salts are separated. From the latter, the optically active acid antipodes 30 can be released by acidification. Basic racemic products can be separated in a similar manner, e.g. by separating the diastereomeric salts with an optically active acid and releasing the optically active base with a base. Thus, racemic compounds can be cleaved in the optical antipodes, e.g.

35 by fractional crystallization of d- or Z ~ (tartrates, mandelates, camphor sulphonates), or of d- or β - (α-methyl-benzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, bruin or strychnine salts. Of the two antipodes, the antipode which has the most potent effect is preferably isolated.

Finally, the compounds of the present invention are available in free form or in the form of salts. A prepared free base can be converted to the corresponding acid addition salt, preferably 10 with acids leading to therapeutically useful acid addition salts, or with anion exchangers. Formed salts can be converted to the corresponding free bases, e.g. by treatment with a stronger base such as with a metal hydroxide or ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchanger. A compound of formula I wherein B is carb-oxy may also be converted to the corresponding metal or ammonium salts. These or other salts, e.g. the picrates, can also be used for the purification of the formed free bases.

The bases are converted to salts, the salts are isolated and the bases released from the salts.

Due to the close relationship between the compounds in free form and in the form of their salts, the previous and subsequent free compounds and the salts may optionally also mean the corresponding salts or free compounds.

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

The pharmaceutical compositions are those suitable for enteral, e.g. oral or rectal, and parenteral administration 35 to mammals and humans. The compositions are used to treat or prevent diseases that respond to the inhibition of thromboxane synthetase. These compositions contain an effective dose 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.

5

The disclosed pharmacologically useful compounds can be used for the preparation of pharmaceutical compositions containing an effective amount of the active substance together with or in admixture with carriers suitable for enteral or parenteral administration. Preferably, tablets or gelatine capsules are used which contain the active compound together with diluents, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Tablets also contain binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone and, if desired, disintegrants, e.g.

starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or shower mixtures or adsorbents, dyes, flavors and sweeteners. Injection preparations are preferably isotonic aqueous solutions or suspensions, and suppositories are primarily fat emulsions or suspensions. The pharmacological compositions may be sterilized and / or contain excipients, e.g. preservatives, stabilizers, wetting agents and / or emulsifiers, solvents, salts for controlling the osmotic pressure and / or buffers. The pharmaceutical compositions which, if desired, may contain other pharmacologically valuable compounds can be prepared in a manner known per se, e.g. by conventional mixing, granulating or coating methods and they contain from ca. 0.1 to approx. 75, 0 27 DK 169104 B1 especially from ca. 1 to approx. 50% active substance. Single doses for mammals with a body weight of about 50-70 kg may contain from 10-100 mg of active ingredient.

The process according to the invention is further illustrated in the following examples. The parts listed are parts by weight. Unless otherwise stated, the evaporation of solvents is carried out under reduced pressure, e.g. between approx. 15 and approx. 100 mm Hg.

10

Example 1 1640 ml of dimethylformamide and 430 g of potassium tert-butoxide are placed in a 76 liter glass container. The solution is stirred under nitrogen and cooled to -8 ° C. Over 0.75 hours, a solution of 682 g of 3-methyl-2- (3-pyridyl) indole in 3280 ml of dimethylformamide is added, keeping the temperature below 0 ° C. The mixture is stirred for 2 hours at -10 ° C and 1640 ml of a solution of 780 g of 8-bromooctanoic acid methyl ester in dimethylformamide is added over 1 hour. The reaction temperature is kept below 0 ° C. The reaction mixture is stirred for 2 hours, then left to stand overnight at room temperature. The rust-colored mixture is then cooled to ca.

5 ° C and treated with 19,700 ml of ice water. The temperature rises 25 to 25 ° C. The mixture is stirred for 0.5 hours and extracted twice with 8,000 ml of ether. The extracts are dried over magnesium sulfate and evaporated in vacuo. 1- (7-methoxy-carbonylheptyl) -3-methyl-2- (3-pyridyl) -indole is obtained as an oil. 1293 g of this oil are treated with 6,530 ml of 1 N 30 sodium hydroxide solution and the mixture is heated on a steam bath for 2.5 hours to 90 ° C. The solution is cooled to room temperature and washed with 3,000 ml of ether.

The aqueous layer is cooled to 10 ° C and adjusted with 3,400 ml of 2N hydrochloric acid to pH 3.5. The resulting heavy suspension is extracted with four times 4,000 ml of methylene chloride.

DK 169104 B1 0 28

The combined extracts are washed once with 4,000 ml of water and dried over magnesium sulfate. The mixture is filtered, the solvent evaporated at 60 ° C, the residue triturated with 2,000 ml of ether and the product dried. 1- (7-5 carboxyheptyl) -3-methyl-2- (3-pyridyl) indole, m.p. 113-115 ° C. After recrystallization from ethanol, the melting point rises to 114-116 ° C.

The 3-methyl-2- (3-pyridyl) indole starting material is prepared substantially using the process described in U.S. Patent No. 3,468,894.

The 8-Bromoctanoic acid methyl ester is prepared from azelaic acid substantially as described in U.S. Pat.

3,852,419 or by direct esterification of the 8-bromooctanoic acid, as follows:

A mixture of methanol (4,700 ml), 8-bromooctanoic acid (912 g) and sulfuric acid (912 ml) is boiled in a suitable reaction vessel 20 ....

for 5 hours at reflux and stirring overnight at room temperature. The solvent is evaporated under reduced pressure (3 mm Hg) and the oily residue is dissolved in ether (4,000 ml). The solution is washed with water (3 x 2,000 ml), saturated aqueous sodium hydrogen carbonate solution (1,000 ml) and saturated aqueous sodium chloride solution. The ether layer is dried over magnesium sulfate and filtered. After evaporation of the solvent and distillation of the crude oil, the 8-bromooctanoic acid methyl ester is obtained, which boils at 73-76 ° C / 0.05 mm Hg.

ώΡ = 1.4614.

30 υ

Example 2

To a suspension prepared by diluting 4.8 g of 50% sodium hydride suspension in mineral oil with 40 ml of dimethylformamide is added dropwise under nitrogen to a solution of 13.5 g of 3-methyl-2- (3-pyridyl) - indole in 80 ml of dimethylformamide. After the addition is complete, the green-yellow mixture is stirred at room temperature for approx. 1 hour. To the reaction mixture is added dropwise with cooling to 0-5 ° C bromoacetic acid ethyl ester (11.2 ml, 0.10 mol) and stirred for 4 hours at room temperature.

5

The reaction mixture is poured into 1,000 ml of ice water and extracted with 3 x 300 ml of ether. The ether layer is extracted with 3 x 300 ml of 1 N hydrochloric acid. The acidic extract is adjusted to pH 9-10 with concentrated ammonium hydroxide and extracted with ether (3 x 250 ml). The mixed ether extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. 1-ethoxycarbonyl-methyl-3-methyl-2- (3-pyridyl) -indole is obtained in the form of an oil.

The oil prepared above is boiled in 500 ml of 1 N hydrochloric acid for 4 hours at reflux. After standing overnight, a yellow solid is separated, which is dried for 12 hours at 60-80 ° C / 30 mm Hg. After recrystallization from ethanol, 1-carboxymethyl-3-methyl-2- (3-pyridyl) -indole hydrochloride is obtained, m.p. 204-207 ° C.

To prepare the free amino acid, adjust the pH of the hydrolysis medium to 3.5.

Examples 3-6

Analogous to the methods described in Examples 1 and 2, compounds of formula II are prepared in which = CH 2 and R 2 = H and R 2 = OH: Eczema-Ester starting C H pyr. Crystallized pellet of oQ from 3 Br (CH2) 5COOEt * (CH2) 5 3-Pyridyl 113-114 Acetonitrile 4 Br (CH2) gCOQMe (CH2) g 3-Eyridyl 106-107.5 Acetonitrile 5 Br (CH2) 4COQMe (CH2 ) 4 3-Pyridyl 123-125 Ethanol 6 Br (CH 2) gCOOEt (O 4 4-Pyridyl 186-188 Acetonitrile * Et = ethyl, Me = methyl 0 DK 169104 B1

The 2- (3- and 4-pyridyl) indoles used as starting compounds are prepared using the method described in U.S. Patent No. 3,468,894.

The ethyl or methyl o-bromo esters used as starting materials are commodities or can be prepared from commercial ω-bromo acids, as illustrated below for the 6-bromo-hexanoic acid methyl ester. To a solution of 6-bromo-hexanoic acid (10 g) in 50 ml of methanol is added 1.0 ml of 10 concentrated sulfuric acid and the mixture is refluxed for 8 hours. The methanol is evaporated and the residue is dissolved in ether. The ether solution is freed from the acid by washing with water and then dried over sodium sulfate and evaporated to dryness. Distillation at 0.8 mm Hg gives 6-bromo-hexanoic acid methyl ester, which boils at 85-90 ° C / 0.8 mm Hg.

1- (7-Carboxyheptyl) -3-methyl-2- (2-pyridyl) indole is prepared analogously to the procedure described in Example 1.

The 3-methyl-2- (2-pyridyl) -20 indole used as starting material is described in J. Chem. Soc. 1955, 2865.

The corresponding compounds of formula II wherein R 1 is hydrogen, Pyr = 2-, 3- or 4-pyridyl, = fluoro, hydrogen or methyl, and R 2 = hydrogen is prepared in an analogous manner using the procedures described in Examples 1 and 2. The starting compounds are used with the necessary ω-bromo esters and the known 2- (pyridyl) indoles.

The 2- (2-, 3- and 4-Pyridyl) indoles are described in Pharm.

30 Bull. Japan 4, 16 (1956), and the 5- (Eluoro and methyl) -2- (3-pyridyl) indoles in Bull. Soc. Chim. France 1969, 4154.

Examples 7 and 8

The compounds of formula II wherein R 1 = CH 3, R 3 = H, Pyr = 35 3-pyridyl, C m H 2 m = (CH 2) 5 and R 4 = OH are prepared using the methods described in the above examples.

0 31 DK 169104 B1

Example Ri, m.p. Salt _ ^ _ 7 5-C1 143-145 8 5-OCH3 175-178 HCl 5

The compound of Example 7 is prepared as follows: To a suspension prepared by diluting 1.39 g of 50% sodium hydride suspension in mineral oil with 30 ml of dimethylformamide is added dropwise with stirring in a nine trogenic tinor sphere at 0 ° C. 5 ° C a solution of 6.59 g of 5-chloro-3-methyl-2- (3-pyridyl) indole (prepared as described in U.S. Pat. No. 3,468,894) in 60 ml of dimethylformamide. After the addition is complete, the suspension is stirred for 1/2 hour at 0 ° C, and a solution of 6.06 g of 6-bromo-hexanoic acid methyl ester in 10 ml of dimethylformamide is added dropwise with cooling to 0 ° C. The reaction mixture is allowed to warm to room temperature, then stirred for 5 hours at room temperature and poured into 400 ml of ice water. The resulting mixture is extracted with 3 x 300 ml of ethyl acetate. The extract 20 is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. 1- (5-methoxycarbonylpentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole is obtained as an oil.

A solution of 3.2 g of the compound prepared above in 30 ml of 3 N sodium hydroxide solution is boiled under reflux for 17 hours. After cooling, the resulting product is filtered off, which is dissolved in 50 ml of water. After acidification with 2N hydrochloric acid to the pH 4-5, the product precipitates, which is purified by suspending in ether. 1- (5-carb-oxypentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole is obtained, m.p. 143-145 ° C.

Similarly, 1- (5-carboxypentyl) -5- 35 methoxy-3-methyl-2- (3-pyridyl) indole is prepared in the form of an oil.

After treatment with ethanolic hydrochloric acid in ethanol and crystallization by the addition of ethyl ether, the compound of Example 8 is obtained, namely 1- (5-carboxypentyl) -5-methoxy-3-methyl-2- (3- pyridyl) -indole hydrochloride, which melts at 175-178 ° C.

1- (5-Carboxypentyl) -5-hydroxy-3-methyl-2- (3-pyridyl) indole is prepared as follows: A solution of 1.70 g of 1- (5-carboxypentyl) -5-methoxyphenyl 3-methyl-2- (3-pyridyl) indole is boiled in 85 ml of 48% hydrogen bromic acid for 30 minutes under reflux. The reaction mixture is evaporated to dryness, the residue is diluted with water and then adjusted to pH 6 with dilute sodium hydroxide solution. The precipitate is isolated and recrystallized from a mixture of acetone and ethyl acetate. 1- (5-carboxypentyl) -5-hydroxy-3-methyl-2- (3-pyridyl) indole is obtained.

15

Examples 9 and 10

The following compounds of formula III wherein C EL ·

P 2P

and the group means 3-pyridyl is prepared using substantially the same procedure as used in Example 2. Condensation of the 3-methyl-2- (3-pyridyl) -indole-5-propionic acid ethyl ester with 6-bromo-hexanoic acid ethyl ester or with 8-bromooctanoic acid methyl ester, the esters of Examples 9a and 10a are obtained. Hydrolysis with hydrochloric acid gives the corresponding diacids of Examples 25 9 and 10.

Example cnH2n SmP · Rg Rg Recrystallized __from 30 9a (CH2) g oil 0C2H5 OC2H5 9 (CH2) ^ 143-145 OH OH Acetonitrile 10a (CH2) 7 oil OCH3 OC2H5 10 (ch2) 7 128-130 OH OH Acetonitrile 35 Carboxyheptyl-3-methyl-2- (4-pyridyl) -indole-5-propionic acid is prepared in an analogous manner.

o 33 DK 169104 B1

The indoles used as starting compounds are prepared as follows: For a suspension of p-hydrazinohydro-cinnamic acid [Manske and Kulka, J. Can. Res. 25 B, 376 (1947), 4.50 g] in 50 ml of absolute ethanol is added under nitrogen at 5 room temperature and stirring 10 ml of saturated ethanolic hydrochloric acid. Over approx. A solution is obtained for 5 minutes. To the red-orange colored solution is added 3.37 g (0.025 mole) of 3-propionylpyridine, the reaction mixture is heated to reflux and then refluxed for 18 hours. The resulting solution is cooled in an ice-water bath and the crystals formed of the 3-methyl-2- (3-pyridyl) -indole-5-propionic acid ethyl ester hydrochloride are isolated, m.p.

249-251 ° C. The free base, ie. 3-Methyl-2- (3-pyridyl) -indole-5-propionic acid ethyl ester is prepared by slurrying the hydrochloride salt in water, then basifying with 3N sodium hydroxide solution, then extracting with ether.

Similarly, 3-methyl-2- (4-pyridyl) -indole-5-propionic acid ethyl ester hydrochloride is prepared, m.p. greater than 275 ° C and the corresponding free base.

A suspension of 7.5 g of 3-methyl-2- (3-pyridyl) -indole-5-propionic acid ethyl ester hydrochloride in 450 ml of 2N hydrochloric acid is heated at reflux for 2 hours, then cooled solid formed material is isolated to give 3-methyl-2- (3-pyridyl) -indole-5-propionic acid hydrochloride, which melts at 290 ° C.

30

By corresponding hydrolysis of 3-methyl-2- (4-pyridyl) -indole-5-propionic acid ethyl ester hydrochloride, 3-methyl-2- (4-pyridyl) -indole-5-propionic acid hydrochloride is obtained, which melts above 305 ° C.

35 DK 169104 Pg 0 34

Example 11 a) A solution of 1- (4-cyanobenzyl) -3-methyl-2- (3-pyridyl) -indole (5.8 g) in 100 ml of a 1: 1 mixture of 20% s hydrochloric acid and glacial acetic acid are refluxed for 20 hours.

After cooling, the solution is poured into 100 ml of ice water and the pH is adjusted with saturated aqueous sodium hydrogen carbonate solution of 4.5-5. The precipitate formed is extracted with ethyl acetate, the extract is washed with water and evaporated to dryness. 1- (4-carboxybenzyl) -3-methyl-2-10 (3-pyridyl) indole is obtained, m.p. 273-275 ° C.

The nitrile used as the starting material 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 is added dropwise under nitrogen at 0-5 ° C over of 20 minutes a solution of 10.4 g (0.05 mol) of 3-methyl-2- (3-pyridyl) indole in 60 ml of dimethylformamide. The reaction mixture is stirred for 1/2 hour at 0-5 ° C, then 9.8 g (0.05 mole) of p-cyanobenzyl bromide is added dropwise in 50 ml of dimethylformamide. The mixture is stirred for 1 hour at 0-10 ° C

and then at room temperature for 30 minutes, after which it is poured into 600 ml of ice water. The solid formed is isolated, dried, washed with petroleum ether and redissolved in 500 ml of ether. The ether solution is first washed with 25 water and then with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, treated with activated carbon and filtered. After evaporation of the ether solution to dryness a yellow solid is obtained. This product is suspended in hot cyclohexane and filtered off.

1- (4-cyanobenzyl) -3-methyl-2- (3-pyridyl) indole is obtained, m.p. 127-129 ° C.

b) Analogously, 1- (4-carboxybenzyl) -5- 35 is prepared chlorine-3-methyl-2- (3-pyridyl) -indole hydrochloride, srap. 217-220 ° C.

Example 12 a) To a suspension of 0.49 g of lithium aluminum hydride in 50 ml of anhydrous tetrahydrofuran is added dropwise in a nitrogen atmosphere at room temperature a solution of 3.92 g of 1- (5-methoxycarbonylpentyl) -5-chloro-3-methyl-2 - (3-pyridyl) indole in 30 ml of anhydrous tetrahydrofuran. After the addition is complete, the suspension is stirred for 1 hour at 10 room temperature, then 50 ml of saturated aqueous ammonium chloride solution is added. The reaction mixture is allowed to stand overnight at room temperature and the organic layer is removed. The aqueous layer is filtered to remove salts and then extracted with 2 x 50 ml of ethyl acetate.

The combined organic layers are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The crude product is purified by trituration with hexane / ether and dissolved in ethanol. The solution is acidified with ethanolic hydrochloric acid and diluted with 20 anhydrous ether to precipitate the crystalline product. The resulting 1- (6-hydroxyhexyl) -5-chloro-3-methyl-2- (3-pyridyl) indole hydrochloride hemihydrate melts at 115-118 ° C.

b) Similarly, 1- (6-hydroxyhexyl) -25 3-methyl-2- (3-pyridyl) indole is prepared in the form of an oil.

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

Example 13

To a suspension of 1.52 g of 1- (5-carboxypentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole in 50 ml of toluene is added dropwise at room temperature under nitrogen 0.31 ml of chloride. The resulting mixture is refluxed for 1 hour, then an additional 0.10 g of thionyl chloride is added and the solution is stirred overnight at room temperature. The resulting suspension is evaporated to dryness. The crude 1- (5-chlorocarbonylpentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole is obtained, which is used directly without further purification.

A suspension of 0.86 g of the above-prepared 1- (5-chlorocarbonylpentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole in 20 ml of concentrated ammonium hydroxide is stirred overnight at room temperature. Filtration of the suspension and slurry of the resulting solid in ether afforded 1- (5-carbamoylpentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole, m.p. 137-140 ° C.

Example 14 10 To a suspension of 2.9 g (0.06 mol) of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide is added dropwise over 20 minutes under nitrogen at 0-5 ° C, a solution of 10 4 g of 3-methyl-2- (3-pyridyl) indole in 60 ml of dimethylformamide. The mixture is stirred at 0-5 ° C for 30 minutes, to which is added dropwise 17.6 g (0.06 mol) of 1-tetrahydropyranyloxy-8-bromooctane in 50 ml of dimethylformamide. The mixture is stirred for 1 hour at 0-10 ° C and for 30 minutes at room temperature, after which it is poured into ice water and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting solution is left at room temperature for 30 minutes, washed with ether, basified with aqueous 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness. 1- (8-hydroxy-octyl) -2- (3-pyridyl) -3-methylindole is obtained.

Example 15

A solution of 4 g of 1- (7-methoxycarbonylheptyl) -3-methyl-2 * - (3-pyridyl) indole in 40 ml of n-butanol is saturated with methyl 30 amine and heated in a pressure vessel for 3 days on a steam bath . The reaction mixture is evaporated to dryness and the product is recrystallized from ethyl acetate. 1- [7- (N-methyl-carbamoyl) -heptyl] -3-methyl-2- (3-pyridyl) -indole is obtained.

37 DK 169104 B1

Example 16

Preparation of 10,000 tablets containing 10 mg of active substance of Example 1 per tablet.

Ingredients 5 1- (7-Carboxyheptyl) -3-methyl-2- (3-pyridyl) indole 100 g Milk Sugar 1157 g

Corn starch 75 g

Polyethylene glycol 6000 75 g 10 Talcum powder 75 g

Magnesium stearate 18 g

Pure water q.s.

Course of action

All powdered components are screened through a screen having a mesh width of 0.6 mm. Then, the active substance is mixed with milk sugar, talc, magnesium stearate and half of the starch in a suitable mixing apparatus. The other half of the starch is suspended in 40 ml of water and the suspension is added to a boiling solution of polyethylene glycol in 150 ml of water. The paste formed is added to the powder mixture and then granulated, optionally with the addition of an additional amount of water. The granulate is dried overnight at 35 ° C, sieved through a sieve with a mesh width of 1.2 mm, and pressed into tablets of 6.4 mm diameter with split groove.

Example 17

Preparation of 10,000 capsules containing 25 mg of active substance of Example 11a per capsule.

Ingredients 1- 1- (4-Carboxybenzyl) -3-methyl-2- (3-pyridyl) indole 250 g Milk sugar 1650 g

Talcum powder 100 g 38 DK 169104 B1

Course of action

All powdered components are screened through a screen having a mesh width of 0.6 mm. Then, the active substance is first homogenized with talc and then with milk sugar 5 in a suitable mixing apparatus. By means of a filling machine, the mixture formed in capsule # 3 is filled to an amount of 200 mg per ml. capsule.

Similarly, tablets and capsules having a content of approx. 10-100 mg of other of the present compounds, e.g. 1- (5-carboxypentyl) -5- (chloro, fluoro, methoxy or methyl) -3-methyl-2- (3-pyridyl) indole, 1- (5-carboxypentyl) -5,6-dichloro-3- methyl 2- (3-pyridyl) indole, or other of the compounds mentioned in the examples.

Example 18 A solution of 50 mg of 1- (5-carbamoylpentyl) -5-chloro-3-methyl-2- (3-pyridyl) -indole in 1 ml of 6N hydrochloric acid is refluxed for 3 hours. After cooling, the hydrochloride salt precipitates. The suspension is evaporated to dryness and the residue is made basic by the addition of saturated aqueous sodium hydrogen carbonate solution. The solution is washed with ether and adjusted with 2N hydrochloric acid to pH 6-7. The crude free acid is obtained, namely 1- (5-carboxypentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole, m.p. 137-141 ° C.

Example 19 To a mixture of 4.17 g of 3-methyl-2- (3-pyridyl) indole, 0.64 g of tetra-n-butyl ammonium bromide and 1.02 g of powdered potassium hydroxide in 500 ml of acetonitrile is stirred. at room temperature under nitrogen 5.06 g of p- (2-bromethoxy) -benzoic acid [prepared as described in U.S. Patent No. 2,790,825]. The suspension is stirred for 5 days. The potassium bromide is filtered off and the filtrate is concentrated to an oil. This is dissolved in ethyl acetate and extracted with 3N hydrochloric acid. The acid layer is isolated and treated with 3 N sodium hydroxide solution. The resulting suspension is extracted with ethyl acetate (3 x 100 ml) and the organic layer is separated. This is dried over magnesium sulfate and concentrated. 1- [2- (4-ethoxycarbonylphenoxy) ethyl] -2- (3-pyridyl) -3-methylindole is obtained in the form of an oil.

Example 20

A mixture of 4/7 g of 1- [2- (4-ethoxycarbonylphenoxy) ethyl] -5 2- (3-pyridyl) -3-methylindole in 220 ml of 2N hydrochloric acid is refluxed for 6 hours. After cooling, the solution is basified with 3N sodium hydroxide solution and extracted with ethyl acetate. The basic solution is filtered and adjusted with 5 N hydrochloric acid to pH 6-7. The solid material is separated, dried and recrystallized from acetone. 1- [2- (4-carboxyphenoxy) ethyl] -2- (3-pyridyl) -3-methylindole, m.p. 190-193 ° C.

Example 21

A solution of 5.9 g of p-mercapto-benzoic acid ethyl ester 15 (prepared according to J.Chem. Soc., 1963, 1947-1954) in 30 ml of dimethylformamide is added dropwise to a porridge made of 1.55 g of 50% sodium hydride mineral oil in 30 ml of dimethylformamide. This mixture is stirred under nitrogen at room temperature for 30 minutes. The solution is added dropwise to a solution of 9.78 g of 1- (2-methylsulfonyloxy-ethyl) -2- (3-pyridyl) -3-methylindole in 60 ml of dimethylformamide at -10 ° C. This mixture is stirred at room temperature overnight and poured into 1000 ml of ice water. The mixture is extracted several times with ether (a total of about 1000 ml). The ether extract is washed with 3 x 200 ml water, dried over magnesium sulfate and evaporated in vacuo. 1- [2- (4-Ethoxy-carbonyl-phenylthio) -ethyl] -2- (3-pyridyl) -3-methylindole is obtained in the form of an oil. NMR (CDCl3) confirms the structure.

The starting compound is prepared as follows: To 11.77 g of 1- (2-ethoxycarbonyl-ethyl) -2- (3-pyridyl) -3-methyl-indole in 400 ml of dry tetrahydrofuran is added at 0 ° C 60 ml of 1 M solution. of lithium aluminum hydride in tetrahydrofuran. The reaction mixture is stirred for 1 hour at room temperature, after which it is cooled in an ice bath and added 2.26 ml of water, 2.26 ml of 15% sodium hydroxide solution and 6.78 ml of water in that order. The mixture is filtered and concentrated. vacuo. The residue is dissolved in ether, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The semi-solid 1- (2-hydroxyethyl) -2- (3-pyridyl) -3-methyl-indole is obtained, which is used directly in the subsequent step.

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

Example 22

A mixture of 6.39 g of 1- [2- (4-ethoxycarbonyl-phenylthio) -ethyl] -2- (3-pyridyl) -3-methylindole in 260 ml of 2N hydrochloric acid is refluxed for 6 hours. After cooling, the pH of the mixture is adjusted to 6-7 with saturated sodium hydrogen carbonate solution (about 500 ml). To the mixture is added 200 ml of ether and stirred for 30 minutes. The solid is separated, washed with water and then with ether and dissolved in 100 ml of absolute ethanol. The solution 25 is filtered and the hot solution is treated with 1.68 ml

6.5 N ethanolic hydrochloric acid. The solution is cooled and diluted with ca. 100 ml of ether. The resulting product is isolated. 1- [2- (4-carboxyphenylthio) ethyl] -2- (3-pyridyl) -3-methylindole hydrochloride, m.p. 222-224 ° C

Example 23

A solution of lithium diisopropylamide (LDA) is prepared by adding n-butyl lithium (7.66 mmol, 1.6 mol in hexane) to a solution of diisopropylamine (7.6 mmol) in 12 ml tetrahydrofuran (THF) at -20 ° C. The LDA solution 35 is cooled to -78 ° C, and 1- (5-methoxy-carbonylpentyl) -2- (3-pyridyl) -3-methyl-indole (2.48 g) is added dropwise in 41 DEG 169104 B1 24 ml of THF over 5 minutes. The mixture is stirred at -78 ° C for 20 minutes, then 1.5 g of phenyl selenyl chloride is added in 12 ml of THF. After 5 minutes, the cooling bath is removed and the mixture is allowed to warm to 5 to 0 ° C. Add 60 ml of saturated aqueous sodium hydrogen carbonate solution and then extract with 3 x 50 ml of ether. The mixed organic extracts are washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over 10 anhydrous magnesium sulfate. When concentrated in vacuo, the crude 1- (5-methoxycarbonyl) -5-phenyl-selenyl-2- (3-pyridyl) -3-methylindole is obtained as a yellow oil. The crude selenide is dissolved in 40 ml of dichloromethane and 1.8 g (16 mmol) of 30% hydrogen peroxide 1.8 ml of water are added dropwise. After the addition of approx. 10% of the hydrogen peroxide enters an exothermic reaction. The temperature rises to 30 ° Q until the addition is complete. The mixture is stirred for an additional 30 minutes, then 40 ml of 5% aqueous sodium carbonate solution is added. The dichloromethane layer is isolated. The aqueous phase is extracted with 25 ml of dichloromethane. The mixed organic phases are washed with 5% aqueous sodium carbonate solution, water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Concentration in vacuo gives 1- (5-methoxycarbonyl-pent-4-enyl) -2- (3-pyridyl) -3-25 methyl-indole as a pale yellow oil. Further purification is performed by short-circuit chromatography (silica gel) with ethyl acetate-hexane (2: 3) as eluent. NMR (COCl 3) δ 5.53-1.0 (d, 1H), 6.65 (m, 1H), IR (liquid) 1720 cm

Example 24 To a solution of the α, β-unsaturated ester, namely 1- (5-methoxycarbonylpent-4-enyl) -2- (3-pyridyl) -3-methylindole (84 mg) in 1 ml of methanol is added 1 ml 1 N aqueous lithium hydroxide solution. The mixture is stirred overnight at room temperature, then evaporated in vacuo to dryness.

The residue is dissolved in 2 ml of water and the solution is washed with 5 ml of diethyl ether. The aqueous phase is acidified to pH 6.6-7.0 and extracted with dichloromethane. The organic extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. A pale yellow oil is obtained which solidifies after trituration with chloroform. 1- (5-carboxypent-4-ethyl) -2- (3-pyridyl) -3-methylindole, m.p. 145-147 ° C.

Example 25

To a solution of Collins reagent prepared under nitrogen at 0-5 ° C of 5.6 mg chromium trioxide and 8.86 g (112 mmol) of pyridine in 150 ml of dichloromethane is added at once 1.8 g of 1- (6-hydroxyhexyl) -3-methyl-2- (3-pyridyl) indole in dichloromethane (15 ml). The mixture is stirred for 25 minutes and filtered through "Celite" ®. The filtrate is placed on a silica gel column and eluted with a 1: 1 mixture of ethyl acetate and dichloromethane (500 ml). When concentrated in vacuo, 1- (5-formylpentyl) -2- (3-pyridyl) -3-methylindole is obtained as a pale yellow oil. NMR (CDCl3) θ 9.7 (t, 1H), IR (liquid) 2710, 1720 cm -1.

Example 26 328 mg of trimethylphosphonoacetate is added dropwise under nitrogen to a solution of 220 mg of potassium tert-butoxide in 20 ml of THF at 0 ° C. The solution is stirred for 20 minutes at 0 ° C, then cooled to -78 ° C and a solution of 1- (5-formyl-pentyl) -2- (3-pyridyl) -3-methylindole (450 mg) is added dropwise ) in THF (5 ml). The mixture is kept at -78 ° C for 15 minutes and the cooling is adjusted. The mixture is stirred overnight at room temperature, diluted with 25 ml of water and extracted with 3 x 25 ml of diethyl ether. The mixed extracts are washed with saturated aqueous sodium hydrogen carbonate solution and with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation in vacuo, 1- (7-methoxycarbonylhept-6-enyl) -2- (3-pyridyl) -3-methylindole is obtained as a pale yellow oil.

IR (liquid) 1735 cm -1.

Example 27

By hydrolysis of 50 mg of 1- (7-methoxycarbonylhept-6-enyl) -2-35 (3-pyridyl) -3-methylindole using the procedure of Example 24, 1- (7-carboxyhept-6-enyl) -2- (3-pyridyl) - 43-methylindole. Mp. 144-146 ° C (recrystallized from dichloromethane-hexane).

Example 28 1- (7-Carboxyhept-6-enyl) -2- (3-pyridyl) -3-methylindole (10 mg) is hydrogenated in 1 ml of absolute ethanol with a catalytic amount of 10% palladium on carbon at a pressure of 1 atmosphere. After 3.5 hours, the catalyst is filtered off and washed with some ml of ethanol. The combined organic extracts are evaporated in vacuo. A colorless oil is obtained which is then brought to crystallization. There is obtained 1- (7-carboxyhept-yl) -3-methyl-2- (3-pyridyl) indole, which is identical to the compound of Example 1. The crude product melts at 110-113 ° C.

Example 29 1- (4-Cyanbutyl) -3-methyl-2- (3-pyridyl) indole (578 mg) is heated at 185 ° C for 30 minutes with 450 mg of powdered sodium hydroxide and 5 ml of ethylene glycol. The mixture is poured into 50 ml of water, washed with ether and adjusted to pH 6 with 2N hydrochloric acid. The resulting oil crystallizes out. There is obtained 1- (4-carboxybutyl) -3-methyl-2- (3-pyridyl) indole, which is identical to the compound of Example 5. Mp. 127-129 ° C.

The starting compound 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 50% sodium hydride mineral oil in 6 ml of DMF at 0 ° C. The mixture is stirred for 30 minutes at 0 ° C, then treated with a solution of 5-bromovaleronitrile 1.78 g in 4 ml of DMF. The mixture is stirred at room temperature overnight, poured into 125 ml of water and extracted with 2 x 50 ml of ether. The extract is washed with 3 x 20 ml of water and dried over magnesium sulfate. 1- (4-cyanbutyl) -3-methyl-2- (3-pyridyl) indole is obtained in the form of an oil.

Example 30

A mixture of 578 mg of 1- (4-cyanbutyl) -3-methyl-2- (3-pyridyl) indole, 173 mg of sodium azide, 142 mg of ammonium chloride and 5 mg of lithium chloride in 2 ml of DMF is heated. overnight at 120 ° C. After cooling, the mixture is filtered and the filtrate is diluted with ca. 25 ml of water. The solution is adjusted with 3 N sodium hydroxide solution to pH 10-11 and the solution is washed with ether to remove unreacted nitrile.

The aqueous phase is adjusted to pH 5-6 with 2N hydrochloric acid and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated in vacuo.

The solid residue is suspended in petroleum ether and isolated. 1- [4- (5-tetrazolyl) butyl] -3-methyl-2- (3-pyridyl) indole is obtained, m.p. 177-179 ° C.

Example 31

A solution of 3-methyl-2- (3-pyridyl) -indole (2.08 g) in 12 ml of DMF is added under nitrogen at 10-15 ° C to a suspension of 0.528 g of 50% sodium hydride solution. mineral oil in 6 ml DMF. After the addition is complete, the mixture is stirred at room temperature for 30 minutes, then 2.39 g of 3- (p-chloromethyl-phenyl) -2-methyl-acrylic acid ethyl ester in 5 ml of DMF is added dropwise. The resulting mixture is stirred overnight at room temperature 20 and poured into 100 ml of water. The resulting mixture is extracted with 2 x 50 ml of ethyl acetate. The organic layers are washed with 100 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. 1- [p- (2-ethoxycarbonylpropen-1-yl) -benzyl] -3-methyl-2- (3-pyridyl) -indole is obtained.

Hydrolysis with 2N hydrochloric acid gives 1- [p- (2-carboxypropen-1-yl) -benzyl] -3-methyl-2- (3-pyridyl) -indole.

The starting compound is prepared as follows: A suspension of 10.0 g of 50% sodium hydride in mineral oil in a 350 ml of freshly distilled dimethoxyethane (DME) is stirred under 30 nitrogen at 10 ° C and then stirred for approx. For 40 minutes, triethyl 2-phosphonopropionate is added. The mixture is stirred for 30 minutes at 10 ° C. With stirring for an additional 1.5 hours, the temperature of the solution rises to room temperature.

This solution is transferred under nitrogen with a cannula 35 to a 500 ml dropping funnel and then dropwise added to a solution of 33.53 g of terephthalaldehyde in dry DME over 1 hour at 22-34 ° C. After completion of the addition, the reaction mixture is mechanically stirred at room temperature for 2 hours, poured into 100 ml of water and extracted with 4 x 500 ml of ether. The ether extract is washed with 700 ml of 5 saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. A yellow oil is obtained, which partially crystallizes on standing. The crude mixture is purified by suspending in a mixture of petroleum ether and ethyl acetate (93: 7). After removal of unreacted dialdehyde 10, the filtrate is concentrated in vacuo.

A mixture is obtained which is further purified by high-pressure liquid chromatography using a mixture of petroleum ether and ethyl acetate (93: 7). The pure 4-formyl-α-methylcinnamic acid ethyl ester is obtained. A solution 15 of 34.80 g of this aldehyde in 820 ml of absolute ethanol is treated with 12.11 g of granulated sodium borohydride at room temperature under nitrogen. The resulting mixture is stirred for 3 hours at room temperature (or until the borohydride is dissolved), concentrated to a volume of approx. 200 ml, dilute with 400 ml of water and extract with 3 x 200 ml of ether. The ether extract is washed with 100 ml of water and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. There is obtained 3- (p-hydroxymethylphenyl) -2-methyl-acrylic acid ethyl ester. To a solution of this product in 350 ml of methylene chloride is added dropwise at room temperature 11.53 ml of thionyl chloride over 25 minutes. The clear colorless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated aqueous sodium bicarbonate solution, 30 ml of water and 100 ml of saturated aqueous sodium chloride solution. The organic layer is dried and evaporated. There is obtained 3- (p-chloromethyl-phenyl) -2-methyl-acrylic acid ethyl ester which is used without further purification.

Example 32 1- (5-Formylpentyl) -3-methyl-2- (3-pyridyl) indole (127 mg) is dissolved in 0.66 ml of DMF and 298 mg of pyridinium dichromate is added in one portion. The mixture is stirred overnight at room temperature, diluted with 25 ml of a mixture of ether and ethyl acetate (4: 1) and filtered. The solid is washed with hot chloroform and the combined filtrates are concentrated in vacuo. A dark brown rubbery material is obtained which is slurried with a mixture of 5 ether and ethyl acetate (4: 1) and extracted with 2 ml of 0.1 N aqueous sodium hydroxide solution. The aqueous extract is adjusted to pH 5.5-6.0 and extracted with chloroform. The chloroform extract is dried and concentrated in vacuo. A yellow oil is obtained. By thin layer chromatography (silica gel, 10 ethyl acetate-hexane (1: 1)), the presence of the desired acid shows. Further chromatography on silica gel using a mixture of ethyl acetate and hexane (1: 1) as eluent gives the desired 1- (5-carboxypentyl) -3-methyl-2- (3-pyridyl) indole, which is identical with the compound of Example 3 prepared.

Example 33

To a solution of 692 mg of sodium hydroxide in 4 ml of water is added 0.344 ml of bromine under cooling with an ice bath. The resulting solution is added to 400 mg of 1- (5-oxohexyl) -3-methyl-2- (3-pyridyl) indole and the mixture is stirred for 2 hours at room temperature. The mixture is washed with ether. The aqueous solution is filtered and adjusted to pH 5.6 with 2N hydrochloric acid. The solid white crude product which melts in the range 108-120 ° C is isolated. Separation 25 using thin layer chromatography (silica gel, methylene chloride-methanol (9: 1)) gives 1- (4-carboxybutyl) -3-methyl-2- (3-pyridyl) indole identical to that of Example 5 compound.

The starting compound is prepared as follows: 1- (4-30 Cyanbutyl) -3-methyl-2- (3-pyridyl) indole (1.5 g) in 15 ml of ether is added to a solution of 0.0103 mol of methyl magnesium bromide. in 15 ml e.ther. The mixture is refluxed for 3 hours. After cooling, 10 ml of 6N hydrochloric acid is added dropwise and the mixture is heated under reflux for several hours. The reaction mixture is washed with ether and adjusted with 3 N sodium hydroxide solution to pH 10-11. After extraction with ether and evaporation of the solvent, 1- (5-oxohexyl) ~ 3-methyl-2- (3-pyridyl) indole is obtained. IR 1720 cm "1, NMR (CDCl13) δ 2.0.

Example 34 1- (7-Carboxyheptyl) -5-chloro-3-methyl-2- (3-pyridyl) -indole-hydrochloride (421 mg) dissolved in 7 ml of tetrahydrofuran is heated and treated with 202 mg (0.278 ml) of triethylamine. . This solution is added dropwise to a solution of 108 mg (0.096 ml) of chloroformic acid ethyl ester in 1 ml of tetrahydrofuran and cooled to 0-5 ° C. The reaction mixture is stirred for 1 hour at this temperature and filtered to remove the triethylamine hydrochloride. The filtrate is treated with a solution of 69 mg of hydroxylamine hydrochloride and 40 mg of sodium hydroxide in 10 ml of methanol. This mixture is stirred for 0.5 hours and then concentrated in vacuo. The residue is treated with 25 ml of ether-methanol (10: 1) and filtered. The filtrate is evaporated in vacuo. A viscous oil is obtained which is dissolved in acetone and treated with 6.5 N ethanolic hydrochloric acid. 1- (7-hydroxycarbamoyl-heptyl) -3-methyl-2- (3-pyridyl) -indole hydrochloride is obtained, m.p. 170-173 ° C.

Example 35 0.14 ml of 7.1 N ethanolic hydrochloric acid is added to 236 mg of N-phenyl-N- (5-methoxycarbonylpentyl) hydrazine in 2 ml of absolute v ethanol, to which 135 mg of 3-propionylpyridine is added. The mixture is refluxed overnight. Then, an additional 0.62 ml of ethanolic hydrochloric acid is added and heated for a further 24 hours at reflux. After cooling, the mixture is filtered and the filtrate is evaporated in vacuo. The residue is stirred in 10 ml of water and adjusted with 1 N sodium hydroxide solution to pH 10-11. This mixture is extracted with ether. The extract is washed with water, dried over magnesium sulfate and evaporated. An oil is obtained which is 1- (5-ethoxycarbonylpentyl) -3-methyl-2- (3-pyridyl) indole.

This ester is hydrolyzed with 10 ml of 2N hydrochloric acid under reflux and the mixture is adjusted to pH approx. 6 with saturated aqueous sodium hydrogen carbonate solution and extracted with ether. By working up the organic extract, 1- (5-carboxypentyl) -3-methyl-2- (3-pyridyl) -indole, which is identical to the compound of Example 3, is obtained. The melting point of the crude product is 511-113 ° C.

The starting compound is prepared as follows: 2.79 g (2.73 ml) of aniline, 6.27 g of β-bromohexanoic acid methyl ester and 12.24 g (0.09 mol) of sodium acetate trihydrate are heated in 15 ml of absolute ethanol overnight at 80-100 ° C. After 10 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. N- (5-methoxycarbonylpentyl) -aniline is obtained.

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

3.6 g of the above-prepared nitroso derivative in 4 ml of glacial acetic acid is added dropwise to 3.94 g of zinc powder in 6 ml of water.

After the exothermic reaction up to a temperature of 35 ° C

the mixture is stirred for 2 hours at room temperature. The zinc is filtered off, the filtrate is washed with ether, adjusted to pH 10-11 with 40% sodium hydroxide solution and extracted with ether. The extract is dried over magnesium sulfate 30 and evaporated in vacuo. A crude oil is obtained. After short-circuit chromatography on silica gel with hexane-acetic acid (5: 1), N-phenyl-N- (5-methoxycarbonylpentyl) -hydrazine is obtained having a purity of approx. 80%. This product is used directly in the Fischer cyclization described above.

49 DK 169104 B1

Example 36

1- [7,7- (bis-methoxycarbonyl) -heptyl] -3-methyl-2- (3-pyridyl) -indole (273 mg) is dissolved in methanol (0.5 ml), and 1.95 is added. ml 1 N aqueous lithium hydroxide solution.

The mixture is stirred for 1 hour at room temperature, then it is refluxed for 2.5 hours. The clear solution is evaporated to dryness, the residue is dissolved in water and the solution is adjusted to pH 6-6.2. A yellow, gummy solid is formed which is extracted in chloroform. The extract is dried over magnesium sulfate and evaporated. Crude 1- [7,7- (bis-carboxy) -heptyl] -3-methyl-2- (3-pyridyl) indole is obtained. NMR (CDCl3) δ 10.60 (2H).

A sample of the crude dicarboxylic acid (28 mg) is heated for 30 minutes in p-xylene (3 ml) containing 0.1 ml of 0.1 N hydrochloric acid. The clear solution is allowed to cool to room temperature. A rubbery material is precipitated which is extracted with sodium hydroxide. The aqueous phase is isolated, adjusted to pH 6-6.2 and extracted with a mixture of ethyl acetate and ether (8: 2). the organic phase is dried over magnesium sulfate and evaporated. A colorless oil is obtained which solidifies upon standing. There is obtained 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) indole, which according to NMR and TLC values is identical to the compound prepared according to Example 1.

The starting compound is prepared as follows: At 0 ° C

0.36 ml of thionyl chloride is added to 1.37 g of 1- (6-hydroxyhexyl) -3-methyl-2- (3-pyridyl) indole and the mixture is stirred for 1 hour at room temperature. Then saturated aqueous sodium hydrogen carbonate solution is added to the mixture, which is extracted with dichloromethane. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate.

After evaporation in vacuo, crude chloride is obtained in the form of an oil. Purification by chromatography on silica gel (methylene chloride / ethyl acetate (19: 1)) gives 1- (6-chlorohexyl) -3-methyl-2- (3-pyridyl) indole in the form of a pale yellow oil. NMR (CDCl3) δ 3.30 (t, 2H), 3.92 (t, 2H).

1- (6-Chlorhexyl) -3-methyl-2- (3-pyridyl) indole (0.5 g) is added to a mixture of 792 mg of dimethyl malonate, 790 mg of potassium carbonate and 11.6 ml of dimethylformamide. and the mixture is heated under nitrogen for 18 hours at 80-90 ° C. The mixture 5 is poured into 80 ml of ice water and acidified with 1N hydrochloric acid and washed with ether. The aqueous layer is adjusted to pH 6 and extracted with ether. The extract is dried over magnesium sulfate and evaporated to a yellow oil. Purification by preparative thin layer chromatography (chloroform-ethyl acetate 10 (9: 1)) gives 1- [7,7- (bis-methoxycarbonyl) -heptyl] -3-methyl-2- (3-pyridyl) indole. NMR (CDCl3) δ 63.32 (t, 1H), 3.78 (s, 6H), 4.03 (t, 2H). IR (liquid) 1750 cm · * ·.

Example 37 1- (6-Chlorohexyl) -3-methyl-2- (3-pyridyl) indole (165 mg) in 2 ml of dry THF is added dropwise to 12 mg of magnesium shavings in 2 ml of dry THF under nitrogen. To initiate the reaction, an iodine crystal is added during the addition. After the addition is complete, the mixture is refluxed for 4 hours, then cooled to 0 ° C. With stirring for 20 minutes, dry carbon dioxide gas is fed to the reaction vessel. The cloudy mixture is poured into 5 ml of 1 N sodium hydroxide solution 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 evaporated to dryness in vacuo. The crude product melts at 106-107 ° C. The product is 1- (6-carboxyhexyl) -3-methyl-2- (3-pyridyl) indole, whose TLC and NMR values are identical to those of the compound prepared according to Example 4.

Example 38 1- (Prop-2-ynyl) -3-methyl-2- (3-pyridyl) -indole (90 mg) is dissolved under nitrogen in 2 ml of THF and the resulting solution is cooled to -78 ° C. A solution of 0.024 ml (1.6 mole in hexane) of n-butyllithium is added dropwise over 1 minute. The orange mixture is stirred for a further 10 minutes at -78 ° C, then 0.031 ml of chloro-formic acid methyl ester is added. The mixture is allowed to warm to room temperature, after which it is poured into saturated aqueous sodium chloride solution and extracted with ether. The extract is washed with water and dried over magnesium sulfate. Evaporation in vacuo gives an oil which is purified by preparative thin layer chromatography. As the solvent, 1: 1 mixture of ethyl acetate and hexane is used. 1- (3-Methoxycarbonyl-prop-2-ynyl) -3-methyl-2- (3-pyridyl) indole is isolated in the form of an oil. NMR (CDCl 3) δ 3.73 (s, 3H), 4.83 (s, 2H). IR (CHCl3) 1715, 2245 cm -1.

The starting compound is prepared as follows: 53 mg sodium hydride in the form of a 50% mineral oil dispersion is washed under nitrogen with petroleum ether. The washed sodium hydride is suspended in 2 ml of dry DMF and 3-methyl-2- (3-pyridyl) indole (208 mg) in DMF (2 ml) is added dropwise.

The mixture is stirred for an additional 30 minutes, then propargyl bromide is added dropwise. The reaction mixture is stirred for an additional 2 hours, then poured into ice water, acidified with 1N hydrochloric acid and extracted with ether. The aqueous phase is made basic with sodium hydrogen carbonate and extracted with ether. The ether extract is washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Evaporation in vacuo gives 1- (prop-2-ynyl) -3-methyl-2- (3-pyridyl) indole. NMR (CDCl3) δ 2.20 (s, 4H), 4.70 (d, 2HJ = 3 Hz), IR (liquid) 3200, 2120 cm 1. The melting point is 104-105 ° C after purification by short-circuit chromatography under using a 1: 1 mixture of ethyl acetate and hexane.

Example 39

By treating 33 mg of 1- (3-methoxycarbonylprop-2-ynyl) -30 3-methyl-2- (3-pyridyl) indole in 1 ml of methanol with 0.3 ml of 1 N lithium hydroxide solution at room temperature, 1- (3) is obtained. - carboxyprop-2-ynyl) -3-methyl-2- (3-pyridyl) indole. IR 1720 -1 cm DK 169104 B1 52

Example 40

Analogous to the methods described in the above examples, the following compounds of formula II are prepared wherein = CH 2, Pyr = 3-pyridyl and = OH.

5 Forbin- Ri Ri C H ~ Salt Mp. ° C

part 2_3 m 2m___ 40/1 5-C1 H (CH2) 7 HCl 173-176 40/2 5-OCH3 Η (CH2) s HBr 188-189 40/3 5-C1 6-C1 (CH2) 5 HCl 178- 180 10 40/4 5-FH (cH2) 5 HCl 216-219 40/5 5-CH3 H (CH2) 5 HCl 185-188 40/6 5 “CH3 H (CH2) 7 - 124-125 40/7 Η H (ch2) 10 - 100-102 40/8 5-0-CH2-0-6 (CH2) 5 15 40/9 5-OH Η (<3Η2) 5 “168-170 40/10 5-SCH3 H ( CH2) 5 "135-137

The N-unsubstituted indoles used as starting materials are known compounds. The novel starting compound for compound 40/10, namely 5-methylthio-3-methyl-2- (3-pyridyl) indole, melts at 160-162 ° C.

Compound 40/9 is prepared by hydrogenolysis of 1- (5-carboxypentyl) -5-benzyloxy-3-methyl-2- (3-pyridyl) indole, m.p. 176-178 ° C. The 5-benzyloxy-3-methyl-2- (3-pyridyl) -indole used as the starting compound melts at 164-166 ° C.

Example 41

By analogy with the methods described in the above examples, the following compounds of formula I, wherein R 1 = CH 3, Ar = 3-pyridyl and B = COOH are prepared.

Connect- R_ R_ A B

30 part_ -5

41/1 Η H C = C- (CH2) 3 COOH

41/2 Η H CH 2 S (CH 2) 2 COOH

41/3 Η H (CH2) 20 (CH2) 2 COOH

41/4 Η H (CH2) 20 (CH2) 3 COOH

53 DK 169104 B1

The alkylating starting compounds for compounds 41/2, 41/3 and 41/4 are prepared according to J. Org. Chem. 3, 4, 2955 (1969), U.S. Patent No. 3,984,459 or Chem. Abstr.

83, 166177b.

5 Effect on thromboxane synthetase from human platelets_

The test is performed using the method described previously. This in vitro inhibition of the thromboxane synthetase enzyme is demonstrated analogously to the method of Sun, Biochem. Biophys. Res. Comm. 7, 1432 (1977).

results

Compound IC50 of Example Thromboxane Synthetase 3 0.003 15 1 0.012 2 1.800 4 0.008 5 0.007 9 0.021 20 10 0.069 11 0.050 6 3.400 7 0.001 12 0.260 25 13 0.013

Claims (2)

An analogous process for the preparation of N-substituted 2-pyridylindoles of the general formula R2 f1 / fc '> Ar <i 3 is R 2 is lower alkyl, Ar is pyridyl, R 2 and R 3 are each independently hydrogen, halogen, carboxylavalkyl or lower alkoxycarbonylllavalkyl, A is alkylene having 1-12 C-15 atoms, phenylene, a direct bond or low alkyl- ( thio or oxyphenylene, B means carboxy, lower alkoxycarbonyl, carbamoyl or hydroxymethyl, or salts thereof, characterized in that 1. condensing a compound of formula 20 R9 R 1 M 25 R 3 in which X means hydrogen, alkali metal or tri-lower alkyl -silyl, and Rlf R 2, R 3 and Ar have the above meanings, with a reactive functional derivative of a compound of the formula HO - CH 2 - A - B (VI) wherein A and B have the above meanings, or the second ring terminates a compound of formula DK 169104 B1 R, 2NA CH9-R, | 1 (vid 5 L · J 1 “N ** N = C" Ar R 3 X CH 2 - a -B 10 wherein Ar, R 2, R 2, R 3, A and B have the meanings given above, or 3. cycles a compound of formula R 2 * CH 9 R , 15 µC 0 <VIII) r / N - C-Ar 3 in CH 2 -AB 20 wherein Ar, R 1; R 2, R 3, A and B have the above meanings, or 4. in a compound of formula R 9 y. R 1 R 3 CH 2 -AC 30 wherein A, Ar, R 2, R 2 and R 3 have the above meanings, and C means a group other than B which can be converted to group B, group C transforms to group B, optionally while extending the chain A within its definition, or 5. for the preparation of compounds of formula I wherein R 1 is lower alkyl, Ar is pyridyl, R 2 and R 3 are each hydrogen, halogen, carboxylavalkyl or lower alkoxy-carbonyl-lower alkyl, A means alkylene having 1-12 C atoms, phenylene or a direct bond, and B means carboxy, lower alkoxycarbonyl, carbamoyl or hydroxymethyl, condenses a compound of d is the formula V wherein X is hydrogen and Rlf R2, R3 and Ar have the meanings indicated immediately above in the introduction to this variant, with a reactive functional derivative of a compound of the formula HO - CH2 - A - Β · (Via) wherein A is as defined above in the introduction to this variant and B 'is carboxy, lower alkoxycarbonyl, carbamoyl, mono- or dilavalkyl-carbamoyl, hydroxymethyl, etherified hydroxymethyl, halogenmethyl, trialkoxymethyl or cyano, 20 R9 R1 pds. R3 CH2-AB '25 wherein B' is different from B as defined above in the introduction to this variant and R1, R2, R3, A and Ar have the meanings given above in the introduction to this variant, converting Group B 'to Group B optionally extending the chain A within its definition, temporarily protecting, if desired or necessary, a disruptive reactive group in all of these processes, and then converting, if necessary, a compound of formula I to another compound with the formula DK 169104 B1 I and / or, if desired or necessary, converts a prepared free compound into a salt or a prepared salt into the free compound or to another salt and / or, if desired, separates a formed mixture of isomers 5 or racemates in the individual isomers or racemates and / or, if desired, split racemates into the optical antipodes. Process according to claim 1, characterized in that 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) -indole or a salt thereof is prepared.