DD204924A5 - PROCESS FOR PREPARING N-SUBSTITUTED 2-PYRIDYLINDOLE - Google Patents

Abstract

The invention relates to a process for the preparation of N-substituted 2-pyridylindolen for use as a medicament, for example for the treatment of thrombosis, atherosclerosis, arrhythmias, migraines, myocardial infarction, angina pectoris u.a. The aim of the invention is the provision of novel compounds with thromboxane synthetase inhibiting properties. According to the invention, N-substituted 2-pyridylindoles of the formula I are prepared in which, for example, R 1 is hydrogen or lower alkyl, unsubstituted or lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl-substituted pyridyl, R 2 and R 3 deep independently of one another hydrogen, lower alkyl, Halogen, trifluoromethyl, hydroxy, lower alkoxy, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy, lower alkoxycarbonyl or lower alkyl (thio, sulfinyl or sulfonyl), A alkylene of 1 to 12 carbon atoms, among others

Description

Berlin, 21.3 .. 1983 AP G 07 D / 244 959/6 (61 632/18)

Process for the preparation of! -Substituted 2-pyridylindoles

Field of application of the invention

The invention relates to a process for the preparation of Η-substituted 2-pyridylindoles with valuable pharmacological, in particular heromboxan synthetase inhibiting properties,

The compounds according to the invention are used as medicaments, for example for the treatment of thrombosis, atherosclerosis, arrhythmias, migraine, myocardial infarction, angina pectoris and the like. a.

Characteristic of the known technical solutions

U.S. Patent 3,404,794 discloses 1-unsubstituted 3-methyl-2- (3- or 4-pyridyl) -indoles as diuretic agents. About 2- (2-pyridyl) -indole-3- (acetic and propionic) acids is z. B. in Pharm. Bull. 4, 16 (1956) or in Chemical Abstracts, j64., 1954Od (1966). Various, optionally substituted, 2- (3-pyridyl) -indole-3-acetic acids are known as chemical Intermediates in Bull. Soc. Chim. Prance 1966, 771-2 and Bull. Soc Chim "Prance 1969> 4154-9 been described» The preparation of 1-cyanoethyl-2- (2-pyridyl) -indol in Pharmacy 22 10) 557-60 (1968).

/ /, Q ^ Q R -1a-21.3.1983

Βκ · tsts * * K * fm ^ ^ J> t * J% 3

_AP C 07 D / 244 959/6 (61 632/18)

Object of the invention

The aim of the invention is the provision of novel compounds with valuable pharmacological properties, in particular with thromboxane synthetase inhibitory activity,

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

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

The aforesaid characteristics contribute to the fact that the! -Substituted 2-pyridylindoles of this invention, when administered, alone or in combination, to mammals, z, B, are useful in the treatment or prevention of diseases related to the inhibition of thromboxane synthetase appeal, are particularly useful. These diseases include cardiovascular disorders such as thrombosis, atherosclerosis,

/ QkQ k - 2 -

* "* 3 * <* J * J \ J% J

Coronary convulsions, arrhythmias, cerebral ischemic attacks, migraine and other vascular headaches, myocardial infarction, angina pectoris, hypertension; Respiratory disorders such as asthma and apnea; and inflammatory diseases. It has also been found that inhibition of thromboxane synthetase reduces metastasis in certain tumor classes. The compounds of the invention may therefore be useful in the treatment of certain cancers.

The present invention therefore relates to 1-substituted 2-pyridylindoles of the formula I.

\ - · ^Λ (D.

> / V \ r ^R 3 I

GH-A-B

wherein R is hydrogen or lower alkyl, Ar is unsubstituted or lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl substituted pyridyl, R and R

Cm -J

independently of one another represent hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, carboxy-lower alkyl, lower alkoxy : lower carbonyl-lower alkyl, carboxy, lower alkoxycarbonyl or lower alkyl- (thio, sulfinyl or sulfonyl), or R ,. and R together, on adjacent carbon atoms, represent lower alkylenedioxy; A is alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, alkynylene of 2 to 12 carbon atoms, lower alkylene-phenylene-lower alkylene, lower alkylene-phenylene, phenylene-lower alkylene, phenylene, a direct bond, lower alkylene (thio or oxy) lower alkylene, (thio or oxy) phenylene, lower alkylene (thio or oxy) phenylene, phenylene (thio or oxy) lower alkylene or phenylene lower alkenylene, B carboxy, lower alkylene

alkoxycarbonyl, carbamoyl, mono- or di-lower-alkyl-carbamoyl, hydroxymethyl, hydroxycarbamoyl, · 5-tetrazolyl or formyl; their N-oxides; and their salts, in particular their therapeutically usable salts, and processes for their preparation, pharmaceutical preparations containing these compounds, as well as their therapeutic use.

Preference is given to compounds of the formula I in which R is hydrogen or lower alkyl, Ar is unsubstituted or substituted by lower alkyl. R 2 is hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, lower alkylthio, carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl; R- is hydrogen, or R and R together, on adjacent carbon atoms Lower alkylenedioxy; A is alkylene of 1 to 12 carbon atoms, phenylene, lower (alkylene-phenylene, alkylene-thiophenylene or alkylene-oxy-phenylene) of 7 to 10 carbon atoms, or a direct bond, B is carboxy, lower alkoxycarbonyl, carbamoyl, hydroxycarbamoyl, 5-tetrazolyl or hydroxymethyl; their N-oxides; and salts, especially their therapeutically acceptable salts.

Further preferred compounds are those of the formula I mentioned above, in which R is bonded to the 5-position of the indole nucleus.

Particularly preferred are the aforementioned compounds of formula I, wherein B is carboxy, lower alkoxycarbonyl, carbamoyl, 5-tetrazolyl or hydroxycarbamoyl.

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

Moreover, the compounds of formula I wherein A is alkylene of 1 to 12 carbon atoms or phenylene are important.

Particularly noteworthy are the compounds of formula II

I Il

> / Γ'ν

^R 3 f _m ^H 2m

COR.

wherein R 'is hydrogen or lower alkyl, R' and R 'are independently hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkylthio or lower alkoxy, or R' and R 'together, on adjacent carbon atoms, methylenedioxy, Pyr 2-, 3 - or 4-pyridyl, m is an integer from 1 to 13, R is hydroxy, lower alkoxy or amino; and their salts, especially their therapeutically acceptable salts.

Preference is given to compounds of the formula II in which R 'is hydrogen-

Also particularly important are compounds of the formula III

° / \ / ^CH 3

• N Pyr

in,

, η 2n COR

wherein η is an integer from 3 to 10, ρ is an integer from 0 to 4, Pyr is 2-, 3- or 4-pyridyl, R_ and R ..

5 ο

ILhShB δ - ⁵ -

independently represent hydroxy or lower alkoxy; and salts, especially their therapeutically acceptable salts.

Preference is given to compounds of the formula III in which η is 4 to 8, ρ is 1 to 4, Pyr is 3 or 4-pyridyl, and R _r and R

ο

Hydroxy.

Valuable are other compounds of formula IV

(IV)

C \ IJ IJ j * I C H } / \ I Il \ /

wherein R 'and R' independently of one another represent hydrogen, lower alkyl, halogen, lower alkoxy, lower alkylthio or hydroxy, or R 'and R' together represent, on adjacent carbon atoms, methylenedioxy; X is oxygen, sulfur or a direct bond, q is an integer from 1 to 4, R is hydroxy or lower alkoxy; Pyr is 2-, 3- or 4-pyridyl, and salts, especially their therapeutically acceptable salts.

Preference is given to compounds of the formula IV in which X is a direct bond. Compounds of formula IV, wherein q is a number from 2 to 4 and X is oxygen or sulfur, are to be emphasized.

.. · & »q,« 4 J J J

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

An alkylene radical means alkylene. having 1 to 12 carbon atoms, which may be straight chain or branched, and preferably propylene; Butylene, pentylene, hexylene or heptylene, wherein said radicals are unsubstituted or substituted by one or more lower alkyl groups, with the proviso that the sum of the carbon atoms is not more than 12.

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

The term alkynylene refers to an alkynylene radical having 2 to 12 carbon atoms, which is straight-chain or branched, and preferably propynylene, 1- or 2-butynylene, 1- or 2-pentynylene, 1-, 2- or hexynylene, l- ,. 2-, 3- or 4-heptynylene. These radicals are unsubstituted or substituted by one or more lower alkyl groups, the sum of the carbon atoms not exceeding 12

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

The term pyridyl means 2-, 3- or 4-pyridyl, in particular 3-pyridyl.

4495

- The term "lower" as defined in the above organic or following groups, radicals or compounds such with up to 7j preferably 4 ₉ I ₅ in particular 2 or 3 carbon atoms ^

A lower alkylene phenylene group, a phenylene lower alkylene group, a lower alkylene-phenylene lower alkylene group, a lower alkylene (thio or oxy) phenylene group, a phenylene (thio or oxy) lower alkylene group, or a phenylene lower alkenylene group contains in each alkylene group. or alkenylene radical preferably 1 to 4 _S, in particular 1 or 2 carbon atoms. The lower alkylene. or lower alkenylene radicals can be straight-chain or branched «

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

A lower alkyl group preferably contains 1-4 carbon atoms and is e.g. for ethyl, propyl or butyl, in particular methyl.

A lower alkylenedioxy group preferably means ethylenedioxy or methylenedioxy.

A lower alkoxy group preferably contains 1 to 4 carbon atoms and is e.g. Aethoxy, propoxy or especially methoxy "A lower alkyl (thio, sulfinyl or sulfonyl) group is preferably methylthio, methylsulfinyl or methylsulfonylo

A lower alkoxycarbonyl group preferably contains 1 to 4 carbon atoms in the alkoxy moiety and means, for example, methoxycarbonyl, propoxycarbonyl or isopropoxycarbonyl, in particular ethoxycarbonyl. A mono- (lower alkyl) -carbamoyl group preferably has 1 to 4 carbon atoms.

? 'J' \ *? * J \ J

In the Alkylte.il and is e.g. N-methylcarbamoyl, N-propylcarbamoyl or especially N-ethylcarbamoyl. A di (lower alkyl) carbamoyl group preferably contains 1 to 4 carbon atoms in each lower alkyl group and is e.g. for Ν, Ν-dimethylcarbamoyl, M-methyl-1-N-ethylcarbamoyl and especially for Ν, Ν-diethylcarbamoyl,

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

Salts are preferably therapeutically useful salts, for example metal or ammonium salts of said compounds of formula I, which have free carboxy, in particular alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, especially easily crystallizing ammonium salts. These are derived from ammonia or organic amines, for example mono- _5- di-tri-lower (alkyl, cycloalkyl or hydroxyalkyl) amines. Lower alkylenediamines or (hydroxy-lower alkyl or aryl-lower alkyl) lower alkylammonium bases, for example methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) aminomethane or benzyltrimethylammonium hydroxide. The compounds of the formula I mentioned form acid addition salts. These are preferably prepared with those acids which give therapeutically useful acid addition salts. Acids which give therapeutically useful acid addition salts are, for example, strong mineral acids, such as hydrohalic acids, eg = hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid; or organic acids, such as aliphatic or aromatic carboxylic or sulphonic acid, for example formic, acetic, propionic, succinic, glycolic, lactic, acetic, tartaric, gluconic, citric, maleic, fumaric, Pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminoslicyl, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyalkanesulfonic, benzenesulfonicp-toluenesulfonic-naphthalenesulfone , Sulfanil or cyclohexyl

sulfamic acid; or the ascorbic acid.

The compounds of the invention show valuable pharmacological properties, e.g. cardiovascular effects by selectively inhibiting thromboxane release in mammals. This inhibition is achieved by selective reduction of the thromboxane synthetase level. The compounds are therefore useful in the treatment of diseases that respond to thromboxane synthetase inhibition in mammals. Such diseases are primarily cardiovascular disorders such as thrombosis, arteriosclerosis, coronary convulsions, carebral ischemic attacks, migraine, other vascular headaches, myocardial infarction, angina pectoris and hypertension.

These effects may be demonstrated by in vitro or in vivo animal experiments, preferably on mammals, e.g. Guinea pigs, mice, rats, cats, dogs or monkeys. The compounds mentioned may be administered enterally or parenterally, preferably orally or subcutaneously, intravenously or intraperitoneally, e.g. by gelatin capsules or in the form of starch-containing suspensions or aqueous solutions. The dose used may range between about 0.01 and 100 mg / kg / day, preferably about 0.05 and 50 mg / kg / day, more preferably about 0.1 and 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).

C-arachidonic acid is used with an enzyme mixture preparation consisting

from solubilized and partially purified prostaglandin cyclooxygenase from sheep seminal vesicles and from a crude microsome preparation of thromboxane synthetase from lysed human blood

platelets, incubated. The test compound (dissolved in a buffer or, if necessary, in venous ethanol) is added to the incubation medium. At the end of the incubation period (30 minutes) prostaglandin E (PGE) is reduced by adding sodium borohydride to a mixture of prostaglandin F "and F" ß [PGF "(a + β)]. The radioactive products and the excess substrate are extracted with ethyl acetate and the extract is evaporated to dryness. The residue is dissolved in acetone, applied dropwise to thin-layer plates and chromatographed with a solvent system of toluene: acetone: glacial acetic acid [100: 100: 3 (v / v)]. The radioactive zones are located. The zones of thromboxane B (TxB ") and PGF" α + β are transferred to scintillation vials for liquids and counted. The quotient of the numerical values of TxB "/ PGF a + β is calculated for each concentration of the test compound and the IC values are determined graphically. This value is the concentration of the test compound at which the quotient of TxB "/ TGF a + β is reduced to 50% of the control value.

The in vitro effect on prostaglandin cyclo-oxygenase is measured according to a modification of the method of Takeguchi et al., Which is described in Biochemistry 10, 2372 (1971). The test procedure is as follows:

Sheep lyophilized seminal vesicle microsomes are used as a prostaglandin-synthesizing enzyme preparation. It will be the

14 Conversion of C-arachidonic acid measured in PGE. The test compounds (dissolved in a buffer or, if necessary, in a little ethanol) are added to the incubation mixture. The prostaglandins are extracted and separated by thin layer chromatography. The plates are checked, the radioactive zones corresponding to the PGE are transferred to scintillation vials for liquids and their radioactivity is counted. The IC values of the inhibition become graphic

- 11 _m

determined. This value means the concentration of the test compound which reduces the amount of synthesized PGE by 50%.

The in vitro effect on prostacyclin (PGI ") synthetase is measured analogously to the method of Sun et al., Prostaglandins, 14, 1055 (1977). The test procedure is as follows:

14.

C-Arachidonic acid is treated with an enzyme mixture consisting of solubilizing

sated and partially purified prostaglandin cyclo-oxygenase from sheep seminal vesicles and from crude PGI "synthetase in the form of a microsome fraction of aortas from cattle, incubated

The test compound (dissolved in a buffer or, if necessary, in a little ethanol) is added to the incubation medium. The reaction mixture is incubated in 100 mM Tris HCl (pH 7.5) for 30 minutes at 37 °, acidified to pH 3 and extracted with ethyl acetate. The extract is evaporated to dryness, the residue dissolved in acetone, applied to thin-layer plates and treated with a method described by Sun et al. described solvent system chromatographed. The radioactive zones are located with a detector. The zones corresponding to the 6-keto-PGFα (a stable endproduct of prostacyclin biotransformation) and PGE are transferred to scintillation vials for liquids and counted. The quotient of the numerical values of 6-keto-PGF o / PGE is calculated for each concentration of the test compound used. The IC values of the inhibition are determined graphically. This value is the concentration of the test compound in which the quotient of 6-keto-PGF a / PGE is reduced to 50% of the control value.

The inhibition of synthesis and throblastan plasma membrane depletion is demonstrated in vivo by administration of the test compound to rats (analogous to those described by Tai et al., In Anual., Biochem., 87, 343, 1978

U W - 12 -

and Salmon in Prostaglandins _15_, 383, 1978) is determined as follows:

Rats are treated with the test substance or vehicle and 2 hours later they are injected with Ionophor A 23187 (0.5 mg / kg) intravenously. Two minutes after ionophore administration, the animals are bled for analysis. In a given single amount of each plasma sample, the thromboxane becomes B, and from further single amounts the 6-keto-PGFα, the stable metabolites of thromboxa are determined.

Thromboxane A or Prostacyclin (PGI) by radioimmunoassay

The compounds of formula I are very potent and selective thromboxane synthetase inhibitors. At effective dose levels and above, neither the beneficial prostacyclin synthetase nor the prostaglandin cyclooxygenase enzyme system is significantly inhibited ^. Surprisingly, prostacyclin levels become significant elevated.

The IC value for a compound of the invention, e.g. for the 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) -indole, 1.2 χ 10 moles for thromboxane synthetase inhibition, while for the inhibition of prostacyclin synthetase and prostacyclin cyclo-oxygenase of

-4 IC ,. Value each several potencies higher, namely about 1 × 10 mol

Furthermore, the IC value for thromboxane synthetase inhibition is 2 × 10 mol for 1- (5-carboxypentyl) -5- (2-carboxyethyl) -3-methyl-2-

-8 (3-pyridyl) indole and 5 x 10 moles for 1- (4-carboxybenzyl) -3-methyl

-9-2- (3-pyridyl) -indole, 1 x 10 moles for 1- (5-carboxypentyl) -5-chloro

_Q

3-methyl-2- (3-pyridyl) -indole and 1χ 10 moles for 1- (5-carbamoyl-pentyl) -5-chloro-3-methyl-2- (3-pyridyl) -indole, 2.6χ10 Mol for

449

as "

- 13 -

1- [2- (4-carboxyphenoxy) ethyl] -3-methyl-2- (3-pyridyl) -indole and 5.8x10 moles for 1- [2- (4-carboxyphenylthio) -ethyl] - 3-methyl-2- (3-pyridyl) indole-hydrochlorido

The 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) -indole. and 1- (5-carboxypentyl) -5-chloro-3-methyl-2- (3-pyridyl) -indole as representative compounds of the invention decrease the plasma level of thromboxane B in the rat at as low an oral dose as 0 , 10 mg / kg, by more than 50%. At this or higher oral doses, a surprising increase in plasma prostacyclin levels is noted.

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

The inhibition of the variously induced aggregation of platelets and thrombocytopenia by the compounds of the invention, e.g. By 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) -indole, shows the usefulness in thromboembolism. Experimentally, the prolongation of the bleeding time in the rat is regarded as an indication of the favorable antithrombotic effect. Thus, e.g. the 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) indole has this effect when administered orally to rats at a dose of about 30 mg / kg.

The beneficial effects of respiratory disorders are indicated by the fact that the compounds of the present invention provide protection against the sudden death that occurs due to the arachidonic acid-induced lung obstruction. So protects e.g. the 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) -indole the mouse against sudden death when administered orally at a dose of 100 mg / kg.

• V ^ ** J V * »<* β?

In addition to the above-mentioned therapeutically useful salts those pharmacological precursors of the novel carboxylic acids, for example, make their esters and amides, · _s which can be converted by solvolysis or under physiological conditions to the said carboxylic acids a further object of this invention.

Such esters are preferably e.g. the unsubstituted or suitably substituted lower alkyl esters, such as pivaloyloxymethyl, 2-diethylaminoethyl, bornyloxycarbonylmethyl, α-carboxyethyl or suitably esterified α-carboxyethyl esters, which can be prepared in a manner known per se.

The said amides are preferably, for example, simple primary or secondary amides and those derived from amino acids or their derivatives, e.g. derived from alanine or phenylalanine

The compounds of the present invention will be described hereinafter. knew methods, preferably produced by that one

1) a compound of formula V

 ? ·

where X is hydrogen, alkali metal or tri-lower alkylsilyl? R, R, R and Ar have the meaning given, with a

reactive functional derivative of a compound of formula VI

HO-CH-A-B (VI),

wherein A and B have the meaning given above, condensed, or

L · ü U Ό J Ό Ό - 15 -

2) a compound of formula VII

L --N - N = C - Ar (VII)

CH ₂ -A- B

wherein Ar, R, R, R, A and B are as defined above, ring-closing, or

3) a compound of formula VIII

/ \ / ^CH 2 ^R 1

• Υο , ,"" ID.

- Ar

CH-A-B

wherein Ar, R, R, R, A and B have the meaning indicated, cyclized, or

4) in a compound of the formula Ia

, Λ

Il Il (Ia)

^R 3 ₂

wherein A, Ar, R, R and R are as defined above, and C is a group other than a group B which can be converted to group B, which converts group C into B, optionally with extension of the chain A within its definition , or

Ό - 16 5) a compound of formula IX

^R 2V \ / ^C00H

• \ e ·

I Il II (IX)

wherein A, Ar, R, 'R and R are decarboxylated _5, and, if desired or necessary, an interfering reactive group temporarily protecting in any of these methods, and, if desired, a resulting compound of formula T. in the abovementioned meaning converts another compound of the invention. and / or _s, if desired, converting a resulting free compound into a salt or a salt obtained, into the free compound or into another salt, and / or, if desired, separating a resulting mixture of isomers or racemates into the individual isomers or racemates , and / or, if desired, ₉ racemate splits into the optical antipodes.

The condensation according to process 1) is preferably carried out under basic conditions, for example with a basic alkali metal salt or a quaternary ammonium salt, for example tetrabutylammonium hydroxide _s . For example, especially compounds of formula V wherein X is hydrogen, preferably in situ, are converted with a reactive metallizing agent into reactive organometallic intermediates. Is preferably carried out with about one molar equivalent of eg a strong alkali metal base such as lithium diisopropylamide, sodium hydride or potassium tert-butoxide, in an inert solvent, for example dimethylformamide or tetrahydrofuran, in a temperature range between -50 ° to +75 ⁰ C, preferably -25 ° and +50 ⁰ C.

The condensation of the 'resulting reactive organometallic compound of the formula V with a reactive fractional derivative of a compound of formula VI is preferably at a temperature in a temperature range between about -25 ° to + 50 ° C, - carried out between 0 ° and 30 ⁰ C. In addition, when B is carboxy, carbamoyl, hydroxycarbamoyl, or mono-lower alkyl-carbamoyl, one molar equivalent of the metalating agent is used "

For example, the starting materials of the formula "V" wherein X is hydrogen are either known (eg, USP 3,468,894, J. Chem. Socl 1955 , 2865, Bull. Soc. Chim., France, 1969 , 4154), or they are prepared analogously of corresponding ^ optionally substituted phenylhydrazines and ketones of the formula ArCOCH R in the presence of condensing agents, for example ethanolic hydrogen chloride or polyphosphoric acid according to the well-known indole synthesis according to Fischer.

The starting materials of the formula VI or of the formula VIa described below are known or, if new, they can be prepared according to known per se, e.g. in U.S. Patent 4,256,757 or British Patent Application 2,016,452A or as described herein in the Examples.

The compounds of the formula I are preferably prepared according to the method 1) thereby; that is a compound of formula V

-2 χ \ Λ

ι Μ π

• ·

Ar

wherein X is hydrogen, R is hydrogen or lower alkyl, Ar is optionally substituted by lower alkyl, carboxy, lower alkoxy

carbonyl or carbamoyl substituted pyridyl, each of the symbols R and R represents hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, carboxy-lower alkyl, lower alkoxy-ycarbonyl-lower alkyl, carboxy or lower alkoxycarbonyl, with a reactive functional derivative of a compound of formula VIa

HO - CH ₂ - A - B '(Via),

where A is alkylene of 1 to 12 carbon atoms _s alkenylene of 2 to 12 carbon atoms alkynylene of 2 to 12 carbon _s lower alkylene-phenylene-lower alkyl, lower alkylene-phenylene ₉ phenylene-lower alkylene, phenylene or a direct bond means _£ and B ^{g is} carboxy, lower alkoxycarbonyl, carbamoyl, Mono- or di-lower alkyl-carbamoyl, hydroxymethyl , etherified hydroxymethyl, · halomethyl, trialkoxymethyl or cyano, preferably condensed under basic conditions, and in a compound of formula Ib

^R 2 χ \ Λ ^R 3

χ / \ s \

(Ib)

wherein B 'differs from B, converts the radical B ¹ , optionally with extension of the chain A within its definition, into the group 3 and, if desired, converts a compound of the formula I obtained into another compound of the invention.

The conversion of the precursor in which B 'differs from B and the conversion of a product obtained into another compound of the invention are carried out according to chemical methods known per se.

The ring closure of the starting material of the formula VII according to process 2) is carried out according to the well-known indole synthesis according to Fischer [as in "Heterocyclic Compounds, Indoles Part I" edited by W.Jo Houlihan, pp. 232-317, described], thermally or preferably carried out in the presence of an acid condensing agent. Working in the presence of, preferably, hydrogen halides, eg ethanolic hydrogen chloride, or polyphosphoric acid, optionally in an inert solvent, at temperatures between about 50 and 100 ⁰ C.

The hydrazone starting materials of the formula VII are either isolated or 'preferably in situ by condensation of a ketone of the formula ArCOCH R, wherein Ar and R have the abovementioned meaning, with a substituted hydrazine of Formel.X

R ₂ ν _m ij Vm ₂ CH-A-B

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

The hydrazine starting materials of formula X are in turn preferably used e.g. by nitrosation of appropriately substituted adenines of the formula XI

(XI)

_. NHCH-AB R ₃ 2

wherein the symbols A, B, R and R have the meanings given above, and subsequent reduction of the N-nitroso derivatives, e.g. with zinc in acetic acid or by other methods known per se.

If said intermediates contain interfering reactive groups, eg hydroxyl or amino groups, such may preferably be temporarily protected at each stage by readily cleavable protecting groups, for example in the form of esters or amides, according to well-known methods _c

The cyclization according to process 3) is carried out under the conditions of the indole synthesis according to Madelung, as in "Heterocyclic Compounds, Indoles Part I", Ed. WoJ. Houlihan "pp" 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. about 300 ° or in an inert high boiling solvent, z, B. Tetrahydronaphthalene, performed.

The starting materials of the formula VIII are obtained by acylation of substituted anilines of the abovementioned formula XI with a compound of the formula ArCOOH or one of its reactive functional derivatives.

The decarboxylation according to process 5) is carried out by methods known per se, for example by heating in a high-boiling solvent or in the presence of a strong acid, for example a mineral acid such as hydrochloric acid _}

The 3-carboxy-substituted indoles used as starting materials are prepared by methods known per se. Thus, e.g.

 JIII,

/ / /, QkQ η _ O ₁ _

£ 1 Ü JKJ JW ^Zi

Compounds of the formula IX in which the substituent in the 3-position is carboxy and one of the radicals R and R is 5-hydroxy, according to the Nenitzescu synthesis, as described in "Heterocyclic Compounds, Indoles Part I," p. 413 described. Condensed e.g. p-Benzoquinone with a β-pyridyl-β- (CH -A-B-substituted amino) - acrylic acid lower alkyl ester, e.g. β- (3-pyridyl) -β- (5-ethoxycarbonylpentylamino) -acrylic acid lower alkyl ester, and hydrolyzes the resulting lower alkyl ester of the corresponding substituted 5-hydroxy-2- (3-pyridyl) -indole-3-carboxylic acid (a compound of the formula I) where R is lower alkoxycarbonyl).

The conversion of a compound of formula Ia according to process 4) in which C is different from B into a compound of formula I, and the optional conversion of a product of formula I obtained to another compound of this invention, are prepared according to chemical means known per se Methods and / or as described here.

Convertible groups C are preferably trialkoxymethyl, esterified hydroxymethyl, etherified hydroxymethyl, halomethyl, cyano, 2-oxazolinyl, dihydro-2-oxazolinyl, lower alkanoyloxymethyl, acetyl, methyl, carboxycarbonyl, trihaloacetyl, di-lower alkoxymethyl. Alkylenedioxymethyl, vinyl, alkynyl, esterified carboxy and amidated carboxy.

The starting materials of the formula Ia are prepared according to processes 1) to 3) or as described herein, using chemical methods known per se.

The individual definitions in the previously described methods have the following meanings:

9 by b ~ ²² -

In a reactive functional derivative of an alcohol of formula VI or VIa, the hydroxy group is z, B. esterified with a strong inorganic or organic acid, especially with a hydrohalic acid, for example hydrochloric, hydrobromic or hydriodic acid, an aliphatic or aromatic Sulfonsäu.re _s eg methanesulfonic or p-toluenesulfonic acid = These compounds are prepared in a conventional manner.

Trialkoxymethyl is preferably tri (lower alkoxy) methyl, in particular triethoxy- or trimethoxy-methyl "

Etherified hydroxymethyl preferably denotes tertiary lower alkoxymethyl, lower alkoxyalkoxymethyl, eg methoxymethoxymethyl, 2-oxa- or 2-thiacycloalkoxymethyl, in particular 2-tetrahydropyranyloxymethyl _e

Esterified hydroxymethyl represents preferably lower alkanoyloxymethyl, advantageously halomethyl, in particular bromomethyl, chloromethyl ₅ but also or iodomethyl.

An alkali metal is preferably lithium _s but it can also be potassium or sodium.

Intermediates of the formulas Ia or Ib in which C or B ^{5 is} halomethyl can preferably be reacted with an alkali metal cyanide, for example potassium cyanide, in a manner known per se. Compounds of the formulas Ia or Ib are obtained in which the chain is extended by one carbon atom: and C or B 'is cyano. These in turn can be converted according to methods known per se into compounds of the formula I in which B is carboxy, alkoxycarbonyl or carbamoyl.

/ / H ^r ^ Q

UHJ <J w

9 6

- 23 -

Thus, compounds of formula Ia or Ib in which C or B ^{1 is} cyano (nitriles) in the compounds of formula I, wherein B is carboxy, by hydrolysis with inorganic acids, for example with hydrohalic acids such as hydrochloric acid or sulfuric acid in aqueous solution, or preferably by hydrolysis with aqueous alkali metal hydroxides, eg potassium hydroxide at reflux temperature.

The conversion of said nitriles to compounds of the formula 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. Hydrochloric acid, preferably at reflux; and 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 in which C or B 'is halomethyl, e.g. In the compounds of formula I wherein B is carboxy and the chain is extended by 2 carbon atoms, chloromethyl may first be prepared by treatment e.g. with a di-lower alkyl malonate, e.g. Diethyl malonate, in the presence of a base, e.g. Potassium carbonate or sodium ethoxide, in a solvent such as dimethylformamide, preferably at a temperature between 50 and 100 °, into substituted di-lower alkyl malonates. These are then washed with an aqueous base, e.g. hydrolyzed dilute sodium hydroxide solution to the corresponding malonic acid, which under standard conditions. e.g. by heating in xylene solution, to give the compound of formula I wherein B is carboxy,

8 - ²⁴ -

is decarboxylated. If the malonic acid di-lower alkyl ester is replaced by a cyanoacetic acid lower alkyl ester, the corresponding compounds of the formula Ia or Ib ₅ in which C or B 'is cyano are obtained.

Compounds of the invention in which A represents a straight-chain or branched alkenylene radical having a terminal double bond can also be prepared from the intermediates of the formula Ia or Ib in which C or B 'is halomethyl. Thus, for example, these intermediates can first be treated with a lower alkyl ester of an a- (aryl or alkyl) thioacetic acid, for example a- (phenylthio) -acetic acid ethyl ester, in the presence of a strong base, for example sodium hydride. Subsequent oxidation of the resulting a-arylthio or α-alkylthio substituted ester to the α-arylsulfinyl or α-alkylsulfinyl ester with, for example, sodium periodate and then heat elimination, eg, by heating in xylene affords a compound of general formula I ( an α , β-unsaturated ester) wherein A is alkenylene and B is, for example, lower alkoxycarbonyl. The chain is simultaneously extended by two carbon atoms. The same conversion is also carried out using eg cr (phenylseleno) acetic acid ethyl ester as described in J. Am. Chem. Soc. _95_, 6137 (1973). Also, the compounds of formula Ia, wherein C is halomethyl, first in the corresponding carboxaldehydes, for example with dimethyl sulfoxide in the presence of triethylamine and silver tetrafluoroborate, or with chromium trioxide and pyridine in methylene chloride, are converted. The 'subsequent Wittig condensation, for example with trimethylphosphonoacetate or (triphenylphosphoranylidene) -acetic acid ethyl ester gives the abovementioned α , β-unsaturated esters.

Compounds of formula I wherein B is lower alkoxycarbonyl can be treated with ammonia, mono- or di-lower alkylamines, e.g. Methylamine or dimethylamine, in an inert solvent, e.g. Low-

alkanol such as butanol, optionally at elevated temperatures, to compounds of the formula I in which B is unsubstituted carbamoyl, mono- or di-lower alkyl-carbamoyl.

Compounds of the formula I in which A is a straight-chain or branched alkenylene radical having a terminal double bond, for example α, β-unsaturated esters may also be prepared from the corresponding β, β-saturated esters by treatment with, for example, phenylselenyl chloride in the presence of a strong base _s according to in Am. Chem., Soc. 95 . 6137 (1973).

The conversion of compounds of formula I or Ib, wherein B or, B ¹ lower alkoxycarbonyl, cyano, unsubstituted, mono- or di-lower alkylcarbamoyl is, in the compounds of formula I wherein B is carboxy is _5, is preferably by hydrolysis with ·. inorganic acids, eg with hydrohalic acids or sulfuric acid, or with aqueous alkalis, preferably with alkali metal hydroxides, for example lithium or sodium hydroxide.

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

The aforementioned alcohols, in turn, can be converted into compounds of formula I, wherein B is carboxy, with conventional oxidizing agents, preferably with pyridine dichromate in dimethylformamide at room temperature.

/? ^ Hi ι 1 s% - 26 -

Free carboxylic acids can be treated with lower alkanols, e.g. Ethanol in the presence of a strong acid, e.g. Sulfuric acid, preferably at elevated temperatures, or with diazo-lower alkanes, e.g. Diazomethane in a solvent, e.g. Aethyläther, preferably at room temperature, to the corresponding esters, namely to such compounds of formula I, wherein B is lower alkoxycarbonyl, esterified.

Further, the free carboxylic acids can be obtained by treating their reactive intermediates, e.g. an acrylic halide such as an acid chloride, or mixed anhydride, e.g. one derived from a lower alkyl halocarbonate, e.g. Ethyl chloroformate, with ammonia, mono- or di-lower alkylamines, in an inert solvent, e.g. Methylene chloride, preferably in the presence of a basic catalyst, e.g. Pyridine into the compounds of formula I in which B is unsubstituted carbamoyl, mono- or di- (lower alkyl) -carbamoyl.

Compounds of formula I in which B is mono-lower alkyl-carbamoyl can be converted into the compounds of formula I in which B is di-lower-alkyl-carbamoyl by treatment with a strong base, e.g. Sodium hydride and then with an alkylating agent, e.g. a lower alkyl halide, in an inert solvent, e.g. Dimethylformamide, "to be transferred"

Further, compounds of the formula I in which A represents a straight-chain or branched alkynylene or alkenylene radical can be obtained by catalytic hydrogenation, preferably under neutral conditions, e.g. with a palladium catalyst at atmospheric

€ 1

Pressure, in an inert solvent, e.g. Ethanol, in the compound, fertilize the formula I, wherein A is straight-chain or branched alkylene, are converted.

3 5

The carboxy aldehydes, namely the compounds of formula I in which B is formyl may be prepared by oxidation of compounds of formula Ia in which C represents hydroxymethyl or halomethyl, e.g. Dimethyl sulfoxide and a catalyst, e.g. a mixture of triethylamine and silver tetrafluoroborate, or with chromium trioxide and pyridine, or with other suitable oxidizing agents known per se. The said carboxaldehydes may be converted into the corresponding acetals, i. Compounds of formula Ia, wherein C is di (lower alkoxy) methyl or alkylenedioxymethyl, e.g., dimethyl acetal by acid, catalysed condensation with an alcohol, e.g. Methanol, to be converted.

Compounds of formula I in which B is carboxy may be converted by the well-known Arndt-Eistert synthesis to compounds of formula I wherein B is carboxy and the chain contains one more carbon atom ₉ . In particular, a reactive functional derivative of the carboxylic acid used as the starting material, for example the acid chloride with diazomethane, for example, treated in diethyl ether to give a compound of formula Ia, wherein C diazoacetyl means j «conversion with eg silver oxide gives said carboxylic acid of formula I. in which: the chain A contains one more carbon atom.

A particular embodiment of process 4) relates to the preparation of compounds of the formula I in which B is carboxy. It consists of, in a compound of the formula Ia ₅ in which C is a radical which can be converted into a carboxy group, the group C, where appropriate under extension of the chain A within its definition, converted into the carboxy group.

Carboxy group-transferable groups are e.g. esterified carboxy groups, anhydrated carboxy groups, including corresponding ones

-fins * ' * - ^{: ί} ii ί · Α ä 28 -

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, e.g. lower alkyl substituted 2-oxazolinyl or dihydro-2-oxazolinyl groups, furthermore methyl, hydroxymethyl, etherified hydroxymethyl, lower alkanoyloxymethyl, trialkoxymethyl, acetyl, trihaloacetyl, halomethyl, carboxycarbonyl (COCOOH), formyl (CHO), di-lower alkoxymethyl, alkylenedioxymethyl, vinyl, Aethynyl, or Diazoacetyl. At the same time, when converted to the carboxy group, the chain A can be extended within its definition.

Esterified Caryboxy groups are preferably in the form of their lower alkyl esters _9, for example methyl-, ethyl- _S n-. or iso- (propyl or butyl) ester. Further in the form of substituted lower alkyl esters, eg wu-amino, uj-mono- or dimethylamino, α-carboxy or α-carbethoxy- (ethyl, propyl or butyl) ester. Other esters are aryl lower alkyl esters, eg benzyl -, (methyl, methoxy, chloro) -substituted benzyl and pyridylmethyl ester; Lower alkanoyloxy-lower alkyl esters, for example pivaloyloxymethyl esters; 3-phthalidyl and methyl, methoxy or chlorine substituted 3-phthalidyl esters derived from corresponding 3-hydroxyphthalic acid esters, (hydroxy, lower alkanoyloxy, lower alkoxy) -substituted lower alkoxymethyl esters, eg, β- (hydroxy, acetyloxy, methoxy) - ethoxymethyl ester; Bicycloalkoxycarbonyl lower alkyl esters, for example those derived from bicyclic monoterpenoid alcohols, for example unsubstituted or lower alkyl substituted bicyclo [2 _s 2, l] heptyloxycarbonyl lower alkyl esters, preferably bornyloxycarbonylmethyl esters; Halogen substituted lower alkyl esters, eg Trichloräthyl- or Jodäthylester.

Amidated Caryboxy groups are preferably Caryboxy groups in the form of their unsubstituted amides; N-mono or di-lower alkylamides, e.g. Mono or di-methylamides; tertiary amides, which are e.g. of pyrrolidine,

α A4 J JJ 0 ²⁹

Piperidine or morpholine are derived; by α-carbonyl lower alkoxy or carboxy-substituted lower alkylamides, for example mono-N- (carboethoxymethyl) amides, and mono-N-carboxymethyl) amides; a-Carboniederalkoxy or carboxy-substituted aryl lower alkyl amides, for example "(carboethoxy or carboxy) substituted Phenyläthylamide; Amino-lower alkylamides ₅ eg β-aminoethylamides and β- (carbobenzyloxyamino) ethylamides «

The conversion into the carboxy group is carried out by methods known per se, as described here or in the examples, for example by solvolysis, such as hydrolytic or acidolytic, or reductive (esterified carboxy groups). For example, trichloroethyl or. 2-Jätäthylester converted by reduction, for example with zinc and a carboxylic acid in the presence of water in the carboxylic acid. Benzyl esters or nitrobenzyl esters can be converted into the carboxy group by catalytic hydrogenation , the latter also with chemical reducing agents, for example sodium dithionite or with zinc and a carboxylic acid. Furthermore, for example, tert-butyl esters can also be cleaved, for example, with trifluoroacetic acid.

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

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

Starting materials of the formula Ia ₃ in which C is acetyl, starting from compounds Ia, wherein C is halomethyl, by

4 9 5

Treatment with a lower acetoacetate, e.g. Ethyl acetoacetate, in the presence of a base, e.g. Sodium hydride and subsequent hydrolysis with a strong base, e.g. with aqueous sodium hydroxide.

The compounds mentioned can also be prepared by condensation of a compound of the formula Ia ₅ in which C is cyano, with, for example, a Grignard or another organometallic reagent, for example methylmagnesium bromide under standard conditions.

Starting materials of the formula Ia in which C represents carboxycarbonyl (COCOOH) are converted by thermal treatment or by oxidation into the compounds of the formula I in which B is carboxy. The starting material is thereby heated to an elevated temperature, e.g. about 200 °, heated in the presence of glass powder, or e.g. with hydrogen peroxide in the presence of a basic agent, e.g. Sodium hydroxide, treated.

The starting materials of the formula Ia in which C represents COCOOH may be e.g. by condensation of a compound of formula Ia wherein C is halomethyl, with e.g. 2-ethoxycarbonyl-1,3-dithiane, and subsequent oxidative hydrolysis, e.g. with N-bromosuccinimide in aqueous acetone and then by treatment with dilute aqueous sodium hydroxide.

Compounds of formula Ia wherein C is formyl, di-lower alkoxy-methyl or alkylenedioxymethyl (formyl protected in the form of an acetal), e.g. Dirnethylacetal means are e.g. with silver nitrate, pyridinium dichromate or ozone to the compounds of formula I wherein B is carboxy oxidized.

Ι Π Γ Π f> - 31 -

A H h H η

Compounds of the formula Ia in which C is vinyl are first converted into the compounds of the formula I in which B is carboxy by ozonolysis into the compounds of the formula I in which B is formyl. These are then added to the compounds of the formula I where B is carboxy, oxidized

Starting materials of the formula Ia in which C is vinyl can also be treated under pressure with nickelcarbonyl and carbon monoxide, compounds of the formula I in which B denotes carboxy and the chain A in addition to the carboxy group contains one double bond

Compounds of the formula Ia in which C is ethynyl can be treated with a strong base, for example butyllithium; then with carbon dioxide or a haloformic acid lower alkyl ester _s z..B. Ethyl chloroformate is condensed and subsequently hydrolyzed. Compounds of the formula I are obtained in which B is carboxy and the chain A in adjacent position to the carboxy group contains a triple bond.

Compounds of the formula Ia in which C is halomethyl can be converted into the corresponding organometallic intermediates, e.g. Copper or magnesium derivatives are converted by methods known per se.

Condensation, e.g. an obtained organic magnesium (Grignard) reagent, e.g. with a compound of formula Ia wherein C is e.g. converted into CH MgCl with carbon dioxide; gives a compound of formula I wherein B is carboxy and the chain is extended by one carbon atom.

Condensation of said Grignard reagent with e.g. a haloacetic acid lower alkyl ester, e.g. Ethyl bromoacetate and subsequent hydrolysis gives a compound of formula I wherein B is carboxy and the chain is extended by 2 carbon atoms.

/ G Γ> Q R - 32 »

Said Grignard reagent may be in the presence of a cuprous halide such as cuprous chloride, with an a, ß-unsaturated acid, or an ester ,, for example with propiolic acid or acrylic acid, are condensed., Wherein a compound of the Formula I wherein B is carboxy and the chain is extended by 3 carbon atoms.

Further, compounds of formula Ia wherein C is halomethyl may be substituted with e.g. the 3-lithio derivative of propiolic acid (prepared in situ, e.g., with lithium diisopropylamide) to give a compound of formula I in which A is a terminal alkynylene. B stands for carboxy and the chain length around 3 carbon: -. atoms is prolonged.

Compounds of formula I wherein A is lower alkylene or a direct bond and B is hydroxymethyl as a reactive functional derivative can be substituted with a lower alkanol (or thiol), or a phenol (or thiophenol) (suitably substituted by B) are), preferably in the presence of a strong base, are condensed. Compounds of formula 1 are obtained in which A is lower alkylene (thio or oxy) phenylene, phenylene (thio or oxy) lower alkylene or lower alkylene (thio or oxy) lower alkylene.

The abovementioned reactions are carried out by methods known per se, in the presence or absence of diluents, preferably in those which are inert towards and dissolve the reagents, catalysts, condensation agents or other agents mentioned above, and / or in an inert atmosphere, under cooling, at Zeller temperature or at elevated temperatures, preferably at the boiling point of the solvent used, at normal or elevated bridge performed. The preferred solvents, catalysts and reaction conditions are disclosed in the accompanying examples.

U Vn U ψ% - 33 -

The invention also relates to modifications of the present process, according to which an intermediate obtained at any stage of the process is used as starting material and the remaining process steps are carried out, or the process is stopped at any stage, or after which a starting material is formed under the reaction conditions, or wherein a starting material is used in the form of a salt or optically pure antipodes logo CNRS logo INIST

In the method of the present invention those starting materials are advantageously .Used which _t lead to the in the above as being especially valuable compounds described

The invention also relates to the novel starting materials and processes for their preparation.

Depending on the choice of starting materials and processes, the novel compounds may be in the form of one of the possible isomers or mixtures of such. So they can e.g. depending on the presence of a double bond and on the number of asymmetric carbon atoms, as pure optical isomers, e.g. as antipodes, or as mixtures of optical isomers, e.g. as racemates, mixtures of diastereomers, mixtures of racemates or mixtures of geometric isomers. The aforesaid possible isomers and their mixtures are within the scope of this invention. Some specific isomers may be preferred.

Resulting mixtures of diastereomers, mixtures of racemates or geometric isomers can be based on the physicochemical differences of the components, in a conventional manner, in the pure isomers, diastereomers, racemates or geometric isomers,

a o

e.g. by chromatography and / or fractional crystallization.

Obtained racemates can be further separated into the optical antipodes in a conventional manner, for example by reacting the acidic end product with an optically active base which forms salts with the racemic acid. These salts can be separated into the diastereomeric salts, for example by fractional crystallization. From the latter, the optically active acid antipodes can be released by acidification. Basic racemic products can be separated in an analogous manner, such as by separating their diastereomeric salts with an optically active acid and liberating the optically active base with a base. Racemic products of the invention can thus into their optical antipodes, eg, by fractional crystallization of d- or t ~ (tartrates, mandelates, camphorsulphonate, or el · * - or £ -. (A-methylbenzylamine, cinchonidine _s cinchonine, quinine, Quinidine, ephedrine, dehydroabietylamine, brucine, or strylyne) salts. Preferably, the two more antipodes isolate the more potent,

Finally, the compounds of the invention in free form or as Säl ^! ze be obtained. A free base obtained may be converted into the corresponding acid addition salt, preferably with acids which yield therapeutically acceptable acid addition salts or with anion exchangers. Preserved salts can be converted to the corresponding free bases, eg, by treatment with a stronger base, such as with a metal hydroxide or ammonium hydroxide, or a basic salt, eg, an alkali metal hydroxide or carbonate, or a cation exchanger. A compound of formula I wherein B is carboxy may also be converted to the corresponding metal or ammonium salts. These or other salts, eg the picrates, can also be used in the purification of the resulting free bases. The bases are in

4 4 ^ 3 ^ ο - ³⁵ -

their salts are transferred, the salts separated and the bases released from the salts.

As a result of the close relationship between the novel compounds in free form and in the form of their salts, the corresponding salts or free compounds are to be understood as meaningful and appropriate in the preceding and following under free compounds and salts.

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

The pharmaceutical preparations according to the invention are those which are suitable for enteral, e.g. oral or rectal and parenteral administration to mammals, including humans, The preparations are used for the treatment or prevention of thromboxane synthetase inhibiting disorders which contain an effective dose of a pharmacologically active A compound of the formula I, or a pharmaceutically

salt thereof, alone or in combination with one or more pharmaceutically acceptable excipients. "

The pharmacologically useful compounds of the present invention can be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with excipients suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules containing the active ingredient 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

/, Cj K Q H -36- 21.3.1983

^{H w} AP C 07 D / 244 959/6

(61 632/18)

Calcium stearate, and / or polyethylene glycol; Tablets also contain binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose 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, Flavorants and Sweeteners * Injectable preparations are preferably isotonic aqueous solutions or suspensions, and suppositories primarily fat emulsions or suspensions. The pharmacological preparations may be sterilized and / or contain excipients, for example preservatives, stabilizers, bulking agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, contain other pharmacologically valuable substances, are prepared in a manner known per se, for example by means of conventional mixing, granulation or coating methods, and contain from about 0.1 % to about 75%. in particular, from about 1 % to about 50% of the active ingredient, unit doses for nipples weighing about 50 to 70 kg may contain between about 10 to 100 mg of the active ingredient.

embodiment

The following examples are illustrative of the invention and should not be construed as limiting its scope. Temperatures are given in degrees Celsius, and the data on parts relate to parts by weight, vYenn'nicht otherwise _s is defined the läindampfen of solvents under reduced pressure, z. B ₉ between about 15 and 100 mg / Hg performed.

Q ^ Q £ -37- 21.3.1983

3 J- <JV AP C 07 D / 244 .959 / 6

(61 632/18)

Example 1: In a glass kettle of 76 liters, 1640 ml of dimethylformamide and 430 g of potassium tert-butoxide are charged. The solution is stirred under nitrogen and cooled to -8 ⁰ G ", a solution of 682 g of 3-methyl-2- (3-pyridyl) -indole It is within 0.75 hour in 3280 ml of dimethylformamide thereto," If the Temperature below 0 ⁰ C. The mixture is stirred for 2 hours at -10 ° 0 and within

1 hour 164Ο ml of a solution of 780 g of 8-bromoctanoic acid methyl ester in dimethylformamide thereto., The reaction temperature is kept below 0 ⁰ G. The reaction mixture is stirred

2 hours and allow it to warm to room temperature over a laugh. The rust colored mixture is then cooled to about 5 ⁰ G and treated with 19700 mL swasser%. The temperature rose to 25 ⁰ C. The mixture is stirred for 0.5 hours and .with 2 χ 8000 ml ether extracted. The extracts are dried over magnesium sulfate and in vacuo; evaporated. 1- (7-Methoxycarbonylheptyl) -3-methyl-2- (3-py2'-dide) -indole is obtained as an oil, 1293 g of this oil are treated with 653O and 1 normal sodium hydroxide solution and the mixture is heated on a steam bath 2.5 hours 90 ⁰ G »the solution is cooled to room temperature and washed with 3 χ 3000 ml of ether. the aqueous layer is cooled to 10 ⁰ G and adjusted to pH 3.5 with 340 ml of 2N Ghlorwasserstoffsäure . the heavy suspension obtained is 4 χ 4000 ml of methylene chloride. the combined extracts are washed once with 4OOO ml of water and dried over magnesium sulfate is filtered., the solvent is evaporated at 60 ⁰ G., the residue triturated with 2000 ml of ether and dried The product gives 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) -indole F, 11-3-115 g. After crystallization from methanol, the melting point rises to 114-116 ⁰ G .

v> a

5Q δ -37- 21.3.1983

• ^ O AP G 07 D / 244 959/6

(61 632/18)

The 3-methyl-2 ~ (3-pyridyl) indole starting material is prepared essentially in accordance with U.S. Patent 3,468,894.

The 8-.beta.octanoic acid ethyl ether is prepared from azelaic acid essentially according to US Pat. No. 3,852,419 or by direct esterification of

u κ υ f \

J J J ^ Tt?

8-bromooctanoic acid prepared as follows:

A mixture of methanol (4700 ml), 8-bromooctanoic acid (912 g) and sulfuric acid (912 ml) is refluxed in a suitable reaction vessel for 5 hours and stirred at room temperature overnight. The solvent is evaporated under reduced pressure (3 mm Hg) and the oily residue is dissolved in ether (4000 ml). The solution is washed with water (3 × 2000 ml), saturated aqueous sodium bicarbonate solution (1000 ml) and saturated aqueous sodium chloride solution. The ether layer is dried over magnesium sulfate and filtered. After evaporation of the solvent and distillation of the crude oil, the 8-bromooctanoic acid

23 methyl ester boiling at 73-76 ° / O, O5 mmHg, n = 1.4614.

Example 2: To a suspension which is obtained by dilution of 4.8 g of a 50% sodium hydride suspension in mineral oil with 40 ml of dimethylformamide is added dropwise, under nitrogen, a solution of 13.5 g of 3-methyl-2 - (3-pyridyl) -indole in 80 ml of dimethylformamide. After completion of the addition, the green-yellow mixture is stirred at room temperature for about 1 hour. The reaction mixture is added dropwise, with cooling to 0-5 °, with ethyl bromoacetate (11.2 ml, 0.10 mol) and stirred for 4 hours at room temperature.

The reaction mixture is poured into 1000 ml of ice-water and extracted with 3 × 300 ml of ether. The ethereal layer is extracted with 3 × 300 ml of 1N hydrochloric acid. The acidic extract is adjusted to pH 9-10 with concentrated ammonium hydroxide and extracted with 3 × 250 ml of ether. The combined ether extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. The 1-ethoxycarbonylmethyl-3-methyl-2- (3-pyridyl) -indole is obtained as an OeI.

7 AA Qh QK "39- 21.3.1983

AP G 07 D / 244 95S / 6 (61 632/18)

The oil previously mentioned, in 500 ml of 1 N hydrochloric acid for 4 hours under reflux cooked "After standing overnight a gelbea solid material is separated, and 12 hours at 60 to 80 ⁰ G / 30 mmHg dried, laughing recrystallization from ethanol there is obtained the 1-carboxymethyl-3-methyl-2- (3-pyridyl) -indole-hydrochloride P, 204-207 °.

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

Examples 3 to 6; Analogously to the processes of Examples 1 and 2, the compounds of the formula II in which R ₁ = CH-, R ₂ and R '= H and R ₄ = OH, are prepared:

example Ester Ausgangsatoff m ^H 2m ^P ? ^r * Recrystallized from 3 Br (CH ₀ ) _c COOE t * (CHg) ₅ 3-pyridyl 113-4 acetonitrile 4 Br (CH ₀ ) 2 COOMe d O (CH ₂ ) ₆ 3-pyridyl 106-7 .Acetonitril 5 Br (GH ₂ ) ₄ GOOMe (GH ₂ ) ₄ 3-pyridyl 123-5 ethanol 6 Br (GH ₂ ) _GOOEt (GH ₂ ) ₅ 4-pyridine

dyl 186-8 acetonitrile

O f * -39a- 21.3.1983

J \ J AP G 07 D / 244 959/6

(61 632/18)

The 2- (3- and 4-pyridyl) -indoles used as starting materials are prepared according to US Pat. No. 3,468,894.

The ethyl or bromo esters used as starting materials are commercially available or are prepared from commercially available α-bromo acids, as illustrated below for the 6-bromohexane-acid methyl ester; A solution of 6-bromo-hexanoic acid (10 g) in 50 ml of methanol is added to 1.0 ml of concentrated sulfuric acid and refluxed for 8 hours. The methanol is evaporated and the residue dissolved in ether. The ether solution is freed from the acid by washing with water, dried over sodium sulfate and evaporated to dryness. The distillation at 0.8 mmHg gives the

244959 6 - «-. .

6-bromo-hexanoic acid methyl ester, boiling at 85-9O ° / o, 8-iranHg.

The 1- (7-carboxyheptyl) -3-methyl-2- (2-pyridyl) -indole is prepared analogously to Example 1. The starting 3-methyl-2- (2-pyridyl) -indole is described in J. Chem. Soc. 1955, 2865 described. ,

The corresponding compounds of the formula II in which R '= hydrogen, Pyr = 2-, 3- or 4-pyridyl and R' = fluorine, hydrogen or methyl, and R '= hydrogen, are prepared in an analogous manner using the methods described in prepared according to Examples 1 and 2. The starting materials used are the required u) -bromo-esters and the below-mentioned known 2- (pyridyl) -indoles: The 2- (2-, 3- and 4-pyridyl) -indoles are described in Pharm. Bull. Japan 4, 16 (1956) and the 5- (fluoro and methyl) -2- (3-pyridyl) -indoles in Bull. Soc. Chim. France 1969 , 4154 describe.

Examples 7 and 8: The following compounds of formula II wherein

R '= CH-, R' = hydrogen, Pyr = 3-pyridyl, CH, = (CHj ₁ and R. = OH 1 ό 3 m Ιτα Zd 4

are prepared analogously to the methods described in the preceding examples.

Example R 'F ° salt

7 5-Cl 143-145

8 5-OCH, 175-178 HCl

The compound of Example 7 is prepared as follows: To a suspension, which is obtained by dilution of 1.39 g of a 50% sodium hydride suspension in mineral oil with 30 ml of dimethylformamide ,, is added with stirring in a nitrogen atmosphere at 0-5 °, a solution of 6.59 g of 5-chloro-3-methyl-2- (3-pyridyl) -indole (prepared according to the US Patent 3,468,894) in 60 ml of dimethylformamide. After completion of the addition, the suspension is stirred for 1/2 hour at 0 ° and then with cooling to 0 ° with a solution of 6; 06 g of methyl 6-bromo-hexanoate in 10 ml

- 41 -

Dimethylformamid added dropwise. The reaction mixture is allowed to warm to room temperature, stirred for 5 hours at room temperature and poured into 400 ml of ice water. The resulting mixture is extracted with ethyl acetate (3 × 300 ml). The extract 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 OeI.

A solution of 3.2 g of the latter compound in 30 ml of 3N sodium hydroxide solution is refluxed for 17 hours. After cooling, the product obtained is filtered off and dissolved in 50 ml of water. After acidification to pH 4-5 _s with 2N hydrochloric acid, the product precipitates. It is purified by suspending in ether. The 1- (5-carboxypentyl) ~ 5-chloro-3-methyl-2- (3-pyridyl) -indole, F, 143-145 is obtained

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

The 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-methoxy 3-Methyl-2- (3-pyridyl) -indole in 85 ml of 48% hydrobromic acid is refluxed for 30 minutes. The reaction mixture is evaporated to dryness, diluted with water and the pH is adjusted to 6 with dilute sodium hydroxide solution , The precipitate is separated and recrystallized from acetone / ethyl acetate. 1- (5-carboxypentyl) -5-hydroxy-3-methyl-2- (3-pyridyl) -indole is obtained.

/ ⁰ I ^ ^Q R 42 U JU <J> U - 42 -

Examples 9 and 10: The following examples of the formula III wherein

CH "is the radical CH -CH ₀ and Pyr is 3-pyridyl, ρ 2p 2 2

prepared essentially according to the method of Example 2. Condensation of ethyl 3-methyl-2- (3-pyridyl) indole-5-propionate with ethyl 6-bromohexanoate or, with methyl 8-bromooctanoate gives the esters of Examples 9a and 10a. Hydrolysis with hydrochloric acid gives the corresponding diacids of Examples 9 and 10.

example ^C n ^H 2n ° F ^R 5 ^R 6 Recrystallized from ^r 9a 9 (CHJ ₅ (CHJ ₅ OeI 143-145 • OC ₂ H ₅ : OH ' OC ₂ H ₅ OH acetonitrile 10a (CHJ ₇ Oei OCH ₃ OC ₂ H ₅ - 10 (CHJ ₇ 128-130 OH OH acetonitrile

The 1-carboxyheptyl-3-methyl-2- (4-pyridyl) -indole-5-propionic acid is prepared in an analogous manner.

The indoles used as starting materials are prepared as follows: A suspension of p-hydrazinohydrocinnamic 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 room temperature, with stirring, with 10 ml of saturated ethanolic hydrogen chloride solution. A solution is obtained in about 5 minutes, 3-propionylpyridine (3.37 g, 0.025 mol) is added to the red-orange solution, the reaction mixture heated to reflux and refluxed for 18 hours. The resulting solution is cooled in an ice-water bath, and the obtained crystals of 3-methyl-2- (3-pyridyl) -indol-5-propionic acid ethyl ester hydrochloride are separated. F. 249-251 °. The free base, namely the 3-methyl-2- (3-pyridyl) indole-5-propionic acid ethyl ester, is prepared by slurrying the hydrochloride salt in water, basifying with 3N sodium hydroxide solution and extracting with ether.

-3 YY Q - 43 -

ΐί.-

In an analogous manner, the 3-methyl-2- (4-pyridyl) -indol-5-propionate ethyl ester hydrochloride, F »greater than 275 ° and the corresponding * free base prepared,

Is heated for 2 hours, a suspension of 7 _; 5 g of 3-methyl-2- (3-pyridyD-indole-S-propionic acid ethyl ester hydrochloride in 450 ml of 2N hydrochloric acid under reflux, it is cooled and separates the resulting solid material to give the 3-methyl --2- (3-pyridyl) indole-5-propionic acid hydrochloride, which melts at 290 °.

Similar hydrolysis of the ethyl 3-methyl-2- (4-pyridyl) -iridol-5-propionate hydrochloride gives the 3-methyl-2- (4-pyridyl) -indole-5-propionic acid hydrochloride which is over 305 ° melts , - ¹

Example 11:

a) A solution of 1- (4-cyanobenzyl) -3-methyl-2- (3-pyridyl) -indole (5.8 g) in 100 ml of a 1: 1 mixture of 20% aqueous hydrochloric acid and glacial acetic acid is refluxed for 20 hours. After cooling, the solution is poured into ice-water (100 ml) and the pH is adjusted to 4.5-5 with saturated aqueous sodium bicarbonate solution. The resulting precipitate is extracted with ethyl acetate, the extract washed with water and evaporated to dryness. The 1- (4-carboxybenzyl) -3-methyl-2- (3-pyridyl) -indolo F. 273-275 ° is obtained.

The nitrile used as starting material is prepared as follows; A suspension of 2.9 g (0.06 mol) of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide is added under nitrogen at 0-5 °, within 20 minutes, with a solution of 10.4 g (0.05 mol ) 3-Methyl-2- (3-pyridyl) -indole in 60 ml of dimethylformamide added dropwise. The reaction mixture is stirred for half an hour at 0-5 °, and then added dropwise with 9.8 g (0.05 mol) of p-cyanobenzyl bromide in 50 ml of dimethylformamide. The mixture is kept at 0-10 ° for 1 hour,

α ό jj υ - 44 -

then stirred at room temperature for 30 minutes and poured into ice-water (600 ml). The resulting solid material is collected, dried, washed with petroleum ether and redissolved in ether (500 ml). The ether solution is washed first with water, then with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, treated with charcoal and filtered. "Evaporation of the ether solution to dryness gives a yellow solid material, this product is slurried in hot cyclohexane and filtered off 1- (4-cyanobenzyl) -3-methyl-2- (3-pyridyl) indole, m.p. 127-129 °.

b) Analogously, the 1- (4-carboxybenzyl) -5-chloro-3-methyl-2- (3-pyridyl) -indole hydrochloride is obtained. F. 217-220 °. ".

Example 12:

a) A suspension of 0.49 g of lithium aluminum hydride in 50 ml of anhydrous tetrahydrofuran is dissolved in a nitrogen atmosphere at room temperature with a solution of 3.92 g of 1- (5-methoxycarbonylpentyl) -5-chloro-3-methyl-2- (3 After completion of the addition, the suspension is stirred for 1 hour at room temperature and treated with 50 ml of saturated aqueous ammonium chloride solution, the reaction mixture is allowed to stand overnight at room temperature and the organic layer The aqueous layer is filtered to remove salts and extracted with ethyl acetate (2 × 50 ml) The combined organic layers are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo The crude product is purified by trituration with hexane / ether cleaned and dissolved in ethanol, the solution is washed with ethanolic chlorine acidified acid and the solution diluted with 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 ° '.

b) In an analogous manner, the 1- (6-hydroxyhexyl) -3-methyl-2- (3-pyridyl) -indole, as an OeI, is obtained

NMR (CDCl3) <S3.5O (t _s 2H), 3.98 (t, 2H).,

Example 13; A suspension of 1.52 g of 1- (5-carboxypentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole in 50 ml of toluene is added dropwise at room temperature under nitrogen with 0.31 ml of thionyl chloride. The resulting mixture is boiled under reflux for 1 hour , in addition with O added ₅ g of thionyl chloride and the solution was stirred overnight at room temperature. The resulting suspension is evaporated to dryness. The crude 1- (5-chloro-2-carbonylpentyl) -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 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 material in ether gives the 1- (5-carbamoylpentyl) -5-chloro-3-methyl-2- (3-pyridyl-indole, mp 137-140 °.

Example 14 A suspension of 2.9 g (0.06 mol) of 50% sodium hydride in mineral oil, in 40 ml of dimethylformamide, is added under nitrogen. 0-5 ° with a solution of 10.4 g of 3-methyl-2- (3-pyridyl) -indole in 60 ml of dimethylformamide added dropwise within 20 minutes The mixture is stirred at 0-5 ° for 30 minutes and then with 17 , 6 g (0.06 mol) of 1-tetrahydropyranyloxy-8-bromooctane in 50 ml of dimethylformamide added dropwise. The mixture is stirred for 1 hour at 0 and 30 minutes at room temperature, poured into ice-water and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting solution kept at room temperature for 30 minutes, washed with ether, with aqueous 3N sodium hydroxide solution

H H H K _ 46 -

made basic and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness. The 1- (8-hydroxyoctyl) -2- (3-pyridyl) -3-methylindole is obtained

Example 15 : A solution of 4 g of 1- (7-methoxycarbonylheptyl) -3-methyl-2- (3-pyridyl) -indole in 40 ml of n-butanol is saturated with methylamine and heated in a pressure vessel for 3 days on a steam bath. The reaction mixture is evaporated to dryness and the product is recrystallized from ethyl acetate. The 1- [7- (N-methylcarbamoyl) heptyl] -3-methyl-2- (3-pyridyl) -indole is obtained.

Example 16 Preparation of 10000 Tablets Containing 10 mg of Active Substance of Example 1

ingredient

l- (7-carboxyheptyl) -3-methyl-2-

- (3-pyridyl) -indole 100 g

Milk sugar. 1157 g

Cornstarch 75 g

Polyethylene glycol 6000 75 g

Talcum powder 75 g

Magnesium stearate 18 g

purified water q.s.

Procedure: All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is mixed with lactose, talc, magnesium stearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension added to the boiling solution of polyethylene glycol in 150 ml of water. The resulting paste is added to the powders and optionally granulated with the addition of another amount of water. The granules are dried overnight at 35 °, forced through a sieve of 1.2 mm mesh size and pressed into tablets of 6.4 mm diameter having a score line.

O / O 'C (S Ρ *

** ¥ * J> J * J W

Example 17 Preparation of 10000 Capsules Containing 25 mg of the Active Substance of Example 11a

ingredients:

1- (4-carboxybenzyl) -3-methyl-2-

(3-pyridyl) -indole "" 250 g

Milk sugar 1650 g

Talcum powder 100 g

Procedure : All powders are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is first homogenized with talc and subsequently with lactose in a suitable mixer. Capsules no. 3 are filled with 200 mg of the resulting mixture in a filling machine.

In an analogous manner tablets and capsules with a content of each be about 10 - 100 mg of the other compounds of the invention, for example, from l- (5-carboxypentyl) -5- (chloro, fluoro, methoxy or _methyl-s) -3-methyl- 2- (3-pyridyl) - but 1, 1- (5-carboxypentyl) -5,6-dichloro-3-methyl-2- (3-pyridyl) indole or other compounds mentioned in the examples ,

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

Example 19: 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

OCQ C -48- 21.3.1983

¹ 3 ^ ^ AP C 07 D / 244 959/6

(61 632/18)

Potassium hydroxide in 500 ml of acetonitrile is added with stirring at room temperature, under nitrogen with 5-.06 g of p- (2-bromoethoxy) benzoic acid prepared according to US Pat. No. 2,790,825 (1957) 7. The suspension is stirred for 5 days. The potassium bromide is filtered off, the filtrate concentrated to an oil. This is dissolved in ethyl acetate and extracted with 3 & or hydrochloric acid. The acid layer is separated and treated with 3 & ormal sodium hydroxide solution. The suspension obtained is extracted with ethyl acetate (3 × 100 ml) and the organic extract is separated off.

This is dried over magnesium sulfate and concentrated ·

The 1- (2- (4-ethoxycarbonylphenoxy) ethyl) 7-2- (3-pyridyl) -3-methylindole is obtained as an oil,

Example 20: A mixture of 4.7 g of 1- (2- (4-ethoxycarbonylphenoxy) ethyl) -2- (3-pyidyl) -3-methylindole in 2N hydrochloric acid 220 ml 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 to pH 6-7 with 5N hydrochloric acid. The solid material is separated, dried and recrystallized from acetone. The 1- (2- (4-carboxyphenoxy) ethyl) -2,7- (3-pyridyl) -3-methylindole "JV 190 -.193 ° _e " is obtained.

Example 21; A solution of 5 _} 9 g of p-mercapto-benzoic acid ethyl ester (prepared according to J. Chem. Soc, 1963, 1947-1954) in 30 ml of dimethylformamide is added dropwise to a slurry of 155 g of 50% sodium hydride mineral oil in 30 ml

-48- 21.3.1983

AP C 07 D / 244 959/6 (61 632/18)

Dimethylformamide added. This mixture is stirred under nitrogen at room temperature for 30 minutes. This solution is added dropwise to a solution of 9 _S 78 g of 1- (2-methylsulfonyloxy-ethyl) -2- (3-pyridyl) -3-methylindole in 60 ml of dimethylformamide at -10 ⁰ G. »This mixture is at room temperature Laughed and poured into 1000 ml of ice water. The mixture is extracted several times with ether (totally about 1000 ml) «

The ether extract is washed with water (3 × 200 ml), dried over magnesium sulfate and evaporated in vacuo. The 1- [2- (4-ethoxycarbonylphenylthio) ethyl] -2- (3-pyridyl) -3-methylindole is obtained as an OeI. NMR (CDCl) confirms the structure »

The starting material is prepared as follows: 11.7 g of 1- (2-ethoxycarbonyl-ethyl) -2- (3-pyridyl) -3-methylindole in 400 ml of dry tetrahydrofuran are added at 0 ° with 60 ml of a 1 molar solution of lithium aluminum hydride in tetrahydrofuran, the B.eaktionsgemisch is stirred for 1 hour at room temperature _s then cooled in an ice bath and decomposed successively with 2 ', 26 ml of water ,, 2.26 ml of a 15% sodium hydroxide solution and 6.78 ml of water , The mixture is filtered and concentrated in vacuo The residue is dissolved _s washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo in ether. This gives the semisolid 1- (2-hydroxyethyl) -2- (3-pyridyl) -3-methylindoij which is used directly in the next step

Is added dropwise, at -10 °, methanesulfonyl chloride (2.70 ml) 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 chloride »The mixture is stirred at room temperature for 30 minutes and poured into 600 ml of ice water» The resulting slurry is extracted with methylene chloride, the extract washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The 1- (2-methylsulfonyloxy-ethyl) -2- (3-pyridyl) -3-methylindole which is used directly in the above reaction is obtained.

Example 22 A mixture of 6.39 g of 1- [2- (4-ethoxycarbonylphenylthio) ethyl] -2- (3-pyridyl) -3-methylindole in 260 ml of 2N hydrochloric acid is allowed to stand for 6 hours Reflux cooked. After cooling, the pH is adjusted to 6-7 with saturated sodium bicarbonate solution (approximately 500 ml). The mixture is treated with 200 ml of ether and stirred for 30 minutes. The solid material is separated

first with water, then with ether: washed and dissolved in 100 ml of absolute ethanol. The solution is filtered, and the still hot solution treated with 1.68 ml of 6.5-normal ethanolic hydrogen chloride. The solution is cooled and diluted with approximately 100 ml of ether. The product obtained is separated off. The 1- [2- (4-carboxyphenylthio) ethyl] -2- (3-pyridyl) -3-methylindole hydrochloride F. 222-224 ° is obtained.

Example 23: A solution of lithium diisopropylamide (LDA) is prepared by adding η-butyl-lithium (7.66 mmol, 1.6 mol in hexane) to a solution of diisopropylamine (7.6 mmol) in tetrahydrofuran (THF, 12 ml) at -20 ° C. The LDA solution is cooled to -78 ° and treated dropwise with 1- (5-methoxycarbonylpentyl) -2- (3-pyridyl) -3-methylindole (2.48 g). in THF, (24 ml) within 5 minutes. The mixture is stirred at -78 ° for 20 minutes and then phenylselenyl chloride (1.5 g) in THF (12 ml) is added. After 5 minutes, remove the cooling bath and allow the mixture to warm to 0 °. Saturated aqueous sodium bicarbonate solution (60 ml) is added and then extracted with ether (3 × 50 ml). The combined organic extracts are washed with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Concentration in vacuo gives the crude 1- (5-methoxycarbonyl-5-phenylselenyl-2- (3-pyridyl) -3-methylindole as a yellow oil, The crude selenide is dissolved in dichloromethane (40 ml) and added dropwise with 30% Hydrogen peroxide (1.8g, 16mmol) in water (1.8ml) After the addition of approximately 10% of the hydrogen peroxide, an exoterme reaction begins and until the addition is complete, the temperature rises to 30 ° stirred for a further 30 minutes and then treated with 5% aqueous sodium carbonate solution (40 ml), the dichloromethane layer is separated, the aqueous phase is extracted with dichloromethane (25 ml) and the combined organic phases are washed with 5% aqueous sodium carbonate,

Water, saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Concentration in vacuo gives! "(S-methoxycarbonyl-pent-A-enyl-Z-CS-pyridyl-S-methylindole as a light yellow oil. Further purification is by short path chromatography (silica gel) with ethyl acetate-hexane (2: 3 ) as eluent, NMR (COCl) 0.53 (d, 1H), 6 ₅ 65 (m, 1H), IR (liquid) 1720 cm ^-1 .

Example 24: A solution of the α, β-unsaturated ester, namely 1- (5-methoxycarbonylpent-4-enyl) -2- (3-pyridyl) -3-methylindole (84 mg) in methanol (1 ml) is added 1 normal aqueous lithium hydroxide solution (1 ml). The mixture is stirred overnight at room temperature and then evaporated to dryness in vacuo. Dissolve the residue in water (2 ml) and diethyl ether (5 ml). ' 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. The 1- (5-carboxypent-4-enyl) -2- (3-pyridyl) -3-methylindolo F, 145-147 ° is obtained.

Example 25: A solution of Collins reagent prepared under nitrogen at 0-5 ° from chromium trioxide (5.6 mg) and pyridine (8.86 g, 112 mmol) in dichloromethane (150 ml) is obtained once . with 1.8 g of 1- (6-hydroxyhexyl) -3-methyl-2- (3-pyridyl) -indole in dichloromethane (15 ml). The mixture is stirred for 25 minutes and filtered through Celite. The filtrate is then placed on a silica gel column and eluted with a 1: 1 mixture of ethyl acetate-dichloromethane (500 ml). Concentration in vacuo gives the 1- (5-formylpentyl) -2- (3-pyridyl) -3-methylindole as a pale yellow oil. NMR (CDCl3) <5.9.7 (t, 1H); IR (liquid) 2710, 1720 cm " ¹ .

'· 9 5 9 ö - ⁵² -

Example 26: Trimethylphosphonoacetate (328 mg) is added dropwise under nitrogen to a solution of potassium tert-butoxide (220 mg) in THF (5 ml) at 0 °. The solution is stirred at 0 ° for 20 minutes, then cooled to -78 ° and treated with a solution of 1- (5-formyl-2-pentyl) -2- (3-pyridyl) -3-methylindole (450 mg) in THF ( 5 ml) was added dropwise. The mixture is held for 15 minutes at -78 ° and the cooling is stopped. The mixture is stirred overnight at room temperature, diluted with water (25 ml) and extracted with diethyl ether (3 × 25 ml). The combined extracts are washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Evaporation in vacuo gives the 1- (7-methoxycarbonylhept-6-enyl) -2- (3-pyridyl) -3-methylindole as a pale yellow oil. IR (liquid) 1735 cm " ¹ .

Example 27: Hydrolysis of 50 mg of 1- (7-methoxycarbonylhept-6-enyl) -2- (3-pyridyl) -3-methylindole according to the procedure of Example 24 gives the 1- (7-carboxyhept-6-enyl) - 2- (3-pyridyl) -3-methylindole. F. 144-146 (recrystallized from dichloromethane-hexane).

Example 28: 1- (7-carboxyhept-6-enyl) -2-3- (pyridyl) -3-methylindole (10 mg) is dissolved in 1 ml of absolute ethanol A with a catalytic amount of 10% palladium on Coal hydrogenated at a pressure of 1 atmosphere. After 3.5 hours, the catalyst is filtered off and washed with a few milliliters of ethanol. The combined organic extracts are evaporated in vacuo. A colorless oil is obtained, which then crystallizes out. The 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) -indole of the example is obtained. The crude product melts at 110-113 °.

Example 29: 1- (4-Cyano-butyl) -3-methyl-2- (3-pyridyl) -indole (578 mg) is heated at 185 ° 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 the pH with 2 normal

Hydrochloric acid adjusted to 6. The resulting OeI crystallizes out. The 1- (4-carboxybutyl) -3-methyl-2- (3-pyridyl) -indole of Example 5 is obtained (mp 127-129 °).

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

Example 30: A mixture of 578 mg of 1- (4-cyano-butyl) -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 added overnight at 120 ° heated. After cooling, the mixture is filtered and the filtrate diluted with approximately 25 ml of water. The pH is 3-normal. Sodium hydroxide solution to 10 - 11, and the solution, washed with ether to remove the unreacted nitrile. The pH of the aqueous phase is adjusted to 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 slurried in petroleum ether and separated. The 1- [4- (5-tetrazolyl) -butyl] -3-methyl-2- (3-pyridyl) -indole is obtained. F. 177-179 °.

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 °, to a suspension of 0.528 g of 50% sodium hydride. Mineral oil in 6 ml DMF. After completion of the addition, the mixture is stirred at room temperature for 30 minutes and washed with 2.39 g of 3- (p-chloromethyl-phenyl) -2-methyl-

acrylic acid ethyl ester in 5 ml of DMF treated dropwise. The resulting mixture is stirred overnight at room temperature and poured into 100 ml of water. The resulting mixture is extracted with ethyl acetate (2 × 50 ml). The organic layer is washed with 100 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. This gives the 1- [p- (2-ethoxycarbonyl-propen-1-yl) -benzyl] -3-methyl-2- (3-pyridyl) -indole.

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

The starting material is prepared as follows: A suspension of 10.0 g of a 50% sodium hydride in mineral oil in freshly distilled dimethoxyethane (DME, 350 ml) is stirred under nitrogen at 10 ° and treated within about 40 minutes with triethyl 2-phosphonopropionate. The mixture is stirred for 30 minutes at 10 °. With stirring for 1.5 more hours, the temperature is allowed to rise to room temperature. This solution is cannulated into a 500 ml dropping funnel under nitrogen and added dropwise to a solution of terephthalaldehyde (33.53 g) in dry DME (475 ml) over 1 hour at 22-34 °. After completion of the addition, the reaction mixture is stirred mechanically at room temperature for 2 hours, poured into 100 ml of water and extracted with 4 × 500 ml of ether. The ether extract is washed with saturated aqueous sodium chloride solution (700 ml, dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil which partially crystallizes upon standing The crude mixture is purified by suspending in petroleum ether-ethyl acetate (93: 7) The filtrate, after removal of the unreacted dialdehyde, is concentrated in vacuo to give a mixture which is further purified by high pressure liquid chromatography (using petroleum ether / ethyl acetate 93: 7)

AA Q ξ QC

is cleaned. The pure 4-formyl-a-methylcinnamonsäure-ethyl ester is obtained. A solution of this aldehyde (34.80 g) 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 dissolves), concentrated to a volume of approximately 200 ml, diluted with 400 ml of water and extracted with 3 × 200 ml of ether. The ether extract is washed with 100 ml of water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The 3- (p-hydroxymethylphenyl) -2-methyl-acrylic acid ethyl ester is obtained. To a solution of this product in 350 ml of methylene chloride is added at room temperature 11.53 ml of thionyl chloride, drip enxreise, within 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, 100 ml of water and 100 ml of saturated aqueous sodium chloride solution. The organic layer is dried and evaporated. This gives the 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 DMF (0.66 ml) and pyridium dichromate (298 mg) is added in one go. The mixture is stirred overnight at room temperature, then diluted with a mixture of ether and ethyl acetate (25 ml, 4: 1) and filtered. The solid material is washed with hot chloroform and the combined filtrates are concentrated in vacuo. A dark brown gummy material is obtained, which is slurried with ether: ethyl acetate (4: 1) and extracted with 0.1 N aqueous sodium hydroxide solution (2 ml). 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. Thin layer chromatography (silica gel, ethyl acetate: hexane, 1: 1)

244359 R - »-

shows the presence of the desired acid. Further chromatography on silica gel using ethyl acetate: hexane (1: 1) as eluant gives the desired 1- (5-carboxypentyl) -3-methyl-2- (3-pyridyl) -indole of Example 3.

Example 33 Bromine (0.344 ml) is added to a solution of 692 mg of sodium hydroxide in 4 ml of water while cooling with 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. ¹ separates a white solid crude product, which melts in a range of 108-120 °. Separation by thin layer chromatography (silica gel, methylene chloride-methanol, 9: 1) gives the 1- (4-carboxybutyl) -3-methyl-2- (3-pyridyl) -indole of Example 5.

The starting material is prepared as follows: 1- (4-cyano-butyl) -3-methyl-2- (3-pyridyl) -indole (1.5 g) in 15 ml of ether becomes a solution of 0.0103 mol of methylmagnesium bromide in 15 ml of ether. The mixture is refluxed for 3 hours. After cooling, 10 ml of 6N hydrochloric acid are added dropwise and the mixture refluxed for several hours. The reaction mixture is washed with ether and adjusted to pH 10-11 with 3N sodium hydroxide solution , After extraction with

Ether and evaporation of the solvent gives the 1- (5-oxoxyl) 2.0 =

hexyl) -3-methyl-2- (3-pyridyl) -indole. IR 1720 cm ^-1 , NMR (CDCl 3)

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.

- 57 -

Ethyl ester in 1 ml of tetrahydrofuran and cooled to 0-5 °. 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 hydroxylamine hydrochloride (69 mg) and sodium hydroxide (40 mg) in 10 ml of methanol. This mixture is stirred for 0.5 h and concentrated in vacuo. The residue is treated with 25 ml of ether-methanol (10: 1) and filtered. The filtrate is evaporated in vacuo. A thick oil is obtained, which is dissolved in acetone and treated with 6.5 normal ethanolic hydrogen chloride. The 1- (7-hydroxycarbamoyl-heptyl) -3-methyl-2- (3-pyridyl) -indole hydrochloride is obtained. Fo 170-173 °. ^: "

Example 35: Ethanolic hydrogen chloride (7.1 normal, 0.14 ml) is added to 236 mg of N-phenyl-N- (5-methoxycarbonylpentyl) -hydrazine in 2 ml of absolute ethanol and then treated with 135 mg of 3-propionylpyridine. The mixture is refluxed overnight. Then it is mixed with more ethanolic hydrogen chloride (0.62 ml) and heated for a further 24 hours under reflux. After cooling, the mixture is filtered and the filtrate evaporated in vacuo. The residue is stirred in 10 ml of water and adjusted to pH with 1 N sodium hydroxide solution. 10 - 11 asked. This mixture is extracted with ether. The extract is washed with water, dried over magnesium sulfate and evaporated. An OeI which is the 1- (5-ethoxycarbonylpentyl) -3-methyl-2- (3-pyridyl) -indole is obtained.

This ester is hydrolyzed with 10 ml of 2N hydrochloric acid at reflux, then the pH is adjusted to about 6 with saturated aqueous sodium bicarbonate solution and extracted with ether. The work-up of the organic extract yields the 1- (5-carboxypentyl) -3-methyl-2- (3-pyridyl) -indole of Example 3 (melting point of the crude product 111-113 °).

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

. A solution of 1.4 g of sodium nitrite in 5 ml water is added dropwise at 0 _s - (10 °, to a mixture of 4.42 g of N- (5-methoxycarbonylpentyl) aniline, 2 _r 9 ml concentrated hydrochloric acid and ice, the The mixture is then stirred for one hour at room temperature and extracted with ether. The extract is washed _s dried over magnesium sulfate and evaporated in vacuum with water. The N-nitroso-N- (5-methoxycarbonylpentyl) -aniline is obtained as an OeI.

The above nitroso derivative (3.6 g) in 4 ml of glacial acetic acid is added dropwise to 3.94 g of zinc powder in 6 ml of water. After the exothermic reaction up to 35 °, the mixture is 2 hours at room temperature. touched. The zinc is filtered off, the filtrate is washed with ether, the pH is adjusted to 10-11 with 40% sodium hydroxide solution and extracted with ether. The extract is dried over magnesium sulfate and evaporated in vacuo. A crude oil is obtained. After short-path chromatography on silica gel with hexane-acetic acid (5: 1) s, the N-phenyl-N- (5-methoxycarbonylpentyl) hydrazine of approximately 80% purity is obtained. This product is used directly in the above-described Fischer cyclization.

Example 36 Dissolve 1- [7- _sec. 7- (bis-methoxycarbonyl) -heptyl] -3-methyl-2- (3-pyridyl) indole (273 mg) in methanol (0.5 ml) and mix 1 Normal aqueous lithium hydroxide solution (1.95 ml). The mixture is stirred for 1 hour at room temperature and then boiled under reflux for 2.5 hours. The clear solution is evaporated to dryness,

^L QK - 59 -

the residue was dissolved in water and the pH adjusted to 6-6.2. The result is a yellow, rubbery, solid material that is extracted in chloroform. The extract is dried over magnesium sulfate and evaporated. The crude 1- [7,7- (bis-carboxy) -heptyl] -3-methyl-2- (3-pyridyl) -indole is obtained. NMR (CDCl 3) S 10.60 (2H).

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

The starting material is prepared as follows: At 0 ° thionyl chloride (0.36 ml), add 1- (6-hydroxyhexyl) -3-methyl-2- (3-pyridyl) -indole (1.37 g) and stir Mixture for 1 hour at room temperature. Then the mixture is treated with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation in vacuo, the crude chloride is obtained as an OeI. Purification by silica gel chromatography (methylene chloride / ethyl acetate 19: 1) gives the 1- (6-chlorohexyl) -3-methyl-2- (3-pyridyl) -indole as a light yellow OeIc NMR (CDCl 3) <3 O 3 ( t, 2H), 3.92 (t, 2H).

The 1- (6-chlorohexyl) -3-methyl-2- (3-pyridyl) -indole (0.5 g) is added to a mixture of dimethyl malonate (792 mg), potassium carbonate (790 mg) and dimethylformamide (11.6 g) ml) and under nitrogen

* *. f * \ τ- fs r *

/ / U K Μ K - - 6o -

4 -J -3 3 ^

Heated for 18 hours at 80-90 °. The mixture is poured into ice-water (80 ml), acidified with 1 N 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 purified by preparative thin-layer chromatography (chloroform-ethyl acetate 9: 1) evaporated to a yellow oil, yields the l- [7,7- (bis-methoxycarbonyl) -heptyl] -3-methyl-2- (3-pyridyl) -indole. NMR (CDCl) ί 3 _S 32 (t _a lH), 3.78 (s, 6H) ₉ 4.03 ₉ Ct 2H). IR (liquid) 1750 cm " ¹ "

Example 3 7: 1- (6-Chlorohexyl) -3-ethyl-2- (3-pyridyl) -indole (165 mg) in dry THF (2 ml) is added dropwise to magnesium turnings (12 mg). in dry THF (2 ml) under nitrogen. To initiate the reaction, a crystal of iodine is added during the addition. The mixture is refluxed for 4 hours after completion of the mixing, cooled to 0 °. While stirring, dry carbon dioxide gas is introduced into the reaction vessel for 15 minutes, 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 ° * The product is 1- (6-carboxyhexyl) -3-methyl-2- (3-pyridyl) -indole ₅ whose TLC and NMR values are identical to the compound of Example 4

Example 38: 1- (Prop-2-ynyl) -3-methyl-2- (3-pyridyl) -indole (90 mg) is dissolved in THF (2 ml) under nitrogen and the resulting solution is cooled to -78 °. A solution of n-butyl-lithium (0.024 ml, 1.6 mol in hexane) is added dropwise over 1 minute. The orange mixture is stirred for an additional 10 minutes at -78 °, then methyl chloroformate (0.031 ml) is added. The mixture is allowed to rise

Heat to room temperature, pour into saturated aqueous sodium chloride solution and extract with ether. The extract is with

"U4953 6

Washed water and dried over magnesium sulfate. Evaporation in vacuo gives an OeI which is purified by preparative thin-layer chromatography. The solvent used is a 1: 1 mixture of ethyl acetate: hexane. The 1- (3-methoxycarbonyl-prop-2-ynyl) -3-methyl-2- (3-pyridyl) -indole is isolated as OeI. NMR (CDCl) i 3.73 (s, 3H), 4.83 (s, 2H); IR (CH 2 Cl 2) 1715.2245 cm ^-1 .

The starting material is prepared as follows: Sodium hydride (50% mineral oil dispersion, 53 mg) is washed under nitrogen with petroleum ether, the washed sodium hydride is suspended in dry DMF (2 ml) and added dropwise with 3-methyl-2- (3 pyridyl) indole (208 mg) in DMF (2 ml) was added. The mixture is stirred for a further 30 minutes and then added dropwise, with propargyl bromide was added. The reaction mixture is stirred for a further 2 hours _s m poured ice-water, with 1 N The aqueous phase is basified with sodium bicarbonate and extracted with ether, the ether extract is washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Evaporation in vacuo gives the 1- (prop-2-ynyl) 3-methyl-2- (3-pyridyl) indole; NMR (CDCl 3) S 2.20 (s, 4H), 4.70 (d, 2H, J = 3Hz), IR (liquid)

3200, 2120 cm. , Melting point 104-105 ° after purification by short-path chromatography, using a 1: 1 mixture of ethyl acetate: hexane.

Example 39: Treatment of 33 mg of 1- (3-methoxycarbonylprop-2-ynyl) -3-methyl-2- (3-pyridyl) -indole in 1 ml of methanol with 0.3 ml of 1 N lithium hydroxide solution at room temperature gives the l- (3-carboxyprop-2-ynyl) -3-methyl-2- (3-pyridyl) -indole. IR 1720 cm

j / / f "5 ϊ f ι *" * _ 52 -

Example 40: Analogously to the processes described in the preceding examples, the following compounds of the formula II in which R ¹ = CH, Pyr = 3-pyridyl and R = OH, are also prepared;

connection R ₂ ' ^R 3 CH ₀ . m 2m salt F, 40/1 5-Cl H (CH ₂ ) ₇ HCl 173-176 ^C 40/2 5-OCH ₃ H (CH ₂ ) HBr 188-189 ° 40/3 5-Cl 6-Cl / ηχχ \ ^ η J π HCl 178-80 ° 40/4 5-F H (CH ₂ ) ₅ HCl 216-219 ° 40/5 5-CH " H HCl. 185-8 ° 40/6 40/7 5-CH "J H H H ^(CE Echo 124-125 ° 100-102 ° 40/8 ' 5-0-CH ₂ -O-6 40/9 5-OH H ^(CH 2 ⁾ 5 - 168-17Q ⁶ 40/10 5-SCH H (CH) - 135-7 °

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

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

Example 41: Analogously to the methods described in the preceding examples, the following compounds of the formula I in which R = CH, Ar = 3-pyridyl and B = COOH are also prepared?

- ⁶³ -

example ^R 2 ^R 3 A B 41/1 H H C = C- (CH ₂ ) ₃ COOH 41/2 H H CH ₂ S (CH ₂ ) ₂ COOH 41/3 H H (CH ₂ ) ₂ O (CH ₂ ) ₂   .COOH 41/4 H H : (CH ₂ ) ₂ O (CH ₂ ) COOH

The alkylating starting materials for the compounds 41/2, 41/3 and 41/4 are prepared according to J. Org. Chem. 34_, 2955 (1969), U.S. Patent 3,984,459 and Chem. Abstr. _83_, 166177b made.

Effect on thromboxane synthetase of human platelets

The method is carried out according to the description given in the introduction This in vitro 'inhibition' of the heromboxane synthetase enzyme has been shown analogously to the method of Sun, Biochem. Biophys. Res. Comm., 74, 1432 (1977).

Results:

Connection - ^ ςη C ¹¹ ^)

the example of thromboxane synthetase

3 0, 003

1 0.012

2 1,800

4 0.008

5 0.007

9 0.021

10 0.069

11 0.050

6 3,400

7 0.001

12 0.260

13 0.013

Claims (13)

α α Ό * J 9 Ö -64- 21.3.19 & 3 AP G 07 D / 244 959/6 (61 632/18) Invention 1) a compound of formula V Vs / I! R ₃ X ΔH H H η k4 W W W W wherein X is hydrogen, alkali metal or tri-lower alkylsilyl, R, R, R and Ar have the meaning given, with a reactive functional derivative of a compound of formula VI HO-CH ₂ -AB (VI), wherein A and B have the meaning given above, condensed, or 1, Process for the preparation of new H-substituted 2-Pyridyiindolen the general formula I. ^R 2 J CD, ·> CH ₂ -A-3 wherein R. is hydrogen or Hiederalkyl, Ar is unsubstituted or substituted by lower alkyl, carboxy _s Hiederalkosycarbonyl or carbamoyl-substituted pyridyl, R p and R, are independently hydrogen, lower alkyl, halogen, hydroxy Trifluormethylj, Hiederalkoxy, Garboxyniederalkyl, liederalkoxycarbonyl-lower alkyl, carboxy, Lower alkoxycarbonyl or lower-alkyl (thio, sulfinyl or sulfonyl), or Rp and R ^ together, on adjacent carbon atoms, represent liedetalkylenedioxy; A is alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, alkynylene of 2 bi 3 12 carbon atoms, lower alkylene phenylene lower alkylene, lower alkylene phenylene, phenylene lower alkylene, phenylene, a direct bond, lower alkylene (thio or oxy) lower alkylene, ( ihio or oxy) phenylene, lower alkylene (thio or oxy) phenylene, phenylene (thio or oxy) lower alkylene or phenylene-lower alkenylene, B represents carboxy, lower alkoxycarbonyl, ^. MRI 1933 * 07801 i * ti 5 9 -6 -64a-21.3.1983 AP G 07 D / 244 959/6 (61 632/18) Carbamoyl, mono- or di-lower alkyl-carbamoyl, 5- Hydroxymethylj Hydroxycarbamoylj ^f ietrasolyl or iOrrnyl means; their I-oxides; and salts of these compounds, characterized in that 2, Process according to item 1, for the preparation of compounds of the formula I shown in point 1, wherein R is hydrogen or .Hiederalkyl, Ar is unsubstituted or durchliederalky 1, carboxy, Nied6raikoxycarbonyl or 'carbamoyl substituted pyridyl, R _p and R un - '. 'Κ - ⁶⁷ - "21.3.1983 _1Ρ α 07 D / 244 959/6 (61 632/18) interdependent hydrogen, liederalkyl, halogen, irifluormethylj Hydroxy _s lliederalkoxy, ^ü arboxyniederalkyl _s Hied.erallcoxycarbonyl-lower alkyl, carboxy or Wiederalkoxy is carbonyl, A is alkylene having 1 to 12 carbon atoms, Älkenylen having 2 to 12 carbon atoms, alkynylene having 2 to 12 carbon atoms , Fiederalkylen-pftenylenniederalkylen, Uiederalkylen-phenylene, phenylene-lower alkylene, phenylene or a direct bond, B is carboxy, lower alkoxycarbonyl, -Garbamoyl, mono-o * the di-lower alkyl-Qarbamoyl or hydroxymethyl means; their U-oxides; and salts of these compounds, characterized in that a compound of the formula 1 g-shown Pormel V, wherein X is hydrogen, and the other symbols have the meanings given above, with a reactive functional derivative of a compound of formula VIa HO-CH ₂ -AB '• / (VIa), wherein A has the meaning given above and B ^{1 is} carboxy, iJiederalkoxycarbonyl, carbamoyl, mono- or di-lower alkyl-carbamoyl, hydroxymethyl, etherified hydroxymethyl, halomethyl, trialkoxymethyl or cyano, condensed, and in a resulting compound of formula Ib R ₂ CH ₂ -AB ¹ -67- 21.3.1983 AP C 07 D / 244 959/6 (61 632/18) in which * B ^{1 is} other than S, the radical B ¹ _$, optionally with extension of the chain A within its definition, is converted into the group B and, if desired, converts a compound of the formula I obtained into another compound of the invention, and / or, if desired, converting a resulting free compound into a salt or a resulting salt into the free compound or into another S _a lz, 'and / or, if desired, a resulting mixture of isomers or Razeinaten into the individual isomers or racemate, and / or razemate obtained, if desired, into the optical antipodes. 2) .a compound of formula VII R · ² X ^Χ . ^CH 2 ^R l V. --Ν - N = C - Ar (VII) • I wherein Ar, R, R, R_, A and B are as defined above, ring-closing, or 3. The method according to item 1, characterized by reacting compounds of formula II I !! rl GOR ₄ wherein R 'is hydrogen or lower alkyl, Ri and Ei are independently hydrogen, lower alkyl, halogen,' Drifluormethyl, hydroxy, Hiederalkylt / hio or Hiederalkoxy, or Ri and Ri together, on adjacent carbon atoms, mean methylenedioxy, Pyr 2 -, * 3 - or 4-pyridyl, m is an integer from 1 to 13, R is hydroxy, lower alkoxy or amino; and their salts are produced « 3) a compound of formula VIII V \ -E-Ar
I - CH-A-B wherein Ar, R, R, R, A and B have the meaning indicated, cyclized, or & 4 J * J J ^ APC 07 D / 244 959/6 (61 632/18) wherein R 'and R ₉ are independently hydrogen lower alkyl, halogen, iiiederalkoxy. Haloalkylthio or hydroxy mean _s or Ri and Rl together, on adjacent carbon atoms are methylenedioxy; X is oxygen, sulfur, or a direct bond, q is an integer from 1 to 4, R _? Hydroxy or lower alkoxy; Pyr is 2-, 3- or 4-pyridyl and produces its salts. 4 · Method according to item 2, characterized in that compounds of the formula III COR wherein η is an integer from 3 to 10, ρ is an integer from 0 to 4, Pyr is 2-, 3- or 4-pyridyl, H, - and R, - independently of one another are hydroxy or lower alkoxy; and their salts. 4) in a compound of the formula Ia > \ Λ I Π Il (Ia), • · ^ Ar
^V 3 -66- 21.3.1983 AP G 07 D / 244 959/6 (61 632/18) where A, Ar, R ₁ , R _? and R 1 are as defined above, and G is a group other than a group B which can be converted into group B, which converts group G into B, optionally with extension of the chain A within its definition, or
5) a compound of formula IX ^R 2 GOOH ] f GH ₂ -AB wherein A, Ar, R ₁ , R p and R 1 are as defined above, decarboxylated, and if desired, if necessary, temporarily protecting an interfering reactive group in all of these processes and, if desired, a compound of formula I obtained converted into another compound of the invention, and / or, if desired, a resulting free compound in a salt or a salt obtained in the free compound or converted into another salt, and / or, if desired, a resulting mixture of isomers or Razematen in the individual isomers or racemates separates, and / or, if desired, obtained racemates splits into the optical antipodes, 5 «method according to item 1, characterized in that compounds of the formula IV VN s / « ^R 2 ^ ^Sl a » COR / QCQ A - ⁶⁹ "- 21.3.1983 6, Process according to item 1, characterized in that 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) -indole and its salts are prepared. 7 «process according to item 2, characterized in that 1- (7-carboxyheptyl) -3-niethyl-2- (3-pyridyl) -ihdol and its salts are produced · 8. The method according to item 1, characterized in that one produces 1- (5- ^ arboxypentyl) -3-ethyl-2- (3-pyriäyl) -indole and its salts ₀ 9. Process according to item 2, characterized in that 1- (5-carboxypentyl) -3-methyl-2- (3-pyridyl) -indole and its salts are prepared, 9 //, QRQ η - ⁶⁸ ~ 21.3.1983 ' AP C 07 D / 244 959/6 (61 632/18) 10, Process according to item 1, characterized in that one produces 1- (4-carboxybutyl) -3-methyl-2- (3-pyridyl) -indole and its salts » / / A QRQ & -70- 21.3.1983 AP G 07 D / 244 959/6 (61 632/18) 11, method according to item 2, characterized in that 1- (4-carboxybutyl) ~ 3-methyl-2-C3-pyridyl) -indole and its salts are prepared » 12, The method of item 1, characterized in that -] _ (5-carboxypentyl) -5-chloro-3 - niethyl-2- (3-pyridyl) -indole and its S _a i _Z e establishes * 13, method according to. Point 2, characterized in ^ that is prepared 1- ^(5-G arboxypentyl) -5-chloro-3-methyl-2- (3-pyridyl) -indole and its salts "