DD253618A5 - PROCESS FOR PREPARING HETEROCYCLIC AMIDE - Google Patents

Abstract

The invention relates to a process for the preparation of novel heterocyclic amides, in particular of novel amidoindole and amidoindazole derivatives for use as medicaments, for example for the treatment of diseases caused by leukotrienes, such as allergic or inflammatory diseases or of endotoxic or traumatic states of shock. The aim of the invention is the provision of novel leukotriene antagonists. According to the invention, compounds of the formula I are prepared in which, for example: the group A ... CRa may be CRbCRa, CHRbCHRa or NCRa, the amide group Re.L may be Re.X.CO.NH, Re.X.CS. NH or Re.NH.CO when attached to the 4, 5 or 6 position of the benzenoid component, Z is an acid selected from carboxy, an acylsulfonamide radical of the formula CO.NH.SOnRa and a tetrazolyl radical of the formula II Radicals Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, n, X, G1, Q and G2 have the meanings defined in the following specification. formula

Description

253 * 18

Process for the preparation of heterocyclic amides Field of application of the invention

The present invention relates to a process for preparing novel heterocyclic amides, especially novel amidoindole and amidoindazole derivatives, which counteract the pharmacological effects of one or more of the arachidonic acid metabilites known as leukotrienes (hereinafter referred to as "leukotriene antagonists Properties "). The novel derivatives are therefore of value in the treatment of those diseases in which leukotrienes are involved, for example in the treatment of allergic or inflammatory diseases or of endotoxic or traumatic shock states. The invention further provides the novel derivative-containing compositions for use in such treatments as well as intermediates and methods for preparing the novel derivatives.

Characteristic of the known technical solutions

EP Patent Application Publication Nos. 54417A1 and 80154A2 describe a series of 3- (pyridylmethyl) indoles and 2- (pyridyl) indoles, respectively, which entail an acidic side chain at the NC) position and which are selective Inhibitors of the enzyme thromboxane synthetase acts.

Aim of the invention;

The aim of the invention is the provision of novel heterocyclic amides having valuable pharmacological properties, which are particularly suitable for the treatment of allergic or inflammatory diseases or of endotoxic or traumatic shock states.

Explanation of the essence of the invention

The invention has for its object to find new heterocyclic amides, in particular novel amidoindole and amidoindazole derivatives having the desired properties and processes for their preparation.

There have now been discovered a number of indole and indazole derivatives which have an amide substituent in the benzenoid ring and which unexpectedly have the ability to counteract one or more of the arachidonic acid metabolites known as leukotrienes.

According to the invention, an arnidic compound of the formula I (as shown below) is prepared in which;

the group A "CRa is selected from di-radicals of the formula -CRb = CRa, -CMRb-CHRa and -I = CRa, in which Ra is hydrogen, methyl, halogen, (2 ... 6C) alkanoyl, ( 2 ... 6C) alkenyl or (2 ... 6C) alkyl, of which the latter two may optionally bear a carboxy or ((1 ... 4C) alkoxy) carbonyl substituent, and Rb is hydrogen or ( 1 ... 4C) alkyl j or

Ra and Rb together form tetramethylene which optionally carries 1 or 2 (1 ... 4C) alkyl substituents and optionally contains 1 or 2 unsaturated bonds;

Rc, Rd and Rf are independently selected from hydrogen, halogen, (1 ... 4C) alkyl and (1 ... 4C) alkoxy;

the group Re.L stands for amide radicals of the formula Re.X.CO.NH-, Re.X.CS.NH- or Re.NH.CO- which are at the position 4, 5 or 6 of the formula below In which Re is (2 to 10C) alkyl which optionally contains one or more fluoro substituents, or Re is (3 to 10C) alkenyl or (3 to 10C) alkynyl; or Re is phenyl, phenyl (1 ... 6C) alkyl or thienyl (1 ... 6C) alkyl, wherein the (1 ... 6C) alkyl component is optionally a (1 ... 4C) alkoxy, (3 * .. 6C) can carry cycloalkyl or phenyl substituents and wherein a phenyl or thi'enyl component can optionally carry one or two substituents which are halogen, (1 ... 4C) alkyl, (1. ..4C) alkoxy and trifluoromethyl were selected; or Re is (3 to 8C) cycloalkyl, (3 to 8C) cycloalkyl (1 to 6C) alkyl or (4 to 6C) oxyheterocyclyl, the cyclic component of which optionally contains an unsaturated bond or a or two (1 ... 4C) alkyl substituents or a phenyl substituent, the latter itself being optionally halo, (1-4C) alkyl, (1 ... 4C) alkoxy or trifluoromethyl Can carry substituents; X is oxy, thio, imino or a direct bond to Re;

Q is a direct bond to G or is oxy, thio, m-phenylene, p-phenylene or heteroarylene;

G ¹ is (1 ... 8C) alkylene or (2 ... 6C) alkenylene;

G is methylene, vinylene or a direct bond to Z;

Z is an acidic group selected from carboxy, an acylsulfonamide radical of the formula -CO.WH.SO.sub.Rg and a tetrazolyl radical of the formula II shown below, in which .eta. Is the integer 1 or 2, Rg is ( 1 ... 6C) alkyl, aryl, heteroaryl, aryl (1 ... 4C) alkyl, wherein in each of these groups the aromatic or heteroaromatic moiety may carry one or two substituents selected from halogen, (1 ... 4C ) Alkyl, (1 ... 4C) alkoxy, trifluoromethyl, Mitrο and amino, and Rh is hydrogen, carboxy (1 ... 3C) alkyl or (carboxyphenyl) methyl

1 2

provided that G, Q and G taken together contain at least 3 carbon atoms and that

ο G is methylene or vinylene, if. Q Oxy or Thio

and Z is carboxy;

or a pharmaceutically acceptable salt derived therefrom.

It will be appreciated that certain compounds of formula I, such as those in which Re contains an asymmetrically-substituted carbon atom, may exist in optically active and racemic forms, or may be isolated as such. In addition, it will be noted that certain compounds of formula I, such as those in which Re, Rc or the bond

1 2

-G .Q.G - contains a vinylene group, in separate stereo

isomeric forms ("Ξ" and "Z") exist around that group or can be isolated as such. It will be understood that the present invention encompasses any racemic, optically active or stereoisomeric form, or mixtures thereof, which possesses leukotriene antagonist properties, although it is well known in the art how to produce optically active forms (e.g. Dissolution of the racemic form or by synthesis from optically active starting materials), how to prepare individual "Ξ" and "Z" ^M stereoisomers (for example, by chromatographic separation of one of their mixtures) and how the leukotriene antagonist properties through the standard assays described below are determined.

In the present specification, Ra, Rb, Re, etc. are generic radicals and, moreover, have no other meaning. It is to be understood that the generic term "(1 ... 6C) alkyl" includes both straight and branched chain alkyl radicals, but references to individual alkyl radicals such as "propyl" apply only to the straight chain ("normal") radical whereas branched chain isomers such as "isopropyl" are specifically referred to. A similar rule applies to other generic groups such as "alkylene" and "alkenylene", etc.

A specific value for Ra, when it is (2 ... 6C) alkyl, for example, ethyl, propyl or butyl, and (2 ... 6C) alkanoyl, for example, acetyl, propionyl or butyryl; in the case of halogen is the specific value, for example, chlorine or

Bromine; and for the Pall of (2. ♦ _O 6C) alkenyl, the specific value is, for example, vinyl, allyl or 1-proponyl.

A specific value for an optional ((1 ... 4C) alkoxy) carbonyl substituent which may be on Ra is, for example, methoxycarbonyl or ethoxycarbonyl.

A specific value for Rb, when it is (1 ... 4C) alkyl, is for example methyl or ethyl.

A specific value of Ra and Rb when they together form tetramethylene having 1 or 2 unsaturated bonds is, for example, 1-butenylene or 1,3-butadienylene; and a specific value for an optional (1 ... 4C) alkyl substituent thereon is, for example, methyl or ethyl.

A specific value for Re, Rd or Rf - if this is halogen - is, for example, fluorine, chlorine or bromine; if it is (1 ... 4C) alkyl, this is, for example, methyl or ethyl; and when it is (1 ... 4C) alkoxy, this is, for example, methoxy or ethoxy.

A specific value for Re - if this is (2 ... 1OC) alkyl - is, for example, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, t-butyl, pentyl, 1-ethylpropyl, hexyl, Heptyl, 1-ethylpentyl or ilonyl; and for the pail of the presence of 1 or more Pluor substituents, this is, for example, 2,2,2-trifluoroethyl or heptafluoropropyl.

A specific value for Re, in the case of (3... 10G) alkenyl, is, for example, allyl, 2-butenyl, 3-butenyl or 1,3-pentadienyl, and if it is (3... 10C) alkynyl, this is, for example, 2-propynyl or 3-utynyl.

Specific values for Re - when it is phenyl (1. -. 6C) alkyl or thienyl (1 .. .6C) alkyl - include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, thien-2 -ylmethyl, thien-3-ylmethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, "1-methyl-1-phenylethyl, 1-phenylbutyl and 1-phenylpentyl; and a specific value for one example (3. Cycloalkyl substituent is, for example, cyclobutyl, cyclopentyl or cyclohexyl, and for an optional (1 to 4C) alkoxy substituent this is, for example, methoxy or ethoxy.

Specific values for certain optional substituents which may be present on or as part of a phenyl or thienyl moiety such as Re include, for example, ":

for halogen: pluor, chlorine and bromine; for (1 ... 4C) alkyl: methyl and ethyl; and for (1 ... 4C) alkoxy: methoxy and ethoxy.

A specific value for Re - if it is (3 ... 8C) cycloalkyl - is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; in the case of (3.times.SC) cycloalkyl- (1-6C) alkyl, this is for example cyclobutylmethyl, cyclopentylmethyl, cyclohexylmetyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclopentylpropyl,

1-cyclohexylpropyl, 1-cyclopentylbutyl, 1-cyclohexylbutyl; and (4 ... 6C) oxyheterocyclyl, this is for example tetrahydrofur-2-yl, tetrahydrofur-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl; and a specific value for such a radical having an unsaturated bond is, for example, cyclohexenyl or cyclohexenyl- (1-6C) alkyl (such as cyclohexenylmethyl or 1- (cyclohexenyl) butyl j and a specific value for an optional (1 .. 4C) Alkyl substituent on the cyclic component of such a radical is, for example, methyl, ethyl or isopropyl.

A specific value for Q, if heteroarylyene, is, for example, 2,5-5'-uranediyl, 2,5-thiophenediyl, 2,5-pyridinediyl and 4,7-benzo (b) furanediyl.

A specific value for G - as far as it is (1 ... 8G) alkylene - is, for example, methylene, ethylene, ethylidene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene or octamethylene; and when it is (2 ... 6C) alkenylene, this is, for example, vinylene, propenylene, 1-3-butylene or 2-butenylene.

A specific value for Rg - if it is (1 .., 6C) alkyl - is for example methyl, ethyl, propyl, isopropyl or butyl; when it is aryl, this is, for example, phenyl, 1-naphthyl or 2-naphthyl; when it is heteroaryl, this is, for example, ifaryl, thienyl or pyridyl; when it is aryl (1 ... 4C) alkyl, this is, for example, benzyl, 1-naphthylmethyl or 2-haphthyl! methyl; and if it is heteroaryl (1 ... 4C) alkyl then this is

ο o

for example furylmethyl, thienylmethyl or pyridylmethyl.

Specific values for optional substituents which may be present on an aromatic or heteroaromatic moiety such as Rg or any of its moieties include those values mentioned above in connection with. a phenyl or thienyl component in Re have been defined.

A specific value for Rh - insofar as it is Carboxy - (. 1 ..3C) alkyl - is, for example, carboxymethyl or 2-carboxyethyl; and if it is (carboxyphenyl) methyl, this is, for example, o-carboxyphenylmethyl.

A typical value for R a is, for example, hydrogen, methyl, ethyl, chlorine, bromine, acetyl, propionyl or butyryl, allyl, 2-carboxyvinyl, 2- (1-ethoxycarbonyl) vinyl or 2- (methoxycarbonyl) ethyl.

A typical value for Rb is, for example, hydrogen or methyl; and for Ra and Rb taken together, this is, for example, tetramethylene or 1,3-butadienylene, optionally bearing a methyl or ethyl substituent.

A typical value for Rc is, for example, hydrogen, methyl, chlorine or bromine.

A typical value for Rd or Rf is, for example, hydrogen, methyl, iviethoxy, butoxy, fluoro, chlorine or bromine, Rf is preferably hydrogen.

- ι ο - 25 3 6 j

Typical values for R include, for example, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, t -butyl, pentyl, 1-ethylpropyl, hexyl, heptyl, 1-ethylpentyl, nonyl, heptafluoropropyl, 1,3-pentadienyl, 3-butynyl, phenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 2-thienyl, benzyl, 4-chlorobenzyl, 4'-trifluoromethylbenzyl, 4-methylbenzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-1 -phenylethyl, thien-2-ylmethyl, 1-phenylpropyl, 1-phenylpentyl, alpha-cyclopentylbenzyl, alpha-methoxybenzyl, benzhydryl, cyclobutyl, cyclopentyl, cyclohexyl, 1-phenylcyclopentyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 1-cyclopentylbutyl, 1 Cyclohexylpropyl, 1-cyclohexylbutyl, 5-methyl-2- (1-methylethyl) cyclohexyl, 1-cyclohexene-4-yl, tetrahydrofur-2-yl and tetrahydrofur-3-yl.

A typical value for Q (one chi ie 131 I Hd and Rf is, for example, a direct bond, oxy, thio, m-phenylene, 2-methoxy-1,3-phenylene, 4-methoxy-1,3-phenylene, g Phenyls, 2-methoxy-1,4-phenylene, 2-butoxy-1,4-phenylene, 2-methyl-1,4-phenylene, 2-pluoro-1,4-phenylene, 2-chloro-1, 4-phenylene, 2-bromo-1,4-phenylene, 2,6-dimethoxy-1,4-phenylene, 2,5-furandiyl, or 4,7-benzo (b) furandiylj wherein G is at position 1 or 4 of Q is attached.

Sin's typical value for G - when Q is m-phenylene or -P -phenylene which is partially substituted as defined above, or when Q is 2,5-purandiyl or 4,7-3enzo (b) furanediyl, is for example methylene or Ethylidene, of which methylene is usually preferred.

Sin typical value for G - if Q stands for oxy or thio - is for example Trimethylen, Pentamethy1en, Hepta-

methylene or 2-butenylene.

A typical value for G - if Q corresponds to a direct bond - is, for example, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or heptamethylene.

A typical value for Rg is, for example, methyl, isopropyl, butyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-aminophenyl, 1-naphthyl, thien- 2-yl or 6-chloropyrid-3-yl.

A typical value for Rh is, for example, hydrogen, carboxymethyl or o_-carboxyphenylmethyl.

Two subgroups of compounds of particular interest within the scope of the present invention comprise:

(i) those compounds of the formula I in which A.GRa is a diradical of the formula -GRb = GRa-, d. H. Indoles of formula III corresponds;

(ii) those compounds of the formula I in which a.GRa is a diradical of the formula -N = GRa, d. H. Indazoles of the formula IV corresponds;

and in each of said groups the radical radical has one of the values defined above; together with their pharmaceutically acceptable salts, if available.

In general, in the compounds of formula III and IV, it is preferred that the group Re.L is at the 6-position

£ 0 J ό j

of the indole or indazole ring is arranged.

A preferred value for Ra is, for example, hydrogen, chlorine, acetyl or butyryl, and for Rb, Rc, Rf or Rh this is for example hydrogen. A preferred value for Rd is, for example, methoxy - and when Q is p_-phenylene, then this is especially methoxy in the ortho

1 position relative to G.

1 2 A preferred value for the combination G .QG (together with Rd) is, for example, 2-methoxy-alpha, 4-toluenediylp. A preferred value for Re.L is, for example, if for a group of the formula Re.X.CO .IiH in which Re and X have any of the meanings defined herein, and even more preferred value is when the radical Re.X.CO- is subject to branched (4 ... 10C) alkanoyl / such as Ethylhexanoyl /, 2 - ((4 · .6 C) cycloalkyl) acetyl / such as 2- (cyclopentyl) acetyl or 2- (cyclohexyl) acetyl /, 2 - ((2 ... 5C) alkyl) -2-phenylacetyl / such as 2-ethyl-2-phenylacetyl- (4 ... 6C) cycloalkyloxycarbonyl or (4..o C) cycloalkyl-. thiolocarbonyl / such as cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclopentylthiolocarbonyl, (4 ... 6C) -cycloalkylcarbonyl / such as cyclopentylcarbonyl / and (3 · ..6C) alkyloxycarbonyl.

The group Re.L is preferably located at position 6 of the nucleus of the compounds of formula I.

A preferred value for Rg is for example Fhenyly which optionally carries a fluoro , chloro, methyl, nitro or amino substituent; and particularly preferred are phenyl or 2-methylphenyl.

253 6 y

A particularly preferred value for Z is, for example, that it is an acylsulfonamide radical of the formula-1 -CO.NH.SOp.Rg (where Rg has one of the meanings defined above).

Specific compounds of formula I are described in the accompanying working examples. Of particular interest in terms of their pronounced properties as leukotriene antagonists are in particular (a) the sulfonamides (Z = GO.NH.SOpRg), as in the embodiments 256, 261, 262, 263, 264, 265 ,. 266, 277, 278, 279, 280, 284, 294 and 298; (b) the carboxylic acids (Z = COpH) as described in Working Examples 114, 122, 170, 176, 209, 221, 222, 224 and 241; and the tetrazoles (Z = 5-1 (H) tetrazolyl) as described in Working Examples 157, 158, 161, 162 and 163; together with their pharmaceutically acceptable base addition salts.

The compounds of formula I may form salts with bases, such salts, if pharmaceutically acceptable, fall within the scope of the invention. Examples of suitable pharmaceutically acceptable salts are salts with bases which form a physiologically acceptable cation such as alkali metal (especially sodium and potassium), alkaline earth metal (especially calcium and magnesium), aluminum and ammonium salts as well as salts of suitable organic bases such as triethylamine, corpholine , Piperidine and triethanolamine.

The compounds of formula I can be prepared using methods as described in Chemistry for.

Preparation of structurally analogous compounds are well known. Such processes for the preparation of a compound of formula I as defined above are taught as further features of the present invention and illustrated by the following procedures:

(a) Purely those compounds of the formula I in which Z corresponds to a garboxylic acid group, this is the decomposition of a suitable ester of the formula V in which Ri is, for example, (1 .. 6C) alkyl partially with an acetoxy group. , (1 ... 4C) alkoxy or (1. .4 C) alkylthio substituents or is phenyl or benzyl.

A specific value for Ri is, for example, methyl, ethyl, propyl, t-butyl, acetoxymethyl, methoxymethyl, 2-methoxyethyl, methylthiomethyl, or phenyl or benzyl.

It will be understood that disassembly may be accomplished using any of the numerous methods of processing well known in organic chemistry. For example, it may be made by conventional hydrolysis under acidic or basic conditions, adjusted as necessary to minimize any hydrolytic removal of other functional groups in the molecule. On the other hand, under certain circumstances - for example when R i is tert-butyl - it may be possible to carry out the decomposition using thermal aids, for example by heating the ester of formula V to a temperature of for example 100 ... 150 ^° C either with the ester alone or with the inclusion of a suitable solvent or diluent such as diphenyl ether. If Ri is _t-butyl, then

For example, the decomposition may be carried out using trimethylsilyl triflate, for example, as described in the accompanying Example 172. Furthermore, under certain circumstances, if it for example is when Ri is benzyl, be possible to carry out the decomposition by reductive means, for example by ^s insatz of hydrogen at about atmospheric pressure in the presence of a suitable catalyst such as palladium or platinum, the latter being present on a carrier such as charcoal.

A preferred method of hydrolyzing an ester of formula V comprises reacting said ester with a suitable base such as an alkali or alkaline earth metal hydroxide or carbonate (such as lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide or potassium carbonate) in a suitable aqueous medium A solvent or diluent such as water optionally together with a water-miscible alkanol, glycol, ketone or ether (such as methanol, ethanol, ethylene glycol, 2-methoxyethanol, acetone, methyl ethyl ketone, tetrahydrofuran or 1,2-dimethoxyethane) at a temperature of, for example 15 ... 100 G and conveniently at or near ambient temperature. When such a process is used, the resulting carboxylic acid of formula I, wherein Z is a carboxylic acid group, is initially recovered as the corresponding salt of the base used for the hydrolysis and can be isolated as such or converted to the free acid form 'by using a conventional acidification process such as reaction with a suitable strong acid such as

£ 0 ό 6 f - 16 - ^y

• hydrochloric or sulfuric acid.

(b) For those compounds of the formula I in which Re.L is a group of the formula Re.X.CO.NH- or Re.X.CS.NH-, this is the acylation of an amine of the formula VI.

A suitable acylating agent - when X is oxy, thio or a direct compound - is for example an acid halide of the formula Re.Xa.CO.Hal or Re.Xa..CS.Hai, wherein Xa corresponds to one of the above-mentioned values for X and wherein Hal is halogen and in particular chlorine or bromine.

If X is an imino group, then a suitable acylating agent is, for example, an isocyanate or isothiocyanate of the formula Re.KCO or Re.N.

When an acid halide is used as the acylating agent, a suitable base such as triethylamine, N-methylmorpholine, pyridine or 2,6-lutidine is suitably used simultaneously, preferably together with a suitable inert solvent or diluent such as methylene chloride, diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane. The same or similar inert solvents or diluents are used when an isocyanate or isothiocyanate is used as the acylating agent.

When X is a direct bond, the acylating agent may also be a carboxylic acid of the formula Re.COpH, in which case in general a suitable condensing agent such as, for example, a carbodiimide (as further described in (g) below)

-17- ^fctfWU delete

or 1,1-arbonyldiimidazole, preferably together with a suitable inert solvent or diluent, as further mentioned above for use in conjunction with an acid halide.

In general, the acylations are .60 ⁰ G and expediently carried out at a temperature in the range, for example 0. _e at or near ambient temperature.

(c) Pur those compounds of formula III or IV, this is the reaction of an indole or Indazolderivats of formula VII - in which A is = CH- or -IT = - with an alkylating agent of formula VIII, in which U is a suitable leaving group, such as halogen (especially chlorine, bromine or iodine) or alkane or arenesulfonyloxy (especially methanesulfonyloxy or p_-toluenesulfonyloxy). ,

The reaction is preferably carried out in the presence of a suitable base such as an alkali metal hydride such as sodium or potassium hydride in a suitable inert solvent or diluent such as tetrahydrofuran, 1,2-dirnethoxyethane, N-methylpyrrolidone or N, N-dimethylformamide. Alternatively, the indole or indazole derivative of Formula VII may be used in the form of its preformed anhydrous alkali metal salt, such as by preliminary reaction with a molecular equivalent of a suitable 3ase such as sodium or potassium methoxide or hydride or butyl lithium; In this case, a wider range of conventional solvents or diluents for the reaction with the alkylating agent of formula VIII

253 6 y

be used. In any event, the alkylation is generally carried out at a temperature in the range, for example, -10 to 40 ° C, conveniently at or near ambient temperature.

(• d) For those compounds of the formula. I, in which Z corresponds to a 1 (H) -triszol-5-yl radical of the formula II (Rh = H), this is the reaction of a cyano derivative of the formula IX with. an azide.

A particularly suitable azide is, for example, an alkali metal allazide such as sodium or potassium azide, preferably together with an ammonium halide such as ammonium chloride, ammonium bromide or triethylammonium chloride. The reaction is preferably carried out in a suitable polar solvent such as Ii, N-dimethylformamide or N-methylpyrrolidone, and conveniently at a temperature in the range, for example 50 ... 160 ^0C.

(e) For those compounds of formula I in which Ra corresponds to a halogen, this is the halogenation of the corresponding compound of formula I in which Ra is hydrogen.

The reaction may be carried out using a conventional halogenation method known in the art of heterocyclic chemistry that is compatible with the other groups present in the compound. Thus, for example, a chloro or bromo substituent can be incorporated by reacting N-chloro or I-i-bromosuccinimide or a comparable N-halo reagent conveniently in a suitable solvent, such as, for example

a halocarbon solvent such as chloroform or carbon tetrachloride at a temperature in the range of, for example, 20 ... 100G.

(f) For a compound of formula I in which Re.L is Re.X.GO.NH. or Re.X.CS.NH where X is oxy or thio, this is the reaction of one of the group Isocyanates or isothiocyanates of the formula X in which Xb is oxygen or sulfur, with the appropriate compound of the formula Re.XH, for example an amine of the formula Re.UHp » ^an alcohol of the formula Re.OH or a thiol of the formula Re. SH.

Generally, the process is carried out at a temperature in the range of, for example, 0-60 ° C and conveniently carried out in a suitable inert diluent or solvent such as methylene chloride, diethyl ether, methyl t-butyl ether, tetrahydrofuran or dioxane. The starting isocyanate or isothiocyanate of Formula X can conveniently be obtained by reaction of the corresponding amine of Formula VI with phosgene or thiophosgene (or an equivalent reagent such as trichloromethyl chloroformate to produce an isocyanate) in a conventional manner.

(g) For a compound of the formula I in which Z corresponds to a group of the formula CO.NH.SO.Rg, this is the reaction of a compound of the formula I in which Z is carboxy (hereinafter "acid of the formula I ") with a sulfonamide derivative of the formula Rg.SO.NHo ·

For example, a free acid of formula I can be treated with a suitable dehydrating agent such as dicyclohexylcarbodiimide or 1- (3- (dimethylamino) propyl) -

3-ethylcarbodiimide or with a hydrochloride or hydrobromide salt derived therefrom optionally together with an organic base such as 4- (dimethylamino) pyridine in the presence of a suitable solvent or diluent such as methylene chloride at a temperature in the range for example, 10 ... 50 ⁰ C - but preferably at or near ambient temperature - can be done.

Alternatively, a reactive derivative of an acid of formula I, such as an acid halide (such as the acid chloride), acid anhydride, or a mixed acid anhydride (such as that prepared from ΙΤ, Ν-diphenylcarboxylic acid and the acid of formula I by reaction the sodium salt of the latter with Ν, ΙΤ-diphenylcarbamoylpyridinium chloride) with an alkali metal salt (such as the lithium, sodium or potassium salt) of the appropriate sulfonamide of the formula Rg.SO ₂ NH p, conveniently at or near Room temperature and in a suitable solvent or diluent such as tetrahydrofuran, N, F-dimethylformamide or methylene chloride.

(h) For a compound of formula I wherein Ra bears a carboxy substituent and / or Rh is carboxy (1 ... 3C) alkyl or (carboxyphenyl) methyl, this is the decomposition of a corresponding ester of formula I. in which Ra is a ((1 ... 6C) alkozy) carbonyl substituent and / or ((1 ... 6C) alkoxy) carbonyl (1 ... 3C) alkyl or ((1 ... 6C) Alkoxycarbony! Phenyl) methyl.

In general, similar decomposition conditions can be used as described for method (a).

(i) For a compound of the formula I in which Z corresponds to an acylsulfonamide group of the formula CO.M.SO.sub.Rg,

ρ η ·

G is a direct bond to Z and Q is oxygen or sulfur, this is the reaction of a compound of formula XI in which Xb is oxy or thio with an isocyanate derivative of formula OGlI.SO.Rg.

The process may be carried out under conditions generally similar to those described above for process (f).

(j) For a compound of formula I in which Z is an acylsulfonamide group of formula GO.NH.SO ₂ .Rg, this is the oxidation of the corresponding acylsulfinamide of formula I in which Z is a group of formula GO.NH Corresponds to .SO.Rg. ,.

The process may be carried out using any conventional oxidizing agent known for the preparation of sulfides of sulfoxide, which is compatible with the presence of other sensitive moieties in the molecule of interest. For example, hydrogen peroxide, gaseous oxygen in the presence of platinum, potassium permanganate, chromium trioxide or alkaline persulfate may be used, conveniently in a suitable polar solvent or diluent such as aqueous acetone or tetrahydrofuran and at the lowest possible temperature, at a convenient reaction rate coupled - for example, near or at ambient temperature, d. H.

in the range of 15 .. · 30 ⁰ C - takes place.

(k) For a compound of formula I in which Ra is (2 ... 6C) alkyl bearing optionally a carboxy or ((1 ... 4C) alkoxy) carbonyl substituent this is Reducing the corresponding compound of formula I in which Ra is (2 ... 6C) alkenyl which partially bears a carboxy or ((1 ... 4C) alkoxy) carbonyl substituent.

The reduction can generally be carried out using conventional hydrogenation conditions, for example using hydrogen at a pressure of, for example, 1 to 4 bar in the presence of a suitable catalyst such as a noble metal catalyst such as palladium or platinum, suitably on an inert A carrier such as carbon in a suitable solvent or diluent such as a (1 ... 4C) alkanol (such as methanol or ethanol) or in tetrahydrofuran, optionally in the presence of water and at a temperature in the range of, for example, 15 .. .35 ⁰ C.

When a pharmaceutically acceptable salt is required subsequent to any of the above procedures, this may be accomplished by reaction of the acidic form of the compound of formula I with a physiologically acceptable cation-providing base, or by any other conventional procedure.

The required starting materials for the procedures described above can be prepared using standard organic chemistry techniques and analogies with the synthesis of known, structurally similar compounds

getting produced. Thus, for example, the starting esters of formula V can be prepared using the procedure described above for process (b), but starting from the analogous amine of formula VI (ie in which Z corresponds to a group of the formula -COpRi) or the general procedure described for the above process (c) can be used, starting from the indole or indazole derivative of the formula VII and the analogous alkylating agent of the formula VIII (ie in which Z is a group of the formula -GOpRi corresponds). The starting amines of formula VI can be prepared, for example, by alkylating a suitable j-nitroindole or nitroindazole derivative of formula XII using an alkylating agent of formula VIII in the presence of a suitable base such as potassium carbonate in a solvent such as acetone followed by conventional reduction to obtain the required amine obtained from the formula VI. Moreover, the amines of the formula VI or the corresponding esters (ie those in which Z corresponds to a group of the formula -CO ₂ Ri) can be suitably used in situ in the above acylation process (b), if used herein Acylating agent is a free carboxylic acid of the formula Re.COpH - is obtained by reduction of the corresponding kitro compound such as by catalytic Hydriei ^ ung or by using a reducing metal system such as iron or zinc dust in an excess of the acid of the formula Re.COpH ,

The starting indole and indazole derivatives of the formula VII can be obtained, for example,

(i) from the nitro derivatives of formula XII, d. h by conventional reduction to the corresponding amine of formula XIII followed by acylation using the same general procedure as described in (b) above; or

(ii) - when Re.L is Re.NH.CO- - from the appropriate indole or Indazolearbonsäureester of formula XIV in which Ri has the abovementioned meaning (preferably methyl, ethyl or phenyl) by reaction with the appropriate amine of the formula Re.NH ₂ .i. i ^e starting materials of the formula XI can be prepared, for example, in analogy with the method described in the embodiment 301 below.

The generation of the majority of the above starting materials is illustrated in the accompanying embodiments.

The ester precursors of formula V are novel and valuable intermediates which are taught as a further feature of the present invention.

As already mentioned, the compounds of the formula I have leukotriene antagonist effects. So they act on the actions of one or more known as Leukotriene Arachidonsäuremet about en such. BC, D, and / or E, which are known to be strong spasmogens (especially in the lung) which enhance vascular permeability and those associated with the pathogenesis of asthma and inflammation (see JL Marx , Science, 1982, 215 , 1380-1383) as well as endotoxic

and traumatic shock. The compounds of the formula I are therefore suitable for the treatment of diseases in which leukotrienes are involved and in which an antagonistic effect on the leukotriene effect is desired. Such diseases include, for example, allergic pulmonary deficiency disorders such as asthma, hay fever and allergic rhinitis as well as certain inflammatory diseases such as bronchitis, ectopic and atopic eczema, psoriasis as well as vasospastic cardiovascular disease and endotoxic and traumatic shock states.

In addition, the compounds of formula I are valuable as pharmacological tools and standards for the development and standardization of new disease models as well as bioassays for their strong properties as leukotriene antagonists. the use in the development of new therapeutic agents for the treatment of the diseases in which the leukotrienes are involved.

When used to treat one or more of the above-mentioned diseases, a compound of formula I will generally be administered in the form of a suitable pharmaceutical composition comprising a compound of formula I as defined above together with a pharmaceutically acceptable diluent or carrier the composition of the selected particular route of administration is adjusted. Such compositions are taught as a further feature of the present invention. They may be recovered using conventional methods and excipients and be in a variety of dosage forms. For example, they may be in the form of tablets,

Capsules, solutions or (suspensions for oral administration, in the form of suppositories for rectal administration, in the form of sterile solutions or suspensions for administration by intravenous or intramuscular injection or infusion, in the form of aerosols or spray solutions or suspensions for administration by Inhalation and in the form of powders together with pharmaceutically acceptable inert solid diluents such as lactose for insufflation administration.

For oral administration, a tablet or capsule containing up to 250 mg (and typically 5 to 100 mg) of a compound of formula I may suitably be used

Similarly, for intravenous or intramuscular injection or infusion, a sterile solution of suspension may be conveniently used containing up to 10 % M / M (and typically 0.05 to 5 % M / M) of a compound of Formula I.

The dose of the compound of formula I to be administered will necessarily be varied according to well-known principles in the art, taking into account the route of administration and the severity of the disease as well as the size and age of the patient being treated. In general, a compound of formula I is administered to a warm-blooded animal (such as man) in a manner such that a dose in the range, for example, 0.05 to 25 mg / kg (and usually 0.5 to 10 mg / kg) be administered.

The leukotriene antagonist properties of a compound of formula I can be demonstrated using standard assays. For example, they can be demonstrated in vitro using the standard preparation of alewollow tracheal strips as described by Krell ( J, Pharmacol. Exp. Ther. 1979, 211 , 436). In this procedure, strips of tracheal tissue are applied in groups of eight, using four strips each as time / carrier controls and four strips for each of the test compounds. All strips are exposed to 8x10 M leukotriene E. (LTE.), Following which the reaction is recorded after a 50 minute equilibration period. This LTE concentration is that which corresponds to about 70-80 % of the maximum agonist activity in this tissue. The LTE is washed out for 40 ... 45 minutes, after which the procedure is repeated twice more to ensure that the LTE. reproducible reactions can be achieved. In the same procedure leukotriene C. (LTC _A ) or D. (LTD.) May be used at a concentration of 8x10 M instead of LTE. be used »

Once the tissue reproducibility has been determined, the test compounds are added to four baths after the 40 ... 45 minute washout period. After a 10 minute incubation with test compound or vehicle, 8x10 ^J M LTE., LTD. or LTC. added, whereupon the reaction is recorded. The percentage inhibition by the test compound or the percentage change in the vehicle controls are calculated for each tissue according to the following equation: % Inhibition = 100 χ (mg increase in rise of the preceding

reaction minus mg increase in the presence of the compound) divided by mg increase in the previous reaction. The mean percent change for vehicle controls and test compound are calculated and tested by Student's t-test for unpaired data for the presence of significant differences. The tissues exposed to the test compounds were reassessed for their reactivity with LTE., LTD., After a 25-minute leaching period. or LTG, tested. If the reactivity of the device in this case corresponded to the reactivity before the treatment with the test compound, then additional investigations were made. If the reactivity was not restored by the washout, then the tissues were discarded. For all determinations, the cyclooxygenase inhibitor indomethacin is present at a concentration of 5x10 "M.

In general, the compounds of formula I exhibit statistically-confirmed activity as LIC.-, LTD ₄ and / or ΙΤΞ antagonists in the above assay at a concentration of about 10 M or substantially lower.

The selectivity of action as leukotriene antagonists against nonspecific depressant smooth Ivluskels can also be represented by the above i n - in vitro method using the non-specific spasmogen barium chloride at a concentration of 1.5x10 M, again in the presence of 5x10 "M Indomethacin.

Activity as a leukotriene antagonist may also be detected in vivo , for example, in a routine guinea pig aerosol test, in which horseradish pigs (generally between 15 minutes and 1 hour), prior to aerosol administration of leukotriene LTD, (30 the effect of the test compound on the average time of leukotriene-initiated change in respiratory behavior (such as the onset of respiratory distress) is recorded and compared with that in untreated control barrow pigs. In general, the compounds of formula I produce a significant increase in the time of onset of leukotriene-initiated respiratory changes after either oral, intravenous or intraperitoneal administration at or well below 100 mg / kg, without evidence of unexpected side effects at multiple of the minimum effective dose become. For example, the compounds described in Examples 262, 158 and 168 produced significant increases in time to onset of leukotriene D, respiratory distress, after 1 to 2 hours prior to leukotriene challenge, at dosages of approximately 5 mg / kg, 43 mg / kg, respectively 50 mg / kg were administered orally.

Execution example

The invention will be illustrated below with reference to the following, non-limiting embodiments, in which --i unless otherwise indicated

(i) all operations at room or ambient temperature, i. H. were carried out at a temperature in the range of 18 ... 25 ° G;

(ii) evaporating the solvent using a rotary evaporator in vacuo at a bath temperature of up to 50 C;

(iii) flash chromatography on Merck silica gel (type 9385) and column chromatography on Merck Kieselgel 60 (type 7734);

(These substances were purchased from E. Merck, Darmstadt, FRG.); Thin Layer Chromatography (TLC) was performed on Analtech 0.25 mm silica gel UHLP plates (Item 21521) available from Altech, Iiewark, DE, USA;

(iv) the melting points are given uncorrected, a decomposition being indicated by "Z";

(v) all end products are essentially pure by TLC;

(vi) the yields are given for the purpose of illustration only and, in the case of crystalline end-products, they refer to the mass of the recrystallized solid, unless otherwise stated

x)

a ^y takes place; Carboxylic acid Sndprodukte were recrystallized example of Bthylacetat / hexane and

(vii) the MviR data may be in the form of delta values

for the major diagnostic protons, in ppm relative to tetramethylsilane (TMS) as an internal standard determined at 80 MHz or 250 MHz using CDCl 3 or dg-DMSO as the solvent; the conventional abbreviations are used for the signal shape, ie ζ. For example, s, singlet; d, doublet; m, multiplet br, wide etc.

Embodiment 1

A stirred solution of 0.45 g of methyl 4 (6-aniynolindol-1-ylmethyl) -3-methoxybenzoate (A) in 10 ml of methylene chloride was cooled to 0 C and 0.30 ml of triethylamine and then 0.22 ml of hexanoyl chloride. The resulting solution was stirred at 0 ^° C. for 15 minutes and then at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and poured into cold water. The organic layer was washed successively with 10% v / v hydrochloric acid, water and brine; dried (MgSO.) and evaporated. The residue was purified by means of flash chromatography on a 4 x 18 cm silica gel column using 35 infer (v / v) ethyl acetate in hexane as eluent to give 0.36 g (61%) of methyl 4- (6-hexanarnidoindol-1-ylmethyl ) -3-methoxybenzoate as white pesticide; miir; 0.9 (t, 3H, CH ₃ CH _2), 1.4 (m, 4H, CH ₃ CH ₂ CH _2), 1.7 (m, 2H, 00.CH ₂ CH _2), 2.3 ( t, 2H, CO.CH ₂ ), 3.9 (s, 3H, OCH ₃ ), 4.0 (s, 3H, OCH ₃ ), 5.3 (s, 2H, WCH ₂ ), 6.5 ( d, 1H, H ³ -Indol), 6.6 (d, 1H, In-MeCC ₆ H ₃ ), 6.9 (d, 1H, H ⁵ -indole), 7.1 (d, 1H, H ² -Indol), 7.2 (br s, 1H, NH), 7.5 (d, 1H, £ - & eO: CgH ₃ ), 7.6 (m, 2H)., 8.0 (br s, IH , H ⁷ -indole).

The aminoester A was obtained as follows:

(a) A solution of 4.0 g of 6-nitroindole and 6.71 g of methyl 4-bromomethyl-3-methoxybenzoate (B) in 125 ml of dry acetone was treated with 4.0 g of anhydrous potassium carbonate. The mixture was heated at reflux for 48 hours. The cloudy mixture was evaporated. The residue was suspended in ethyl acetate and the gum was removed by filtration. The filtrate was evaporated and the residual oil was purified by flash chromatography on a 6 × 30 cm silica gel column using 50% (V / 7) methylene chloride, in hexane as eluent, 8.0 g (95 %). To give methyl 3-methoxy-4- (6-nitroindol-1-ylmethyl) benzoate (0) as a light yellow powder; HMR: 3.9 (s, 3H, OCH _3), 4.0 (s, 3H, OCH _3), 5.4 (s, 2H, HCH _2), 6.7 (dd, 1H, H ³ -indole ), 6.8 (d, 1H, m-Me0.CgH ₃₎ 7.4 (d, 1H, H ² -indole), 7.5 ... 7.7 (m, 3H), 8.0 ( dd, 1H, H ⁵ -indole), 8, -3 (br s, 1H, H ⁷ -indol).

(b) A solution of 1.38 g of C in 15 ml of ethyl acetate, which

2 drops of 20% (v / v) acetic acid in ethyl acetate was added to a suspension of 0.34 g of prereduced 10% MAI palladium on charcoal in 5 ml of ethyl acetate. The mixture was shaken under a hydrogen pressure of 3.45 bar for 24 hours and then filtered through diatomaceous earth. The residue was washed with hot chloroform and the combined filtrate and washings were evaporated to give 1.19 g (95 %) of methyl 4- (6-aminoindol-1-ylmethyl) -3-methoxybenzoate (A) as a to give lohfarbe- NEN powder; IiR: 3.6 (br, 2H, NH), 3.9 (s, 3H, OCH ₃ ), 4.0 (s, 3H, OCH ₃ ), 5.3 (s, 2H, NCH ₂ ), 6.4 (d, 1H, H ³ -indole), 6.5 (s, 1H, H ⁷ -indole), 6.6 (m, 2H), 6.9 (d, 2H

H ² indole), 7.5 (m, 3H).

The starting bromoethyl compound B itself was recovered as follows:

(c) A solution of 6.0 g of 3-methoxy-4-methylbenzoic acid in 120 ml of methanol was treated with 6 ml of acetyl chloride and stirred for 36 hours. The solution was evaporated. The residue was dissolved in 100 ml of methanol, whereupon the solution was evaporated. This procedure was repeated to give 6.34 g (98 %) of methyl 3-methoxy-4-methylbenzoate (D) as a colorless oil; M ¹ IRi2.2 (s, 3H, CHo), 3.9 (2s, 6H, OGH-,), 7.1 (d, 1H, m-MeO.C.Hj, 7.5 (m, 2H ).

(d) A stirred solution of 121.2 g D in 1.4 L carbon tetrachloride was warmed under careful reflux with a 35 O watt tungsten lamp and subjected to an air purge by means of a T-tube connected to a water jet pump. Over 4 hours, a solution of 107.2 g of bromine in 500 ml of carbon tetrachloride was added dropwise. Evaporation of the solvent gave a light yellow pesticide, which was triturated with 500 ml of 10% (v / v) ether in hexane. The Peststoff was collected by filtration to give 111.7 g (64%) to give methyl 4-bromomethyl-3-methoxybenzoate (B) in the form of a pale yellow Peststoffes, melting point 87 ... 90 ⁰ C; MIR: 3.9 (2s, 6H, OG ¹ H ₃ ), 4.5 (s, 2H, BrCH ₂ ), 7.4 (m, 3H, aromatic H).

Exemplary embodiments 2 to 8

Using a similar procedure as described in Example 1, were - starting

S * V \ J

from the appropriate acid chloride of formula Re.CO.Cl - the following Eater of formula 1 obtained: -

Ausfhr

 bspl

re

yield

Partial Mir

propyl

heptyl

ETonyl

100

96

70

1,3-pentadiene5 ^r l 60

benzyl

2-phenylethyl

3-phenylpropyl

79 41

0.9 (t, 3H, ₂₃

2.6 (m, 2H, CH ₃ CH _2), 2.3 Ct, 2H, CCCH ₂₎

0.9 (t, 3H, CH ₂ CH ₃ ), 1.2 (m, 8H), 1.6 (m, 2H, CCCH ₂ CH ₂ ), 2.3 (t, 2H, CCCH ₂ )

0.9 (t, 3H ₁ CH ₂ CH ₃ ), '1.3 (m, 12H), 1.7 (m, 2H, 00.CH ₂ CH ₂ ), 2.4 (t, 2H, CO. CH ₂ )

1.9 (m, 3H, CHCH ₃ ),

5.8 ... 6.2 (m, 3H, vinyl)

DMSOs 3.6 (s, 2H, C (O) CH ₂ )

2.7 (t, 2H, PhCH ₂ ), 3.0 (t, 2H, CO.CH ₂ )

2.0 ... 2.4 (m, 4H, 2.7 (t, 2H, CO.CH ₂ )

^J Note: Acid chloride was prepared in situ with thionyl chloride

Embodiment 9

A solution of 0.318 g of 2-phenylbutyric acid and 0.335 g of 1,1'-carbonyldiimidazbl in 2 ml of iviethylene chloride was heated under reflux for 30 minutes and then treated with a solution of 0.5 g of methyl 4- (6-aminoindol-1-ylmethyl). 3-methoxybenzoate (A) in 2 ml of methylene chloride. The

Mixture was heated at reflux for 30 minutes, stirred for 24 hours at room temperature and then diluted with ethyl acetate. This organic solution was washed successively with 10% V / 7 hydrochloric acid, water, brine, dried (MgSO 4) and evaporated. The residue was purified by flash chromatography on a 4 x 18 cm silica gel column using 60% v / v ethyl acetate in hexane as eluent to give 0.493 g (74 %) of methyl 3-methoxy-4- (6 (2-phenylbutanamido) indole 1-ylmethyl) benzoate in the form of a white pesticide; MvIRi 0.9 (1, 3H, CH ₂ CH ₃ ), 2.0 (m, 2H, CH ₃ CH ₂ ), 3.4 (m, 1H, PhCH), 3.9 (s, 3H, OCH ₃ ), 4.0 (s, 3H, OCH ₃ ), 5.3 (s, 2H, IiCH ₂ ), 6.5 (d, 1H, H ³ -indole), 6.7 (m, 2H), 7 , 1 (d, 1H, H ² -Indol), 7.2 (br, 1H, IJH), 7.4 (m, 8H, aromatic H), 7.9 (br s, '1H, H ⁷ -Indol ) ..

Exemplary embodiments 10 to, 14

Using a procedure similar to that described in Example 9 but starting with the corresponding carboxylic acid of the formula Re.CO ₂ H, the following esters of formula 1 were obtained:

Ausf.- bspl. - Re yield 2.0 (M, Partial MkR HC = C), 10 3-butyn-1-yl 95 2.6 (br 1H, ^ f it ) OU · OiIp UIIp J 3.7 (S, s CO.CH ₂ ) 11 4-chlorobenzyl 100 3.7 . (S, 2H, CO.CH ₂ ) 12 4-CF - benzyl 62 5.1 . (S, 2H, CO. CH) ,, 13 benzhydryl 64 7-, 3 (S, 1H, , (G ₆ H ₅ ) ₂ ) 3.9 (M, 1 OH 2 OCH ₃ + 14 2-Thieny! Methyl 47 CO. CH ₂ ) 8H,

Exemplary embodiment I5

Using an analogous procedure as described in Example 1 but starting from 6-nitroindoline, methyl 4- (6-hexanamidoindolin-1-ylmethyl) -3-methoxybenzoate was prepared in the form of an amber syrup in 28 % yield. won; MMRi 0.9 (br t, 3H, CH ₃ GH ₂ ), 1.3 (m, 4H, GH ₃ GH ₂ CH ₂ ), 1.7 (m, 2H, CO.CH ₂ GH ₂ ), 2, 3 (t, 2H, GCCH ₂ ), 3.0 (m, 2H, NCH ₂ CH ₂ ), 3.5 (m, 2H, NGH ₂ CH ₂ ), 3.9 (s, 6H, OCH ₃ ), 4.3 (s, 2H, NCH ₂ ), 6.6 ... 7.0 (m, 3H, aromatic-H), 7.3 ... 7.7 (m, 3H, aromatic-H).

Embodiment 16

A solution of 2.50 g of methyl 4- (6-aminoindol-1-yl-diethyl) -3-methoxybenzoate (A) in 20 ml of methylene chloride was mixed with 0.92 ml of butyl isocyanate and then stirred for 72 hours. Evaporation gave an oil which solidified on trituration with ethyl acetate to give 3.3 g (100 %) of methyl 4- (6-N'-butylureidoindol-1-ylmethyl) -3-methoxybenzoate; MkRs 0.9 (m, 3H, CH ₂ CH ₃ ), 1.3 (m, 4H, CH CH CHg), 3.2 (br q, 2HNHCH ₂ ), 3.9 (s, 3H, OCH ₃ ) , 4.0 (s, 3H, OGH ₃ ), 4.9 (br t, 1H, .CH ₂ NH), 5.3 (s, 2H, NCH ₂ ), 6.4 (br s, 1H, ArNH ), 6.5 (d, 1H, H ³ -indole), 6.7 (d, 1H, m-MeÖCgH-), 6.8 (dd, 1H, H ⁵ -indole), 7.1 (d, 1H, H ² -Indol), 7.5 (m, 4H).

Embodiment 17 to 20

Using an analogous procedure as described in Example 16, but starting from the appropriate isocyanate or isothiocyanate, the following esters of formula 2 were obtained:

- ι

Ausf.-bspl.

Xa

Yield %

Partial HMR

17 -t-butyl 18 hexyl

19 benzyl

20 butyl

46

85

100

68

1.3 (s, 9H, 1-Bu), 4.6 (brs, 1H, t-BuHH)

0.9 (m, 3H, CH ₂ CH ₃ ), 1.3 (m, 8H) 3.2 (br q,

2H, IJHCH ₂ ), 5.0 (br t, 1H,

4.4 (d, 2H, PhCH ₂ ), 5.1 (br t, 1H, CH

0.9 (m, 3H, CH ₂ CH ₃ ), 1.4 (m, 4H, 'CH ₃ CH ₂ CH ₂ ), 3.6 (br q, 2H, NHCH ₂ ), 5.9 (br , CH ₂ HH).

Embodiment 21

Using a similar procedure as described in Example 9, but starting from cyclopentanecarboxylic acid instead of 2-phenylrbutyric acid, methyl 4- (6-cyclopentanecarboxamidoindol-1-ylmethyl) -3-niethoxybenzoate was prepared as a pesticide in 56 % yield recovered; Partial CMR: 1.5-2.0 (br m, 8H, (CHg) ₄ ), 2.5 ... 2.8 (br m, 1H, (CHg) ₄ CH), 7.2 ( br s, 1H, HH).

Embodiment 22

A solution of 3.0 g of methyl 4- (6-aminoindole-1-ylmethyl) -3-methoxybenzoate (A) in 48 ml of methylene chloride was cooled to 0 ⁰ C and treated with 2.02 ml of triethylamine and with the aid

Finally, treated with 1.35 ml of butyl chloroformate. The resulting solution was stirred at 0 C for 15 min and then stirred at room temperature for 24 h. A precipitate was removed by filtration. The filtrate was evaporated and the residue was purified by flash chromatography on a 6 × 25 cm silica gel column using 35 % V / V. Ethyl acetate in hexane as eluent. In this way, 1.96 g (45 %) of methyl 4- (6 (IT-butoxycarbonyl) aminoindol-1-ylmethyl) -3-methoxybenzoate was recovered in the form of an off-white solid. BMRj 0.9 '(t, 3H, CH ₂ GH ₃ ), 1.5 (m, 4H, CH ₃ CH ₂ -CH ₂ ), 3.9 (s, 3H, OCH ₃ ), 4.0 (m , 3H, OCH ₃ ), 4.2 (t, 2H, OCH ₂ ), 6.5 (dd, 1H, H ^ -indole), 6.7 (m, 2H), 6.9. (Dd, 1H , H ⁵ -indole), 7.1 (d, 1H, H ² -indole), 7.5 (m, 4H).

Embodiment 23

To a stirred slurry of 24 mg sodium hydride (washed out) in 1 ml dry dimethylformamide (DMF) was added a solution of 230 mg 6-hexanamidoindole (Ξ) in 8 ml DMF. The dark mixture was stirred for 30 minutes, then treated with a solution of 275 mg of methyl 4-bromoethyl benzoate (F) in 1 ml DIvIF and stirred overnight. The reaction was quenched by adding saturated aqueous ammonium chloride, poured into water and extracted with ethyl acetate. The pooled extracts were washed with water, dried (MgSO 4) and evaporated to give 300 mg (79 %) of methyl 4- (6-hexanamidoindol-1-ylmethyl) benzoate as a dark oil; CLOCK: 0.9 (m, 3H, CH ₂ CH ₃ ), 1.4 (m, 4H, CH ₃ CH ₂ CH ₂ ), 1.7 (m, 2H, CO.CH ₂ CH ₂ ), 2, 3 (t, 2H, CO.CH ₂ ), 3.9 (s, 3H, OCH ₃ ), 5 _t 3 (s, 2H, ITCH ₂ ), 6.5 (d, 1H, H ³ -indole), 6.9 (dd, 1H, H ⁵ -indole), 7.0 ... 8.0 (m, 8H).

The starting material (E) was obtained as follows:

(a) A yellow solution of 5.2 g of 6-nitroindole in 150 mL of ethyl ac et al was added to 1.25 g of previously reduced 10% W./IHi palladium on charcoal catalyst in 50 mL of ethyl acetate. The mixture was shaken under 3.45 bar hydrogen overnight and then filtered through diatomaceous earth. The residue was washed with 150 ml of hot chloroform and the combined colorless filtrate and washings were evaporated to give a quantitative yield of 6-aminoindole as a dark oil; MR: 3.5 (br s, 2H, IIH ₂ ), 6.4 (m, 1H, H ³ ), 6.5 (m, 2H,

H ⁵ + H ⁷ ), 7.0 (dd, 1H, H ² ), 7.4 (d, 1H, H ⁴ ), 7.8 (br, 1H, NH).

(b) A solution of 4.24 g of 6-aminoindole in 300 ml of methylene chloride was stirred at 0 ⁰ C and treated with 5.4 ml of triethylamine and then added 4.2 ml of hexanoyl chloride "The dark mixture was stirred for 1 hour and then filtered to remove a white precipitate. The silica was diluted with methylene chloride, then washed successively with 10% M / V sodium bisulfate water and brine, dried (MgSO 4) and evaporated. The residue was crystallized from ethyl acetate and hexane to give 6-hexanamidoindole (E) as a white solid. Partial evaporation of the mother liquor gave a second crop of pesticide, resulting in a total yield of 4.5 g (65 %) ; NMR: 0.9 (t, 3H, GH ₃ ), 1.4 (in, 4H, GH ₃ CH ₂ CH ₂ ), 1.8 (m, 2H, CO-CH ₂ CH ₂ ), 2.4 ( t, 2H, CCCH ₂ ), 6.5 (m, 1H, H ³ ), 6.8 (dd, 1H, H ⁵ ),

^{2 4}

(m, 2H, CO.NH + H ² ), 7.5 (d, 1H, H ⁴ ), 8.1 (bs, 1H, H *), 8.3 (br, 1H, NH) ₀

The starting bromoester (P) was prepared as follows;

To 200 ml of methanol at 0 ⁰ G (o) were added with stirring over 20 min to? / eg 48.4 g of 4-methylbenzoyl chloride, ^ fter the addition the reaction mixture was stirred for one hour at room temperature. The methanol was evaporated and the residue was distilled to give 43 g of methyl 4-meth-. ylbenzoate as a colorless liquid, boiling point 103 ... 108 ⁰ C at 20 mm Hg to give.

(d) Bromination of methyl 4-methylbenzoate using the part (d) of Embodiment 1 described procedure gave a 97th% yield of methyl 4-bromomethylbenzoat (F) in the form of an oil, boiling point 88 ... 95 ⁰ C at 0.16 mm Hg, which crystallized after distillation.

Embodiment 24

Using a procedure similar to that described in Example 23 but replacing the bromoester (P) with methyl 5-chloromethyl-furan-2-carboxylate, methyl 5- (6-hexanamidoindol-1-ylmethyl) furan-2-one was added. carboxylate recovered in 34% yield as a white pesticide; partial HER: 3.9 (s, 3H, OCH.,), 5.3 (s, 2H, HCH ₂ ), 6.2 (d, 1H, H ⁴ -furan).

Embodiment 25

Starting from 2,3,5-trimethyl-6-nitroindole (G) and using methods analogous to those described in Example 1, methyl 4- (6-hexanaffiido-2,3,3-triynethylindol-1-ylmethyl) - was obtained. O-inethoxyb.enzoat in a yield of

40% obtained as a greenish pesticide; HMR: 0.9 (m, 3H, CH ₂ CH ₃ ), 1.3 (m, .., 4H, CH ₃ CH ₂ CH ₂ ), 1.7 (m, 2H, CCCH ₂ CH ₂ ), 2 , 2 ... 2.4 (11H, 3CH ₃ + CCCH _2), 3.9 (s, i3H, OCH _3), 4.0 Cs, 3H, OCH _3), 5.3 (s, 2H, ITCH ₂₎ β, 3 (d, 1H, 51-MeO-C ₆ H _3, 6.9 (br, 1H, ITH) ,. 7.3 .. .7,6. (3H, aromatic H), 7 , 7 (br s, 1H, H ⁷ -Indol).

The starting indole G was obtained as follows:

(a) A vigorously stirred slurry of 4.0 g of powdered 4-methyl-3-nitroaniline in 8.4 ml of concentrated hydrochloric acid and 30 ml of water was cooled to 0 C and added dropwise to a solution of 2.4 g of sodium nitrite in 4 ml of water treated at such a rate that the temperature of the reaction mixture s below 5 C remained. A small amount of insoluble material was removed by rapid filtration. The clear yellow mushroom was immediately added to a vigorously stirred solution of 9.0 g of sodium sulfite and 0.8 g of sodium hydroxide in 30 ml of water at 0 ° C. The resulting dark mixture was stirred at room temperature for one hour and then treated with concentrated hydrochloric acid until the color lightened and a precipitate appeared. The mixture was then warmed to 40 ^° C, acidified to pH 1 and allowed to stand at room temperature overnight. The orange precipitate was collected by filtration and. in 50 ml of hot water to give a dark red solution, which was filtered hot and diluted to 100 ml with concentrated hydrochloric acid. After cooling, 2.12 g of 4-l-ethyl-3-nitrophenylhydrazine hydrochloride (H) was collected with a slight contamination by sodium chloride by filtration in the form of a light brown pesticide and used directly.

(b) a mulled at 60 ⁰ G mixture of 4, OGH and 60 ml of anhydrous ethanol was added 2 ml of methyl ethyl ketone added. The resulting red solution was heated under reflux for 2 hours. Filtration of the hot solution removed a small amount of white pesticide. The filtrate was evaporated. The recovered gummy orange residue of the hydrazone was mixed with 50 ml of acetic acid and 3.3 ml of boron trifluoride etherate. The mixture was heated under reflux for 2 hours, after which the pesticide was removed by hot filtration. The dark green filtrate was evaporated to a green oil, which was dissolved in ethyl acetate. The solution was washed with 10 tigern M / V of sodium carbonate and then washed by means of flash chromatography on a 6 χ 20 cm column of silica gel using 30% v / v ethyl acetate in hexane. Evaporation of the early fractions yielded 0.64 g (16%) of 2,3,5-trimethyl-6-nitroindole (G) as an orange solid; MiR: 2.3 (s, 3H, GH _3), 2.5 (s, 3H, GH _3), 2.7

(s, 3H, CHO, 7.3 (s, 1H, H ⁴ ), 8.0 (br, 1H, ITH), 8.1 (s,

1H, H). Later fractions yielded 0.43 g of 2,3 ', 5-tri-

methyl 4-nitroindole in the form of an orange solid; MSi: 2.1 (s, 3H, CH _3), 2.4 (2s, 6H, 2GH _3), 6.9 (d, IH), 7.3 (d, 1H) and 7.9 (br, 1H, UH).

Exemplary embodiments 26 to 32

Using a similar procedure as described in Example 1, the following esters of formula 3 were obtained, starting from the appropriate 4- or 6-aminoindole derivatives of the formula 4

and the latter derivatives were obtained from known ilitro-indoles using the procedures described in the preceding embodiments:

Ausf.-bspl.

R, Ra

re

Yield Partial MvIR

26 GH. 4 pentyl 6 68 2,2 2,3 (s, (s, 3H, 3H, GH ₃ ), GH ₃ ) 27 (GH) U Cyclopentyl .O 6 90 1.55 8H, 1H, ... 1 (CH ₂ GHO) , 86> 4 >> (br hi, 5.15 (m, 28 (GH ₂ 4 pentyl 6 99 1.9 2.7 (m, (m, 4H), 4H) 2.5 .... 29 30 CH ₃ (CH) H Pentyl cyclopentyloCH ₂ 4 6 72 78 2.2 2.5 2.35 CHCH (s, (s, (br 2> 3H, 3H, s, CH ₃ ), CH ₃ ) 3H, 31 (GH ₂ 4 pentyl 4 99 1.9 2.7 (m, (m, 4H), 4H) 2.5 ... 32 (CH) pentyl 4 31 6.4. Ar + • · 8, NH) 2 (1 1H,

^; Position of amide attachment at the indole nucleus

Embodiment 33

Using the procedure described in Example 1, but starting from methyl 4- (6-aminoindazolyt-1-ylmethyl) benzoate (obtained by catalytic reduction of methyl 4- (6-nitroindazol-1-ylmethyl) benzoate (J)), methyl became 4 - benzoate (6-hexanamidoindazol-1-ylmethyl)

OB W ^ WJ

obtained in the form of a white pesticide; Melting point 122.5 ... 123 ⁰ C

The starting nitroester (J) was obtained as follows:

A mixture of 3.7 g of sodium. 6-nitroindazolide, 4.58 g of methyl 4-bromomethylbenzoate (P) and 120 ml of acetone was heated under reflux for 54 hours in a nitrogen atmosphere and then diluted with 250 ml of ethyl acetate and 40 ml of 50 successive M / V brine. The organic layer was separated, washed with brine, dried (MgSO 4) and evaporated to give a brown pesticide. Early fractions of the chromatograph of the pesticide on a Waters 500 HPLC column (SiO ₂ , 25% V / V ethyl acetate in hexane) yielded a pest that was crystallized from ethyl acetate to yield methyl 4- (6-nitroindazol-1-yl). -methylbenzoate (J), in the form of light yellow needles, 1.71 g (28%) melting point 171 i ... 172.5 ⁰ C; Partial ¹³ C NMRi 134.10 (C-3).

Embodiment 34

A mixture of 0.505 g of methyl 4- (6-hexanamido-2,3-dimethylindol-1-ylmethyl) -3-methoxybenzoate, 0.29 g of lithium hydroxide hydrate, 7 ml of tetrahydrofuran, 2 ml of methanol and 2 ml of water was stirred overnight. The mixture was then evaporated. The recovered white pesticide was dissolved in 40 ml of water. Acidification of this homogeneous alkaline solution by dropwise addition of 10% v / v hydrochloric acid gave a fine white precipitate, which was collected by filtration and recrystallized from ethyl acetate / hexane. In this way, 0.33 g (68 %) of A- (G-

Hexanamido-2,3-dimethylindol-1-ylmethyl) -3-niethoxybenzoic acid in the form of a white powder; Melting point 220 ... 222 (Z) ⁰ G; Microanalysis found: G, 71.07; H, 7:14; IT, 6.38 % \ G ₂₅ H ₃₀ H ₂ O ₄ requires: G, 71.07; H, 7,16; N, 6.63 %. '

Exemplary embodiments 35 to 66

Using the general procedure described in Example 34, the following acids of Formula 5 can be obtained by hydrolysis of the corresponding methyl esters of Formula 1:

Ausf.- "-Smelt-. yield

bspl. ^e point ( ⁰ C). (%)

35 pentyl 221 ... 223 (Z) 39 36 propyl 225 ... 228 24 37 heptyl 200 ... 201 40 38 nonyl 194 ... 196 74 39 • 1.3-pentadienyl 238 ... 240 (Z) 27 40 benzyl   249 ... 250 29 41 2-phenylethyl 225 ... 227 62 42 3-phenylpropyl 186 ... 188 49 43 1-phenylpropyl 215 ... 216 52 44 3-3utyn-1-yl 230 ... 231 34 45 ' • 4-chlorobenzyl 225 45 46 4-Benzyl-CFo > 250 49 47 benzhydryl 262 ... 263 39 48 2-Thieny! Methyl 244 ... 245 62

Similarly, starting from the corresponding methyl ester (Example 15) 4- (6-hexahamido-

indolin-1-ylmethyl) -3-niethoxybenzoic acid (Example 49). recovered as a solid, mp 145-148 (Z) ⁰ C, yield 39 %.

As an example, the following acids of formula 6 were obtained from the appropriate methyl ester starting materials.

Ausf.- ~ γ _v melt yield bspl. ^{Re Ά Ά &} point ( ⁰ G) {%)

50 butyl ΈΕ 0 193 .. .194 (Z) 76 51 t-3utyl NH 0 181 .. .182 30 52 hexyl NH 0 204 .. .205 (Z) 73 53 benzyl ΉΕ 0 204 .. .205 VJL 54. butyl HH S 200 .. .201 62 55 Cyelo- direct 0 271 .. .272 ⁺ 26 pentyl  binding 56 butyl 0 0 174 .. .175 21

partial hydrate.

Similarly, the following acids of formula I can be obtained i-

Ausf.- _r 1 _HA l ^ t ~ ^1Z yield

bsp. ^G -Q- ^ ° 2 ^HA Pg ^

57 4-carboxybenzyl CH 194th ..195 26 58 5-Carboxyfur-2-ylmethyl CH 200th ..202 ^x 80 59 4-carboxybenzyl N 215th ..215, 5 ^Χ 8Ί

Similarly, the following acids of formula 8 can be obtained (embodiments 60, 62, 63, 65, 66; Re = pentyl; embodiment 61: Re = cyclopentyl.O; embodiment 64: Re = cyclopentyl.CH ₉ ): -

253 6

Ausf.-bspl.

R, Ra

Amide position

re

Melting point (C)

yield

60 methyl 61 (GH) ₄ 62 (GH ₂ L 63 methyl 64 (GH), 65 (CH ₂ ) ₄ 66 CCH) .

6 6 6 4 6 4 4

5-Methyl 278 ... 280 (Z) H 254 ... 255 ⁺ H 194 ... 195 (Z) H . 190 (Z) H 288 ... 289 ⁺ H 222 ... 223 (Z) H 245

XX

46 54 14 51 65 51 37

Remarks: xx _{recrystallizes from} aqueous ethanol »

partial hydrate.

Exemplary embodiment 67

A mixture of 189 mg 6-Hexanarnido-1- (4-cyano-2-methoxybenzyl) indole, 99 mg sodium azide, 105 mg of triethylamine hydrochloride and 3.7 ml of N-methylpyrrolidone was heated at 150 ⁰ G under nitrogen for 3.5 h long mulled. On cooling, the reaction mixture was diluted with 20 ml of water, acidified to pH 1 with 10% V / V hydrochloric acid and extracted with ethyl acetate. The organic layer was extracted with 10% M / V sodium hydroxide The alkaline extract was washed with ether and then acidified The ethyl acetate extraction of this acidified aqueous layer, after evaporation, gave a pesticide, which was recrystallized from aqueous methanol 90 mg (43 %) of 6-hexanamido-1- (2-methoxy-4- (1 (H) -tetrazol-5-yl) -benzyl) -indole, melting point 210-212 g, microcrystalline analysis, found: C, 65.62; H, 6.15; N, 20.08 ^; G ₂₃ H ₂₆ N ₆ O ₂ requires: C, 66.01; H, 6.26; N, 20.28.

The starting amidonitrile was prepared as follows:

(a) To a stirred suspension of 9.97 g of refluxing 3-methoxy-4-methylbenzoic acid in 18 ml of methylene chloride was added dropwise over 45 minutes a solution of 5.35 ml of ulforesulfonyl isocyanate (1.025 equivalents) in 3 ml of methylene chloride , The resulting homogeneous, bright red solution was heated at reflux for 45 minutes, cooled in an ^A bath and treated dropwise with 9.5 mL of dimethylformamide over 15 minutes. After 30 minutes of stirring at 0 C, the orange solution to £ <i _s was poured. The organic layer was separated, washed five times with 20 ml of water, dried (MgSO 4) and evaporated. The residue was chromatographed on a Waters 500 HPLC column (SiO ₂ , 10% (v / v) hexane in toluene) to give 5.28 g (60 %) of 3-methoxy-4-methylbenzonitrile as a white To give solid, mp 51 ... 52.5 ⁰ G.

(b) A solution of 2.65 g of 3-methoxy-4-methylbenzonitrile in 90 ml of dry carbon tetrachloride was treated with 3.20 g of IJ-bromosuccinimide and 5 mg of benzoyl peroxide. The mixture was then refluxed with a 250-7 / ATV oil -frame for 15 minutes. The cooled reaction mixture ⁽⁰ ... 80 G boiling point 60) diluted with 90 ml petroleum ether, insoluble material was removed by filtration, and the filtrate was evaporated. The solid residue was recrystallized from methylene chloride-petroleum ether to give 2.64 g (65 %), 4-bromomethyl-3-methoxybenzonitrile as a white solid, m.p. 87 ... 91G.

(c) Using the procedure described in Example 23, but starting from 4-bromomethyl-

3-Niethoxybeninonitrile instead of methyl 4-bromomethylbenzoate, 6-hexanamido-1- (4-cyano-2-methoxybenzyl) indole, m.p. 136 ... 13S ⁰ C, was obtained in a yield of 68 % .

Embodiment 68

Using the procedure described in Example 67, but starting from 1- (4-cyanophenylmethyl) -6-hexanamidoindole, 6-hexanamido-1- (4- (1 (H) -tetrazol-5-yl) -benzyl) was obtained. indole obtained in 50% ± ger yield as a ^hemihydrate: melting point 134 ... 136 ⁰ G. the starting material was prepared analogously to that described in embodiment procedure, but using 4-Bromomethylbenzonitril was used instead of ^Jii ethyl-4-bromomethylbenzoat and the starting material being obtained in 59% yield in the form of a pesticide, mp 106-109G.

Exemplary embodiments 69 to 72

Using a procedure similar to that described in Example 67, the following tetrazoles of Formula 9 were recovered from the corresponding nitriles of Formula 10:

_, ________ _ Nitr.il TC

-, G melt yield melting. Yield ^osp1 · point C ⁰ G) (%) point ( ⁰ C) (%)

69 (CE ₂ ) ₃ -149 ... 15O ^x . 51 '96 .., 98 30

70 (GH ₂ ) ₄ 114 ... 115 43 xx '67

71 (GH ₂ ) ₅ 158 ... 161 ^X 73 71 ... 72 70 72 (CH ₀ ). 133 ... 135 72 86 ... 88 55

-. 50 -

Partial hydrate

^xx partial NMR; 1.6 (in, 2H, NCH ₂ CH ₂ ), 2.0 (m, 2H,

CH ₂ CH ₂ ClJ), 2,4 (t, 2H, CH ₂ CN), 4,2 (t, 2H, IJCH ₂ ). -

The above nitriles of formula 10 were obtained using the general procedure of Example 23, starting from 6-hexanamidoindole and the appropriate bromonitrile of the formula Br.G.CN.

Embodiment 73

A stirred suspension of 19 mg of sodium hydride in 5 ml of dry dimethylformamide was treated at 0 C under a nitrogen atmosphere with 33 mg of 1 (H) -ethrazole-5-thiol. After 10 minutes, the mixture was warmed to room temperature and treated with 76 mg of 6-hexanarnido-1- (3-chloropropyl) indole (K). After stirring for 25 minutes, this mixture was diluted with 30 ml of water, acidified to pH 2 with 1N hydrochloric acid and then extracted with ethyl acetate. The extracts were dried (MgSO 4) and evaporated. The oily residue crystallized from ethyl acetate / hexane. Recrystallization from aqueous methanol gave 22.8 mg (25 %) of 6-hexanamido-1- (3- (1 (H) -tetrazol-5-ylthiol) propyl) indole as a white solid; Melting point 117 ... 119 ⁰ C; Microanalysis found: C, 57.97j H, 6.43; N, 22.22%; C ₁₈ H ₂₄ N ₆ OS requires: C, 58.04; H, 6:49; N, 22.56 %.

The starting indole derivative (K) was recovered as a white solid (partial WJH 2.4 (m, 2H, NCH ₂ CH ₂ ), 3.4 (t, 2H, CH ₂ Cl), 4.3 (t, 2H , CH ₂ N)), using the same general procedure as described in US Pat.

Example 23, except that methyl 4-bromomethylbenzoate was replaced by i-bromo-3-chloropropane.

Embodiment 74

A solution of 1.10 g of 2-phenylbutyric acid in 10 ml of methylene chloride was treated with 1.09 g of 1,1'-carbonyldiimidazole in several portions. After bubbling had begun, the mixture was heated at reflux for 5 minutes and then cooled to room temperature. To this mixture was added a solution of 0.70 g of methyl 4- (6-aminoindazol-1-ylmethyl) -3-methoxybenzoate (L) in 10 ml of methylene chloride and then 0.027 g of 4-N, N-dimethylaminopyridine. The resulting mixture was stirred for 24 h and then diluted with 75 mL of ethyl acetate. This organic solution was washed successively with 0.5 M hydrochloric acid, saturated sodium carbonate and brine, dried (MgSO 4) and evaporated. The residue was purified by means of flash chromatography on 30 g of silica gel using 30% v / v ethyl acetate in petroleum ether (boiling point 60 ... 80 ⁰ G) as eluent to give 1.0 g (97%) of methyl 4- (6- (2-phenylbutanamido) indazol-1-ylmethyl) -3-methoxybenzoate in the form of a light pink-colored pesticide; Melting point 57 ... 61 ⁰ G.

The starting Sster (L) was obtained in 92% yield as a pesticide, melting point 131.5 ... 132 ⁰ G, which was carried out analogously to the procedure described in Example 33, but of methyl 4-bromo «sfchyl · 3-methoxybenzoate and the intermediate isolation of methyl 4- (6-nitroindazol-1-ylmethyl) -3-methoxybenzoate in

28 % yield, as pale yellow powder, melting point 162 .. # 165 G, was assumed.

Embodiment 75

A solution of 0.70 g of methyl 4- (6-aminoindazol-1-ylmethyl) · 3-methoxybenzoate (L) and 0.33 ml 2,6-lutidine in 10 ml of methylene chloride was cooled under a nitrogen atmosphere to -20 ⁰ G and formatted.

Cooled to ⁰ ° C. and added dropwise with 0.30 ml of n-butylchloroethane.

The recovered solution was stirred at room temperature for 2 hours and then diluted with 75 ml of ethyl acetate. This mixture was washed successively with saturated sodium carbonate and brine, dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography on 25 g of silica gel using 25% V / 7 ethyl acetate in petroleum ether (b.p. 60-80 G) and the recovered solid was purified from 50% V / V ether / petroleum ether (b.p. ... 60 ⁰ C) recrystallized to 0.79 g (85%) of methyl 4- (6- (butoxycarbonyl) =: gain aminoindazol-1-ylmethyl) -3-methoxybeiizoat as a white solid; Melting point 112.. .112,5 ⁰ Gj microanalysis, found: C, 64,16;

H, 6.17 j Ii, 9.85 % \ ^G 22 ^H 25 ^N 3 ° 5 ^{; G} »64,22; H, 6.1 % Έ, 10.2%.

Exemplary embodiments 76 to 77

Following the similar procedure to that described in Example 34, the following compounds were prepared, starting from the corresponding ethyl esters:

(Embodiment 76)

4- (6- (2-Phenylbutanamido) indazol-1-ylmethyl) -3-methoxybenzoic acid as a white material Pest j foiger in 76 yield, melting point 244 ... 245 (Z) ⁰ G; Microanalysis, found:

C, 70.18; H, 5.56; N, 9.25 % \ ^C ₂ 6 ^H 25 ^F 3 ° 4 ^{requires: G} >70.40; H, 5.68; N, 9.47%.

(Embodiment 77)

4- (6- (Butoxycarbonyl) aminoindazol-1-ylmethyl) -3-methoxybenzoic acid as white pesticide in 88% yield; Melting point 213.5 ... 214 (Z) ⁰ C; Microanalysis, found; C, 63.11; H, 6,17; H, 10.31 % \ G ₂₁ H ₂₃ N ₃ O ₅ requires: G, 63.45; H, 5.83; N, 10.57%.

Exemplary embodiments 78 to 83

Following the same procedure as described in Example 9, but starting from the appropriate carboxylic acid of the formula Re.COpH, the following E of the formula I were obtained:

Execution · bspl.

re

yield

Partial NMR

78 1-Ph-ethyr

79 1-Ph-pentyl 80. 3-heptyl

46

55

36

1.6 (d, 3H, CH _3), 3.6 (t, 1H, PhCH), 7.3 (s, 5H, Ph)

0.9 (t, 3H, ₃

3.4 (t, 1H, PhCH), 7.3 (s, 5H, Ph)

0.9 (t, 6H, 2CH ₃ ),

1.5 (m, 9H)

3 6 1

Ausf.-bspl.

re

yield

Partial MiR

81 cyclopentylmethyl 22 82 4-methylbenzyl

72

1.6 (m, 9H),

2.3 (s, 2H, GH ₂ )

2.4 (s, 3H, CH _3), 3.6 (s, 2H, PhCH ₂₎

Ph = phenyl

, Were prepared from methyl similarly 4-06-aniino-2,3,5-trimethylindole-1-ylmethyl) -3-methoxybenzoate (itself, using the procedures described for A in ^X1 usführungsbeispiel 1, but starting from 2 3,5-trimethyl-6-nitroindole (G) was recovered) and 2-phenylbutyric acid

Methyl 3-methoxy-4- (2,3,5-trimethyl-6- (2-phenylbutanamido) indol-1-ylmethyl) benzoate (Example 83) was obtained in 32% yield as a white pesticide; partial NMR. · 0.9 (t, 3H, CH ₂ CH ₃ ), 1.2 (m, 2H, CH ₂ CH ₃ ), 3.4 (t, 1H, CHPh), 7.3 (s, 5H , Ph).

Exemplary embodiments 84 to 85

Using a procedure similar to that described in Example 16, but starting from the appropriate isocyanate, we recovered 1-

(Execution ^ example 84)

Methyl 4- (6-l-cyclohexylureidoindol-1-ylmethyl) -3-methoxybenzoate in 51% yield as a pest; Partial MRI 1.4 (bra, 10H), 4.5 (br d, 1H);

(Embodiment 85)

Methyl 3-methoxy-4- (6-N'-ε-trifluoromethylphenylureidoindol-1-ylmethyl) benzoate in 63% yield as a pest; partial MIvIRi 6.3. ..7.5 (aromatic H).

Exemplary embodiments 86 to 89

Using a procedure analogous to that described in Example 22, but starting from the appropriate chloroformate of the formula "ReO.CO.Cl, the following esters of the formula II were obtained:

Ausf.- -. Yield -n. , -, _Ί ,, ^ ₇₀ • _n xie / ^ x Partial M

bspl. (%;

86 hexyl 99 1.9 (t, 3H, CH ₃ ),

1.3 (m, 6H), 1.7 (m, 2H), 4.1 (t, 2H ₉ OCH ₂ ) -

87 1-] ilenthol ⁺ 76 '0.8 (d, 3H, CH ₃ ),

0.9 (d, 6H, CH _3), 4.6 (m, 1H, OCH)

88 benzyl. 99 5.2 (s, 2H, CH

7.3 (2.5H, Ph)

derived from 1-menthol)

Similarly, starting from ethyl 4- (6-amino-2,3,5-trimethylindol-1-ylmethyl) -3-methoxybenzoate and butylchloroformate, 4-ethyl-4- (6- (butoxycarbonyl) amino-2, 3,5-trimethylindol-1-ylmethyl) -3-methoxybenzoate ( Example 39) in 99% yield as a white solid; partial NIiIR: 0.9 (t, 3H, CH ₂ CH ₃ ), 1.3 (m, 2H,

CH ₂ CH ₃ ), 1.5 (m, 2H, CH ₂ OCH ₂ O), 4.1 (t, 2H, CH ₂ O), 4.1 (t, 2H, CH ₂ O).

Embodiment 90

A solution of 0.80 g of methyl 4- (6-aminoindol-1-ylmethyl) -3-methoxybenzoate (A) in 13 ml of anhydrous dioxane was treated with a solution of 0.31 ml of trichloromethylchloroformate in 13 ml of dioxane. The reaction vessel was purged continuously with nitrogen and the outgoing medium bubbled through aqueous potassium hydroxide to destroy any liberated phosgene. The in situ formation of the isocyanate of A was followed by thin layer chromatography. After 30 minutes, 0.75 ml of cyclopentanol and a catalytic amount of triethylamine were added to the reaction solution, whereupon the reaction mixture was heated to 80 ^° C. for 2.5 hours and then evaporated has been. The resulting residue was purified by flash chromatography on a 6 × 25 cm silica gel column using 7% V / V ethyl acetate in toluene as eluent to give 0.92 g (84 %) of methyl 4- (6- (cyclopentyloxycarbonyl) amidoindole-1. ylmethyl) -3-methoxybenzoate in the form of a white pesticide; MxRi 1.7 (m, 8H, (GHg) ₄ ), 3.9 (s, 3H, OCH ₇ ), - 4.0 (s, 3H, OCH ₃ ), 5.2 (br, 1H, CHO) , 5.3 (s, 2H, 'NCH ₂ ), 6.5 (dd, 1H, H ³ -indole), 6.6 (br, d, 2H, aromatic + UH), 6.8 (dd , 1H, H ⁵ -indole), 7.1 (d, 1H, H ² -indole), 7.2 (d, 1 aromatic H), 7.4 · ..7.5 (m, 3 aromatic H) , 7.6 (br s, 1H, H ⁷ -Indol).

Exemplary embodiments 91 to 95

Analogous to the procedure described in Example 90, but starting from the appropriate alcohol, the following lister of the formula 11 were obtained:

έ Ο J

Ausf.- '~ Yield □,. -, -,. ", -

bspl. ^Re (%) partial HMl

91 3-pentyl. 65 i 0.9 (t, 6H, 2CH ₃ ),

1.5 (m, 4H, 2CHg),

4.6 (m, 1H, CHO)

92. cyclobutyl 57 0.9 (br m, 6H, '

5.0 (t, 1H, CHO).

93 1-phenylpropyl 31 0.9 (t, 3H, CH ₃ ),

1.8 (m, 2H, CH ₂ ),

5.6 (t, 1H, CHO),

7.3 (s, 5H, Ph)

94 t-butyl 21 1,4 (s, 9H, C (CH ₃ ) _,)

95 cyclohexyl 69 1.1 to 1.8 (br m, 1 OH,

.4,6 (br, TH, CHO)

Version beep 96 .

Similar to the procedure described in Example 90, but using cyclopentyiamine in place of cyclopentanol, methyl 4- (6-! T'-cyclopentylureidoindol-1-ylmethyl) -3-methoxybenzoate was recovered in 54% yield as a pale yellow pesticide; partial MRi 1.2 ... 2.0 (br m, 8H, (CHg) ₄ ), 4.4 (m, 1H, CHOH), 4.9 (d, 1Hj CHIiH).

Embodiment 97

Similar to the procedure described in Example 22, but starting from methyl 5- (6-aminoindol-1-ylmethyl) furan-2-carboxylate and cyclopentyl chloroformate

methyl 5- (6- (cyclopentyloxycarbonyl) aminoindol-1-ylmethyl) furan-2-carboxylate was recovered in 53 % yield as a whitish pesticide; partial MiRs 1.5 ... 2.0 (br m, 8H, (OHg) ₄ ), 6.2 (d, 1H, CH.CH = G), 6.6 (br s, 1H, NH)

The starting aminoindole was prepared as a pesticide with a yield of 99 % and partial MR: 3.5 (s, 2H,

3.9 (s, 3H, OCH ₃ ), 5.2 (s, 2H, NCH ₂ ) was recovered using a procedure similar to that in parts (a) and (b) of Example 1, except that of methyl 5-chloromethylfuran-2-carboxylate was assumed.

Exemplary embodiment 98

Similar to the procedure described in Example 23, but replacing the bromoester (F) with methyl 7-bromoheptanoate, methyl 7- (6-hexanamidoindol-1-ylmethyl) -heptanoate was obtained in 35 % yield as a pesticide, mp 61 ... 63 ⁰ C.

Embodiment 99

Similar to the procedure described in Example 23, but using 6- (2-ethylhexanainido) indole (M) instead of 6-hexanamidoindole (E), methyl was 4- (6- (2-ethylheptanaaiido) indol-1-ylmethyl). benzoate obtained as a white Peststoff in a yield of 32%, melting point 139 ... 141 ⁰ C.

The starting indole M was obtained analogously to that described in part (b) of Example 23 for 6-hexanamidoindole (Ξ) except that 2-ethylhexanoyl chloride was used in place of hexanoyl chloride, and wherein

light brown powder was obtained in 56 % yield, mp 154 *. »156 ⁰ G.

Exemplary embodiments 100 to 104

Similar to the procedure described in Example 99, the following esters of Formula 12 (in which R = methyl) were recovered using the appropriate benzylbromide derivative of Formula 13:

Ausf.- H G ² (and location binding (3) Out 1 enamel bspl. 2-F on Q) binding (4) prey 1 point, ⁰ C 100 2-OGH ₃ direct binding Mn · TiQ y »+ 39 1 25 ... 126 101 3-Br direct binding (4) 40 55 ... 157 102 2-0.Butyl Vinyl (5) (4) 42 50 ... 152 103 Notes: x direct  - egg 33 X 104 direct 63 XX 1 c TJRiP α fa

1 aromatic H),

non-crystalline; Microanalysis, found :. C, 73.00; H, 8.04; IT, 5.60 %; O ₂₉ H ₃₈ Ii ₂ O ₄ requires: C, 72.77; H 8,00; N, 5 ^ 85 %.

Methyl 4-bromomethyl-3-butoxybenzoate (required for Example 104) can be used in an overall yield of 66 % as an oil (partial SIIiR: 3.94 (s, 3H, CO ₂ CH ₃ ), 4.10 (m, 2H, CH ₂ O) 4.58 (s, 2H, GH ₂ Br)) by bromination of methyl 3-butoxy-4-methylbenzoate (Ti) using the general procedure described for (B) in Example 1 (d) are, however, wherein the cleaning by flash chromatography on silica gel using 2% v / v ethyl acetate 'in petroleum ether (boiling point 60 ... 80 ⁰ G) is performed. the output Sesterheim N itself was a pale yellow as a

Oil in 92 % yield (partial MVIR: 2.2.6 (s, 3H, CH ₃ .G), 3.90 (s, 3H, GO ₂ GH ₃ ), 4.03 (m, 2H, GH ₂ O )) by alkylation of methyl 3-hydroxy-4-methylbenzoate (O) using butyl bromide and potassium carbonate in refluxing acetone. The ester 0 was obtained in a yield of 73% as a Peststoff, melting point 112 ... 114 G, (recrystallized from ether / petroleum ether (boiling point 40 ... 60 ⁰ C)) and this by means of a conventional acid-catalyzed esterification of 3 -Hydroxy-4-methylbenzoic acid.

Exemplary embodiments 105 to 110

Using a similar procedure as described in embodiment 1, the following esters of formula 14 were obtained by acylation of the appropriate 6-aminoindole ester of formula 4 using the appropriate acid chloride of the formula Re.X.CO.Cl required starting ester of formula 4 can be obtained from known 6-Nitroindole.n using methods which are analogous to the procedures described in the preceding embodiments J-

Ausf.-. _ _"V education Partial bspl. ^{R ita Re X} prey. "..

105 (GHp) ₂ .CH (Et) CH ₂ pentyl direct 99 1.0 (t, 3H,

, Binding GH ₂ GH ₃ )

106 (GH) ₂ .CH (Et) CH pentyl direct 40 2,8 (q, 2H,

Bond.

107 CH ₃ CH ₃ Ph.GH (Et) direct 49 0.9 (t, 3H,

Bond CH ₂ OH ₃ ),

2.0 (m, 2H, CH ₂ CH ₃ )

Ausfobspl.

Ra

re

yield

partial

MR

108 GH

butyl

70

butyl

44

0.9 (T, 3H, GH ₂ C 4.1 / tin ) (t, 2H, och. C ,) 2.3 I 3H, 6.3 (s, 1H, H ³ -indole).

Annotation; (i) In Embodiment 105, 106, the methylene adjacent to "CH (Et)" is attached to the 0 of indole, d, h. to Ra;

(ii) Ph = phenyl, et = ethyl.

Similarly, starting from methyl 4- (4-aminoindol-1-ylmethyl) -3-methoxybenzoate and hexanoyl chloride, methyl 4- (4-hexanamidoindol-1-ylmethyl) -3-methoxybenzoate (Example 110) was obtained in a yield recovered from 74% as a non-crystalline pesticide, partial MvIR: 7.0 (t, 1H, H ⁶ -indole), 7.1 (d, 1H, H ⁵ -indole), 7.6 (d, 1H, H ⁷ indole).

Embodiments 111 to 145

Using the general procedure described in Example 34, the following acids of formula. 5 are obtained by hydrolysis of their corresponding methyl esters:

Ausf, - ρ melting 'yield

bspl. point ( ⁰ C) (%)

111 1-phenylethyl 209th ..210 ^X 38 112 1-phenylpentyl 230 '. ..231 62 113 3-heptyl 230 ..231 ^Z - 68 114 ^ yclopentylmethyl 259th ..260 35 115 4-methylbenzyl 254th ..255 5A

Isolated as a partial hydrate.

Similarly, the following acids of formula 6 (Xa = oxygen) were obtained by hydrolysis of their corresponding methyl esters:

Ausf.- bspl. re X Melting point ( ⁰ C) ..254 (Z) Yield (%) 116 cyclohexyl WH 252nd ..225 H ₂ O) 41 117 2-phenyl-Ciy HH 223. (0.5 ..174 6 118 hexyl 0 172nd ..206 36 119 1-MenthyI 0 205th ..178 55 120 benzyl 0 176th ..233 13 121 3-pentyl. 0 232nd ..239 20 122 CycIobutyl 0 238th ..198 67 123 1-phenylpropyl 0 197th ..201 36 124 t-butyl 0 200th , .243 48 125 cyclohexyl 0 242nd '..248 (Z) 49 126 cyclopentyl NH 247th 42

Similarly, the following acids of the formula (R = hydrogen) were obtained by hydrolysis of their corresponding methyl esters:

Ausf.- bspl. Rd G ² (and Location aui 'Q) binding (4) From booty 208 Melting point ⁰ C 127 H direct binding (4) binding (4) 91 216 ... 210 128 ^ H' direct Binding- (3) 98 215 ... 218 129 2-F direct Binding (4) 96 202 ... 216.5 130 2-OCH ₃ Vinyl (5) '. 75 186 ... 205 131 3-Br direct 43 197 ... 187 132 2-Q (CH ₀ KCH ο direct 70 ... 199

Similarly, the following acids of the formula were obtained by hydrolysis of their corresponding methyl esters;

Ausf.- bspl. 'R Ra re X rc hard point .243 Output e 36 et Hydrate isolated 133 GH ₃ CH ₁ Ph. CH (Et-) - H 242 .. .281 ⁺ (Z). 6 = Eti 134 CH ₃ Ph.CH (Et) - CH ₃ 280 .. .189 (Z) 36 iyl 135 CH., CH ^ butyl 0 H · 188 .. .226 29 136 OH ₃ butyl 0 CH ₃ 225 .. .146 46 137 CH ₃ H-. butyl 0 H 145 .. .208 61 138 .. H Cl butyl 0 H 207 .. .249 50 139 H COCH ₃ 1-Et-pentyl - H 248 .. .268 47 140 H CH ₃ 1-Et-pentyl - H 267 .. For the embodiments 133 (Z) Remarks : (i) 139 and 140 , 134, X corresponds to a direct one binding ⁺ as a partial (G) Ph = phenyl, (Iii)

Similarly, the following acids of formula I were obtained by hydrolysis of their corresponding methyl esters:

(Embodiment 141)

4- (6-Bthyl-2-hexanamidocarbazol-9-ylmethyl) -3-methoxybenzoic acid, in 29 % yield as solid monohydrate, m.p. 185 ... 186 ⁰ g

(Embodiment 142)

4- (3-ethyl-7_hexanainido-1,2,3,4-tetrahydrocarbazole-9-ylmethyl) -3-methoxybenzoic acid, in 38% yield as a solid, melting point 241 ... 242 ⁰ G;

(Embodiment 143)

4- (4-Hexana nidoindol ^{r-1-ylmethyl)} -3-methoxybenzoic acid, dissolved in 78% yield as a solid, melting point 204 ... 205 ⁰ G.

(Embodiment 144)

6- (6-Hexanamidoindol-i-yl) hexanoic acid acid in 56% yield as a solid, melting point 86 ... 89 ⁰ C; and.

(Embodiment 145)

S-IOE iCyclopentyloxycarbonyliaminoindol-i-ylmethyli-furan-2-carboxylic acid in 60% yield as a solid, melting point 208 ... 209 ⁰ C-.

Embodiments 146 to

Similar to the procedure described in Example 67, but starting from the appropriate citrile, the following tetrazole derivatives were obtained:

Sm V

(Embodiment 146)

6-hexanamido-1- (7- (1 (H) -tetrazol-5-yl) -heptyl) -indole in 15% yield as a pesticide, m.p.

135 ⁰ G, starting from 6-hexanamido-1- (7-cyanoheptyl) -indole (P);

(Execution Example 147)

6-hexanamido-.1- (8- (1 (H) -tetrazol-5-yl) octyl) indole dissolved in 23% yield as a partial hydrate, melting point 129 ... 131 ⁰ C, starting from 6-Hexanainido- 1- (8-cyanooctyl) indole (Q);

(Example 148)

6-hexanamido-1- (4- (1 (H) -tetrazol-5-yl) benzyl) indole

50% yield as a hernihydrate, mp 134 ...

136 ⁰ G ,, starting from 1- (4-cyanobenzyl) -6-hexanamiäoihdol (R); and

(Embodiment 149)

6-hexanamido-1- (3- (1 (H) -tetrazol-5-yl) benzyl) indole

51% yield as a pesticide, m.p. 214-216 G, starting from 1- (3-cyanobenzyl) -6-hexanamidoindole (S).

The required starting material P was obtained as follows:

A stirred solution of 140 mg of 1- (7-bromoheptyl) -6-hexanamidoindole (weight in 69 % yield as a light yellow powder, mp 98-101C ,

hydride alkylation of 6-Hexanamidoindol with 1,7-dibromoheptane according to the general method of A _U sführungsbeispiel 23) in 6 ml of dimethyl sulfoxide, maintained under a nitrogen atmosphere with 54 mg Uatriurncyanid and then by 100 mg of 18-crown-6 (1 , 4,7,10,13,16-hexaoxacyloctadecane). After one hour the solution was diluted with water and extracted with ethyl acetate. The pooled extracts were washed with water and then brine, dried (EIgSO.) And evaporated to give, after recrystallization from ethyl acetate / hexane 1- (7-cyanoheptyl) indole (P) as a white pesticide (82 mg, 67 % yield ), M.p. 85-86 ° C.

The starting material Q was prepared in analogous V / else using 1,8-dibromooctane and washed in 77% yield as a white solid, melting point 104 ... 105 ⁰ G recovered. ·

The starting materials R and S were as solids with melting points of 106 ... 109 ⁰ G and 133 .... 136 ° ü in yields of 59% bsw. 44 % by atrium hydride alkylation of 6-Hexanamidoindol with 4 bromomethyl or 3-bromomethylbenzonitrile using the general method of Example 23 won.

Embodiment 150

Following a procedure similar to that described in Example 67 but starting from 1- (4-gyano-2-methoxybenzyl) -6- (2-ethylhexanamido) indole (T), 6- (2-ethylhexanamido) -1- (2 -methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) -indole in a yield of 73 % as a solid, melting point

point 211 ... 212 ⁰ G, won.

The starting nitrile T was obtained in 53% yield as a white Peststoff, mp 177 · ⁰ ..178 G, by sodium hydride alkylation of 6- (2-ethylhexanamido) indole with 4-bromomethyl-3-methoxybenzonitrile using the general Method of embodiment 23 won.

Exemplary embodiments 151 to 154

Following a similar procedure as described in Example 67, the following tetrazole derivatives of Formula 16 were prepared from the corresponding nitriles of Formula 17:

Ausf.- 2-0CH ₃ G (+ position on melting Out- bspl. H Ring Q) punki X) O) 151 H direct bond (4) 118 .. 29 152 H Vinyl (4) 252 .. 15 153 ! »! Ethylene (4) 151 .. 23 154 Methylene (3) 167 .. 76 ;, ⁰ G ..120 ^x , .255 ^X ..153 ..170 ^x

^x Hemihydrate

The necessary nitriles of Formula 17 for Working Examples 151 and 152 were obtained by sodium hydride alkylation of 6- (2-phenylbutanamido) indole (U) with the appropriate bromomethylbenzene using the general procedure of Example 23 and had the following properties: -

(a) (for embodiment 151) J solid, mp 70 ... 72 G, recovered in 54% yield using 4-bromomethyl-3-methoxybenzonitrile and U;

(b) (for embodiment 153): pesticide, m.p. 132-134 C, recovered in 51% yield using 3- (4-3-romomethylphenyl) acrylonitrile and U.I.

The required nitriles of Formula 17 for Embodiments 1 53 and 154 were obtained analogously to the procedure described in Example 146 for P, i. H. by sodium hydride alkylation of U with the appropriate alpha, alpha'-dibromooxylene and subsequent reaction of the intermediate 1- (3-romethylbenzyl) -6- (2-phenylbutanamido) indole with sodium cyanide in the presence of 18-crown-6. The nitriles and the intermediate bromomethylbenzyl derivatives would be used without characterization.

The starting indole U was obtained as follows:

To a solution of 221 mg of 1,1'-carbonyldiimidazole in 2 ml of methylene chloride, which had been refluxed for 30 minutes in a nitrogen atmosphere and then cooled, was added a solution of 200 mg of 6-aminoindole in 2 ml of methylene chloride. The mixture was stirred for 16 h and then diluted with ethyl acetate. The ethyl acetate solution was then washed successively with 10% H / V aqueous hydrochloric acid, water and saturated brine, then dried (K 2 SO 4) and evaporated. The recovered residual oil was purified by chromatography on Xieselgei using 20% V / V ethyl acetate / hexane as eluent to give 6- (2-phenylbutanamido) indole (U) in 69% yield as a pesticide, mp 143-144 ⁰ C, to surrender.

Exemplary embodiments 155 to 156

Wake similar procedure, as described in Example 73, the preparation of the following tetrazoles j- '

(Execution Example 155)

6-hexanamido-1- (7- (1 (H) -tetrazol-5-ylthio) -heptyl) -indole, in 11% yield as a partial hydrate, m.p. 116-117 ⁰ G, starting from 1- (7 -Bromoheptyl) -6-hexanamidoindol; and

(Publication No. 156),.

6-hexanamido-1- (5- (1 (H) -tetrazol-5-ylthio) -pentyl) indole, in 21% yield as a pesticide, m.p. 108.109 G, starting from 1- (5-bromopentyl ) -6-hexa, namidoindole (in turn obtained in 61% yield as a pesticide, mp 60.5 ... 62 ⁰ G, by sodium hydride alkylation of 6-Hexanamidoindol with 1,5-dibromopentane using the described in Example 23 general procedure).

Embodiment 157

A solution of 4.0 g of 6-amino- (2-methoxy-4- (1 (H) -tetrazol-5-yl) -benzyl) indole (V) in a mixture of 10 ml of N-methylpyrrolidone, 10 ml of tetrahydrofuran and 2.2 ml of 2,6-lutidine was added dropwise to a stirred, ice-cooled solution of 2.57 g of butyl chloroformate in 10 ml of tetrahydrofuran, which was kept under a nitrogen atmosphere. The mixture was given the opportunity to take room temperature for a period of 2 hours, after which it

14 ώ. was left standing for a long time. The gum was removed by filtration and the filtrate was concentrated under reduced pressure. The oily residue was dissolved in 35 ml of 20% M / V potassium carbonate solution, basified to pH 10 with 10% L / V IT sodium hydroxide solution and extracted with ethyl acetate. These extracts were discarded. The aqueous phase was acidified to pH 1 with 6M hydrochloric acid and reextracted with ethyl acetate. These extracts were pooled, washed with water and then with saturated brine . wash, dried (LgSO.) and evaporated. The solid residue was recrystallized from ethyl acetate to give 2.8 g (54 %) of 6- (butoxycarbonyl) amino-1- (2-methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) indole as a yellow To give powder, mp 194 ... 195 ° G; Microanalysis found: G, 62.69j H, 5.72j N, 20.00 %; C ₂₂ H ₂₄ IIgO ₃ requires: C, 62.58; H, 5.75j N, 19.99 %.

The starting material V was obtained as follows t-

(a) 6-iTitroindole was alkylated with 4-3romomethyl-3-methoxybenzonitrile in the presence of potassium carbonate using the procedure described in Example 1 (a) to give 1- (4-gyano-2-methoxybenzyl) To give -6-nitroindole (W) in a yield of 78 % as a pesticide, mp 190.5 ... 191 ° C.

(b) The nitrile W was converted to the corresponding tetrazole, 1- (2-lethoxy-4- (1- (H) -tetrazol-5-yl) -benzyl) -indole (X), which was prepared using the general procedure of embodiment 67 dissolved in 86% yield as a yellow _i: rüner Peststoff, mp 258 260 ⁰ G (Z) was recovered ....

(c) A solution of 4.76 g of Σ in 2.3 ml of potassium hydroxide 6IvI and 180 ml of methanol was treated with 480 mg of 10% M / M palladium on charcoal and then at a pressure of 3.45 bar for 2 hours long hydrogenated. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. Treatment of the residual oil with saturated monobasic sodium phosphate solution gave a precipitate, which was collected and dried to give 6-amino-1- (2-methoxy-4- (1 (H) -tetrazol-1 -5-yl) benzyl). indole (V) in quantitative yield as a gray powder; HMR: 4.0 (s, 3H, OGH _3), 5.2 (s, 2H, NGH _2), 6.3 (d, 1H, H ³ -indole), 6.4 (d ,. 1H, H ^5- indole), 6.5 '(s, 1 aromatic H), 6.7 (d, 1 aromatic H), 7.1 (d, 1H, H ² -indole), 7.2 (d, 1H, H ⁴ -Indol), 7.5 (d, 1 aromatic H), 7.7 (s, 1H, H ⁷ -indole).

Embodiments 158 to 160

Using a procedure similar to that described in Example 157 but employing glyclopentyl chloroformate as the acylating agent, 6- (glyclopentyloxycarbonyl) amino-1- (2-methosyl-4- (1 (H) -tetraal-5- yl) benzyl) indole (Ex. 158) in 57 ige yield as a solid, mp 216 ... 218 ⁰ G won; Microanalysis, found; G, 6.3, 63; H, 5.28, II, 19.21 % i ^G 23 ^H 24 ^N 6 ^O ^ ^{requires: G} >63.87; H, 5.59; N, 19.43 %.

In similar manner, using butyl chloroformate and 6-amino-1- (6- (1 (H) -tetrazol-5-yl) hexyl) indole (Y) 6- (3-oxycarbony1) amino-1 - (6- (1 (H) -1e-trazol-5-yl) hexyl) -indole (Example 159) in 44% yield as

a white solid, mp 117 ... 118 ⁰ G won. Microanalysis found: C, 62.27; K, 7:34; N, 21.67%; C ₂₀ H ₂₈ N ₆ O ₂ requires: C, 62.48; H, 7:34; U, 21.86%.

Similarly, using cyclopentyl chloroformate and indole Y, 6- (cyclopentyloxycarbonyl) amino-1- (6- (1 (H) -tetrazol-5-yl) hexyl) indole (Example 160) was prepared in 28 % yield pale yellow powder, mp 141.5 ... 142.5 C; Microanalysis found: C, 63.78; H, 7,10; IT, 21.03 % \ ^C ₂ 1 ^H 28 ^N 6 ° 2 ^requires: C, 63, -62; H, 7:12; IT, 21.20-%.

The starting material Y was obtained from 6-jtfitroindole and 7-3romoheptanonitrile using a similar procedure as indicated for V in Example 159.

Embodiment 161

6-Arnino (2-methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) indazole (Z) was acylated with butyl chloroformate using the procedure described in Example 159 to give 6- (butyloxycarbonyl) amino. 1 - (2-methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) indazole in 40% yield as a white pesticide, mp 210.5 ... 211.5 ° C (Z), to surrender; Microanalysis found: C, 59.84; H, 5.69; Ii, 23.17 % \ C ₂₁ H ₂₃ LI O ₃ requires: C, 59.84; H, 5.50; Έ, 23.26 %.

The starting material Z was obtained as follows:

(a) 4- (6-Lititroindazol-1-yl) methyl-3-methoxybenzonitrile (AA) was obtained in 24/50 yield as a pest, m.p.

207 ... 208 ⁰ C, of l \ Tetrium-6-nitroindazolid donated 4-3romomethyl-3-nieth.oxybenzonitril using an analogous procedure as described for J in embodiment 33rd

(b) 1- (2-Ivethoxy-4- (1 (H) -tetrazol-5-yl) benzyl-6-nitroindazole (BB) was prepared in 98% yield as a pesticide, m.p. 152-153. 5 ⁰ G (Z), by reaction of enzonitrile AA with sodium azide and triethylamine hydrochloride in N-methylpyrrolidone at 150 G for 3 h under a nitrogen atmosphere using the procedure described for embodiment 67 won.

(c) 6-Aniino-1- (2-methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) indazole (Z) was found to be 79% yield as a pale yellow pest, mp 247. .248 ° C (decomposition), obtained by hydrogenation with a catalyst of 10 Έ / Μ palladium on charcoal (1.1 bar for 2 hours) of the nitro compound B3 using the procedure described for V in Example 157.

Embodiment 162

Using a procedure similar to that described in Example 161 but using 'glylopentyl chloroformate as the acylating agent, 6- (glyclopentyloxycarbonyl) amino-1- (2-methoxy-4- (1 (H) -tetrazole -5-yl) benzyl) indazole as a white solid in 66% yield, m.p. 203.5 ... 204.5 g (decomp.); Microanalysis, found: G, 60.90; H, 5:43; E, 22.24 % \ G ₂₂ H ₃₃ N ₇ O ₃ calls; G, 60.95; H, 5.34; 6 '

Embodiment 163

Using a similar procedure as described in Example 161 but starting from 2-ethylhexanoyl chloride and 6-amino-1- (2-methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) indazole (V), 6- (2-ethylhexanamido) -1- (2-methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) -indazole was obtained in 56% yield as a v / eisser solid, Melting point 203 ... 204 ⁰ C, recovered; Microanalysis, found; C, 64.35; H, 6:43; H, 21.80%; C ₂₄ H ₂₉ N ₇ O ₂ requires: G, 64.41; H, 6.53; N, 21.90. $. ,

Embodiment 164

Using a similar procedure as described in Example 9, but starting from 2-phenylbutyric acid and 6-amino-1- (2-methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) indazole ( V), 1- (2-J, iethoxy-4- (1 (H) -tetrazol-5-yl) benzyl) -6- (2-phenylbutan-anido) indazole was obtained in 48% yield as a pale pink solid, mp 202 »..203 G (decomposition), obtained by: microanalysis, found: C, 66.05; H, 5.40; N, 20.70%; G ₂₆ H ₂ -W ₇ O ₂ .0.25 H ₂ O requires; G, 66.15; H, 5:44; N, 20.77 %.

Exemplary embodiment 165

Using an analogous procedure as described in Example 1 but starting from methyl 4- (6-aminoindazol-1-ylmethyl) -3-methoxybenzoate and 2-kthylhexanoyl chloride, methyl 4- (6- (2-ethylhexanamido) indazol-1-ylmethyl) -3-methoxybenzoate in 68 / Siger yield as a white solid, mp 135.5 ... 136.5 won ⁰ G; Microanalysis found: G, 68.37;

H, 7,10; IT, 9.43 % i G ₂₅ H ₃₁ ^ N ₃ O ₄ requires: C, .68.64; H, 7:14; M, 9.60 %.

Embodiment 166

Using an analogous procedure as described in Example 75 but starting from cyclopentyl chloroformate and methyl 4- (6-aminoindazol-1-ylmethyl) -3-methoxybenzoate, ethyl 4- (6- (cyclopentyloxycarbonyl) aminoindazol-1 was added. ylmethyl) -3-rnethoxybenzoat .. ₀ 151 won C, in 73% yield as a pale pink Peststoff, melting point 150; Microanalysis found G, 65.05; K, 5.95; N, 9.47 % \ O ₂ H ₂₅ I ₃ O ₅ requires: C, 65.24; H, 5.95; ii, 9.92 %.

Exemplary embodiments 167 to 170

Using a procedure similar to that described in Example 34, the following carboxylic acids of Formula 18 were obtained by hydrolysis of the corresponding methyl esters.

Ausf.-bspl. ·

re

melting point, G

yield

167 168 169 170

1-phenylpropyl butoxy 3-heptyl cyclopentyloxy

244 ... 245 (Z) 213.5 ... 214 (Z) 249 ... 250.5 235 ... 236.5

76 88 69 39

Embodiment 171

A solution of 0.52 g of t-butyl 4- (6-aminoindol-1-yinietyl) 3-methoxybenzoate (GQ) and 0.31 ml of triethylamine in 8 ml

Methylene chloride was treated at 0 ⁰ C with 0,24.ml Heptafluorobutyrylchlorid. After stirring for 24 hours, the solution was diluted with methylene chloride, washed successively with 10 % v / v hydrochloric acid, water and brine and then dried (MgSO 4) and evaporated. The residue was purified by flash chromatography on a 6 × 20 cm silica gel column using 5 / v / v ethyl acetate in hexane as eluent to give 0.41 g (51 %) of tert-butyl 4- (6-heptafluorobutanamidoindol-1-yl -methyl) -3-methoxybenzoate as a yellow pesticide; MiR: 1.6 (s, 9H, (CH ₃ ) ₃ C)., 3 »9 (s, -3H, OCH ₂ ), 5.3 (s, 2H, ₂ , 6.5 (d, 1H, H ³ -indole), '6,7 (d, 1H, Ar) j 7,0 (d, 1H, H ⁵ -indole), 7,4 (d, 1H, H ² -indole), 7, S ( d, 1H, H ⁷ -indole) j 8.0 (s, 1H, CO.NH).

The starting amine (CC) was recovered on any occasion : ~

(A) A solution of 10.0 g of 3-methoxy-4-methylbenzoic acid, 1 ml of concentrated sulfuric acid and 200 ml of condensed isobutylene in 200 ml of methylene chloride was placed in a pressure vessel and Λ 6 hours stirred. The vessel was then opened to vent isobutylene which had not reacted. The remaining liquid was poured into 150 ml of 10% (iVi / V) sodium hydroxide solution and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO 4) and evaporated. The residue was purified by slit chromotography on a 7 x 18 cm silica gel column using 10% v / v ethyl acetate in hexane as eluent, yielding 9.1 g (70 %) of t-butyl 3-methoxy-4-meth-2-benzoate as a to give colorless oil; MvJTi: 1.6 (s, 9H, C _(CH3 J _3), 2.27 (s, 3H, CH _3), 3.86 (s, 3H, OCH _3), 7.11 (d, lH) / 7.49 (m, 2H).

(b) A suspension of 8.92 g of t_-butyl 3-me thoxy-4-methylbenzoate, 8.57 g of H-bromosuccinimide and 0.1 g of benzoyl peroxide in 150 ml of carbon tetrachloride was heated to reflux and washed with a high heel for 1 h long irradiated. After cooling to room temperature, the pest was removed by filtration from the suspension. The filtrate was evaporated. The resulting residue was purified by flash chromatography on a 7 σ 18 cm silica gel column using 5% V / V ethyl acetate in hexane as eluent to give 11.52 g (95 %) of Jt ₁ -butyl 3-methoxy-4 bromomethylbenzoate as a pale yellow oil, MJR, 1.5 (s, 9H, C (CH ₃ ) ₃ ), 3.9 (s, 3H, OCH ₃ ), 4.5 (s, 2H, CH ₂ Br ), 7.15 (d, 1H), 7.4 (m, 2H).

(c) _t-Butyl 3-methoxy-4-bromomethylbenzoate was reacted with 6-hitroindole and potassium carbonate according to the procedure described in part (a) of Example 1 to give t-butyl 4- (6-) in 98% yield. nitroindol-1-ylmethyl) -3-methoxybenzoate as a yellow pesticide; KIiR: 0.6 (s, 9H, 0 (CH) ₃ ), 4.9 ^: (s, 3H, OCH ₃ ), ^: . 5.4 (s, 2H, NCH ₂ ), 6.6 (dd, 1H, H ³ -indole), 6.8 (d, 1 aromatic H), '6.8 ... 8.0 (m, 5H, Ar), 8.4 (d, 1H, H ⁷ -Indol).

(d) t-butyl. 4- (6-nitroindol-1-ylmethyl) -3-methoxybenzoate was catalytically hydrogenated using the procedure described in part (b) of Example 1 to give a quantitative yield of _t-butyl 4- (6-amino-nol-1-ylmethyl ) To give 3-methoxybenzoate (CC) as a light brown pesticide; partial rIT, .R: 1.6 (s, 9H, (.CH ₃ ) -, C), 4.1 (br. d, 2H, NH ₂ ), 5.2 (s, 2H,

- 7R -

Exemplary embodiment 172

Bine solution of 0.25 g of t-butyl 4- (6-heptafluorobutanamidoindol-1-ylmethyl) -3-methoxybenzoate and 152.3 cc of triethylamine in 1.0 ml of dioxane was treated with 185 microliters of trimethylsilyl triflate, whereupon the mixture was allowed to stand for 48 h was stirred for a long time. Subsequent addition of Yv'asser gave a precipitate which was collected by filtration and recrystallized from ethyl acetate / hexane to provide 22 mg (10 %) of 4- (6-heptafluorobutanamidoindol-1-ylmethyl) -3-methoxybenzoic acid as a light brown powder yielded, melting point 213 ... 215 ⁰ C; Microanalysis found: G, 51.27; H, 3:24; N, 5.47 % \ G ₂₁ H ₁₅ S ₂ O ₄ P ₇ requires; C, 51.23; H, 3.07; Ή, 5.69 %.

Embodiment 173

A solution of 0.76 g of methyl 4- (6- (U-butoxycarbonyl) aminoindol-1-ylmethyl) -3-methoxybenzoate in 10 ml of carbon tetrachloride was added to a suspension of 0.25 g of T-chlorosuccinimide in 9 ml of carbon tetrachloride added. The mixture was heated under reflux conditions for 45 minutes, cooled, and then freed from succinimide by filtration. The filtrate was washed with saturated sodium bicarbonate solution and then brine, dried (K 2 SO 4) and evaporated. The residue was purified by flash chromatography on a 4 x 20 cm silica gel column using 25% v / v in methylene chloride as an oil to give 0.36 g (44 %) of methyl 4- (6 - (butoxycarbonyl) amino-3-chloroindol-1-ylmethyl) -3-methoxybenzoate as a white solid ; ITkR; 0.9 (t, 3H, (GHq) -, GH-,), 1.4 (bra , 4H, CH ₂ (CH ₂ J ₂ CH ₃ ), 3.8 (s, 3K, OCH ₃ ), 3.9 '(s,

3H, OCH ₃ ), 4.1 (t, 2H, CH ₂ (CH ₂ ) ₂ CH ₃ ), 5.2 (s, 2H, NCH ₂ ), 6.6 (d, 1 aromatic H), 6 , 75 (dd, 1H, H ⁵ -indole), 6.8 (s, 1H, ITH), 7.0 (3, 1H, H ² -indole), 7.4 (d, 1 'aromatic H), 7.5 (s, 1 aromatic H), 7.7 (s, 1H), H ⁷ -indole). -

Embodiment 174 .

A solution of 0.5 g of 3-acetyl-6- (2-ethylhexanamido) indole (DD) in 4 ml of dimethylformamide was added to a slurry of 0.072 g of sodium hydride in 2 ml of dimethylformamide, and the mixture was stirred for 1 hr. Then, a solution of 0.518 g of methyl 4-bromomethyl-3-β-diethoxybenzoate in 2 ml of dimethylformamide was added and the mixture was stirred for an additional 1 hour. The reaction mixture was then quenched by adding saturated ammonium chloride solution, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and then with saturated brine, dried (MgSO 4) and evaporated. The residue was purified by flash chromatography on a 5 x 20 cm silica gel column using 50% v / v ethyl acetate in hexane as eluent to give 0.3 g of methyl 4- (3-acetyl-6- (2-ethylhexanamido) indole. 1-ylmethyl) -3-methoxybenzoate as a white solid; ÜLIR: 0.9 (t, 6H, 2CH ₀ ), 2,1- (t, 1H, CO.CH), 2,4 (s, 3H, CO.CH ₃ ), 3,8 (s, 3H, OCH,), 3.9 - (s, 3H, OCH _3), 5.3 (s, 2H, JTCH ₂₎ 'β, 8 (d, 1 aromatic H), 6.9 (dd, 1H , H ³ -indole), 7.3 (s, 1H, NH), 7.48 (dd, 1 aromatic H), 7.5 (s, 1H, H -indole), 7.6 (s, 1 aromatic H), 8.2 (d, 1H, H ⁴ -indole), 8.3 (s, 1H, H ⁷ -indole).

The starting indole DD was obtained as follows:

1.9 g of phosphorus oxychloride were added slowly at 0 C to 1.48 g of Ν, Ν-dimethylacetamide. i) In the mixture was allowed to warm to room temperature, whereupon a solution of 1.0 g of 6- (2-ethylhexanamido) indole in 2 ml of Ii, N-dimethylacetamide was added. After 15 minutes, the reaction solution was alkalized to pH 14 with 20 % K / V sodium hydroxide solution, heated briefly under reflux conditions, then cooled and extracted with ethyl acetate. The pooled extracts were washed with water and then with brine, dried (MgSO 4) and evaporated to give 0.93 g (80 %) of 3-acetyl-6- (2-ethylhexanamido) indole (DB) as an orange powder yield; partial MiRi 2.5 (s, 3H), COCH ₃ ), 7.7 (d, 1H, H ² -indole), 9.8 (br s, 1H, NH).

Implementation Example 175 "

Using a procedure similar to that described in Example 174, but starting from 6- (2-ethylhexanilanido) -3-xylenedimethylol (ΞΞ) and methyl 4-bromomethyl-3-methoxybenzoate. 6- (2-ethylhexanamido) -3-methylindol-1-ylmethyl) -3-methoxybenzoate recovered in 42% yield as a white pesticide; partial β: R: 0.9 (t, 6a, 2CH,), 2,3 (d, 3H, indole-CH ₃ ),

3.8 (s, 3H, OCH ₃ ), 3.9 (s, 3H, OCH ₃ ), 5.2 (s, 2H, ₂ 6.6 (d, 1H, Ea-OCH ₃ ), 6.8 (dd, 1H, H ⁵ -indole), 7.2 (s, 1H, NH), 8.0 (d, 1H, H ⁷ -indole).

The 3-I-ethylindole EE was obtained as follows i-

(a) D- (2-Ethylhexanaiiiido) -3-formylindole was isolated in 71 / fig yield as a white pesticide (partial Nidi; 8,7

(d, 1H, H ² -Indol), 11.0 (s, 1H, COoH), 11.7 (br s, 1N, UH)) using a procedure similar to that described for DD in Exercise 176 was analogous, but instead of Ii, N-DimethyIacetamid dimethylformamide was used.

(b) 0.239 g of lithium aluminum hydride was added slowly to a solution of 0.9 g of 6- (2-ethylhexanazaido) -3-forrnylindole in freshly distilled tetrahydrofuran. The mixture was heated at reflux for 30 minutes, then cooled to room temperature and treated dropwise with 10 % w / v sodium sulfate solution until the mousse ceased. The resulting white, granular precipitate was removed by filtration. The filtrate was dried (MgSO 4) and evaporated. The residue was purified by flash chromatography on a 6 × 20 cm silica gel column using 25% V / V ethyl acetate in hexane as eluent to give 0 ×, 51 g (60 %) of 6- (2-ethylhexanamido) -3- methylindole (EE) as a white powder} partial miR: 2,3 (s, 3H, indole-CH,).

Embodiment 176

Using a similar procedure * as described in Example 34, 4- (6- (cyclopentyloxycarbonyl) aminoindol-1-ylmethyl) -3-methoxybenzoic acid was obtained in 55% yield as a white solid, m.p. · 238 C, obtained by hydrolysis of the corresponding IV-ethyl ester.

Execution ^ Examples 177 to 179

By a similar procedure to that described in Example 9, but starting from the appropriate carboxylic acid of the formula Re.GO ₂ H, the following Formula 1 compounds were obtained: -r

«« ^AU (%) ^Ute Partielle. Μ "

177 cyclohexylmethyl 57 2,2 (d, -2H, GH ₂

7.2 (br s, 1H, NH)

178 1-phenylpropyl ⁺ .62 '(0.91 (t, 3H, GH ₂ CH ₃ ),

(3.4 (t, 1H, GHCH ₂ ),. (7.1 (br s, 1H ₅ ! TH),

179 1-Phenylpropyl ⁺⁺ 71 (7.4 (s, .5H, Ph)

⁺ starting from R (-) - 2-phenylbutyric acid ⁺⁺ starting from S (+) - 2-phenylbutyric acid

Exemplary embodiments 180 to 181

Using the same chlorination procedure as described in Example 173, it was obtained:

(Embodiment 180)

Ethyl 4- (3-chloro-6- (cyclopentyloxycarbonyl) aminoindole-1-yl-yl-ethyl) -3-methoxybenzoate, in 21% yield as a solid, partial Ml: 1.7 to 1.8 (br , 8H, (CHg) ₄ ), 3.88 (s, 3H, OGH.), 3.94 (s, 3H, OCH,), 6.6 (br s, IH, Mi),

7.0 (s, 1H, H -Inrlol), starting from Liey 1 4- (6- (1-t-cyclopentyioxycarbonylamino) indol-1-ylmethyl) -3-diethoxybenzoate j and

(Export Example Example 181)

Methyl 4- (3-chloro-6- (2-cyclopentylacetamido) indol-1-ylmethyl) -3-methoxybenzoate, in 75% yield as a pest, partial: & R j 2,3 (br s, 3H, CHCH ₂ ), 3.88 (s, 3H, OCH ₃ ), 3.93 (s, 3H, OCH ₃ ), 7.0. (s, 1H, H ² -Indol), 7.2 (br s, IK,! 7H), starting from ethyl 4- (6- (2-cyclopentyl-aceta-azo) -indol-1-ylmethyl; 3-inethoxybenzoat.

Exemplary embodiments 182 to 184

Following the same procedure as described in Example 90, but starting from the appropriate alcohol, the following jüster of formula 11 were obtained;

Ausf.- He yield -,. _Ί,, ". _τ .

Partial hitx.

182 isopropyl. · 71 1.9 (d, 6H, CE (OE) ₂ ) _t

3.87 + 3.94 (2s, 2x3H, OCH _3), 4.8 ... 5.2 (m, 1H, CK _(CH3 J ₂₎

183 tetrahydrofur-3-yl 68 1.9 to 2.3 (m, 2H, CH ₂ CH),

3.7 .. '4.1 (m, 4H, CH ₂ OCH ₂ ) 5.2 ... 5.4 (m, 1H, CH.0)

184 i-Cyclohexen-4-yl 56 1.5 ... 2.5 (m, 6H, CH ₂ GH.

(CHp) ₂ ), 4.9 ... 5.2 (m, 1H, CK.Ö), 5.2 ... 5.7 (m, 2H, CH = CH)

Aus e rs s ρ i e1 185

A mixture of 0.91 g of iviethyl 4- (6-aminoindol-1-ylmethyl) -3-methoxybenzoate, 0.57 g of 1- (3-dimethylaminopropyl) -3-ethyl-

Carbodiimide hydrochloride, 0.37 g of 4-dimethylaminopyridine and 0.61 g of 2-cyclopentyl-2-phenylacetic acid in 15 ml of methylene chloride was stirred for 24 hours. The reaction solution was diluted with methylene chloride and washed successively with 10% v / v hydrochloric acid, water, 20 ml of M / V sodium hydroxide, water and brine; then dried (kgS0 <) and evaporated to give 0.96 g (66 %) of methyl 4- (6- (2-cyclopentyl-2-phenylacetaraidoindol) -1-ylmethyl) -3-methoxybenzoate as a light brown solid; MüR: 0.9r..1.8 (br η, 8H, (GH ₂ ),), 2.6 (m, 1H, GHGHCO), 3.87 '(s, 3H, OCH ₃ ), 3.9 (s, 3H, OCH ₃ ), 5.2 (s, 2H, JIGH ₂ ), 6.5 (d, 1H, H ³ -indole), 6.6 (d, 1H, In-MeO-G ₅ H - ^), 6.8 (dd, 1H, H ⁵ -indole), 7.1 (d, 1H, Η ² -Ιηάο1), 8.0 (br s, 1H, H ⁷ -indole).

Exemplary embodiments 186 to 190

Following the similar procedure to that described in Example 185, but starting from the appropriate acid He.GO ₂ H, the following esters of formula 1 were obtained:

Example Re. _{Off Pnr + ipllp} ™™ bspl. booty {% ^}} ^ ^art2 - ^elle ^ - ^

186 1-cyclohexylpropyl 40 0.74 ... 1.3 (br m, 5H,

GH ₂ GH ₃ ), 1.4 ... 2.0 (br m, 12H)

187 1-methyl-1-phenylethyl 59 1.65 (s, 6H, GCCH ₃ ) ₂ )

188 1-Phenyicyclopentyi 30 1.5 ... 2.8 (br m, 9H,

(GH ₂ ) ₄ CH), 6.69 (br,

> 1H, HH)

Ausf.-bspl.

189 alpha-methoxybenzyl 46 3,4 (s, 3H, OCH ₃ ), 4,7

(s, 1H, GHOGH _3), 8.6 br s, 1H, NH)

190 1-cyclopentylbutyl 34 0.9 (t, 3H, GH ₂ CH ₃ ),

1.0 ... 2.1 (br m, 14H, (OH ₂ ) ₄ CH, CH- (CH ₂ -) ₂ ), 7.1 (br s, 1H, Wd)

Embodiment 191

Following a procedure similar to that described in Example 174 but starting from 3-acetyl-6- (N-cyclopentyloxycarbonyl-aminoindole and methyl 4-bromomethyl-3-methoxybenzoate and using potassium carbonate instead of sodium hydride, methyl 4- (3-acetyl-G -N-cyclopentyloxycarbonylamino) indol-1-ylmethyl) -. 3-methoxybenzoate in 78% yield as a whitish pesticide; partial MvIRi 1.5 ... 2.0 (br m, 8H, (CH ₂ ) ₄ ), 2.5 (s, 3H, GO.CH ₃ ), 3.88 (s, 3H, OCH ₃ ), 3.94 (s, 3H, OCH _3), 5.2 (m, 1H, CH.0). _:

The starting indole was isolated using a procedure similar to that described in Example 174 for the indole DD, but starting from 6- (K-cyclopentyloxycarbonylamino) indole, and isolated in 31% yield as a light brown powder, partial WB ι 1.5 ... 2.0 (br m, 8H, ". (GH ₂ ) ₄ ), 2.5 (s, 3H, 00.GH ₃ ), 5.2 (m, 1H, CH.0) , 7.3 (d, 1H, H ² -indole).

G- (1'-cyclopentyloxycarbonylaminol) indole, in turn, was isolated in 44/5 yield as a white pesticide; "JLR : 1.5 ... 2.0 C br m, 8 H, (CHg) ₄ ), 5.1 ... 5.4 (m, 1Fi, CH. 0), 6.4 (m , 1H, Η " ^3- indole), 6.5 (br s, 1H, pi !!), 7.1 (m, UI, H ² -indole); by reaction of 6-aryninoindole with cyclopentyl chloroformate using a similar procedure to that described in Example 22.

Execution games 19 2

ϊ-Tach a similar manner to that described in vie embodiment 165, but starting from L.ethyl 4- (6-arr.iiioinaolin-1-ylir.6t.hyl) -3-- ^r nethoxyben2Oat and 2-Cyciopcntylessigsiiure was kethyl (4- C- (2-cyclopanlyiacetaniic.o) indlin-1-yl-yl-Stii; ^7- l) -3-ffisthoxybenzioate recovered in 26-weighted yield as a female solid, partial Li nn .; 2.3

(br s, 3H, CHCH p), 3.0 (t, 2H, H ³ -indoline), 3.4 (t, 2H,

H -indoline).

Application example-193

^ Jine Lüsun ^ of 0.5 g of 5- (L "-pentylcaroan-oyl) indole (P ' ¹ ) in 7:"; 1 ΐί, Ιί-lJi lethylformaruia (DLP ¹ ) vrarc ^ e a cased Aufschi Miarnung of 0.095 -glytrium hydride in 2 ml LO 'added. After 3 hours, a solution of 0.68 g of I. ethyl 4-bromo- ₁ -ethyl-3-ethylethoxybenzoate in 5 ml of Dj.- was added. sugesetzt. Stirring was continued for 24 hours, whereupon the reaction was quenched by adding saturated.-Un / noniuia-chloride solution. Las geige was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and oil, dried (LgSC _x ,), and evaporated. The residue was removed by bliochroniato-

purified graphite (β χ 20 cm silica gel column) using 30% V / V ethyl acetate in hexane as a sluent, * to 0.51 g (57 %) of lethyl 3-methoxy-4- (5- (N-pentylcarbamoyl) -indole 1-ylmethyl) benzoate as a whitish pesticide; partially NKR: 0.9 (t, 3H, (CHg) ₄ (GH), 1.2 ... 1.8 (br in, 6H, _CH3 (CHg) _3), 3.3 ... 3 , 6 (m, 2H, (GKg) ₃ CH ₂ ), 3.87 (s, 3H, OGH ₃ ), 3.9 (s, 3H, OCH ₃ ), 5.4 (s, 2H, MGH ₂ ) ,

The starting garbamoylindole FP was obtained as follows:

A solution of 0.5 g of indole-5-carboxylic acid and 0.54 g of 1,1'-carbonyldiimidazole in 10 ml of methylene chloride was heated under reflux conditions for 30 minutes. A solution of 0.3 g of pentylamine in 2 ml. Ethylene chloride was added, where the refluxing was continued for a further 30 min. The reaction mixture was diluted with chloroform, washed successively with 10% v / v hydrochloric acid, water and brine, then dried (MgSO 4) and evaporated to give 0.51 g (71 %) of 5- (B -pentylcarbamoyl) indole To give form of a whitish pesticide; partial MoH: 0.9 (t, 3H, CH ₃ (CH _{2) 4),} 1.2 ... 1.9 (br E, 8H, _CH3 (CHg) _4, 6.2 (br s, I 'd, Η ¹ -Ιηάο1), 6.6 (m, 1Η, H ³ -indole), 8.6 (br s, 1H, NH).

Exercise 194

Following a similar procedure to that described in Example 174 but starting from 3-eutyryl-6-cyclopentylacetamidoindole, ethyl 4- (3-butyryl-6-cyclopentylacetamiaoindol-1-ylmethyl) -3-methoxybenzoate was obtained in 77% strength Yield recovered as a white pesticide; COURSE: 0.94

Ct, 3H, CH ₂ CH ₃ ), 2.26 (br 'S, 3H, CHCH ₂ ), 2.79 (t, 2H, COCH ₂ ) 3.83 (s, 3H, OCH ₃ ), 3.97 (a, 3H, OCH ₃ ), 5.42 (s, 2H, NCH ₂ ), 6.89 (d, 1H, m -CHO.C ₆ H ₃ ), 7.24 (dd, 111, H ⁵ -Indol) 9.81 (s, 1H,! JH).

a guide example 195

Solution of 1.54 g of t-butyl 4- (6- (2-ethyl) hexanilo (iido) -3-forir: ylindol-1-ylmethyl) -3-methoxybenzoate and 2.24 g of I-ethyl (triphenylphosphoranylindene ) Acetaldehyde in 30 ml of moxan was heated under reflux conditions for 2 days. The solvent was evaporated and the mash was purified by flash chromatography (6χ20 cm silica gel column) using 20 % ± ßora v / v. Hexane in ethyl acetate as eluant to give 1.69 g (99 %). ) To give but-t-butyl 4- (3- (2-inethoxycarbonyl-ethylindenyl) -6- (2-ethylhexanamiao) in aol-1-yl-methyl) -3-methoxybenzoate as a white solid; partial NLK: 0.96 (t, 6H, (OH ₂ CH ₃ ) - ₂ ), 1.54 (s, 9H, C (CH ₃ ) ₃ ), 3.79 (s, 3H, OCH ₃ ), 3 , 92 (s, 3H, UCH ₃ ), 2.89 (s, 2H, ICH ₂ ), 6.35 (d, 1H-, CH = CH), 7.83 (d, 1H, CH = CH).

The starting indole was recovered by a straightforward procedure as described in Example 174, but starting from 6- (2-ethylhexanarrioc) o) -3-formylindoi and t-butyl 4-bromomethyl-3-methoxybenzoate, and found in 77 cowardly yield isolated as a white pesticide; M-IR: 0.96 (t, 6H, CH ₂ CH ₃ ).,), 1.57 (s, 9H, C (GH ₃ ) ₃ ), 3.92 (s, 3H, OCH ₃ ), 5 , 34 (s, 2H ^ NCH ₂ ), 9.92 (s, 1H, 00.H).

Embodiment 196

A digestion of 0.075 g of 4- (3- (2-Letaoxycarbonyivinyl β- (2-ethylhexanajnido) indol-1-ylinetiiyl) -3-methoxy-

benzoic acid in 5 ml of ethanol were added to 25% excess of 6k potassium hydroxide solution. The recovered solution was hydrogenated in the presence of 0.02 g of 10% h / L · palladium on charcoal using hydrogen at a pressure of 3.45 bar. The catalyst was then removed by filtration through diatomaceous earth. The filtrate was acidified (10% It./V hydrochloric acid). The resulting precipitate was collected by filtration and recrystallized from ethyl acetate / hexane to give 15.6 mg (21 %) of 4- (3- (2-lethoxycarbonylethyl) -6- (2-ethylhexanamido) -indol-1-ylmethyl) -3 -methoxybenzoic acid in the form of a white pesticide, melting point 189 ... 1S0 ⁰ O; Liquor analysis, found: C, 65.92; H, 7.05; 4.93%; C ₂₉ OH ₇₆ N ₂ Og. H ₂ O requires: G, 66,14; H, 7:27; Έ, 5.31%.

Embodiment 197 '"·

Following a procedure similar to that described in Example 185, but starting from! Viethyl 4- (6-amino-5-bromoindol-1-ylmethyl) -3-methoxybenzoate (GG) and Cyciopentylessigsaure,. Lethyl 4- (5-bromo-6-cyclo-'pentylacetairiidoindol-1-ylmethyl) -3-methoxybenzoate was recovered in 60 % ± gQi yield as a whitish pesticide; .partielle "MIR 1.6 (br a, 8H, (CHg) _4), 3.8 (s, 3H, OGH ₃₎ J, 9 (s, 3H, OuH _3), 5.3 (s, 2H , NCH ₂ ), 6.4 (dd, 1H, H ³ -indole), 7.1 (d, 1H, H ² -Incol), 7.7 (br, 1H, ITII), 7.8 (s, 1H, H ⁴ -Indol), 8.5 (br s, 1H, H ⁷ -Indol).

The starting 5-bromoindole GG was obtained as follows:

(a) - A solution of 1.21 g of 5-bromo-6-nitroinciolin and 1.35 g of ciiloranil in 30 ml of xylene was refluxed

Heated for 4.5 hours. The dark mixture was filtered. The filtrate was washed twice with 10% v / v sodium hydroxide, then with water, then with brine and then dried (MgSO 4) and evaporated. The residue was purified by flash chromatography (6 x 18 cm silica gel column) using 20% V / V hexane in methylene chloride as eluent to give 0.68 g (57 %) of 5-bromo-6-nitroindole as a yellow solid ; BMR: 6.6 (br m, 1 H, ^H3), 7.5 (dd, 1H, H ^2), 7.9 (s, 1H, H ^4), 8.1 (dd, 1H, H ⁷ ), 8.6 (br, 1H, HH).

(b) In the same manner as described in part (a) of Example 1, 5-bromo-6-nitroindole was reacted with methyl 4-bromomethyl-3-methoxybenzoate to obtain. To give methyl 4- (5-bromo-6-nitroindol-1-ylmethyl) -3-methoxybenzoate (HH) in 65 % yield as well as a pale yellow pesticide; partial NMRI 3.89 (s, 3H, OCH,), 3.94 (s, 3H, OGH _3), 5.35 (s, 2H, NCH _2), 6.53 (dd, 1H, H ³ -indole ), ^{2 4}

7.38 (d, 1H, H ² -indole), 7.89 (s, 1H, H ⁴ -indole), 8.03 (br s, 1H, H ⁷ -indole).

(c) A solution of 0.66 g HH in 100 ml of 10% v / v acetic acid in ethyl acetate in the presence of 0.10 g 5 conclude E / M is platinum on carbon is hydrogenated, where hydrogen for 4 hours at a pressure of 2.76 bar was used. The catalyst was removed by diatomaceous earth filtration. The filtrate was washed successively with 10M sodium hydroxide solution, water and brine, then dried (MgSO 4) and evaporated to give 0.61 g of methyl 4- (6-amino-5-bromoindol-1-ylmethyl) -3-methoxybenzoate ( GG) in shape

to give a 01s; partial NIvIRi 6.37 (dd, 1H, H -indole), 6.59 Cs, 1H, H ⁷ -indole), 6.93 (d, 1H, H ² -indole), 7.69 (s, 1H, H ⁴ -indole).

Embodiment 198 "

According to a procedure similar to that described in Example 193 but starting from 5-N- (2-methylpropyl) -carbamoylindole, methyl 4- (5-N- (2-methylpropyl) -carbamoylindole- 1-ylmethyl) -3-methoxybenzoate in 4% yield as a white pesticide; IWiR: 1.00 (d, 6H, (CH ₃ ) ₂ CH), 3.31 (t, 2H, · GHGH ₂ ), 3.88 (s, 3H, OCH ₃ ), 3.94 (s, 3H , OCH ₃ ), 5.36 (s, 2H, NGH ₂ ), 5.14 (br s, 1H, NH).

The starting carbamoyl indole was recovered following a similar procedure to that described for the starting indole of Working Example 193, using isobutylamine in place of pentylamine and isolating in white, foamy, white-foam; MMRi 0.95 (s, 3H, GH ₃ GH), 1.03 (s, 3H, GH ₃ GH), 3.32 (t, 2H, GHCH ₂ ), 6.23 (br s, 1H, FH) , 6.57 (m, 1H, H ³ -indole), 8.07 (br s, 1H, H ⁴ -indole), 8.73 (br s, 1H, NH).

Exemplary embodiment 199

Following the similar procedure to that described in Example 193 but starting from 6-N- (cyclopentylmethyl) carbamoylol (II), methyl was .3-methoxy3 '- 4- (6-N- (cyclopentylmethyl) carbamoylindol-1-yl-yl-dimethyl ) obtained benzoate in 37 % yield as an off-white solid; NLR: 1.41 ... 1.79 (m, 8H, (GHg) ₄ ), 3.39 (t, 2H, GH ₂ NH), 3.88 (s, 3H, OCH ₃ ), 3.92 (s, 3H, OCH ₃ ), 4.24 (s, 2H, NCH ₂ ), 6.17 (t, 1H, CH ₂ NH), 6.62 (d, 1H, H ³ -indole), 6, 72 (d, 1H, Hi-CH ₃ OG ₆ H ₃ ), 7.91 (s, 1H, H ⁷ -indole).

The starting indole II was obtained as follows:

(a) a solution of 4.46 g of methyl 4-methyl-3-nitrobenzoate

in 23 ml of DMP was treated with 8.18 g of N, N-dimethylformamide dimethyl acetal and heated to 130 ⁰ G for 2 h. The DMP was evaporated and the residue was triturated with ether to give 5.58 g (98%) of methyl 4- (2E-N, lT-dimethylaminovinyl-3-nitrobenzoate (JJ) as a red powder; IEiR: 2 , 98 (s, 6H, B- (CHJ ₂ ), 5.90 (ά, 1H, CHlO, 7.14 (d, 1H, GH-CHlO), 7.45 (d, 1H, phenyl-H ⁵ ) , 7.90 (dd, 1H, 5-phenyl-H ⁶ ), 8.47 (d, 1H, phenyl-H ² ).

(b) A solution of 5.58 g of JJ in 100 ml of THP was hydrogenated at 3.45 bar in the presence of 1.1 g of 10% M / M palladium on carbon for 35 minutes. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. The residue was dissolved in ethyl acetate and the resulting solution washed successively with 10% Y / V hydrochloric acid, water and brine, then dried (MgSO 4) and evaporated to give 3.32 g (85 %). To give methyl indole-6-carboxylate as a white pesticide; NMR: 3.92 (s, 3H, OCH ₃ ), 6.57 (m, 1H, H ³ -indole), 7.32 (t, 1H, H ² -indole), 7.10 (d, 1H, H ⁴ -Indol), 7.87 (d, d, 1H, H ⁵ -indole), 8.16 (br s, 1H, H ⁷ -indole).

(c) A solution of 3.32 g of methyl indole-6-carboxylate in 48 ml THF and 48 ml of methanol was .for 50 ⁰ C stirred for 2 hours with a solution of 4.78 g of lithium hydroxide monohydrate in 19 ml water. The solvent was evaporated and the residue was dissolved in water. The alkaline solution thus obtained was slowly acidified (HCl) and the resulting precipitate was collected to give 2.8 g (92 %) of indole-6-carboxylic acid as a brown. To give powder; IMR: 6.51 (m, 1H, H ³ -indole), 8.04 (m, 1H, H 1 -indole), 11.43

(brs, 1H, ITH), 12.42 (brs, 1H, OH).

(d) Following the similar procedure to that described for Indole GG in Example 193, indole-6-carboxylic acid was reacted with 1-cyclopentylmetylamine to add δ-N-i-cyclopentylmethylcarbamoylol (II) in a yield of 42 % as a pale pink powder yield; NMR: · 3.19 (d, 2H, CH ₂ IiH), 6.46 (d, 1H, H ³ -indole), 7.91 (d, 1H, H ⁷ -indole), 8.29 (t, 1H,

/ - - ' Embodiment 200

Following a similar procedure to that described in Example 99, but using methyl 7- (bromomethyl) benzo (b) furan-4-carboxylate (KK) as the alkylating agent, methyl was added to 7- (6- (2- ethylhexanamido) indole 1-ylmethyl) benzo (b) furan-4-carboxylät in 23% yield recovered as Peststoff, melting point 164 ... 167 ⁰ C; part of the EMR (250'MHz; dgDMSO) : 0.84 (2t, 6H, 2XCH ₃ ), 1.0 ... 1.6 (m, 8H); 2.25 (m, 1H, CHCO) ₅ 3.89 (m, 3H, OCH ₃ ); 5.75 (s, 2H, N)

The starting material JJ was obtained as follows: -

( a) A mixture of 3.46 g of potassium carbonate, 3.32 g of lethyl 3-hydroxy-4-methylbenzoate and 2.16 ml of allyl bromide in 80 ml of acetone was heated at reflux for 6 hours The mixture was separated by filtration, the filter cake was washed with acetone and the washings were combined with the filtrate and evaporated to give 3.85 g (93 %) of methyl 3-allyloxy-4-methylbenzoate as a clear oil; partial MViR "2.3 (s, 3H, C-CH _3), 3.9 (s, 3H, 0.CH _3), 4.6 (m, 2H, 0

-. 94 -

(b) 1.2 g of the 3-allyloxy compound of (a) were added ₎

Nitrogen atmosphere for 5 h at 200 ⁰ C, cooled and purified by flash chromatography (5 cm diameter silica gel column) using 92: 8 v / v hexane in ethyl acetate as eluent to 0.79 g (66 %) of methyl 2-allyl -3-hydroxy-4-methylbenzoate in the form of a white pesticide, m.p. 53 · ..56 ⁰ C, satisfactory BMR spectrum.

(c) In a solution of 0.78 g of 2-allyl compound from (b) in 25 ml methanol was bubbled 10 minutes at -78 ⁰ C a stream of ozone in oxygen. The reaction was then deoxygenated by bubbling nitrogen through the solution for two minutes and then adding 1.5 ml of dimethyl sulfide, whereupon the mixture was allowed to reach room temperature. After 3 h, the solvent was evaporated and the residual oil was purified by flash chromatography (4 cm diameter silica gel column) using 40:60 v / v ethyl acetate in hexane as eluent to give 0.33 g (42 %) of methyl 2-. hydroxy-7-methyl-2,3-dihydrobenzo (b) furan-4-carboxylate as a white solid, mp 112-115 ° C, with a satisfactory BER spectrum.

(d) 0.5 g of the benzo (b) furan obtained in (c) was dissolved in toluene (10 ml) and 3 mg of p-toluenesulfonic acid was added. The mixture was stirred and heated under reflux for 6 hours. The cooled mixture was diluted with ether and washed successively with saturated sodium hydrogen carbonate solution, water and brine, and dried, whereupon the solvent was evaporated to thereby yield 0.43 g of (94/2) methyl 7-methylbenzo (b ) furan

To provide 4-carboxylate as a colorless oil; BMRj 2.58 (s, 3H, CCH _3), 3.96 (s, 3H, 0.CH _3), 7.10 (d J = 7.7 Hz, 1H, ^H6), 7.35 (d J = 2.1 Hz, 1H, H ³ ), 7.90 (d J = 7.7 Hz, 1H, H ⁵ ).

(e) A mixture of 0.42 g of the ester obtained in (d) together with 0.409 g of Ii-bromosuccinimide and 5 mg of 3-benzoyl peroxide in 20 ml of carbon tetrachloride was stirred and heated under reflux for 3 hours with infrared irradiation. The cooled semis was concentrated in vacuo and the residue was purified by flash chromatography (4 cm diameter silica gel column) using 2.5: 97.5 v / v ether in hexane as eluent to give 1-ethyl 7- (bromomethyl) benzo ( b) furan-4-carboxylate (JJ) as a solid to give, which was purified by recrystallization ATIS hexane at -20 ⁰ g, (0.27 g 47%) bljaßgelben Peststoff, melting point 73 · ..80 ⁰ C, with a satisfactory MiR spectrum. -

Exemplary embodiments 201 to 206

Similar to the procedure described in Example 99, but using the appropriate

Neten Bromoinethyl compound of formula 13 (R = 011-,) were

1 ^

the following esters of formula 12 (R = CH,) are obtained:

Ausf.- ", G (and position Aus Schmelzbspl. ^Λα on Q). prey {%) point, ⁰ G

201 2-OCH ₃ direct binding (3) 37 107 .. .110 202 4-OCH ₃ direct binding (3) 45 144 .. .145 203 3-0CH ₇ direct binding (3) 23 (+) 204 2-Cl direct binding (4) 38 (++) 205 2,6- (0CH ₃ ) ₂ direct -Binding (4) 65 185 .. .186 206 2-GH ₃ direct binding (4) 55 169 .. .171

⁽⁺⁾ partial MR: 5.2 (s, 2H, GH ₂ H), 3.85 (s, 3H, 0.CH ₃ ),

3.78 (s, 3H, 0.GH ₃ ), 2.0 (m, 1H, GH.CO).

( ⁺⁺ ) Microanalysis, found: G, 67.85ί Η, 6.94; Ii, 5.62 %; ^a 25 ^H 29 ^C1H 2 ° 3 ^requires ' ^G ' . ⁶⁸ , 09; H, 6.63s IT, 6.35 %.

The required starting materials of formula 13 (R = CH-) were obtained as follows using procedures similar to those described in parts (c) and (d) of Example 1:

(a) (for embodiment 201)

Methyl 3-bromomethyl-2-metho: x: benzoate, obtained in 72% yield as 01}. EliR: 3.9 (s, 3H, OGH ₃ ), 4.0 (s, 3H, OGH ₃ ), 4 , 6 (s, 2H, GH ₂ Br), 7.07 ... 7.8 (m, 3H); by noting of. Methyl 2-methoxy-3-methylbenzoate, which in turn was recovered as an oil in 87% yield by esterification of the corresponding acid.

(b) (for embodiment 202)

Methyl S-bromomethyl-methoxybenzoate, obtained in 47 % yield as a white pesticide, m.p. 78-79 ° C, by bromination of methyl 2-methoxy-5-methylbenzoate which, in turn, is esterified by esterification of the corresponding acid as an oil was won.

(c) (for embodiment 203)

Methyl 4-bromomethyl-2-methoxybenzoate, obtained as an oil by bromination of methyl 2-methoxy-4-methylbenzoate, was recovered in turn by esterification of the corresponding acid as an oil

(ά) (for embodiment 204)

Methyl 4-bromomethyl-3-chlorobenzoate, recovered as an oil by bromination of methyl 3-chloro-4-methylbenzoate.

(c) (for embodiment 205)

Methyl 4-bromomethyl-3,5-dimethoxybenzoate, obtained in 85% yield as a Peststoff, melting point 117 ... 118 ⁰ C (recrystallized from ether / petroleum ether (40 ... 60 C boiling point), by Ή- Bromosuccinimid- Bromination of methyl 3,5-dimethoxy-5-methylbenzoate using a similar procedure as described in part (e) of embodiment 200 and diethyl 3,5-dimethoxy-5-methylbenzoate, recovered in 71% strength yield as Peststoff, melting point 98 ... 99 ⁰ G, by reaction of 3,5-dihydroxy-4-methylbenzoic with dimethyl sulphate and potassium carbonate in boiling acetone for 16 hours away;

(f) (for embodiment 206)

Methyl 4-bromomethyl-3-methylbenzoate was obtained as follows:

1.36 g of triphenylphosphine were added in portions over 35 minutes to a solution of 722 mg of methyl 4-hydroxymethyl-3-methylbenzoate and 1.72 g of carbon tetrabromide in 10 ml of CH 2 O at 0 G, and for an additional 40 minutes, added to the stirred mixture was an extra amount of Added 118 mg triphenylphosphine. After a further 30 minutes, the reaction mixture was absorbed on silica gel and the solvent was evaporated. The residue was added to the top of a silica gel column, whereupon a chromato-

Graphical determination using 60:40 v / v methylene chloride in hexane as the eluent. In this case, 0.914 g (94 %) of methyl 4-bromomethyl-3-methylbenzoate was recovered in the form of an oil; partial MiRi 2.45 (s, 3H, GH ₃ ), 3.90 (s, 3H, 0.GH ₃ ), 4.50 (s, 2H, CH ₂ Br),

Embodiments 207 to 208

"Wax similar procedure as described in Working Example 23 the following esters of formula I were obtained i-

(Embodiment 207)

Sthyl 6- (6- (2-ethylhexanarnido) indol-1-yl) -4 (S) -hexenoate in 40% yield as a white pesticide, m.p. 65 ° C (after purification by flash chromatography on silica using of 1:20 v / v of ethyl acetate in toluene as the eluent), by reaction of ethyl-6-bromo-4 (E) -hexenoate with 6- (2-ethylhexanamido) indole j

(Embodiment example 208)

Methyl 4- (1- (6- (2-cyclopentylacetamido) indol-1-yl) ethyl) benzoate in 30 % yield as a mineral, partial miR (d ⁶ -DMSO): 1.88 (d, 3H, CH ₃ ), 3.81 (s, 3H, OGH ₃ ), 5.75 (q, 1H, CH), by reaction of methyl 4- (1-bromoethyl) benzoate with 6- (2-glylopentylacetamido) indole.

Methyl 4- (1-bromoethyl) benzoate was obtained as follows:

(a) 2M methanolic hydrochloric acid was added portionwise to a stirred suspension of 3.6 g of methyl 4-acetylbenzoate

so that a red color was maintained (by conventional esterification of the corresponding acid 'as a Peststoff, melting point 90 ... 92 ⁰ C, obtained) and 1.4 g of sodium cyanoborohydride in methanol, a single crystal of the indicator methyl orange containing added , After 4 hours, an additional 173 mg of sodium cyanoborohydride was added and the red coloration was further maintained by adding 2M methanolic hydrochloric acid. One hour after the last addition of reagents, the solvents were evaporated and the residue was dissolved in water. The recovered solution was extracted with ether. The extracts were then dried (Na 2 SO 4) and evaporated. The residue was purified by chromatography. Silica mqterial using 3i97 V / V ether and chloroform as the eluent to afford 2.9 g (80 %) of methyl 4- (1-hydroxyethyl) benzoate as a yellow oil; partial MR: 1.50 (d, 3H, CH _3), 3.91 (s, 3H, OCH _3), 4.94 (q, 1H, CH.OH).

(b) A solution of 1.47 g of methyl 4- (1-hydroxyethyl) benzoate and 3.61 g of carbon tetrabromide in 25 ml of methylene chloride was treated with 2.70 g of triphenylphosphine. After 1 h, the solvent was evaporated and the residue was purified by chromatography on silica gel using methylene chloride in hexane as eluant to afford 1.52 g (67 %) of & ethyl-4- (1-bromoethyl) benzoate as an oil yield; partial NInIR: 2.04 (d, 3H, CH _3), 3.91 (s, 3H, OCH _3), 5.10 (q, 1H, CH.Br).

Embodiments 209 to 238

Following a similar hydrolysis procedure as the one in

Embodiment 34 described, the following carboxylic acids of formula 5 can be obtained by hydrolysis of the corresponding methyl esters:

Ausf.- Λο enamel ..253 yield bspl. Cyc1ohexylme thyI point ⁰ C ..278 (%) 209 1-cyclohexylpropyl 252nd ..231  67 210 1-phenylpropyl ⁴ " 277th ..231 66 211 1-phenylpropyl ⁺⁺ 230th ..210 17 212 1-methyl-1-phenylethyl 230th ..147 30 213 1-phenyl-cyclopentyl 209th ..195 12 214 Alpha-methoxybenzyl 145th ..237 (Z) , 54 215 Alpha Cyclopentylbenzyl 193rd ..269 98 216 1-cyclopentylbutyl 236th 39 217 268th 63

⁺ from R (-) - 2-phenylbutyric acid ⁺⁺ from S (+) - 2-phenylbutyric acid

Similarly, the following carboxylic acids of formula 15 (R = H) were obtained by hydrolysis of the corresponding ethyl esters:

Ausf.- ~ -ν- 'T3 " ^ _n melt yield

bspl. ^Re ' ^{X. Ra Ro} point ° C (56)

218 isopropyloxy H H 235th ..356 ⁺ 58 219 'Tetrahydrofuran-3-yloxy H H 214th , .215 36 220 1-cyclohexen-4-yloxy H H 236th ..237 43 221 cyclopentyloxy Cl H 234th ..235 ⁺ 12 222 Cyclopentyloxy CO .CH ₃ H 262nd ..263 36 223 Cyclopentylmethyi H br 237th ..238 63 224 cyclopentylmethyl Cl H 263rd ..264 (Z) 67 225 Cyclopentylmethyi CO. C ₃ H ₇ H 237th ..238 69

⁺ isolated as a partial hydrate.

Similarly, the following carboxylic acids of formula 12 (R = H) were obtained by hydrolysis of the corresponding methyl esters.

Exp. P, G (and position melt yield

bspl. on Q) point,

226 2-OCH ₃   direct binding (3) 200th ..201 (Z) 64 227 , 4-OCH ₃ direct binding (3) 171. ..174 (Z) 69 228 3-OCH ₃ direct binding (4) 189th ..190 69 229 2-01 direct binding (4) 222nd ..232 45 230 2,6- (0CH ₃ ) ₂ direct binding (4) 274th ..275 83 231 2-CH ₃ direct -binding (4) 239th ..240 91

Similarly, the following carboxylic acids of Formula I were obtained by hydrolysis of their corresponding methyl esters (in Example 238, the ethyl ester was used): -.

(Embodiment 232)

4- (6- (2-cyclopentylacetamido) indolin-1-ylmethyl) -3-methoxybenzoic acid, dissolved in 14% yield as a solid ^ melting point 212 ... 213 ⁰ C;

(Embodiment 233)

4- (5- (N-isobutyl) carbamoylindöl-1-yliaethyl) -3-methoxybenzoic acid, dissolved in 32% yield as a hemihydrate, m.p. 157 ... 158 ⁰ C;

(Example 234)

4- (6- (lT-cyclopentylmethyl) carbamoylindol-1-ylmethyl) -3-methoxybenzoic acid, in 50% yield as a pesticide,

Melting point 245 ... 246 ⁰ Cj

(Embodiment 235)

4- (5- (N-pentyl) carbamoylindol-1-ylmethyl) -3-methoxybenzoic acid, in 86% yield as a Lger Peststoff, melting point 142 ... 143 ⁰ C;

(Embodiment 236)

4- (1- (6- (2-cyclopentylacetamido) indol-1-yl) ethyl) benzoic acid, dissolved in 56% yield as a Peststoff, melting point 216. ..217,5 ⁰ G; -

(Embodiment 237)

7- (6- (2-Bthylhexanamido) indol-1-ylmethyl) benzo (b) furan-4-carboxylic acid in 60% yield as a Peststoff, mp 249 · ⁰ ..251 C; and

(Embodiment 238)

6- (6- (2-ethylhexanamido) indol-1-yl) -4 (Ξ) -hexenoic acid, dissolved in 89% yield, as a Peststoff, melting point 113 ... 114 ⁰ C.

Embodiment 239

By a similar procedure to that described in Example 90, but starting from cyclopentanethiol and t-butyl-4- (6-aminoindol-1-ylmethyl) -3-methoxybenzoate, t_ -sutyl was 4- (6- (cyclopentylthiocarbonyl) aminoindole-1 -ylmethyl) -3-methoxybenzoate in 38% yield as

a white foam obtained in partial miR: 1.5 (s, 9ΓΙ »G (CH ₃ ) ₃ , 1.6 (m, 6H, (CHg) ₃ ), 2.0 (m, 2H, -GH ₂ -) , 3.6 (br, 1H, CHS), 3.9 (s, 3H, OCH.), 5.3 (s, 2H, NCH ₉ ), .6,4 (d, IH,

3 ^

H -indole), 6.6 (d, 1H, aromatic), 7.0 (d, 1H, aromatic), 7.3 ... 7.4 (m, 4H, aromat-ish), 7.6 ( br s, 1H, H ⁷ -Indol), 10.0 (br s, 1H, IiH).

Exemplary embodiments 240 to 241

Following the similar procedure to that described in Example 172, the following acids of formula I were obtained from the corresponding Jb-butyl esters:.

(Embodiment 240)

4- (6- (Gyclopentylthioolocarbonyl) aminoindole-1-ylmethyl) -3-methoxybenzoic acid, in ± 68% yield as a ger Peststoff, melting point 228 ... 230 ⁰ G (dec); and

(Embodiment 241)

4- (3- (2-methoxycarbonylvinyl) -6- (2-ethylhexanamido) indol-1-ylmethyl) -3-methoxybenzoic acid, dissolved in 54% yield as a Peststoff, melting point 242 ... 243 ⁰ G.

Exemplary embodiments 242 to 243

Following the similar procedure to that described in Example 67, the following tetrazole derivatives of formula I were obtained:

(Embodiment 242)

6- (2-phenylbutanamido) -1- (6- (1 (H) -tetrazol-5-yl) hexyl) indole, in 45% yield as a pest, melting point

163.5 ... 165 ° C, starting from 1- (6-cyanohexyl) -6- (2-phenyl-butanamido) indole, which in turn as a solid melting point 105 ... 106 ⁰ C, by sodium hydride alkylation of 6- (2-benzylbutanainido) indole was obtained with 7-bromoheptanonitrile using similar conditions as described in Example 23; and

(Embodiment 243)

6- (2-ethylhexanamido) -1- (6- (1 (H) -tetrazol-5-yl) hexyl) indole, in 58 f ~ _s follower yield as a partial hydrate, melting. point 149 ... 150 ⁰ C, starting from 1- (6-cyanohexyl) -6- (2-ethylhexanamido) indole which in turn as a solid, melting point 98 ... 99 ⁰ C, by sodium hydride alkylation of 6- (2-Ethylhexanamido) indole with 7 bromoheptanonitrile was obtained using similar conditions as described in Example 23.

Exemplary embodiments 244 to 248

Following the procedure described in Example 157, the following tetrazole derivatives of the formula I were obtained:

(Embodiment 244)

6- (N '- (1-Phenylethyl) ureido) -1- (6- (1 (H) -tetrazol-5-yl) -hexyl) -indole, in 20 % yield, as a solid, mp 114. ..116 C (recrystallized from aqueous acetonitrile) using 6-amino-1- (6- (1- (H) -tetrazol-5-yl) hexyl) indole and S (-) - alpha-methylbenzyl isocyanate;

(Embodiment 245)

^x 6- (¥ '- (1-phenylethyl) ureido) -1- (6- (1 (H) -tetrazol-5-yD-hexyl) indole, in 10% yield as a pesticide, m.p. 116 ^° C (recrystallized from aqueous acetonitrile) using 6-amino-1- (6- (1 (H) -tetrazol-5-yl) hexyl) indole and R (+) - alpha-methylbenzyl isocyanate j

(Embodiment 246)

6- (N-Cyclopentyloxycarbonylamino) -1- (8- (1 (H) -tetrazol-5-yl) octyl) indole, in 23% yield as a pest, m.p. 138-140 G, using cyanopentyl chloroformate and 6-amino-1- (8- (1 (H) -tetrazol-5-yl) octyl) -indole, which in turn is obtained by alkylation of 6-nitroindole with 8-bromo-octanonitrile and subsequent catalytic reduction by an analogous method obtained for V in Embodiment 157.

(Embodiment 247)

6- (lT-butoxycarbonylamino) -1- (8- (1 (H) -tetrazol-5-yl) octyl) indole, in 37 yield as a follower Peststoff, melting point 122 ... 123 ⁰ G, using Butyl chloroformate and 6-amino-1- (8- (1 (H) -tetrazol-5-yl) octyl) indole; and

(Embodiment 248)

6- (N-Cyclopentyloxycarbonylamino) -1- (4- (1 (H) -tetrazol-5-yl) -butyl) indole, in 54% yield as a pest, mp 163-165G, using glyclopentylchloroformate and 6-amino-1- (4- (1 (H) -tetrazol-5-yl) -butyl) -

indole, which in turn was analogous to 6-amino-1- (8- (1 (H) -tetrazol-5-yl) octyl) indole initially obtained from 6-nitroindole and 4-bromobutyronitrile.

Embodiment 249

By a similar procedure to that described in Example 73, 6- (2-cyclopentylacetamido) -1- (4 - ((1H) -tetrazol-5-ylthiol) -2E-butenyl) indole was obtained in 40% yield as a white solid Melting point 134-135 ⁰ C, obtained from 1- (4-bromo-2-butenyl) -6- (2-cyclopentylacetamido) indole, the latter in turn being obtained in 12% yield by sodium hydride alkylation of 6- (2-Cyclopentylacetaraido) indole was recovered with 1,4-dibromo-2-butene using similar reaction conditions as described in Example 23.

Exemplary embodiment 250

By analogy with the procedure described in Example 9, but starting from 6-amino-1- (6- (1- (H) -tetrazol-5-yl) hexyl) indole and 3-cyclopentylpropionic acid, 6- (3-Cyclopentylpropionamido ) -1- (6- (1 (H) -tetrazol-5-yl) hexyl) indole in 41% yield, melting point 143 ... 145 ⁰ C won.

Exemplary embodiments 251 to 254

To a suspension of 340 mg of ethyl 5- (4- (6- (1-butoxycarbonylamino) indol-1-ylmethyl) -3-methoxyphenyl (-3 (H) -tetrazole-3-acetate in 5 ml of 1M sodium hydroxide was added 5 ml of ethanol After 1.5 h, the reaction mixture was diluted with water and a 2: 3 v / v mixture of ethyl acetate / hexane,

acidified COM HCl) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO ₄ ) and evaporated. The residue was chromatographed on 16 g of silica gel (treated with octadecylsilane) using a methanol / phosphate buffer gradient (50/50/60/40 v / v) as the eluent. Acidification of the appropriate fractions afforded 240 mg (75%) of 5 (4 - (- butoxycarbonyl) -aminoindol-1-ylmethyl) -3-methoxyphenyl) -3 (H) -tetrazole-3-acetic acid (Example 251) in the form of a white solid, melting point 92 ... 95 ⁰ C; Microanalysis, found? C, 59.92j H, 5.35; N, 17.33%; C ₂₄ H ₂₆ N ₆ O ₅ requires: C, 60.25; H, 5:47; 17,5, 17.56 %.

Using a similar procedure, the following carboxylic acids of formula I were obtained by hydrolysis of the corresponding methyl or ethyl esters:

(Embodiment 252)

5- (4- (6- (Butoxycarbonyl) aminoindol-1-ylmethyl) -3-methoxyphenyl) -1 (H) -tetrazole-i-acetic acid isolated as a solid in 40% yield; Microanalysis found: C, 60.5 % H, 5.49; N, 17.47 ^ i ^G 24 ^H 26 ^N 6 ° 5 requires: C, 60.25; H, 5:47; N, 17.56;

, (Embodiment 253)

£ - (5- (4- (6- (ϊΤ-Butoxycarbonylamino) indole-1-ylmethyl) -3-methoxyphenyl) -3 (H) -tetrazol-3-ylmethyl) benzoic acid, in a Yield of 63% isolated as a solid; Microanalysis found: C, 62.64; H, 5:26; N, 14.36 %; ^C 3o ^H ₃₀ ⁰ 6 ^1T 5 * ^H 2 ⁰ requires: C, 62.94; H, 5.59; N, 14.69 %.

(Execution example 254)

Ε - (5- (4- (6- (N-Butoxycarbonylaraino) indol-1-ylmethyl) -3-methoxyphenyl) -1 (H) -tetrazol-1-ylin-ethyl) benzoic acid isolated in 48% yield as a pesticide j Microanalysis found: C, 64.85; H, 5.57; N, 14.97 %; ^C _3O ^H 3O ^H requires 6 ° 5 '; C, 64.97; H, 5.45; N, 15.4 %.

The starting esters were obtained as follows: - (a) (For Embodiments 251, 252)

To a suspension of 500 mg of 6-butoxycarbonyl) amino-1- (2-methoxy-4- (2 (H) -tetrazol-5-yl) benzyl) indole, 67 mg of potassium iodide and 167 mg of potassium carbonate in 12 ml of 2-butanone 0.14 ml of ethyl bromoacetate added. The mixture was heated under reflux for 3 hours. The gum was removed by filtration and the filtrate was evaporated. The residue was purified by chromatography on 35 g of silica gel using an ethyl acetate / toluene gradient (1:15 ... 1:10 v / 7) as eluent. In this way, 348 mg (57 %) of ethyl 5- (4- (6- (butoxycarbonyl) aminoindol-1-ylmethyl) -3 (H) -tetrazole-3-acetate in the form of a pesticide, mp 46-48 ⁰ G recovered, partial MMR (dg-DMSO), 1.21 (t, 3H, OCH ₂ CH ₃ ), 4.00 (s, 3H, OCH ₃ ), 4.10 (q, 2H, OCH ₂ CH ₃ ), 5.33 (s, 2H, benzyl-CH ₂ ), 5.86 (s, 2H, CH ₂ CH ₂ ), and 77 mg (12 %) of ethyl 5- (4- (6- (butoxycarbonyl) aminoindo1-1-ylmethyl) -3-methoxyphenyl) -1 (H) -tetrazole-i-acetate in the form of an O 1; partial MR Cd ₆ DKSO): 1.04 (t, 3H, OCH ₂ CH ₃ ), 3, 96 (s, 3H, OCH ₃ ), 4.06 (q, 2H, OCH ₂ CH ₃ ), 5.35 (s, 2H, benzyl-CH ₂ ), 5.63 (s, 2H, CH ₀ CO ₀ ).

(b) (For embodiments 253 «254)

Following the similar procedure to that described for (a) above, but using methyl 2-bromomethylbenzoate instead of ethyl bromoacetate, methyl _o- (5- (4- (6- (butoxycarbonyl) aminoindol-1-ylmethyl) - 3-methoxy- 'phenyl) -3 (H) -tetrazol-3-ylmethyl) benzoate obtained as a Peststoff in a yield of 76%, melting point 55 ... 58 ⁰ Cj partial MMR ^(d6-DMSO); 3.81 (s, 3H, GO ₂ GH ₃ ), 3.98 (s, 3H ₁ OCH ₃ ), 5.32 (s, 2H, INO in CH ₂ ), 6.28 (s, 2H, tetrazole -Chg); and methyl £ - (5- (4- (6- (butoxycarbonyl) aminoindol-1-ylmethyl) -3-methoxyphenyl) -1 (H) -tetrazol-1-ylmethyl) benzoate, isolated as an oil in 9 % yield · Partial NMR (dgDMSO): 3.66 (s, 3H, CO ₂ CH ₃ ), 3.88 (s, 3H, OCH ₃ ), 5.33 (s, 2H, indole CH ₂ ); 6.03 (s, 2H, tetrazole CH ₂ ).

Embodiment 255

99 mg of sodium hydride (50% MAi dispersion in mineral oil) was washed twice with hexane and suspended in 1 ml of dry dimethylformamide (DHP). The suspension was stirred and treated with a solution of 355 mg of benzenesulfonamide in 1 ml of DMP. The mixture was stirred for 1 h until the mousse stopped. Next, a solution of 253 mg of 4- (6- (2-ethylhexanamido) indol-1-ylmethyl) -3-methoxybenzoyl-1-N-diphenylcarbamide anhydride in 0.5 ml of DMP was added. The mixture was stirred for an additional hour and poured into 20 ml of water. The aqueous mixture was acidified to pH 6 with acetic acid and extracted with ethyl acetate. The extracts were washed with water and then with saturated brine, dried (MgSO 4) and evaporated. The resulting residue was purified by flash chromatography (using 8% V / V ethyl acetate in

Toluene purified with a content of 1% v / v acetic acid) and then by recrystallization (from Bthylacetat / petroleum ether (boiling point 60 ... 80 ⁰ C)) to obtain 130 mg (57%) N- (4- (6- ( 2-ethylhexanamido) indol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide as a white pesticide, mp 216.5 ... 218 ⁰ G; Microanalysis found: C, 66, Hj H, 6.34; N, 7.13 % C ₃₁ H ₃₅ N ₃ O ₅ S requires: C, 66.29; H, 6.28; N, 7.48 %.

The starting diphenylcarbamide anhydride was obtained as follows:

A solution of 3.1 g of 4- (6- (2-methylhexanamido) indol-1-ylmethyl) -3-methoxybenzoic acid and 1.0 ml of triethylamine in 30 ml of methanol was treated with a solution of 2.5 g of N, N- Diphenylcarbamoylpyridinium chloride in 30.ml methanol. The resulting precipitate was collected by filtration, washed with methanol and dried under vacuum to give 3.54 g (79 %) of 4- (6- (2-ethylhexanamido) indol-1-ylmethyl) -3-methoxybenzoic-N, to give N-diphenylcarbamidsäureanhydrid as a white Peststoff, melting point 159 ... 162 ⁰ C; Microanalysis, found: C, 73.77; H, 6:37; U, 6, 67; C ₃₈ H ₃₉ U ₃ O ₅ requires: C, 73.88; H, 6:36; N, 6.80 %.

Exemplary embodiments 256 to 257

Following a similar procedure as described in exemplary embodiments game 255, the following compounds of formula I were obtained s-

( Embodiment 256) N- (4- (6- (Cyclopentyloxycarbonyl) aminoindol-1-ylmethyl) -3-

methoxybenzoyl) benzenesulfonamide, in 34% yield as a hemihydrate, mp 186 ... 188 ⁰ C; and

(Embodiment 257)

U- (4- (6- (2-Phenylbutanamido) indol-1-ylmethyl-3-methoxybenzoyl) benzenesulfonamide, in a yield of 41% as a monohydrate, melting point 214 ... 216 ⁰ G.

The starting N 2 -tiphenylcarbamic acid anhydrides were prepared from the corresponding benzoic acids of Pormel I analogously to the procedure described in Example 255.

Exemplary embodiments 258 to 260

Following a procedure similar to that described in Example 255, but starting from the appropriate arylsulfonamide, it was obtained;

(Embodiment 258)

N- (4- (6-2-ethylhexanamido) ind.ol-1-ylmethyl) -3-methoxybenzoyl) methanesulphonamide in a yield of 55% as a Peststoff, melting point 214 ... 21 5 5 ⁰ C '.

(Embodiment 259)

U- (4- (6- (2-ethylhexanamido) indol-1-ylmethyl) -3-methoxybenzoyl) -jD-toluenesulfonamide in 48 % yield as a pesticide, mp 228-229 ° C.

(Embodiment 260)

N- (4- (6- (2-ethylhexanamido) indol-1-ylmethyl) -3-metlioxybenzoyl-o-toluenesulfonamide in 27 % yield

a pesticide, mp 221 ... 222 ⁰ C.

Embodiment 261 . ,

48 mg of sodium hydride (50 percent MOM dispersion in mineral oil) were washed twice with petroleum ether (boiling point 40 ... 60 ⁰ C) and suspended in 2 ml of dry dimethylformamide (DKP). The reaction vessel was purged with nitrogen and treated with 188 mg of benzenesulfonamide. The mixture was stirred for 30 minutes until the mousse stopped. Then, a solution of 260 mg of 3-methoxy-4- (6- (2-phenylbutanamido) indazol-1-ylmethyl) benzoic-N, N-diphenylcarbamic acid anhydride in 1 ml of DMF was added and the mixture was stirred for 30 minutes. The reaction mixture was diluted with 30 ml of ethyl acetate and washed successively with 5 ml of 1M hydrochloric acid, 5 ml of water (2 ×) and 5 ml of saturated brine, then dried (MgSO 4) and evaporated. The obtained residue was purified by means of flash chromatography using 30 v / v ethyl acetate in toluene tigern with 1% v / v acetic acid as eluent to give a Peststoff which / petroleum ether (from ethyl acetate · boiling point 60 ... 80 ⁰ C) was recrystallized. In this manner, 161 mg (69%) N- (4- (6- (2-Phenylbutanamido) indazol-1-ylmethyl ·) -3-methoxybenzoyl) benzenesulfonamide as a white Peststoff, · Melting point 140 ».. ⁰ G I4I , won}. Microanalysis, found: G, $ 65.94 H, 5.18; N, 9.31 %; C ₃₂ H ₃₀ N ₄ O ₅ S requires: G, 65.95; H, 5.19} N, 9.61 %.

The starting iTiN-diphenylcarbamic acid anhydride was obtained as follows.

A mixture of 177 mg of 3-methoxy-4- (6- (2-phenylbutanamido) -indazol-1-ylmethyl) benzoic acid, 2.5 ml of methanol and 0.4 ml of 1IvI sodium hydroxide solution was added to a solution of 149 mg

ITjN-diphenylcarbamoylpyridinium chloride in 0.8 ml of methanol. The reaction mixture was stirred for 20 minutes and diluted with 30 ml of ethyl acetate. The mixture was then washed with 5 ml of water and then with 5 ml of brine, dried (MgSO 4) and evaporated to give 260 mg of 3-methoxy-4- (6- (2-phenylbutanamido) indazol-1-ylmethyl) benzoic acid. To give N, N-diphenylcarbamic acid anhydride as a yellow oil, which by thin layer chromatography (retention factor = 0.8 on SiO ₂ , eluent 50 % ± v / V ethyl acetate / toluene with 2 % acetic acid) was essentially pure and which was without further purification or characterization was used.

Embodiment 262

204 mg of 4- (6- (cyclopentyloxycarbonyl) aminoindazol-1-ylmethyl) -3-methoxybenzoic acid were added to a stirred solution of 79 mg of benzenesulfonamide, 4-dimethylaminopyridine and 96 mg of 1- (3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride in Added 5 ml of dry methylene chloride. After 15 minutes, the mixture became homogeneous. It was stirred for a further 18 hours, then diluted with 20 ml of methylene chloride and washed successively with 20 ml portions of 1N hydrochloric acid, water and saturated brine. The solution was then dried (MgSO 4) and evaporated to give 27.8 mg of an amorphous pesticide. This was recrystallized from a mixture of methylene chloride, diethyl ether and petroleum ether (boiling point 40 ... 60 ⁰ C) crystallized to 184 mg (67%) IT (4- (6- (cyclopentyloxycarbonyl) aminoindazol-1-ylmethyl) -3- methoxybenzoyl) to give benzenesulfonamide as a white solid, 181 ... -Schmelzpunkt 182.5 ⁰ C; Microanalysis, found C, 61.46; H, 5:17; N, 10.19 % \ ^G ₂ 8 ^H 28 ^N 4 ° 6 ^S requires; G, 61.30; H, 5.14; N, 10.21%.

Embodiments 263 to 264

Following the procedure described in Example 2'62, the following sulfonamides of the formula I were obtained:

(Embodiment 263)

L ·! - (4- (6- (2-cyclopentylacetamido) indazol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide, isolated in 48 % yield as a pesticide, mp 167-169 ° C; Microanalysis found: G, 63.73; H, 5.61; N, 9.98 %; C ₂₉ H ₃₀ N ₄ O ₅ S requires: C, 63.72; H, 5.53; Ii, 10.25%;

(Embodiment 264) :

N- (4- (6- (2-Cyclopentylacetamido) indazol-1-ylmethyl) -3-methoxybenzoyl) - £ -toluenesulfonamide, isolated in 60 % yield as a solid, mp 183.5 ... 185 ° C Microanalysis, found: G, 64.27; H, 5.81; N, 9.78%; C ₃₀ H ₃₂ N ₄ O ₅ S requires: G, 64.27; H, 5.75; N, 9.99 % \

Exemplary embodiments 265 to 269

Following the procedure described in Example 262 but starting from the appropriate carboxylic acid of Formula I (Z = CO ₂ H) and the sulfonamide of the formula HpH.SO ₂ .Rg, the following sulfonamide derivatives of Formula 19 (Ha = H, ReX = cyclopentylmethyl): -. · ·

Ausf, - melt yield

bspl. Rg point, ⁰ C {%)

265 £ tolyl 218th ..220 63 266 2-aminophenyl 140th ..155 30

Ausf.- bspl. hg Melting point, ⁰ G ..148 ..147 ..246 (Z) Yield (56). 267 268 269 2-thienyl 1 -naphthyl 6-chloro-3-pyridyl 144 .. 144 .. 244., 64 60 42 Embodiments 270 to 276

The procedure similar to that described in Exemplary Embodiment 255, but starting from the suitable sulfonamide derivatives of the formula 19 (Ra = H, ReX = 1-ethylpentyl), was obtained:

Ausf.-bspl.

Melting point, G

Yield (56)

270 4-Kethoxyphenyl- 197 ... 199 - 18 271 benzyl 212 ... 213.5 73 272 4-Chlorοphenyl 182 , 5 ... 184 64 273 4-fluorophenyl 176 ... 178 65th 274 4-nitrophenyl 212 ... 214 45 275 isopropyl 206 ... 207 32 276 butyl 157 ... 159 20 Embodiment 277

A solution of 8.9 g of 4- (3-acetyl-6- (cyclopentyloxycarbonyl) -aminoindol-1-ylmethyl) -3-methoxybenzoic acid, 2.5 g of 4-N, N-dimethylaminopyridine, 4.0 g of hydrochloride, and 3 , 2 g of benzenesulfonamide in 100 ml of methylene chloride was stirred for 24 hours and then diluted with ethyl acetate. The mixture was washed successively with dilute hydrochloric acid (about 2M), water and

Brine, The organic layer was dried (MgSO 4), and the solvent was evaporated. The residue was purified by recrystallization from a mixture of methanol, THP and water to give 7.5 g (64 %) of N- (4- (3-acetyl-6- (cyclopentyloxycarbonyl) aminoindol-1-ylmethyl) -3-methoxybenzoyl ) benzenesulfonamide in the form of a white Peststoffes to provide, melting point 245 ... 246 ⁰ C. microanalysis, found: G, 62.98; H, 5:37; N, 6.94%; C ₃₁ H ₃₁ -N ₃ O ₇ S requires: C, 63>14; H, 5.30; N, 7.13 %.

Embodiments 278 to

Following the similar procedure to that described in Example 277 but starting from the appropriate 4- (indol-1-yl or indolin-1-ylmethyl) -3-methoxybenzoic acid, the following N-benzenesulfonamide derivatives of the formula-19 (Rg = phenyl, Ra = H, except in Embodiment 279, where Ra = chlorine, and except for Example 283 in which Ra = 2 (E) (methoxycarbonyl) vinyl): -

Ausf.- ρ _T melt yield

bspl. ^Ke ' ^A point, ⁰ C (%)

Note: ⁺ konohydrate

cyclopentyl 225th ..226 (Z) ⁺ 52 cyclopentyloxy 199th ..200 (Z) 18 cyclopentylmethyl 194th ..196 42 cyclopentylamino 227th ..228 50 Tetrahydrofur-3-yloxy 183rd ..184 25 1-ethylpentyl 199th ..201 54

(Embodiment 284)

H- (4- (β- (2-cyclopentylacetamido) indolin-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide, in a yield of 7% as a solid, melting point 136 ... 137 ⁰ C (dihydrate);

(Embodiment 285)

N- (4- (6- (N-cyclopentylmethylcarbamoyl) indol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide, in a yield of 63% as a Peststoff, melting point 207 ... 208 ⁰ G.

(Embodiment 286)

1- (4- (5- (N-pentylcarbamoyl) indol-1-ylmethyl) -3-methoxybenzoyDbenzensulfonamid, in a yield of 56% as a Peststoff, melting point 223 ... 225 ⁰ G;

(Embodiment 287)

N- (5- (6- (N-Cyclopentyloxycarbonylamino) indole-1-ylmethyl) -2-furoyl) benzenesulfonamide, in a yield of 29% as a Peststoff, melting point 228 ... 229 ⁰ Gj and

(Embodiment 288)

Ii- (4- (6- (2-ethylhexanamido) indol-1-ylmethyl) -2-methoxybenzoyl) benzenesulfonamide, in a yield of 71 $ as a Peststoff, melting point 134 ... 136 ⁰ G.

Embodiment 289

Following a procedure similar to that described in Example 255 but starting from benzenesulfinamide, N- (4- (6- (2-ethylhexanamido) indol-1-ylmethyl) -

3-methoxybenzoyl) benzensulfinamid in a yield of 28% recovered as a Peststoff, melting point 122 ... 126 ⁰ Cj microanalysis, found: C, 67.61 j H, 6.97; N, 7,39; C ₁ H ^ IT ₃ O ₄ S requires: G, 68.23; H, 6:46; N, 7,70.

Benzensulfinamid was prepared by reacting Benzensulfinylchlorid with ammonia in ether initially at -78 ⁰ C and finally at ambient temperature and in a yield of 17% isolated as a Peststoff, mp 112 115 ⁰ C.

Embodiment 290

Following a similar procedure to that described in Example 157, but starting from 2-cyclopentylacetyl chloride and N- (4- (6-amino-indol-1-ylmethyl) -3-methoxybenzoyl) -benzenesulfonamide, N- (4- (6- Cyclopentylacetamido) indol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide as a pesticide which is substantially identical in physical properties to that obtained in Example 280.

The starting aminoindole derivative was recovered as follows i.

(a) Nitrogen was passed through a solution containing 1.39 g of methyl 3-methoxy-4- (6-nitroindol-1-ylmethyl) benzoate in 1: 1 v / v methanol and THP together with 0.86 g of lithium hydroxide monohydrate in 25 ml of water. After 1 minute, the reaction mixture was sealed and stirred for 3 days. The solvent was evaporated. The residue was diluted with water, acidified (1M hydrochloric acid) and extracted with ethyl acetate. The extracts

were washed with water and then with brine and then dried (MgSO 4). Evaporation of the solvent gave a benzoic acid 3-methoxy-4- (6-nitroindol-1-ylmethyl) in a yield of 91% as Peststoff, melting point 243 ·· .245,5 ⁰ G, which was used without further purification.

(b) A suspension of 1.22 g of nitric acid from above (a) in 15 ml of methanol and 3.7 ml of 1Lu. Sodium hydroxide solution was treated with 1.38 g of N, N-diphenylcarbamoylpyridinium chloride for one minute. Then, 50 ml of ethyl acetate and then enough HtP were added to produce a homogeneous solution. .. This solution was washed with water and then with brine, then dried (MsSO.).

^W 4 and finally evaporated to give 3-methoxy-4- (6-nitroindol-1-ylmethyl) benzoic-N, N-diphenylcarbamide anhydride as a yellow oil. This was then reacted with benzenesulfonamide following a procedure similar to that described in Working Example 255 to add N- (3-methoxy-4- (6-nitroindol-1-ylmethyl) benzoyl) benzenesulfonamide in 77 % yield as a pest yield; partial HKR (dg-DMSO) i 3.93 (s, 3H, OCH _3), 5.56 (s, 2H, NCH _2).

(c) The nitrosulfonamide derivative of the above (b) was reduced by a procedure similar to that described in part (c) of Example 157 to give N- (4- (6-aminoindol-1-ylmethyl) -3-methoxybenzoyl ) benzenesulfonamide in a yield of 80 % as a pesticide, m.p. 151-155 ° C.

Exemplary embodiment 291

A mixture of 306 mg of 4- (6- (cyclopentyloxycarbonyl) aminoindazol-1-ylmethyl) -3-methoxybenzoic acid in 4 ml of methanol and 6 ml of methylene chloride was treated with 0.75 ml of 1N sodium hydroxide solution the mixture was evaporated and the residue was recrystallized from ether / methylene chloride / methanol to give sodium 4- (6- (cyclopentyloxycarbonyl) aminoindazol-1-ylmethyl) -3-methoxybenzoate in a yield of 78 % as a pestle, m.p. > 280 ^° C (decomposition); microanalysis, found: C,

59.80 ;. H, 5.06; N, 9.20 %% of G ₂₂ H ₂ PH ₃ O ₅ Na.0.5H ₂ O required .; G, 59.99; H, 5:26; N, 9.54 %.

Exemplary embodiments 292 to 293

Following the similar procedure to that described in Example 292 but using the equivalent amounts of sodium hydroxide solution, the sodium salts of N-4- (6- (2-ethylhexanamido) indol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide ( i) and 6-glyclopentyloxy-, carbonyl) amino-1- (2-methoxy-4- (1 (H) -tetrazol-5-yl) -benzyl) indazole (ii) as solids:

(i) in a yield of 93 %, mp 258 ... 259 ⁰ C; Microanalysis found: C, 63.74; H, 5.93; N, 7.35 %; G ₃ .HN ₃ O ₅ SNa, requires: G ₅ 63.79; H, 5.87; N, 7.20 %; and

(ii) in essentially quantitative yield (not recrystallised), m.p. 200 ... 210 ⁰ C (decomposed); Microanalysis found: G, 55.91; H, 5.54; N, 20.76 %;

H ₂ O requires: C, 55.81; H, 5:11; N, 20.70% _o '

Embodiment 294 '

Following the similar procedure to that described in Example 261, U- (4- (6- (butoxycarbonyl) amino indazol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide was obtained in 35 % yield as a solid, mp 153. .154 ° C microanalysis, found j G, 60.34; H, 5:16; N, 10.52 %; ^C ₂ 7 ^H 28 ^IT 4 ° 6 ^{S requires: G} » ^6o » 42; H, 5:25; IT, 10.44%.

Embodiment 295

Following a similar procedure to that described in Example 67, 6- (2-cyclopentylacetamido) -1- (2-methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) indole was obtained in 29% yield a solid, mp 218 ... 220 ⁰ C (1/4 HpO) was obtained, starting from 6- (2-glyclopentylacetamido) -1- (4'-cyano-2-methoxybenzyl) indole, which in turn by Alkylation of 6- (2-cyclopentylacetamido) indole was obtained using a similar procedure to that described in Example 67 (c).

Embodiment Examples 296 to 297

Following a procedure similar to that described in Example 262, but starting from the appropriate carboxylic acids of the formula I (Z = CO ₂ H), the following were used:

(Item 296)

M- (4- (6- (2-ethylhexanamido) indol-1-ylmethyl) -3,5-dimethoxy-benzoyl) benzenesulfonamide, in a yield of 39% as a solid, mp '220 ... ⁰ Gj 221.5 Microanalysis .

found: C, 65.19; H, 6.65; N, 6.53%; G ₃₂ H ₇ H ₃ OgS requires: G, 64.97 j H, 6.30; N, 7.1%; and

(Embodiment 297)

N- (4- (6- (2-ethylhexanamido) indol-1-ylmethyl) benzoyl) benzenesulfonamide, in a yield of 37 % as a pest, m.p. 166 ... 174 ⁰ G; Microanalysis found: C, 64.16; H, 6.03; N, 7.87 % \ C ₃₀ H ₃₃ II ₃ O ₄ S.! 1/2 H ₂ O requires: G, 64.49; H, 6:49; N, 7.52 %. "...

Embodiment 298

Following the similar procedure to that described in Example 185, ethyl 4- (6- (2-cyclopentylacetamido) indazole-T-ylmethyl) -3-methoxybenzoate was obtained in 79 % yield, with methyl 4- (6-aminoindazole-1 -ylmethyl) -3-methoxybenzoate and 2-cyclopentylacetic acid and the isolation was carried out as a solid, mp 195-197.5 °; Microanalysis found: G, 68.07; H, 6:37; N, 9.57 %; G ₂₄ H ₃₇ N ₃ O ₄ requires: C, 68.39; H, 6:46; N, 9,96 %.

Exemplary embodiment 299

According to a similar hydrolysis procedure as in the described Ausfahrungsbeispiel 34 4- (6- (indazol-1-ylmethyl 2-cyclopentylacetamido)) -3-methoxybenzoic acid in a yield of 99% recovered as a Peststoff, melting point 254 ... 256 ⁰ C; Microanalysis found: G, -67.41; H, 6:37; N, 10.28%; C ₂ ^H 3 ^I 25 ^{I> I} 3 ° 4 ^{requires: G} > ⁶ 7.79; H, 6.18; N, 10.31 %.

Execution ^ example 300

A solution of 0.16 g of 3-butyryl-6- (2-cyclopentylacetamido) -indole in 0.5 ml of DMF was added to a stirred slurry of 9 mg of sodium hydride in 0.2 ml of EMF at 0 to 4 ^° C. The mixture was stirred at this temperature for 30 minutes and then treated with a solution of 0.16 g of N- (4-bromomethyl-3-methoxybenzoyl) benzenesulfonamide and 10 mg of sodium hydride in 1.5 ml of DLiF. The reaction mixture was stirred at ambient temperature for 24 h, which was stirred and then cooled to ⁰ C 0 ... 4. An additional 9 mg of sodium hydride was added, followed by stirring at ambient temperature for 30 minutes. The reaction mixture was recooled to 0-4 ° C and the excess sodium hydride was destroyed by adding a saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate. The extracts were washed successively with water and brine and then dried (MgSO 4). and evaporated. The residue was recrystallized first from THF / petroleum ether (b.p. 60 ... 80 ° C) _a and then from methanol / water to give 12.8 mg (5 %) of N- (4- (3-butyryl-6- (2 -cyclopentylacet amido) indol-1-ylmethyl) -3-me thoxybenzoyl) to give benzenesulfonamide in the form of a white solid, melting point 143 ... 145 ⁰ G; Microanalysis found: C, 64.47; H, 6.00; N, 6.41 % \ C ₃₄ H ₃₇ N ₃ OgS ₁ H ₂ O ₂ Required: C, 64.44; H, 6.20; N, 6.63 %.

The starting butyrylindole derivative was prepared analogously to that described for the acetylindole (DD) in Example 174 except that 6- (2-cyclopentylacetamido) indole and Ν, Ν-dimethylbutyramide were used and the isolation was carried out in a yield of

99 % took place in the form of a pesticide; partial 1.03 (t, 3H, CH _3), 2.40 (br s, 3H, CHCH _2), 2.89 (t, 2H, CO.CH _2), 7.24 (dd, 1H, ^H5 -Indol), 8.30 (d, 1H, H ² -indole), 9, $ 0 (s, 1H, EfH), 11.90 (br s, 1H, M).

The starting sulfonamide derivative was recovered by lightly catalyzed N-bromosuccinimide / benzoyl peroxide bromination using a similar procedure as described in part (e) of Example 200, except that N- (3-methoxy-4 -methylbenzoyl) benzensulfonamide was assumed. Thus, N- (4-3romomethyl-3-methoxybenzoyl) benzenesulfonamide was recovered in substantially quantitative yield as a white solid, m.p. 190-195 ° C. N- (3-methoxy-4-methylbenzoyl) benzenesulfonamide, for its part, was recovered by a similar procedure to that described in Example 277, but using 3-methoxy-4-methylbenzoic acid and benzenesulfonamide, and isolating it in 67 % yield Solid was carried out, melting point 159 ... 160 ⁰ C.

Embodiment 301

Following a similar procedure as described in Example 1, N- (7- (6-Hexanamidoindol-1-yl) -heptanoyl) benzenesulfonamide in a yield of 13% as a solid, mp 97 ... recovered 99 ⁰ C, wherein hexanoyl chloride and N- (7- (6-aminoindole-1-yl) heptanoyl) benzene sulfonamide. The latter compound was obtained as follows:

First, methyl 7- (6-nitroindol-1-yl) heptanoate was obtained as a solid in a yield of 52% and with satisfactory results.

The IMR spectrum was obtained by proceeding analogously to that described for C in Example 1 (but using methyl 7-bromoheptanoate as the alkylating agent), followed by hydrolyzing conditions similar to those used to give the corresponding acid. 'This has been associated with Benzensulfonarnid and dicyclohexylcarbodiimide for the reaction, with similar conditions as the embodiment described were applied 277 to give N- (7-nitroindole-1-yl) heptanoyl) benzenesulfonamide as a yellow Peststoff, melting point 117 ... 121 ⁰ G to surrender; Microanalysis, found: C, 58.74; .H, 5.44; N, 9.47 %; G ₂₁ H ₂₃ N ₃ O ₅ S requires i G, 58,73 ;. H, 5.40; N, 9.78%. This 6-nitro derivative was then reduced under conditions similar to those described in part (c) of Example 157 to give N- (7- (6-aminoindol-1-yl) -heptanoyl) benzenesulfonamide to provide in essential quantitative yield as a pesticide which was reused without characterization.

Embodiment 302

Following the similar procedure to that described in Example 157 but using cyclopentyl chloroformate and N- (7- (6-aminoindol-1-yl) -heptanoyl) -benzenesulfonamide, N- (7- (6- (cyclopentyloxycarbonyl) -aminoindole- 1-yl) heptamoyl) benzenesulfonamide in a yield of 51 % as a pesticide, m.p. 74o.o7β C; Microanalysis found: C, 62.74; H, 6.54; N, 7.84 %; G ₂₇ H ₃₃ N ₃ O ₅ S, 1/4 H ₃ O requires: C, 62.83; H, 6.54; N, 8.14 %. - ".

Embodiment 303

Bine solution of 220 mg of benzenesulfonyl isocyanate in 5 ml of benzene and 6 ml of methylene flouride was combined with 221 mg of 3- (6-hexanamidoindol-1-yl) propanol. After 15 minutes, the mixture was added slowly with stirring to 75 ml of hexane. The resulting gum was collected by filtration and purified by chromatography on silica gel (using 10 % V / V hexane / ethyl acetate as Bluent). The non-crystalline product was dissolved in a mixture of 2 ml of ethanol and 4 ml of ethyl acetate. Addition of this solution to a vigorously stirred mixture of 40 mL of ether and 20 mL of hexane gave N- (1- (6-hexanamidoindol-1-yl) propoxycarbonyl) benzenesulfonamide in 14% yield as a white pesticide, m.p. ⁰ C (decomposition); Microanalysis, found; C, 57.61; H, 5.89} N, 8.10%; C ₂₄ H ₂₉ W ₃ O ₅ S!!, 40 H ₃ O requires i C, 58.02; H, 6.45; N, 8.46%.

The starting material was obtained as follows:

(a) A solution of 4.61 g of 3-bromopropanol in 150 ml of methylene chloride at 0 C was treated with 5.1 ml of dihydropropyran followed by 55 mg of p-toluenesulfonic acid and then warmed to room temperature. pH: 7.5). The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The recovered yellow oil was purified by chromatography on triethylamine-treated silica gel using a gradient solvent system (pure hexane - 50% v / v ethyl ether / hexane) as eluent to give 2- (3-bromopropyl) tetrahydro-2H-pyran in a yield of 69 % as an oil with satisfactory MiR spectrum.

(b) 6-Hexanamidoindole was alkylated with 2- (3-bromopropyl) tetrahydro-2H-pyran following a similar procedure to that described in Example 23 to give 2- (3- (6-hexanemi <3cindol-1-yl) propyl). tetrahydro-2H-pyran in 81 % yield as an oil which was used without characterization.

(c) A solution of 656 mg of the pyran derivative to the above (b) in 10 ml of methanol and 2 ml of water was treated with 10 mg of 1-toluenesulfonic acid. After 72 hours, the mixture was treated with phosphate buffer (pH 7.5) and the methanol was evaporated. The residue was extracted with ethyl acetate. The extracts were washed with sodium bicarbonate solution and then with brine, then dried (MgSO 4) and evaporated. The residual yellow oil was purified by chromatography on silica gel using a gradient solvent system (17 % v / v, ether / methylene chloride to 50% v / v ether / ethyl chloride eluent to give 3- (6-hexanamidoindol-1-yl ) to give propanol in a yield of 77 % as a white pesticide, mp 87 ··· 88 C.

Embodiment 304

By a similar hydrolysis method to that described in Example 34, N- (4- (3- (2 (E) -carboxyvinyl) -6- (2-ethylhexanamido) indol-1-ylmethyl) -3-methoxybenzoyl) -benzenesulfonamide was obtained in a yield of 52 % as a pesticide, melting point 200... O201 ⁰ C, based on the corresponding methyl ester (Example 283) was assumed.

Embodiment 305

Following a similar procedure to that described in Example 277, N- (4- (6- (cyclopentylthiolocarbonyl) aminoindol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide was obtained in 38% yield as a pesticide, mp 199-200 G, starting from 4- (6- (cyclopentylthiolocarbonyl) aminoindol-1-ylmethyl) -3-niethoxybenzoic acid and benzenesulfonamide.

XXXXXXXX

Note i The methyl (6-aminoindazol-1-ylmethyl) -3-methoxybenzoate (L) used as the starting material in, for example, Example 74 can also be obtained as follows.

A mixture of 2.19 g of sodium 3-chloro-6-nitroindazolide

in 50 ml of methanol was stirred for 2 h.lang with 2.85 g of methyl 3-methoxy-4-bromomethylbenzoat. After adding 150 ml of water, the resulting precipitate was collected and recrystallized from ethyl acetate to give methyl 4- (3-chloro-6-nitroindazol-1-ylmethyl) -3-methoxybenzoate in a yield of 70 % as a pest, mp 167. A mixture of 1.25 g of this pesticide was dissolved in 20 ml of ethyl acetate and 20 ml of methanol for 3 hours in the presence of 385 mg of 5% M / M palladium on calcium carbonate pressure of 1.1 bar of hydrogen. the catalyst was removed by means of filtration through diatomaceous earth. the Piltrat was concentrated in vacuo to low volume and the residue (ca. 3 ml) was treated with ether and petroleum ether (boiling point 40 ... 60 ⁰ G) diluted and cooled to -20 ⁰ G. The precipitated Peststoff was entire

dried and dried at 80 G to give the ester L in a yield of 90 %, melting point 131 ... 131 »5 ° G.

Embodiment 306

Representative representative pharmaceutical dosage forms which may be used for the therapeutic or prophylactic administration of an acidic compound of Formula I (ie, Z as defined above for an acidic compound) or one of its pharmaceutically acceptable salts (hereinafter referred to as Compound X) are illustrated below: -

Tablet 1 mg / tablet Connection X 100 Lactose Ph.lur. 132.75 AcDiSoI · 12.0 Corn Starch Paste ($ 5 M / M Paste) 2.25 magnesium stearate 3.0 Tablet 2 mg / tablet Connection X 20 Microcrystalline cellulose 420 Polyvinylpyrrolidone (5% M / V paste) 14.0 Starch (pre-gelatinized) 43.0 magnesium stearate 3.0 Capsule' mg / capsule Connection X 10 Lactose Ph.Sur. 488.5 magnesium stearate 1.5

(iv) Injection 1 (10 mg / ml)

Compound X (free acid form) 1.0 % M / V

Sodium phosphate BP '3.6 % M / V

0.1 M sodium hydroxide solution .15.0 % M / V water for injection .... up to 100%

(v) Injection 2 (buffered to pH 6) (1 mg / ml)

Compound X (free acid form) 0.1 % M / V

Sodium phosphate BP. 2.26% M / V

Citric acid 0.38% M / V

Polyethylene glycol 400 '3.5% E / V

(vi) aerosol mg / ml

Compound X 0.2

Sorbitan trioleate 0.27

Trichlorofluoromethane 70.0

Dichlorofluoromethane '280.0

Dichlorotetrafluoroethane 1094.0

It will be understood that the above pharmaceutical compositions may be varied while maintaining the well-known pharmaceutical techniques for accommodating different amounts and types of the active ingredient X. The aerosol (vi) can be used in conjunction with a standard, metered pressure atomiser can «

xxxxxxx

In the original of the patent follow 8 pages of formula records - d.U.

Claims (7)

Srfindungsanspruch A process for the preparation of novel indole derivatives of the formula I (according to the formula listing in the Appendix), in which the group A *! * CRa is selected from di-radicals of the formula: -CRb = CRa-, -CHRb.CHRa- and -N = CRa-, in which Ra is hydrogen, keto, halogen, (2) 6C) alkenoyl, (2 ... 6C) alkenyl or (2 ... 6C) alkyl, of which the latter two may optionally bear a carboxy or ((1 ... 4C) alkoxy) carbonyl substituent, (V and Rb is hydrogen or (1 to 40) alkyl; or Ra and Rb together form tetramethylene which optionally carries 1 or 2 (1 to 4C) alkyl substituents and optionally contains 1 or 2 unsaturated bonds; Rc, Rd, Rf are independently selected from hydrogen, halogen, (1 ... 4C) alkyl and (1 ... 4C) alkoxy; , ' the group Re.L stands for amidic radicals of the formula; Re.X. "CO.WH-, Re.X.CS.NH- or Re.NH.CO-, which are attached at the position 4, 5 or 6 of the benzenoid component shown below in formula I and in which is Re (2 ... 10C) alkyl which optionally contains 1 or more fluoro substituents, or Re is (3 ... 10C) alkenyl or (3 ... 1OC) alkenyl; or Re is phenyl,. Phenyl (1 ... 60) alkyl or thionyl (1 ... 6C) alkyl, wherein the (1 ... 6C) alkyl moiety optionally contains a (1 'to 4C) alkoxy, ( 3 ... 6C) can carry cycloalkyl or phenyl substituents and wherein a phenyl or thienyl-Xompo- - ίο optionally one or two substituents which have been selected from halogen, (1 .... 4C) alkyl, (1 .. .4C) alkoxy and trifluoromethyl; or Re is (3 ... 8C) cycloalkyl, (3 ... 8C) cycloalkyl (1 ... 6C) alkyl or (4 · .6C) oxyheterocyclyl, their cyclic moieties optionally containing an unsaturated bond or a or two (1 ... 4C) alkyl substituents or a phenyl substituent, the latter itself optionally containing a halogen, (1 ... 4C) alkyl, (1 ... 4G) alkoxy or Can carry trifluoromethyl substituents; X is oxy, thio, imino or a direct bond to Re; Q is a direct bond to G or is oxy, thio, m-phenylene, r> phenylene or heteroarylene; G ¹ is (1 ... 8C) alkylene or (2 ... 6C) alkenylene; G is methylene, vinylene or a direct bond to Z; Z is an acidic group selected from carboxy, an acylsulfonamide radical of the formula -CO.NH.SO.sub.Rg and a tetrazolyl radical of the formula II (as shown in the accompanying drawings) in which .eta. Is the integer 1 or 2 Rg is (1 ... 6C) alkyl, aryl, heteroaryl, aryl (1 ... 4C) alkyl, wherein in each of these groups the aromatic or heteroaromatic moiety may carry one or two substituents selected from halogen, ( 1 ... 4C) alkyl, (1 ... 4C) alkoxy, trifluoromethyl, Itfitro and amino were selected, and. Rh is hydrogen, carboxy (1 .. .3C) alkyl or (carboxyphenyl) methyl; 1 2 this on the condition that G,. Q and G taken together contain at least 3 carbon atoms and that G is methylene or vinylene when Q is oxy or thio and Z is carboxy; or a pharmaceutically acceptable salt derived therefrom, characterized in that it consists; ( _a ) for a compound of formula I in which Z corresponds to a carboxylic acid group, from the decomposition of a suitable ester of formula V in which Ri is (1 ... 6C) alkyl with either an acetoxy-, (1. ..4C) alkoxy or (1 ... 4C) alkylthio substituents or represents phenyl, or benzyl} (b) for a compound of the formula I in which Re.L is a group of the formula Re.X.GO.ITH- or Re.X. CS.ITH is, from the acylation of an amine of formula VI; (c) for a compound of formula I in which the group A.CRa is the di-radical -CRb = CRa- or -N = CRa, from the reaction of an indole or indazole derivative of the formula VII, in which A is = CH- or -IT =, with an alkylating agent of the formula VIII, in which U corresponds to a suitable leaving group; (d) in the case of a compound of the formula I in which Z corresponds to a 1 (H) -tetrazol-5-yl radical, - from the reaction of a cyano derivative of the formula IX with an azide; (e) in the case of a compound of the formula I in which R a is halogen, - from the halogenation of the corresponding compound of the formula I in which R a is hydrogen; (f) in the case of a compound of the formula I in which the group Re.L is a group of the formula Re.X.CO.NH- or Re.X.CS.NH-, in which X is Oxy or Thio is, from the reaction of an isocyanate or isothiocyanate of the formula X, in which Xb is oxygen or sulfur, with the appropriate compound of the formula Re.XH5 (g) for a compound of formula I in which Z is a group of the formula -CO.IH.SO.Rg, - reacting a compound of formula I in which Z is carboxy with a sulfonamide derivative of the formula Rg.SO NH ₂ ; (h) for a compound of the formula I in which ^s Ra bears a carboxy substituent and / or Rh stands for carboxy (1 ... 3C) alkyl or (carboxyphenyl) methyl, from the decomposition of a corresponding ester of the formula I. in which R a ((1 ... 6C) alkoxy) carbonyl and / or Rh ((1 ... 6C) alkoxycarbonyl) - (1 ... 3Oalkyl or ((1 ... 6C) alkoxycarbonylphenyl) methyl carries ;. (I). for a compound of the formula I in which Z is an acylsulfonamide group of the formula CO.NH.SO.Rg 2 ⁿ corresponds to G is a direct bond to Z and Q is oxygen or sulfur, - from the -.135 - Reacting a compound of formula XI in which Xb is oxy or thio. With an isocyanate derivative of formula ONC.SO Rgj (j) for a compound of the formula I in which Z corresponds to an acylsulfonamide group of the formula CO.NH.SO ₂ .Hg, - from the oxidation of the corresponding acylsulfonamide of the formula I in which Z is a group of the formula CO Corresponds to .NH.SO.Rg; or (k) for a compound of formula I in which Ra is (2 ... 6C) alkyl with either a carboxy or ((1 ... 4C) alkoxy) carbonyl substituent, - from reducing the corresponding compound of formula I wherein Ra is (2 ... 6C) alkenyl with either a carboxy or ((1 ... 4C) alkoxy) carbonyl substituent; where, when a pharmaceutically acceptable salt is required, the product can be recovered by reaction of the acidic form of the compound of formula I with a base providing a physiologically acceptable cation; and wherein the formulas I to XI have the structures shown in the accompanying figure and wherein Ra, Rb, Ru, Rd, Re, Rf, Rg, Rh, A, L, G ¹ , G ² , Q and η are those in the points 1 to 7 carry defined meanings. 2. The method according to item 1, characterized in that compounds of formula I are prepared wherein Ra is Is hydrogen, methyl, chloro, bromo, acetyl, propionyl or butyryl; or ethyl, propyl, butyl, vinyl, allyl or i-propenyl optionally with a carboxy, methoxy. carbonyl or ethoxy. carbonyl substituent is en; and wherein Rb, if present, is hydrogen, methyl or ethyl; or Ra and Rb together form 1-butenylene or 1,3-butadienylene with optionally 1 or 2-carboxyl or ethyl substituents; Rc, Rd and Rf are independently selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy and ethoxy; Re is ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 1-ethyl-propyl, hexyl, heptyl, 1-ethylpentyl, 2,2,2-trifluoroethyl, allyl, 2-butenyl, 3 -Butenyl, 1,3-pentadienyl, 2-propynyl or 3-butyryl; or phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, thien-2-ylmethyl, thien-3-ylmethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-methyl-1-phenylethyl or 1-phenylbutyl: wherein the alkyl component may optionally bear a methoxy, ethoxy, cyclobutyl, cyclopentyl, cyclohexyl or phenyl substituent, and. wherein a phenyl or thienyl moiety may optionally bear one or two substituents selected from fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy and trifluoromethyl; or Re is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexyltiethyl, 1-cyclopentylmethyl, 2-cyclopentylmethyl, 1-cyclopentylpropyl, 1-cyclohexylpropyl, 1-cyclopentyibutyl, 1-cyclohexylbutyl, tetrahydrofur-2 yl, T6-tetrahydrofur-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, uyclohexenyl, Cyclohexenylmethyl or 1- (cyclohexenyl) butylί wherein the cyclic moiety may optionally have 1 or 2 methyl, ethyl, isopropyl or phenyl substituents and the latter in turn optionally having a fluoro, chloro, bromo, methyl, Can carry methoxy or trifluoromethyl substituents; 'Q is a direct bond to G or is oxy, thio, m-phenylene, p-phenylene, 2,5-furandiyl, 2,5-thiophenediyl, 2,5-pyridinediyl or 4,7-benzo (b) furanediyl ; G is kethylene, ethylene, ethylidene, trimethylene, tetramethylene, pentemethylene, hexamethylene, heptamethylene, octamethylene, vinylene, propylene, 1-butenylene or 2-butenylene, Rg is F, ethyl, ethyl, propyl, isopropyl or Butyl or is phenyl, 1-naphthyl, 2-naphthyl, furyl, thienyl, pyridyl, benzyl, 1-naphthylmethyl, 2-naphthyl! Methyl, methyl Fury !, Thieny! Methyl or pyridylmethyl % being their aromatic or heteroaromatic component optionally may bear 1 or 2 substituents independently selected from fluoro be ^s, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, nitro and amino, and Rh is hydrogen, carboxymethyl, 2-carboxyethyl or £ -Carböxyphenylmethyl. 3. The method according to item 1, characterized in that compounds of formula I are prepared wherein Ra is hydrogen, methyl, ethyl, chlorine, bromine, acetyl, propionyl, butyryl, allyl, 2-Car boxy vinyl, 2- (Iv. ethoxycarbonyl) vinyl or 2- (liethoxycarbonyl) ethyl; and Rb, if present, is hydrogen or methyl; or Ra and Rb together form tetramethylene or 1,3-butadienylene with optionally a methyl or ethyl substituent; Rc is hydrogen, JLethyl, chloro or bromo; Rd and Rf are independently selected from hydrogen, methyl, methoxy-butoxy, fluoro, chloro and bromo; Re is ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, t -butyl, pentyl, 1-ethylpropyl, hexyl, heptyl, 1-ethylpentyl, nonyl, heptafluoropropyl, 1,3-pentadienyl, 3-butynyl, phenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 2-thienyl, benzyl, 4-chlorobenzyl, 4-trifluoromethylbenzyl, 4-ethylbenzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-1-phenylethyl, thien-2-ylmethyl, 1-phenylpropyl, 1-phenylpentyl, alpha-cyclopentylbenzyl, alpha-methoxybenzyl, benzylaryl, cyclobutyl, cyclopentyl, cyclohexyl, 1-phenylcyclopentyl, cyclopentylmethyl, cyclohexylraethyl, 2-cyclopentylethyl, 1-cyclopentylbutyl, 1-cyclohexylpropyl, 1-cyclohexylbutyl, 5- Methyl 2- (1-methylethyl) cyclohexyl, 1-cyclohexen-4-yl, tetrahydrofur-2-yl or tetrahydrofur-3-yl> Q, including the optional substituents Rd Lind Rf, is a direct bond, oxy, thio, m-phenylene, 2-ivethoxy-1,3-phenylene, 4-methoxy-1,3-phenylene, -P-phenylene, 2 -Methoxy-1,4-phenylene, 2-3 -utoxy-1,4-phenylene, 2-liethyl-1,4-phenylene, 2-chloro-1,4-phenylene, 2-chloro-1,4-phenylene ,. 2-3romo-1,4-phenylene, 2,6-dimethoxy-1,4-phen-ylene, 2,5-furandiyl or 4,7-benzo (b) furanediyl: wherein Q is in position 1 and 4 on G is attached; G (when Q is optionally substituted phenylene or 1,5-JP uranediyl or 4,7-benzo (b) furanediyl as defined above) is methylene or ethylidene. or (when Q is oxy or thio) is trimethylene, pentamethylene, heptamethylene or 2-butenylene; or (if Q corresponds to a direct bond) it stands for ethylene, Trimethylene, tetramethylene, pentamethylene, hexamethylene or heptamethylene; Rg is methyl, isopropyl, butyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-aminophenyl, 1-naphthyl, thien-2-yl or 6- Chloropyrid-3-yl; and Rh is hydrogen, carboxymethyl or cj-carboxyphenylmethyl. , Process according to item 1, characterized in that compounds of the formula I are prepared in which the group A.CRa is a. Di-radical of the formula -GRb = GRa- or -N = CRa-., In which Ra, Rb ', Rc, Rd, Rf, Rg, 12 Rh, G, G, .Z and the group Re.L has any of the meanings defined in item 1, 2 or 3. Process according to any one of the preceding claims, characterized in that compounds of the formula I are prepared in which Ra is hydrogen, chlorine, acetyl, butyryl and in that Rb, if present, is hydrogen; Rc, Rf and Rh are hydrogen; the group Re.L stands for a group of the formula Re.X.CO.NH-, in which the radical Re.X.CO is selected from branched (4 · ..10C) alkanoyl, 2 - ((4) 6C) Cycloalk2rl) acetyl, 2 - ((2 .. _o 5G) alkyl) -2-phenylacetyl, (4 ... 6C) cycloalkyloxycarbonyl, (4 '' 6C) Cycloalkylthiolocarbonyl, (4 ... 6G) Gycloalkylcarbonyl. and (3 ... 6G) alkyloxycarbonyl; 1 2 the arrangement G. .G (together with Rd) is 2-methoxy-alpha, 4-toluenediyl Rg is phenyl optionally having a fluoro, chloro, methyl, nitro or amino substituent; and η is 2 ₀ 6. The method according to item 1, characterized in that compounds are prepared according to item 5, wherein the group Re.L is located at the 6-position of the nucleus. Process according to item 1, characterized in that compounds according to any one of the preceding paragraphs are prepared wherein Z corresponds to an acylsulfonyl radical of the formula -COoIIHSOaR. in which Rg any <- g having the meanings defined in any one of items 1 to 6. 8. The method according to item 1, characterized in that a compound of formula I is prepared, which is selected from: IT- (4 (6- (cyclopentyloxycarbonyl) aminoindol-1-y-methyl) -3-methoxy-benzoyl) -benzenesulfonamide; U_ (4- (6- (2-phenylbutanarnido) indazole-1-ylmethyl) 3-methoxybenzoyl) -benzenesulfonamide; Ή- (4- (6-Cyclopentyloxycarbonyl) aminoindazol-1-ylmethyl) 3-methoxybenzoyl) benzenesulfonamide N- (4- (6- (2-glylopentylacetamido) indazol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfoamide; N- (4- (6- (2-glylopentylacetamido) indazol-1-ylmethyl) -3-methoxybenzoyl) -o_-toluenesulfonamide; U- (4 (6- (2-glylopentylacetamido) indol-1-ylmethyl) -3-methoxybenzoyl) o-toluenesulfonamido 2-amino-N- (4- (6- (2-C3'-clopenty! Acetamido) -indole 1-ylmetyl) -3-methoxybenzoyl) benzenesulfonamide; benzenesulfonamide T- (4- (3-acetyl-6- (cyclopentyloxycarbonyl) aminoindole-1-ylmethyl) -3-methoxybenzoyl!); U- (4- (6- (cyclopentylcarbonyl) aminoindol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide; N- (4- (3-chloro ~ 6- (2-cyclopentylacetamido) indol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide; Li (4- (6- (2-cyclopentylacetamido) indolin-1-ylnieth.yl) -3-methoxybenzoyl) benzenesulfonamide; Ή- (4 (6- (2-Cyclopentylacetamido) indol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide; H- (4- (6- (Butoxycarbonyl) aminoindazol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide; N- (4- (3-Butyryl-6- (2-cyclopentylacetamido) indol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide; N- (6- (2-cyclopentylacetamido) indol-1-ylmethyl) -3- . methoxybenzoesliure; 4- (6- (Cyclobutyloxycarbony1) aminoindole-1-ylmethyl) -3-methoxybenzoic acid; 4- (6- (cyclopentyloxycarbonyl) aminoindazol-1-ylmethyl) -3-methoxybenzoic acid; 4- (6- (glylopentyl.oxycarbonyl) aminoindol-1-ylmethyl) -3-methoxybenzoic acid, 4- (β- (2-cyclohexylacetamido) indol-1-ylmethyl) -3-methoxybenzoic acid j 4- (3-Chlorο-β- (cyclopentyloxycarbonyl) aminoindole-1-y1-methyl-3-methoxybenzoic acid; 4- (3-Acetyl-6- (cyclopentyloxycarbonyl) aminoindol-1-ylmethyl) -3-methoxybenzoic acid j 4- (3-chloro-G- (2-cyclopenty! Acetamido) indol-1-ylmethyl) 3-methoxybenzoic acid; 4- (3- (2- (methoxycarbonyl) vinyl) -6- (2-ethylhexanamido) indol-1-ylmethyl) -3-methoxybenzoesäurej 6- (Butoxycarbonyl) aynino-1- (2-methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) .indole j 6- (cyclopentyloxycarbonyl) amino-1 ~ (2-methoxy-4- (1 (H) -tetrazole-5-yl) benzyl) indole j ~ 6- (butoxycarbonyl) amino-1- (2-methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) indazole; 6- (cyclopentyloxycarbonyl) amino-1- (2-methoxy-4- (1 (H) -tetrazol-5-yl) benzyl) indazole; and 6- (2-ethylhexanamido) -1- (2-methoxy-4- (1 (H) -tet razol-5-yl) benzyl) indazolj or a pharmaceutically acceptable salt derived therefrom. ○ A method according to item 1, characterized in that l_ (4- (6- (Cyclopentylos: ycarbonyl} aminoindazol-1-ylmethyl) -3-methoxybenzoyl) benzenesulfonamide, or one of its pharmaceutically acceptable salts
becomes. A method according to item 1, characterized in that a salt of a compound according to any one of the preceding paragraphs which is a salt with a 3ase which forms a physiologically acceptable cation is prepared. 8 Be