DD251348A5 - PROCESS FOR THE PREPARATION OF HETEROCYCLIC AMID DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of heterocyclic amide derivatives for use as medicaments. The aim of the invention is the provision of novel heterocyclic amide derivatives having activity against one or more arachidonic acid metabolites. According to the invention, compounds of the formula I are prepared in which, for example, the group X-Y-Z-; CRc-CRaRb-NRd, N-CRaN, N-NN, N-NC.ORd and the like. al .; Ra is hydrogen or (1-4C-) alkyl; Rb and Rc are each hydrogen or, together with the existing carbon-carbon bond, an unsaturated bond; Rd is hydrogen or (1-10C) alkyl; R1 .L amidic radicals; R2 hydrogen. Halo, (1-4C) alkyl or (1-4C) alkoxy; Q is optionally substituted phenylene; A1 (1-2C) alkylene or vinylene; A2 methylene, vinylene or a direct bond to M; M is an acidic group such as carboxy, 1H-tetrazol-5-yl and an acylsulfonamido radical; a. Formula I

Description

"" - ... j

Field of application of the invention

The invention relates to a process for the preparation of novel heterocyclic amide derivatives and in particular to novel types

Amides derived from benzoheterocyclylalkanoic acids (and related tetrazoles and acylsulfonamides) which are I

counteract the pharmacological effects of one or more of the arachidonic acid metabolites known as leukotrienes (hereinafter referred to as "leukotriene antagonist properties") .The novel derivatives are useful when such counteraction is desired The invention also provides pharmaceutical compositions containing the novel derivatives for use in such treatments, and includes methods and intermediates for the preparation of novel derivatives.

Characteristic of the known technical solutions

to the US-PS 3271416 and 3470298 B-Azetamido-i-benzylalpha ^ -dimethylindole-S-acetic acid derivatives or (5-Azetamido-1-benzyl-1 H-indazolyl-3) oxyessigsäurederivate are described as compounds for combating inflammation: N-acyl derivatives of 6-amino-1-benzylindazole have been described (See E.Hannig et al., Pharmacy (1974), 29, pp. 685-687), and 6- (acetylamino) -2,3-dihydro-4H-1,4 methyl benzoate-4-propanoate was registered (Chemical Abstracts Registry Number 27802-53-5) (Chem. Abs. 74: 4635 [M]).

ZFeI the invention

Zief of the invention is the provision of novel heterocyclic amide derivatives with valuable pharmacological properties, in particular with effect against one or more Arachidonsäuremetaboliten.

Explanation of the essence of the invention

The invention has for its object to find new heterocyclic amide derivatives having the desired properties and processes for their preparation.

We have now discovered a number of benzoheterocyclic derivatives which have an amide substituent in the benzene ring and which unexpectedly have the property of counteracting one or more arachidonic acid metabolites known as leukotrienes and that is the basis of the present invention.

According to the invention, compounds of the formula I

wherein the group> X-Y-Z- is selected from the group:;

(a)> CRc-CRaRb-NRd- ^;

(b)> C = N-Za

(c)> C = CRa-Zb

(d)> N-CRa = N-

(e)> N-CRbRe-CRcRf-Zb-

(f)> N-N = N-

(g)> N-NRg-CO (h)> N-N = CORd-

where "" indicates two separate bonds, Ra is hydrogen or (1-4C) alkyl; Rb and Rc are each hydrogen or together with the carbon present to form an unsaturated bond to the carbon bond;

Rd is hydrogen or (1-10C-) alkyl optionally containing one or two double or triple bonds and wherein one carbon atom may optionally be replaced by oxygen or sulfur, said (1-10C) alkyl optionally bearing additionally a substituent which was selected from the group consisting of (1-4C) alkoxy, cyano, carboxy, 1H-tetrazolyl-5, carbamoyl, N- (1-4C) -carbamoyl, N, N-di [(1-4C-) Alkyl] carbamoyl and (1-4C) alkoxy carbonyl, or Rd (3-8C) cycloalkyl, (3-8C) cycloalkyl (1-4C) alkyl, (2-6C) alkanoyl or phenyl (1-4C-) alkyl, said phenyl component optionally bearing a substituent selected from the group consisting of cyano, halo (1-4C) alkyl, (1-4C) alkoxy and trifluoromethyl;

Re and Rf are independently hydrogen or (1-4C) alkyl;

Rg is (1-4C) alkyl;

Za is oxy, thio or substituted imino of the formula -N (Rd) -, wherein Rd has the meanings defined above; For example, oxy or thio is;

the group R ¹ X represents the amide radicals of the formula R ¹ .W.C0.NH or R ¹ .W.CS.NH-wherein R ¹ is (2-1C-O-) alkyl optionally contains one or more fluorine substituents; or R ^{1 is} phenyl (1-6C) alkyl, wherein the (1-6C) alkyl moiety may optionally bear a fluoro or (1-4C) alkoxy substituent, and wherein the phenyl moiety may optionally bear a substituent selected was selected from the group consisting of halogen, (1-4C) alkyl, (1-4C) alkoxy and trifluoromethyl; or R ^{1 is} (3-8C-) cycloalkyl or (3-8C-) cycloalkyl- (1-6C-) alkyl, the cyclic moiety each optionally containing an unsaturated bond and optionally one or two (1-4C-) ) Can carry alkyl substituents; W is oxy, thio, imino or a direct bond to R ¹ ;

R ^{2 is} hydrogen, halo (1-4C) alkyl or (1-4C) alkoxyl;

Q is phenylene optionally bearing one or more substituents independently selected from the group consisting of halogen, hydroxyl, (1-4C) alkyl, (1-4) alkoxy and trifluoromethyl; A is ¹ (1-2C) -alkylene or vinylene;

A ^{2 is} methylene, vinylene or a direct bond to M, and

M is an acid group selected from the group consisting of: carbonic acid, an acylsulfonamide radical having the formula -CO.NH-SO _m R ³ and 1H-tetrazolyl-5, where m is the integer 1 or 2 and R ³ is (1-6C-) alkyl, (3-8C-) cycloalkyl, (6-12C) -aryl, heteroaryl of 5-12 atoms, at least one of which is carbon and at least one is selected from the group consisting of oxygen, sulfur and nitrogen, (6-12C -) - aryl- (1-4C) -alkyl, wherein the aromatic or heteroaromatic moiety may each carry one or two substituents selected from the group consisting of is halogen, (1-4C) alkyl, (1-4C) alkoxy, trifluoromethyl, nitro and amino; or their pharmaceutically acceptable salts.

It can be seen that certain of the compounds of formula I, for example those in which R ^{1 contains} an asymmetrically substituted carbon atom, can be present and isolated in optically active and racemic form.

In addition one can recognize that certain connections with the forms! I, for example those in which Rd or the bond -A ¹ .QA ² - contains a vinylene group, in separate stereoisometric forms (, E 'and, Z') to be present around this group and can be isolated. Some compounds may exist in more than one tautomeric form.

Have some associations with ojymorphism. It is to be understood that the present invention is all

racemic, optically active, tautomeric Ti-morphi or stereoisomeric forms or mixtures thereof which have leukotriene-counteracting properties, being well known in the art, such as the optically active ones

Forms (for example, by dissolution of the racemic form or by synthesis of optically active starting materials) and how to produce individual, E 'and, Z' stereoisomers (for example by chromatographic separation of a mixture of the two) and as the leukotriene-counteracting properties be determined by the standard experiments described below.

In this specification, Ra, Rb, Rc, etc. are generic radicals and have no other meaning. It is to be understood that the generic term "(1-6C) alkyl" includes both straight and branched chain radicals, while the reference to individual alkyl radicals such as "propyl" refers to only the straight chain ("normal") radical while isomers with branched chain such as "isopropyl" specifically named. A similar convention applies to other generic groups such as "alkylene" and "alkenylene", etc.

Particular values for the generic radicals described above as ranges under Ra, Rb, Rc, etc. are as follows:

A particular value of Ra, Re, Rf, Rg or R ² when it is (1-4C-) alkyl is, for example, methyl, ethyl or propyl.

A particular value for R ² when it is (1-4C-) alkoxy is, for example, methoxy or ethoxy; and when it is halogen, for example fluorine, chlorine or bromine.

A particular value of Rd when it is (1-10C-) alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 3-methylbutyl, pentyl or hexyl; when it is an alkyl having one or two double or triple bonds, for example, vinyl, allyl, 1-propenyl, 2-methylallyl, 3-methylbut-2-enyl, 1,3-pentadienyl, 2-propyny or 3-butynyl; and when it is an alkyl in which one or two carbon atoms are replaced by oxygen or sulfur, a particular value is, for example, 2-methoxyethyl or 2-methylthioethyl.

A particular value for an optional substituent on Rd is, for example:

for (1-4C) alkoxy methoxy or ethoxy;

for N- (1-4C) -alkylcarbamoyl-N-methyl- or N-ethyl-carbamoyl,

for N, N-di (1-4C) alkylcarbamoyl N, N-dimethylcarbamoyl;

for (1-4C) alkoxy carbonyl methoxy carbonyl, ethoxy carbonyl or tert-butoxy carbonyl.

A particular value of Rd when it is (3-8 C-) cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl; when it is (3-8C-) cycloalkyl- (1-4C) -alkyl, a specific value is, for example, cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl; when it is (2-6C-) alkanoyl, a particular value is, for example, acetyl or propionyl; and when it is phenyl (1-4C) -alkyl, particular value is, for example, benzyl, 1-phenylethyl or 2-phenylethyl.

A particular value for R ¹ when it is (2-10C-) alkyl is, for example, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 1-ethylpropyl, hexyl, heptyl, 1 Ethylpentyl or nonyl; and when it contains one or more fluorine substituents, a particular value is, for example, 2,2,2-trifluoroethyl or heptafluoropropyl.

Particular values for R ¹ when it is phenyl (1-6C) alkyl include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-methyl-i-phenylethyl, 1-phenylbutyl and 1-phenylpentyl; and a particular value for an optional (1-4C) alkoxy substituent on the (1-6C) alkyl moiety is, for example, methoxy or ethoxy.

Particular values for certain optional substituents which may be present on or as part of a phenyl component of R ¹ or R d, as defined above, include, for example:

for halogen: a member of the group consisting of fluorine, bromine and chlorine; for (1-4C-) alkyl: a member of the group consisting of methyl and ethyl and for (1-4C-) alkoxy: a member of the group consisting of methoxy and ethoxy.

A particular value for R ¹ when it is (3-8C-) cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; when it is (3-8C-) cycloalkyl- (1-6C) -alkyl, a specific value is, for example, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclopentylpropyl, 1-cyclohexylpropyl, 1-cyclopentylbutyl, 1 -cyclohexylbutyl; and a particular value for a radical containing an unsaturated bond in the cycloalkyl ring is, for example, cyclohexenyl or cyclohexenyl (1-6C) alkyl (such as cyclohexenylmethyl or 1- (cyclohexenyl) butyl); and a particular value for an optional (1-4C) alkyl substituent on the cyclic component of such a radical is, for example, methyl, ethyl or isopropyl.

A particular value of Q is m-phenylene or p-phenylene, preferably with a fluoro, chloro. (1-4C-) alkyl,

(1-4C-) alkoxy oderTrifluoromethylsubstituenten. , , , ,

A particular value for R ³ when it is (1-6C) alkyl is, for example, methyl, ethyl, propyl, isopropyl or butyl; when it is (3-8C-) cycloalkyl, a specific value is, for example, cyclopentyl or cyclohexyl; when it is (6-12C -) - aryl, a particular value is, for example, phenyl, 1-naphthyl or 2-naphthyl; when it is a heteroaryl, a particular value is, for example, furyl, thienyl or pyridyl; when it is (6-12C-) aryl- (1-4C) -alkyl, a particular value is, for example, benzyl, 1-naphthylmethyl or 2-naphthylmethyl; and when it is a heteroaryl (1-4C) alkyl, a preferred value is, for example, furylmethyl, thienylmethyl or pyridylmethyl.

Particular values for optical substituents which may be present on an aromatic or heteroaromatic component of R ³ or on part thereof include above in the context of a phenyl moiety in R ¹ .

For example, particularly preferred values for the groups listed above include the values selected from the following groups:

for R ¹ : ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethylpropyl, hexyl, heptyl, 1-ethylpentyl, nonyl, heptafluoropropyl, benzyl, 4-chlorobenzyl, 4-trifluoromethylbenzyl, 4-methylbenzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-1-phenylethyl, 1-phenylpropyl, 1-phenylpentyt, alpha-fluorobenzyl, alpha-methoxybenzyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 1-cyclopentylbutyl, 1-cyclohexylpropyl, 1-cyclohexylbutyl, 5-methyl-2- (1-methylethyl) -cyclohexyl and 1-cyclohexenyt-4,

for R ² : hydrogen, fluoro, chloro, bromo-methyf and methoxy radical;

for R ³ : methyl, isopropyl, butyl, cyclopentyi, phenyl, 4-chlorophenyl, 4-methylphenyl, 2-methylphenyl, naphthyl, trienyl-2 and e-chloropyridyl-S;

for Ra: hydrogen and methyl;

for Rb and Rc: hydrogen, Rb and Rc, together with the carbon present for carbon bonding, form an unsaturated compound;

for Rd: hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, allyl, propargyl, 3-methylbutyl, 3-methylbut-2-enyl, 2-carbamoylethyl, carboxymethyl, caroxyethyl, N-ethylcarbamoylmethyl, Ν, Ν Dimethylcarbamoylmethyl, 2-carboxyvinyl, 2- (methoxycarbonyl) vinyl, 2-methoxyethyl, 3-methoxypropyl, cyclopentyl, cyclopropylmethyl, acetyl, benzyl, 3-cyanobenzyl and 4-chlorobenzyl;

for Re and Rf: hydrogen, methyl and ethyl;

for Rg: methyl, ethyl and propyl;

for A ¹ : methylene and ethylene;

for A ² : a direct bond and methylene;

for Q: m-phenylene and p-phenylene (optionally with a fluoro, chloro, hydroxy, methyl, methoxy or trifluoromethyl substituent); and

for W: oxy, imino, thioradial and a direct bond.

Examples of particular groups of particular interest to the invention are those selected from the following groups:

For R ¹ : butyl, pentyl, 1-ethylpentyl, i-phenylpropyl.alpha-fluorobenzyl, alpha-methoxybenzyl, cyclopentyl and cyclopentylmethyl;

for R ² : hydrogen;

for R ³ : phenyl and methylphenyl;

For Ra: hydrogen;

Rb and Rc are hydrogen, and Rb and Rc together with the carbon present form an unsaturated bond to the carbon bond;

for Rd: hydrogen, methyl, ethyl, propyl, hexyl, allyl, propargyl, 3-methylbutyl, 3-methylbut-2-enyl, carboxymethyl, carboxyethyl, N-ethoxycarbamoylmethyl, N, N-dimethylcarbamoylmethyl, 2-methoxyethyl, cyclopentyl, cyclopropylmethyl, acetyl Benzyl and 3-cyanobenzyl;

for Re and Rf: hydrogen;

for Rg: propyl;

for A ¹ : methylene;

for A ² : a direct bond;

for Q: m-phenylene and p-phenylene (optionally with a hydroxy or methoxy substituent); and for W: oxy, imino radical and a direct bond.

It will be appreciated that within the scope of the above definitions, a number of studies of compounds are included, for example:

(i) Indoles and indolines of the formula Ia:

Ra

(ii) benzisoxazoles, benzisothiazoles and indazoles of the formula I b:

.Q.A.M

(iii) benzo [b] furans and benzo [b] thiophenes of the formula Ic:

~ ^ ^{1 l} .QA .M

(iv) Benzimidazoles having the formula Id:

id

1 ¹ .QA ² .M

(v) 1,4-benzoxazines and 1,4-benzothiazines of the formula Ie:

le

(vi) Benzotriazoles of the formula If: E ²

If

I ¹ .QA ² . U

(vii) indazolones of the formula I g:

_π 2

-rg

1 2

a'.q.a .μ

(viii) indazoles of the formula Ih:

lh

₁₂

A -: -. Q.A.M

and wherein in each sub-group m R 1, R ³ , Ra-Rg, Za, Zb, A ¹ , A ² , Q, W and M have any of the meanings defined above;

together with their pharmaceutically acceptable salts.

Within the above-mentioned subgroups, further subgroups of compounds of the invention consist of

following:

(ix) the compounds of the formula Ia in which Rb and Rc together with the carbon present to the

Carbon bond form an unsaturated bond;

(x) the compounds of the formula Ie in which Zb is oxo or thioradical and Rb and Rc are hydrogen;

and wherein in each of subgroups (ix) and (x) the remaining generic radicals have one of the meanings defined above

have, together with their pharmaceutically acceptable salts.

Both of the abovementioned subgroups is a preferred value for A ^1, for example methylene; a preferred value for A ² is, for example, a direct bond to M; a preferred value for Q is, for example, p-phenylene (optionally substituted with methoxy, especially methoxy in the ortho position to A ¹ ); and a preferred value for M is carboxy, 1H-tetrazol-5-yl or a radical of the formula -CO.NH-SO ₂ R ⁴ , wherein R ^{4 is} phenyl, optionally substituted as defined above for R ³ ,

for example, 2-methylphenyi. In general, it is preferred that the R ¹ .L- group of the benzene moiety of Formula I be assigned such that it has a meta relationship to the X group but no ortho to the Z group. A preferred value for R ¹ .L- is, for example, R ¹ .W.C0.NH-; a preferred value for W is, for example, oxy, imino or a direct one

Binding; a preferred value for R ¹ when W is oxy or imino is, for example, cyclopentyl; and a preferred value for

R ¹ , when W is a direct bond, is, for example, cyclopentylmethyl. ""

Preferred groups of compounds of the invention include the indole derivatives of the following formula IIa

R ¹ .W.CO.

Ua

.QA ² .M

the indazole derivatives having the following formula II b

R ¹ . W. CO. Νϊί

lib

the benzo [b] thiophene derivatives having the following formula lic

, 2 "

r:

R ¹ .W.CO.

₍ .QA ² .M

the benzimidazole derivatives having the following formula II d

2

.w.co.π:

_o . Q. AS M

the 2,3-dihydrobenz-1,4-oxazine derivatives having the following formula He

2

R ¹ .W.CO.IH

CH.QA ² .M

the benzotriazole derivatives having the following formula Hf

2

! R'.W.CO.

> CH ₂ .QA ^ .M

and the indazole derivatives having the following formula Hg

IR ²

lic

Hd let

Hf

wherein R ¹ , R ² , Ra, R d, Re, R f, W, Q, A ² and M have any of the meanings defined above; together with their pharmaceutically acceptable salts. Particularly preferred values of Rd for the derivatives of formula IIa and Hb are, when M is carboxy, methyl, propyl, 2-methoxyethyl, N-ethylcarbamoylmethyl and cyclopentyl. Particularly preferred values of Rd for the derivatives Ha and IIb are when M is a radical having the formula -CO-NH-SO ₂ R ⁴ , wherein R ^{4 is} phenyl, hydrogen, methyl, 2-methoxyethyl and n-ethylcarbamoylmethyl , Particularly preferred values of Rd for derivatives IIa and Ub are when M is a radical of the formula -CO.NH.SO ₂ R ⁴ wherein R ^{4 is} 2-methylphenyl, methyl and Ν, Ν-dimethylcarbamoylmethyl. For the derivatives Hg, when R ^{1 is} .L-, R ^{1 is} .W.C0.NH-, where R ^{1 is} W cyclopentyloxy, and M is carboxy or -CO.NH.SO ₂ R ⁴ ,

wherein R ^{4 is} phenyl, a particularly preferred value of Rd is methyl. For the derivatives, Mg is when R ₁ ¹ L is R 1 is W.CO.NH-, where R ^{1 is} cyclopentylmethyl and W is a direct bond, and M is carboxy or -CO.NH.SO ₂ R ⁴ wherein R ^{4 is} 2-methylphenyl, a particularly preferred value of Rd is N-ethylcarbamoylmethyl.

Specific compounds of the invention are described in the accompanying examples. More preferably, however, these compounds include N- [4- [5- (cyclopentyloxycarbonyl) -amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide, NW-fS-i-cyclopentyloxycarbonyloxyamino-i-IN-ethylcarbamoylmethyindole -S-ylmethyll-S-methoxybenzoyl] benzenesulfonamide, N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindazol-3-ylmethyl] -3-methoxybenzoylbenzenesulfonamide, N- [4- [5- (cyclopentyloxycarbonyl) amino- 1-methylindol-3-ylmethyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide, N- [4- [5- (2-cyclopentylazetamido) -1- (N, N-dimethylcarbamoylmethyl) indol-3-ylmethyl] 3-methoxybenzoyl] -2-methylbenzenesulfonamide, N- [4- [6- (cyclopentyloxycarbonyl) amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzene [y] benzenesulfonamide, N- [4 [6- (2-cyclopentylazetamido) -2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzene [y] benzenesulfonamide, N- [4- [5- (cyclopentyloxycarbonyl) aminobenzo [b ] thien-3-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide, N- [4- [6- (2-cyclopentylazetamido) benzimidazol-1-ylmethyl] -3-methoxybenz ol [y] benzene sulfonamide, N- [4- [6- (2-cyclopentylazetamido) -2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide, N [4- [6- (cyclopentyloxycarbonyl) amino-3-methoxyindazol-1-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide, N- [4- [5- (N'-cyclopentylureido) -1-methylindol-3-ylmethyl] 3-methoxybenzoyl] -2-methylbenzenesulfonamide, N- [4- [6- (2-cyclopentylazetamido) -benzotriazol-1-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide, [[] [5- (cyclopentyloxycarbonyl) aminoindole 3-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide, N- [4- [5- (cyclopentyloxycarbonyl) -amino-1- (2-methoxyethyl) indol-3-ylmethyl] -3-methoxybenzoyl] -benzenesulfonamide, N - [4- [5- (2-cyclopentylazetamido) -1-methylindol-3-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide, N- [4- [6- (2-cyclopentylazetamido) -3- (N-ethylcarbamoylmethoxy) indazole 1-ylmethyl] -3-methoxbenzoyl] -2-methylbenzenesulfonamide and N-4-6- (cyclopenthyloxycarbonyl) aminobenzimidazol-1-ylmethyl-3-methoxybenzoylbenzenesulfonamide and may be in the free S acid, or be used as their corresponding pharmaceutically acceptable salts. Examples of suitable pharmaceutically acceptable salts are the salts formed with bases which form a physiologically acceptable cation, for example alkali metal (especially potassium and sodium), alkaline earth metal (especially calcium and magnesium), aluminum and ammonium salts, as well as the salts prepared with corresponding organic bases, for example triethylamine, morpholine, piperidine and triethanolamine. For the compounds of formula I, which are sufficiently basic, examples of suitable pharmaceutically acceptable salts and the like are given. a. Acid addition salts, such as those prepared with a strong acid, for example, hydrochloric, sulfuric or phosphoric acid.

The compounds of formula I can be prepared by methods known in the chemical arts for the preparation of structurally analogous heterocyclic compounds. Such methods for the preparation of a compound of formula I defined above constitute a further feature of the invention and are illustrated by the following methods, in which the meaning of the generic radicals corresponds to those defined above, T is defined as a group consisting of Group consisting of COORh (where Rh has the values defined below), CN and the values given above for M; U is defined as a suitable residual group, for example a halogeno (especially chloro, bromo or iodo) or alkane or arenesulfonyloxy group (especially methanesulfonyloxy or p-toluenesulfonyloxy group), and Hal is defined as halogen, in particular chlorine, bromine or iodine

 (A) In the compounds where M is a carboxylic acid group. Decomposition of a suitable ester of formula III

A ¹ . Q. A ² . CO ₂ Rh

wherein Rh is a suitably removed acid protecting group, for example, (1-6C) alkyl optionally with an acetoxy, (1-4C) alkoxy or (1-4C) alkylthio substituent, or phenyl or benzyl.

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

Certain of the starting esters of formula III may already have inherently leukotriene-counteracting properties (for example, by in vivo conversion to the corresponding carboxylic acid), for example, those in which R is (1-6C) alkyl, and these are included of the invention included.

It can be seen that decomposition can be achieved by any of a variety of methods known in organic chemistry. For example, it can be carried out by conventional hydrolysis under acidic or basic conditions, which have been tailored to minimize the hydrolytic removal of other functional groups from the molecule. When Rh is methyl, the ester may also be decomposed into Ν, Ν'-dimethylpropylurea by nucleophilic demethylation with, for example, lithium thioethoxide. Alternatively, it may in certain circumstances, for example, when Rh is t -butyl, be possible to carry out the decomposition by heat, for example by heating the ester of formula III at a temperature of for example 100 ° C-150 ⁰ C, alone or in a suitable solvent or in a diluent such as diphenyl ether. In addition, when Rh is t-butyl, the decomposition can be carried out by the use of, for example, trimethylsilyl triflate and then water in the conventional manner. Another possibility, for example when Rh is benzyl, is to carry out the decomposition by reductive measures, for example by the use of hydrogen at about atmospheric pressure in the presence of a suitable catalyst, for example palladium or platinum, advantageously on charcoal as a support.

A preferred method of decomposing an ester of formula III is to react the ester with a suitable base, for example, an alkali or alkaline earth metal hydroxide or carbonate (e.g., lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide or potassium carbonate) in a suitable aqueous solvent or diluent For example, 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 ° C- 100 ° C and advantageous to react at or near ambient temperature. When operating this method, the resulting carboxylic acid of formula I in which M is a carboxy group is first obtained as the corresponding salt of the base used for the hydrolysis, which can then be isolated as such or converted to the free acid. for example by the use of such a conventional acidification process as the reaction with a suitable strong acid such as hydrochloric or sulfuric acid. (B) Azylating an amine of formula IV

IV

however, T is selected from the values defined for M.

When W is an oxy, thioradical or a direct bond, a suitable acylating agent is, for example, an acid halide having the formula R ¹ .Xa.CO.Hal, wherein Xa has one of the meanings given above for W.

For example, when W is an imino radical, a suitable acylating agent is an isocyanate of the formula R ¹ .NCO.

If an acid halide is used as the acylating agent, advantageously also a suitable base such as triethylamine, N methylmorpholine, pyridine, 2,6-lutidine or 4- (dimethylamino) pyridine is used, preferably together with a suitable inert solvent or diluent, for example dichloromethane, Diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane. The same or similar solvents or diluents can be used when an isocyanate or isothiocyanate is used as the acylating agent.

When W is a direct bond, the acylating agent may also be a carboxylic acid having the formula R \ CO ₂ H. In this case, a suitable condensing agent such as a carbodiimide (such as dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or a salt thereof) or a 1,1'-carbonyldiimidazole is also used, preferably together with a suitable inert solution or diluent, for example one of those mentioned above in connection with the use of an acid halide.

In general, the acylation is carried out at a temperature in the range, for example -20 ° C to 60 ⁰ C, preferably at or near environmental temperature.

(C) For a compound of the formula I in which> XYZ has the value (a) or (b) as defined above, but Za is a substituted imino of the formula -N (Rd) -, reaction of an imino compound with the Formula V

t 1 O

A ¹ .Q. AT. T

wherein> D-E-G is a group having the formula CRc-CRbRa-NH- or> C = N-NH-, but T is selected from the values defined for M, with an acylating agent having the formula Rd.U.

This method is particularly suitable for the preparation of, for example, compounds of the formula IIa.

The reaction is preferably carried out in the presence of a suitable base, for example an alkali metal hydride, such as a sodium or potassium hydride, in a suitable inert solvent or diluent, for example tetrahydrofuran, 1,2-dimethoxyethane, N-methylpyrrolidone, Ν, Ν-dimethylformamide. Alternatively, the compound of formula V can be used in the form of the previously prepared anhydrous alkali metal salt, for example by prior reaction with a suitable base such as sodium or potassium methoxide, t-butoxide or hydride or butyllithium; in this case, a wider range of conventional solvents or diluents can be used for the reaction with the acylating agent.

In both cases, the acylation generally at a temperature in the range, for example-1O ⁰ C to 40 ⁰ C and advantageously is carried out at or close to environmental temperature.

(D) In the case of a compound of the formula I in which> X-Y-Z has the value (a) defined above, but Rb and Rc form an unsaturated bond together with the carbon-carbon bond present. Reaction of an indole with the formula VI

Vl

with an acylating agent of the formula UA ¹ .QA ² .M in the presence of a suitable Lewis acid.

A particularly suitable Lewis acid is, for example, silver oxide, silver carbonate, silver fluoroborate, silver trifluoroacetate, silver trifluoromethanesulfonate, zinc chloride, iron (III) chloride or tin (IV) chloride.

The process is best carried out in a suitable solvent or diluent, for example in acetone, dichloromethane, acetonitrile or an ethereal solvent such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran, optionally together with a hydrocarbon diluent such as toluene or xylene, and at a temperature in the range for example, 15 ° C to 100 ⁰ C and preferably in the range of 4O ⁰ C to 80 ⁰ C.

(E) For a compound of formula I in which M is a 1H-tetrazol-5-yl radical, reaction of a cyano derivative of formula VII

VII

with an azide.

A particularly suitable azide is, for example, an alkali metal azide, for example sodium or potassium azide, preferably together with an ammonium chloride or an ammonium bromide or in particular with triethylammonium chloride. The reaction is preferably carried out in a suitable polar solvent, for example N, N-dimethylformamide or N-methylpyrrolidone, and most preferably at a temperature in the range, for example, 50 ^° C. to 160 ^° C.

(F) For a compound of formula I wherein R ¹ .L- is a group of the formula R \ Wa.C0.NH- or R ¹ -Wa.CS.NH-wherein Wa is oxy, imino or Thio is reaction of an isocyanate or isothiocyanate with the formula VIII

Xb. CiM ^ HJ γ viii

A'.Q.AST

wherein T is selected from the values defined for M and Xb is oxygen or sulfur, with a suitable compound of the formula R ¹ .WaH, for example an amine of the formula R ¹ .NH ₂ , an alcohol of the formula R ¹ .OH or a thiol having the formula R'.SH.

In general, the process is carried out at a temperature in the range, for example, from ⁰ ° C. to 60 ° C., and advantageously in a suitable inert diluent or solvent, such as dichloromethane, diethyl ether, methyl t-butyl ether, tetrahydrofuran or dioxane. The starting isocyanate or isothiocyanate of formula VIII can be obtained by the reaction of the corresponding amine of formula IV with phosgene or thiophosgene (or an equivalent reagent such as trichloromethyl chloroformate for the preparation of an isocyanate) in the conventional manner.

(G) For a compound of formula I in which M is a group of the formula CO.NH.SO _m .R ³ , reaction of a compound of formula I in which M is carboxy (a compound hereinafter referred to as "Acid of formula I"), with a sulfonamide derivative of the formula R ³ .SO _m .NH ₂ in the presence of a dehydrating agent.

Thus, for example, a free acid of formula I may be reacted with a suitable dehydrating agent, for example with dicyclohexylcarbodiimide or 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide, or with a hydrochloride or hydrobromide salt thereof, optionally together with an organic base, for example 4- (dimethylamino) pyridine, in the presence of a suitable solvent or diluent, for example dichloromethane, at a temperature in the range, for example, 10 ^° C to 50 ^° C, but preferably at or near ambient temperature.

Alternatively, the reactive derivative of a acid of the formula I, for example an acid halide (such as the acid chloride), acid anhydride or mixed acid anhydride (such as that of Ν, Ν-diphenylcarboxylic acid and the acid of formula I by reaction of the sodium salt of the latter with Ν , Ν-diphenylcarbamoylpyridinium chloride), with an alkali metal salt (such as lithium, sodium or potassium salt) of the corresponding sulfonamide of the formula R ⁴ .SO ₂ .NH ₂ , preferably at or near room temperature and in a suitable solvent or diluent For example, tetrahydrofuran, N, N-dimethylformamide or dichloromethane.

(H) An alternative method to the above-mentioned method (D) for a compound of the formula I in which> XYZ the above-defined value (e) h &t; Rb and Rc but together with the carbon-carbon bond present an unsaturated bond form, the reaction of an indole of formula VI with an alkylating agent having the formula \ YES \ QA ² M.

The process is generally best carried out in a suitable solvent or diluent, for example in a polar solvent (such as N, N-dimethylformamide, Ν, Ν'-dimethylpropyleneurea or N-methylpyrrolidone) or in an ethereal solvent (such as dioxane or 1,2 -Dimethoxyethane), optionally together with a hydrocarbon diluent such as toluene or xylene.

The alkylation is best carried out generally at a temperature in the range, for example 50 ⁰ C to 160 ° C and preferably at a temperature in the range of 70 ⁰ C to 100 ⁰ C.

(I) For a compound of the formula I in which> X-Y-Z has the value (b) defined above but Za is a substituted imino group of the formula -N (Rd) -. Dehydrogenation of an amino oxime of formula IX

IX

but T is selected from the values defined for M, by first reacting a compound of formula IX with a suitable condensing agent, for example a carboxylic acid anhydride (such as an acetic or propionic anhydride), preferably together with a suitable solvent or diluent, for example a chlorinated hydrocarbon solvent (such as dichloromethane or dichloroethane) in the presence of an organic base (for example 4- (dimethylamino) pyridine), followed by heating the resulting O-azyloxime, preferably in the absence of a solvent or diluent, but heating also in one suitable inert solvent or diluent, for example a hydrocarbon solvent (such as toluene or xylene), and at a temperature in the range of 80 ^° C to 250 ⁰ C, but preferably in the range of 140 ⁰ C to 200 ⁰ C. The dehydrogenation of connections with the molds l IX can also be carried out without prior derivatization on the azyl derivatives by heating, preferably in the absence of a solvent or diluent, but heating may also be carried out in a suitable solvent or diluent, such as those mentioned above, at a temperature in the range of 150 ⁰ C to 300 ⁰ C, but preferably in the range of 150 ⁰ C to 25O ⁰ C are performed. However, compounds of formula IX wherein T has been selected from the values defined above for M can be prepared from compounds of formula X by the standard known methods

Δ Ο A Φ

but T is selected from the values defined for M, for those compounds of formula X derived from compounds of formula Ia wherein Rb and Rc together with the carbon-carbon bond present form an unsaturated bond oxidative cleavage of said unsaturated bond using known methods.

(J) For a compound of the formula I in which> X-Y-Z has the value (c) defined above, but Zb is oxy, by dehydrating a hydroxy compound of the formula XI

xl

A .Q.A

but Taus is selected to be the values defined for M, for example by treatment with an acid (eg paratoluene sulfonic acid or hydrochloric acid) in a suitable inert solvent or diluent, for example a hydrocarbon solvent (such as toluene or xylene) or in an ether solvent (such as dioxane or tetrahydrofuran ).

In general, the reaction can be carried out at a temperature in the range, for example 50 ⁰ C to 150 ⁰ C, but preferably in the range of 80 ⁰ C to 120 ° C.

Compounds of formula XI can be prepared by known standard oxidative techniques from corresponding compounds of formula XII

XII

however, T is selected from the values defined for M.

(K) For a compound of formula I in which> XYZ has the value (b) defined above, but Za is an oxy group, by de hydrogenation of a hydroxyoxinrent of formula XIII

, 2 """ -

XlIl

but T has been selected from the group defined for M, by methods similar to those described above for method (I).

Compounds of formula XIII in which T is selected from the values defined for M can be obtained by known standard methods from compounds of formula XIV

XIV

.QA ² .T

wherein T is selected from the values defined for Μ, which in turn is derived from compounds of formula I c in which Zb is an oxy group, by the oxidative cleavage of the unsaturated bonds bearing Ra, by the known methods.

(L) For a compound of formula I in which> X-Y- has the value defined above for (c), but Zb is an oxy or thio group, by the reaction of a benzofuran or a benzothiophene of formula XV

XV

with an alkylating agent having the above defined formula UA ¹ .QA ² .M by similar methods as described above for

Method (D) were described.

(M) For a compound of formula I in which> XYZ has the value (a) defined above, but Rb and Rc are hydrogen, by catalytic hydrogenation of an indole of formula I, where> XYZ has the value defined above (a ), but Rb and Rc together with the existing carbon-carbon bond form an unsaturated bond.

Particularly suitable catalytic hydrogenation bonds are those of catalytic hydrogen transfer, for example palladium on carbon (10% w / w) and formic acid (99%), a temperature in the range, for example, 15 ° C to

100 ⁰ C and in particular in the range of 70 ° C to 85 ⁰ C.

(N) For a compound of the formula I in which> XYZ- has the value (b) defined above but Za has the value -N (Rd) - and A ^{1 is} methylene, a modified version of the processes described above ( A) or (E), consisting of the

Cross-linking of an indazole with the formula XVI

XVI

with a compound of the formula Hal.CH ₂ .QA ² .T, wherein T is COORh or CN, and wherein the symbol Hai is the same or different than XVI, to give the corresponding compound of formula III or VII where> XYZ has the value (b) defined above while Za has the value -N (Rd) and A ^{1 is} methylene; followed by the conversion of the group COORh or CN into one of the values defined above for M by using the method (A) or (E).

The process can be carried out, for example, by using a stoichiometric amount of activated zinc dust and a catalytic amount of a transition metal catalyst, such as dichloro [1,1'-bis-diphenylphosphinoiferro palladium O or dichlorobisitriphenyll-nicke KII), to link, for example, 3-bromo-5- (cyclopentyloxycarbonyl) -amino i -methylindazole with, for example, methyl-bromomethyl-S-methoxybenzoate to give methyl 4- [5- (cyclopentyloxy-carbonyl) amino-1-methylindazol-3-ylmethyl] -3-methoxybenzoate; followed by decomposition of the ester to give 4- [5- (cyclopentyloxycarbonyl) amino-1-methylindazol-3-ylmethyl] -3-methoxybenzoic acid. (O) For a compound of formula I in which> X- for the group> N-, alkylation of an amino compound of the formula XVIII

XVII

with an alkylating agent of the formula UA ¹ .QA * .M in the presence of a suitable base such as potassium carbonate or sodium methoxide in a solvent such as acetone, methanol or dimethylformamide.

When a compound of the formula I is used in which M is a carboxylic acid, it is generally preferred to use the abovementioned processes (B), (C), (D), (F), (H), (I ), (J), (K), (L), (M), (N) and (O) using a suitable carboxylic ester and, as a final step using the above method (A), the required acid

release.

Pharmaceutically acceptable salts can be prepared by well known standard methods, for example, by the reaction of a compound of formula I with a suitable base yielding a physiologically acceptable cation, or by the reaction of a sufficiently basic compound of formula I with a suitable acid, which gives a physiologically acceptable anion.

The necessary starting materials for the above processes can be prepared by methods selected from standard herero-cyclic chemistry methods, analogous to the synthesis of known, structurally similar compounds, and methods analogous to those described above. For example, certain of the Formula III starting or certain Formula VII starting nitriles may be prepared using general procedures similar to those described under (D), (H), (L) and (O). where UA ¹ .QA ² .COORh or UA ¹ .QA ² .CN are used as alkylating agents. Certain of the starting esters of the formula III and certain of the starting nitriles of the formula VII may also be prepared using methods generally similar to those described in (B), (C), (F), (I), (J) and (K) the corresponding intermediates IV, V, VIII, IX, XI and XIlI are prepared, but T is in said intermediates for COORh or CN. The intermediates IX where T is COORh and CN can in turn be obtained from the corresponding intermediates X where T is COORh and CN and the intermediates X where T is COORh and CN can each be selected from the corresponding compounds III and VII wherein>XYZ-is> CRc-CRaRb-NRd- and Rb and Rc together with the existing carbon-carbon bond form an unsaturated bond. Intermediates XI, where T is COORh and CN, can each be obtained from the corresponding intermediates XII, where T is COORh and CN. Intermediates XIII, where T is COORh and CN, can each be obtained from the corresponding intermediates XIV, where T is COORh and CN, and the intermediates XIV, where T is COORh and CN, can be recovered the corresponding intermediates III and VII, in which> XYZ- stands for> C = CRa-Zb-, in which Zb is an oxy group.

By way of illustration, the amines of formula IV in which> X-Y-Z for the group> C = CRa-NRd- may be obtained, for example, by the alkylation of a corresponding nitroindole of formula XVIII

XVIII

using a corresponding alkylating agent of the formula U.A'.Q.A ^ T in the presence of a suitable Lewis acid such as silver oxide, and in a solvent such as dioxane, followed by conventional reduction as described in the accompanying Examples. As another similar illustration, the amines of formula IV wherein T is COORh, CN or one of the values defined for M and where> XYZ-is> C = CRa-Zb-where Zb is S can be obtained, for example Alkylation of a corresponding nitrobenzothiophene having the structure XIX

XIX

using a corresponding alkylating agent of the formula U.A.Q.AVT in the presence of a suitable Lewis acid, such as tin tetrachloride, and in a solvent, the dichloromethane, followed by a conventional reduction, as described in the accompanying Examples. As further illustration, the amines of formula IV in which> X- represents the group> N- can be obtained, for example, by the alkylation of a corresponding nitrobenzimidazole, nitrobenzoxazine, nitrobenzotriazole or nitroindazole of formula XX

XX

using a corresponding alkylating agent of the formula UA ¹ .QA ² .T in the presence of a suitable base such as potassium carbonate or sodium methoxide in a solvent such as acetone or methanol followed by conventional reduction to obtain the required amine of formula IV as illustrated in the accompanying examples.

The nitriles of the formula VII can be obtained from the corresponding compounds of the formula I in which M is a carboxy group, by treatment with, for example, chlorosulfonyl isocyanate and Ν, Ν-dimethylformamide. Alternatively, the cyano compounds of formula VII can be obtained by conventional dehydration of the primary amide of the corresponding carboxylic acid of formula I in which M is a carboxy group.

It can be seen that the starting materials of formula V for process (C) are also compounds of formula I in which Rd is hydrogen and can be obtained by any of the methods described above for these compounds.

The starting materials of formula VI can be obtained by catalytic reduction of the corresponding nitroindole of formula XVIII, followed by the acylation of the resulting aminoindole using the same general procedure as described under (B) above.

Starting materials of formula XV in which Zb has a thio value can be obtained by conventional reduction of a nitro group of the corresponding nitrobenzothiophene of formula XIX, followed by conversion of the resulting aminobenzothiophene into said starting material XV by analogous methods to those in ( B) or (F) described.

Starting materials of formula XVI can be obtained by conventional reduction of the nitro group of a corresponding nitroindazole of formula XXI

followed by the conversion of the resulting aminoindazole into said starting material XVI by analogous methods to those described in (B) and (F).

The majority of the starting materials of formula III, IV (and their nitro precursor), VI (Rd other than hydrogen), VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI and XVII are novel and are provided as further features of the invention on the basis of their suitability as chemical intermediates.

As already stated, the compounds of the formula I have leukotriene-counteracting properties. Thus, they counteract the actions of one or more of the arachidonic acid metabolites known as leukotrienes, for example C ₄ , D ₄ and / or E ₄ , known as strong spasmogens (especially in the lung) to increase vascular permeability, and have been used in the pathogenesis of asthma and inflammation (see JL Marx, Science, 1982, 215, 1380-1383) as well as the endotoxic shock (see JA Cook et al., J. Pharmacol. Exp. Ther., 1985, 235, 470) and of traumatic shocks (see C. Denzlinger et al., Science, 1985, 230, 30330). The compounds of formula I are therefore useful in the treatment of diseases in which leukotrienes play a role and in which their action is to be counteracted. These diseases include, for example, allergic pulmonary disorders such as asthma, hay fever and allergic rhinitis and certain inflammatory diseases such as bronchitis, ectopic and atopic eczema, psoriasis as well as vasospastic cardiovascular diseases and endotoxic and traumatic shock states.

The compounds of formula I are potent leukotriene antagonists and are always applicable when such activity is desired. For example, the compounds of formula I are important as pharmacological standards for the development and standardization of new disease models and as samples for use in the development of new therapeutic agents for the treatment of diseases in which leukotrienes play a role.

When used in the treatment of any of the above-mentioned diseases, the compounds of formula I will generally be administered as an appropriate pharmaceutical composition consisting of a compound of formula I as defined above together with a pharmaceutically acceptable diluent or vehicle, the composition being adapted to the particular route of administration chosen. These compositions are to be considered as a further feature of the invention. They can be prepared using conventional procedures and excipients and have a variety of dosage forms. For example, they may take the form of tablets, capsules, solutions or suspensions for oral administration; to have; the form of suppositories for rectal administration the form of sterile solutions or suspensions for administration by intravenous or intramuscular injection or infusion; the form of aerosols or nebulizer solutions or suspensions for administration by inhalation and the form of powders together with pharmaceutically acceptable, inert solid diluents such as lactose for administration by insufflation.

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 be advantageously used. Also, for intravenous or intramuscular injection or infusion, a sterile solution or suspension containing up to 10% by weight (and typically 0.05 to 5% by weight) of a compound of formula I may be used.

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

The leukotriene-counteracting properties of a compound of formula I can be detected by standard tests. Thus, for example, they can be detected in vitro by the standard preparation guinea pig trachea strip described by Krell (J. Pharmacol., Exp. Ther., 1979, 214, 436). Using this method, tracheal tissue strips are assembled in groups of eight, with four being used as time-vehicle controls and four for each test compound. All strips are exposed to 8 χ 1 / " ⁹ M leukotriene E ₄ (LTE ⁴ ) after the equilibration period of 50 min and the reaction is recorded This concentration of 8 χ 10" ⁹ M LTE ₄ is the concentration equal to a contraction approximately 70 to 80% of the maximum effect of the agonist in this tissue causes. The LTE ₄ is washed out for 40 to 45 minutes and the procedure is repeated twice to ensure that reproducible reactions with LTE _{4 are} achieved. In the same method, the leukotrienes C ₄ (LTC ₄₎ or D ⁴ M, instead of LTE _{4 4} (LTD ₄₎ in a concentration of 8 χ 10 "are used.

After tissue reproducibility is determined, test compounds are added to four baths after the 40-45 minute washout period, and after 10 minutes of incubation with the test compound or vehicle, 8χ 10 " ⁹ M LTE ₄ , LTD ₄ or LTC _{4 are} added and the reaction registered. The percent inhibition by the test compound or the percent change in vehicle control samples is calculated for each tissue according to the following equation:% inhibition = 100 times (mg increase in previous reaction pressure minus mg increase in presence of compound) divided by mg increase in voltage The mean percent change for vehicle control and test compound are calculated and scored for significant differences by Student's t-test for unpaired data. Tissue-matched tissues were harvested after a 25-minute washout period tested for their response to LTE ₄ , LTD ₄ and LTC ₄ . When the tissue responsiveness equaled the response before exposure to the test compound, additional studies were performed. If the response was not restored by the wash procedure, the tissue was discarded. The cyclooxygenase inhibitor, indomethacin, is present at 5χ10 " ⁶ M in all determinations Generally, compounds of Formula I have statistically significant activity as LTC ₄ , LTD ₄ and / or LTE ₄ antagonists in the above assay in a concentration of about 10 " ⁵ M or much less. Selectivity of action as a leukotriene antagonist against the action of nonspecific smooth muscle depressants may be accomplished by carrying out the in vitro method outlined above using the nonspecific spasmogen barium chloride at a concentration of 1.5 x 10 ^-3 M, again in the presence of Indomethazine in a concentration of 5 x 10 " ⁶ M, can be detected.

Activity as a leukotriene antagonist may also be detected in vivo on laboratory animals, for example, in a guinea pig aerosol routine test in which guinea pigs receive in advance a dose of the test compound (usually 15 min to 1 h) before leukotriene LTD ₄ (30/1) The effect of the test compound on the average time of leukotriene-initiated change in the respiratory regimen (such as the onset of dyspnoea) is registered and compared with that of untreated guinea pigs In general, compounds of Formula I cause a significant increase in the time to onset of leukotriene-initiated respiratory changes after oral or intravenous administration or inhalation of a dose of 100 mg / kg or much less, with no evidence of adverse side effects at several multiples of the minimum effective dose.

embodiment

The invention will now be illustrated by the following non-limiting examples, which, unless stated otherwise, have the following similarities:

(i) all measures are carried out at room or environmental temperature, ie at a temperature in the range of 18 ⁰ C to

(ii) evaporation of solvent was carried out at a bath temperature of up to 60 ⁰ C using a rotary evaporator under reduced pressure (600 to 4000 Pa, 4.5-30 mm Hg); (iii) Relaxation chromatography was performed on Merck silica gel (Art. 9385) and column chromatography on Merck Kieselgel 60 (Art. 7734); (These materials were purchased from E. Merck, Darmstadt, Federal Republic of Germany); Thin layer chromatography was performed on 0.25 mm Analtech silica gel GHLF plates (Art 21521) available from Analtech, Newark, DE, USA;

(iv) the course of the reaction was monitored by thin layer chromatography and reaction times are given by way of illustration only;

(v) melting points are uncorrected, and "d" denotes decomposition, the melting points given are those determined for the materials prepared in the manner described, polymorphism may result in the isolation of materials having different melting points in certain preparations;

(vi) all final products were essentially pure by thin layer chromatography and had satisfactory nuclear magnetic resonance (NMR) spectra and microanalytical data;

(vii) yields are given by way of illustration only and are based on the weight of the recrystallized solid in crystalline end products;

(viii) When NMR data are given, they take the form of major diagnostic proton delta values, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 80 MHz or 250 MHz using CDCI ₃ , DMSO-d ₆ or CD ₃ OD as solvent; conventional abbreviations are used for the signaiform, for example s - single, d - doublet, m - multiple, br - wide etc; In addition, "Ar" denotes an aromatic signal;

(ix) reduced pressures are given as absolute pressures in Pascals; other pressures are given as barometric pressures;

(x) chemical symbols have their usual meaning; In addition, the following abbreviations were used: ν (volume), w (weight), m. p. (Melting point), I (liters), ml (milliliters), g (grams); in certain examples and tables, " and &phis; are used to indicate that an explanatory footnote is given, and in certain tables, Formula 1 and Formula 2 denote the indicated ones.

Example 1 Methyl 4- (5-hexanamidoindol-3-ylmethyl) -3-methoxybenzoate

A stirred solution of methyl 4- (5-aminoindol-3-ylmethyl) -3-methoxybenzoate (A) (O, 2g) in dichloromethane (5ml) under a nitrogen atmosphere was treated with N-methylmorpholine (0.25g). followed by hexanoyl chloride (0.103g). After stirring for 2 hours, the mixture was poured into 1 M hydrochloric acid (20 ml). This mixture was extracted with ethyl acetate (2 x 20ml). The combined organic extracts were dried (MgSO 4) and evaporated, The recovered yellow oil was purified by flash chromatography on silica gel (75 ml), eluted with 6: 4 v / v ethyl acetate: hexane to give the title compound (0.24 g, 92%) as a colorless oil NMR: 0.83 (t, 3H, CH ₂ CH ₃ ), 1.36 (m, 4H, CH ₂ .CH ₂ .CH ₃ ), 1.57 (quintet, 2H, CH ₂ .CH ₂ -CON), 2.24 (t, 2 H, CH ₂ · CON), 3.80 (s, 3 H, COOCH _3), 3.90 (s, 3 H, _OCH3), 3.99 (s , 2H, CH ₂ .Ar), 7.1 (m, 2H), 7.21 (m, 2H), 7.44 (m, 2H), 7.69 (s, 1H, H ⁴ -indole ), 9.59 (s, 1H, CONH), 10.77 (s, 1H, H ¹ -indole). The aminoester (A) was prepared as follows:

(a) Silver Oxide (I) (7.15g) was added to a solution of 5-nitroindole (5g) and methyl 4-bromomethyl-3-methoxybenzoate (B) (7.99g) in dioxane (30ml) under a vacuum Nitrogen atmosphere added. The mixture was stirred for 20 hours at 60 C ^0, dioxane removed by evaporation and the residual ethyl acetate (50ml) was added. The resulting suspension was separated by filtering through diatomaceous earth. The filtrate was evaporated to give a dark, viscous oil, which was purified by flash chromatography on silica gel (600 ml) and eluted with 3: 7 v / v ethyl acetate: hexane. The recovered viscous yellow oil was crystallized from a mixture of dichloromethane and hexane to give 3-methox-4- (5-nitroindol-3-ylmethyl) benzoate (C) (4.6g, 45%) as yellow needles, mp 153 ° C-155 ° C. NMR: 3.83 (s, 3 H, COOCH _3), 3.93 (s, 3 H, _OCH3), 4.12 (s, 2H, CH ₂ x Ar), 7.25 (d, 1 H ), 7.43 (d, 1H), 7.49 (m, 3H), 7.95 (dd, 1H, H ⁶ -indole, 8.47 (d, 1H, H ⁴ -indole, 11 , 65 (wide s,

(b) Palladium on carbon (10% w / w, 0.25g) was added to a solution of (C) (1.5g) in tetrahydrofuran (50ml) in a hydrogenation flask. The mixture was hydrogenated at 3.45 bar for 2 hours. The catalyst was removed by filtering through diatomaceous earth and the filtrate was evaporated. The residual oil was purified by flash chromatography on silica gel (200 ml) and eluted with 1: 1 v / v ethyl acetate: hexane to give methyl 4- (5-aminoindol-3-ylmethyl) -3-methoxybenzoate (A) (1.12 g, 82%) as a viscous oil; NMR: 3.29 (br, 2H, NH ₂ ), 3.88 (s, 3H, CO x OCH ₃ ), 3.91 (s, 3H, OCH ₃ ), 4.03 (s, 2H, CH ₂ Ar), 6.64 (dd, 1H), 6.78 (m, 2H), 7.10 (m, 2H), 7.44 (m, 2H), 7.68 (br, 1H, H 'indole).

The bromomethyl starting compound (B) itself was prepared as follows:

(c) A solution of 3-methoxy-4-methylbenzoic acid (6.0 g) in methanol (120 ml) was treated with acetyl chloride (6 ml) and stirred for 36 hours. The solution was evaporated. The residue was dissolved in methanol (100 ml) and the solution evaporated. This procedure was repeated to give methyl 3-methoxy-4-methylbenzoate (6.34 g, 98%) as a colorless oil; NMR: 2.2 (s, 3H, CH ₃₎ 3.9 (2s, 6H, 2 x _OCH3), 7.1 (d, 1 H), 7.5 (m, 2H).

(d) A stirred solution of the ester from (c) (121.2 g) in carbon tetrachloride (1.41) was heated under light reflux with a 350W tungsten lamp and subjected to an air purge with a T-tube attached to a water jet pump , Over 4 hours, a solution of bromine (107.2 g) in carbon tetrachloride (500 ml) was added dropwise. Evaporation of the solvent gave a light yellow solid which was triturated with 500 ml of 1: 9 v / v etherhexane. The solid was collected by filtration to give methyl 4-bromomethyl-3-methoxybenzoate (B) (111.7 g, 64%) as a pale yellow solid, mp 87 ° C-90 ° C; NMR: 3.9 (2s, 6H, 2 χ OCH ₃ ), 4.5 (s, 2H, BrCH ₂ ), 7.4 (m, 3H).

Example 2 Methyl 4- [5- (2-ethylhexanarnido) indol-3-ylmethyl] -3-methoxybenzoate

Using a procedure as described in Example 1 but starting with 2-ethylhexanoyl chloride and (A), the title compound was obtained in 76% yield; partial NMR: 0.84 (m, 6H, 2 χ CH ₃ ), 1.24 m, 6 H, (CH ₂ ) ₃ , 2.24 (m, 1 H, CHCON), 10.78 (d, 1H, NH).

Example 3 Methyl 4- [5-cyclopentyloxycarbonyl) aminoindol-3-ylmethyl] -3-methoxybenzoate Cyclopsyl chloroformate was added to a stirred solution of the aminoester (A) (0.15g) and N-methylmorpholine (0.27g) in dichloromethane (3ml). at 0-5 ⁰ C added under a nitrogen atmosphere. The mixture was stirred for 30 min at 0 ⁰ C to 5 ⁰ C, the cooling bath removed and stirring continued for a further hour. Then, the mixture was poured into 1 M hydrochloric acid (15 ml) and extracted with ethyl acetate. The combined extracts were dried (MgSO ₄ ) and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml) eluting with 3: 7 v / v ethyl acetate: hexane to give the title compound (0.18 g, 89%) as a colorless oil; NMR: 1.66 (m, 6H), 1.82 (m, 2H), 3.83 (s, 3H, CO OCH ₃ ), 3.92 (s, 3H, OCH ₃ ), 3.97 (s , 2H, CH ₂ .Ar), 5.04 (m, 1 Η, -CHO -), 7.09 (m, 3H), 7.22 (d, 1H), 7.42 (dd, 1H ), 7.48 (d, 1H), 7.57, (br, 1H), 9.18 (br, 1H, CONH), 10.57 (s, 1H, H'-indole).

Example 4 Methyl 4- (5-hexanamido-1-methylindol-3-ylmethyl) -3-methoxybenzoate

Hexanoyl chloride (0.029g) was added to a stirred solution of methyl 4- (5-amino-1-methylindol-3-ylmethyl) -3-methoxybenzoate (D) (0.05g) and N-methylmorpholine (0.05g) in dichloromethane (3ml) under a nitrogen atmosphere. The mixture was stirred for two hours and then poured into 1 M hydrochloric acid (15 ml). This mixture was extracted with ethyl acetate (2 x 20ml). The combined extracts were dried (MgSO ₄ ) and evaporated. The residual oil was purified by flash chromatography on silica gel (50 mL), eluted with 4: 6 v / v ethyl acetate: hexane to give a colorless oil which was crystallized from a mixture of toluene and hexane to give the title compound (0.05 g, 65 %) as a white powder; NMR: 0.86 (t, 3H, CH ₂ .CH ₃ ), 1.28 (m, 4H, CH ₂ .CH ₂ .CH ₃ ), 1.57 (quintet, 2H, CH ₂ .CH ₂ .CON ), 2.25 (t, 2H, CH ₂ .CH ₂ .CON), 3.69 (s, 3H, NCH ₃ ), 3.82 (s, 3H, CO x OCH ₃ ), 3.92 (s , 3H, OCH ₃ ), 3.97 (s, 2H, CH ₂ .Ar), 7.05 (s, 1H), 7.13 (d, 1H), 7.27 "(d, 1H ), 7.28 (d, 1H), 7.40 (dd, 1H), 7.48 (s, 1H), 7.74 (s, 1H), 9.61 (s, 1H ).

The aminoester (D) was prepared as follows:

(a) Methyl 3-methoxy-4- (5-nitroindol-3-ylmethyl) benzoate (0.44g) was added to a stirred suspension of oil-free sodium hydride (0.031g) in dry tetrahydrofuran (10ml) under a nitrogen atmosphere , The dark red solution was stirred for 10 min and iodomethane (0.18 g) was added. The mixture was stirred for 30 minutes and poured into 1 M hydrochloric acid (30 ml). The resulting mixture was extracted with ethyl acetate (2 × 50 ml), then dried (MgSO ₄ ) and evaporated. The recovered yellow oil was purified by flash chromatography on silica gel (50 ml), eluted with 50: 45: 5v / v / v hexane: dichloromethane: ethyl acetate, to give methyl 3-methoxy-4- (1-methyl-5-nitroindole). 3-ylmethoxybenzoate (E) (0.33g, 72%) as a yellow oil, which was crystallized from dichloromethane / hexane to give a yellow oil, mp 144 ° -146 ° C, NMR: 3.81 (s, 3H, (N · CH _3), 3.83 (s, 3H, CO · OCH _3), 3.92 s, 3H, OCH _3), 4.11 (s, 2H, CH ₂ x Ar), 7.27 (d , 1H), 7.37 (s, 1H, H ² -indole), 7.49 (m, 2H), 7.60 (d, 1H), 8.01 (dd, 1H, H ⁶ -indole), 8.50 (d, 1H, H ⁴ -indole).

(b) A solution of (E) (0.56g) in tetrahydrofuran (30ml) was hydrogenated in the presence of palladium on carbon (10% w / w, 0.1g) as for the amino acid ester (A). in Example 1, to give methyl 4- (5-amino-1-methylindol-3-ylmethyl) -3-methoxybenzoate (D) (0.50 g, 98%) as a pale yellow foam; NMR: 3.6 (s, 3H, NCH ₃ ), 3.8 (s, 3H, CO.OCH ₃ ), 3.9, (br, s, 5H, OCH ₃ and CH ₂ .Ar), 4, 45 (br, 2H, NH ₂ ), 6.54 (m, 2H), 6.86 (s, 1H), 7.04 (m, 2H), 7.40 (m, 2H).

Example 5 Methyl 4- [5- (2-ethylhexanamido) -1-methylindol-3-ylmethyl] -3-methoxybenzoate Using the same procedure as in Example 4 but starting from 2-ethylhexanoyl chloride and (C), the title compound was obtained a yield of 80% recovered as a viscous oil; partial NMR: 0.84 (m, 6H, 2 o CH ₃ ), 1.24 [m, 6H, (CH ₂ I ₃ ], 2.23 (m, 1 H, CH, CON), 3.70 ( s, 3H, NCH ₃ ).

Example 6 Methyl 4- (1-benzyl-5-hexanamidoindol-3-ylmethyl) 3-methoxybenzoate

Potassium t-butoxide (0.04g) was added to a stirred solution of methyl 4- (5-hexanamidoindol-3-yl-ethyl) methoxybenzoate (0.15g) in dry tetrahydrofuran (5ml) under a nitrogen atmosphere. The resulting dark green mixture was stirred for 30 minutes. Benzyl bromide (0.062 g) was added, changing the color to light brown. After 1 hour, the mixture was poured into 1 M hydrochloric acid (20 ml). This mixture was extracted with ethyl acetate (2 × 25 ml). The combined extracts were dried (MgSO ₄ ) and evaporated. The recovered brown oil was purified by flash chromatography on silica gel (50 ml) eluting with 3: 7 v / v ethyl acetate: hexane to give the title compound (0.04 g, 17%) as an oil; NMR: 0.86 (t, 3H, CH ₂ .CH ₃ ), 1.27 (m, 4H, CH ₂ .CH ₂ .CH ₃ ), 1.57 (m, 2H, CH ₂ .CH ₂ .CON ), 2.24 (t, 2H, CH ₂ .CH ₂ -CON), 3.82 (s, 3 H, CO x OCH ₃ ), 3.91 (s, 3 H, OCH ₃ ), 3.99 (s, 2 H, CH ₂ Ar), 5.32 (s, 2 H, NCH ₂ Ph), 7.21 (m, 10 H), 7.44 (m, 2H), 7.75 (d, 1H), 9.64 (s, 1H, NH).

Example 7 Methyl 4- (1-allyl-5-hexanamidoindol-3-ylmethyl) -3-methoxybenzoate

Using a similar procedure as in Example 6 but using allyl bromide in place of benzyl bromide, the title compound was recovered in 36% yield as a viscous oil; partial NMR: 0.86 (t, 3H, CH ₂ , CH ₃ ), 1.27 (m, 4H, CH ₂ .CH ₂ .CH ₃ ), 1.57 (quintet, 2H, CH ₂ .CH ₂ CON ), 2.24 (t, 2H, CH ₂ .CON), 4.72 (d, 2H, NCH ₂ ), 5.07 (dd, 2H, CH x CH ₂ ), 5.99 (m, 1H , CH · CH ₂ ).

Example 8 Methyl 4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoate Cyclopedyl chloroformate (0.11 g) was added to a stirred solution of methyl 4- (5-amino-1-methylindole 3-ylmethyl) -3-methoxybenzoate (D) (0.25g) and N-methylmorpholine (0.23g) in dichloromethane (3ml) under a nitrogen atmosphere. The mixture was stirred for two hours and then poured into 1M hydrochloric acid (20ml). This acid mixture was extracted with ethyl acetate (2 x 30 ml). The combined extracts were washed with brine (20 ml), dried (MgSO ₄ ) and evaporated to give a viscous oil. Purified by flash chromatography on silica gel (50ml), eluting with 3: 7v / v ethyl acetate-hexane to give the title compound as a foam (0.25g, 74%); NMR: 1.62 [m, 8H, (CH ₂ J ₄ ], 3.68 (s, 3H, NCH ₃ ), 3.83 (s, 3H, CO OCH ₃ ) 3.91 (s, 3H, OCH ₃ ), 3.95 (s, 2H, CH ₂ .Ar), 5.05 (m, 1H, -CHO-), 7.11 (m, 2H), 7.26 (d, 1H), 7.43 (m, 2H), 7.59 (br, 1H), 9.18 (br, 1H, NH)

Example 9

4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoic acid. A stirred solution of methyl 4- [5- (cyclopentyloxy-carbonyl) amino-1-methylindol-3-ylmethyl] -3- Methoxybenzoate (0.25g) in methanol (5ml) and tetrahydrofuran (4ml) under a nitrogen atmosphere was treated with a solution of lithium hydroxide monohydrate (0.12g) in water [ 2ml). The mixture was stirred for 20 hours and then concentrated to remove the tetrahydrofuran. The resulting aqueous solution was acidified with 1 M hydrochloric acid (20 ml). The resulting white precipitate was collected by filtration, washed with a little water and recrystallized from a mixture of toluene and hexane to give the title compound (0.212 g, 88%) as an off-white powder; Melting point 157 ⁰ C-158 ° C

Analysis calculated for: C ₂₄ H ₂₆ N ₂ O _5: C - 68.23; H - 6,20; N - 6.63 Determined: C -68.36; H-6,19; N -6.36

Examples 10 to 19

Using a procedure similar to Example 9, the following acids of formula 1 were obtained by the hydrolysis of the corresponding methyl esters:

Ex. R ¹ W Rd melting point Yield

10 pentyl 11 1-ethylpentyl 12 cyclopentyl 13 pentyl 14 1-ethylpentyl 15 cyclopentyl 16 pentyl 17 pentyl 18 Alpha-fluorobenzyl 19 Alpha-methoxybenzyl

H 205-210 * 77 H 202-203 87 H 184-186 80 methyl 227-228 66 methyl 204-208 66 methyl 157-158 88 allyl 203-204 39 benzyl 210-211 67 methyl 188-190 83 methyl 124-126 * 53

* Isolated as partial hydrate (0.25H ₂ O) - Direct bond to R ¹

The starting methyl esters for Examples 18 and 19 were prepared by conventional acylation of methyl 4- (5-amino-1-methylindol-3-ylmethyl) -3-methoxybenzoate (D) with alpha-fluorophenylacetic acid and alpha-methoxyphenylacetic acid in the presence of 1- [3 - (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 4- (dimethylamino) pyridine in dichloromethane at ambient temperature. The methyl esters were recovered as viscous oils with satisfactory NMR spectra.

Example 20 N- [4- [5- (Cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide Ν, Ν-Diphenylcarbamoylpyridinium hydrochloride (0.132g) was added to a stirred solution of 4- [5- (cyclopentyloxycarbonyl ) -amino-T-methylindol-3-ylmethyl] -3-methoxybenzoic acid (prepared as in Example 9) (0.15g) and sodium hydroxide (0.35ml of a 1M aqueous solution) in absolute ethanol (6ml) under a nitrogen atmosphere , The mixture was stirred for 15 min and then partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was washed successively with 1M hydrochloric acid (20ml) and saturated brine (20ml), then dried (MgSO ₄ ) and evaporated to give 4- [5- (cyclopentyloxycarbonyl) amio-1-methylindol-3-ylmethyl] -3 methoxybenzoic N, N-diphenylcarboxamide anhydride as a white foam. This foam was dissolved in Ν, Ν-dimethylformamide (DMF) (3 mL) and added to a stirred solution of sodium salt of benzenesulfonamide (0.19 g) on DMF (6 mL) under a nitrogen atmosphere. The mixture was stirred for 1 hour and then poured into 1 M hydrochloric acid (40 ml). The acid mixture was extracted with ethyl acetate (2 x 30 ml). The combined extracts were dried (MgSO ₄ ) and evaporated. The recovered oil was purified by the following sequential procedures:

(a) Relaxation chromatography on silica gel (50ml), eluting with 3: 7v / v acetonitrile: dichloromethane;

(b) crystallization from the mixture of dichloromethane and hexane;

(c) flash chromatography on silica gel (50ml), eluting with dichloromethane (200ml), then with 3: 1 v / v dichloromethane: ethyl acetate (200ml) followed by 1: 1 v / v dichloromethane: ethyl acetate, and

(d) crystallizing from a mixture of ethyl acetate and hexane to give the title compound (15.9 g, 8%) as a white solid; Melting point 125-13O ⁰ C.

Analysis calculated for:

C ₃₀ H ₃₁ N ₃ O ₆ S: C-64.15; H -5.56; N -7.48 Determined: C-64.18; H -5.33; N-7.36

Example 21 N- [3-Methoxy-4- [5- (2-ethylhexanamido) -1-methylindol-3-ylmethyl] benzoyl] benzenesulfonamide Using the procedure described in Example 20, the title compound was obtained with a yield of 20% Solid, melting point 169 ⁰ C-171 ⁰ C, when 4- [5- (2-ethylhexanamido) -1-methylindol-3-ylmethyl] -3-methoxybenzoic acid was used as starting material.

Example 22 Methyl 4- [5- (cyclopentyloxycarbonyl) amino-1-cyclopropylmethylinol-3-ylmethyl] -3-methoxybenzoate Using a similar procedure to Example 8, the title compound was recovered as a viscous oil with a yield of 90%. ; partial NMR: 0.32 (m, 2H), 0.46 (m, 2H), 2.18 (m, 1H), 1.67 (m, 6H), 3.82 (s, 3H, OCH ₃ ) 3.92 (s, 3H, OCH ₃ ). The compound was prepared with the starting material methyl 4- (5-amino-1-cyclopropylmethylindol-3-ylmethyl) -3-methoxybenzoate (which in turn was prepared analogously to (D) in Example 4, ie by the reaction of the nitroindole derivative (C with cyclopropalmethylbromide in the presence of sodium hydride, followed by catalytic hydration of the product).

Example 23 Methyl 4- [5- (cyclopentyloxycarbonyl) amino-1- (3-methylbut-2-enyl) indol-3-ylmethyl] -3-methoxybenzoate Using a similar method to Example 8, the title compound was obtained in a yield of 70% recovered as a viscous oil; partial NMR: 1.64 (m, 4H), 1.69 (s, 3H, CH _3), 1.78 (s, 3H, CH _3), 3.82 (s, 3H, OCH ₃₎ 3, 92 (s, 3H, OCH ₃ ), 4.64 (d, 2H, NCH ₂ ). The compound was prepared from the starting material 4- [5-amino-1- (3-methylbut-2-enyl) indol-3-ylmethyl] -3-methoxybenzoate (F).

The aminoindole derivative (F) was obtained as follows:

A slurry of methyl 4- [1- (3-methylbut-2-enyl) -5-nitroindol-3-ylmethyl] -3-methoxybenzoate (0.22g) and stannous chloride dihydrate (1.6g) in absolute ethanol (8ml). was heated under reflux under a nitrogen atmosphere for 24 hours and stirred. The cooled mixture was poured into saturated sodium bicarbonate solution (30 ml). The mixture was then extracted with dichloromethane (2 × 30 ml). The combined extracts were washed with saturated brine (25 ml), dried and evaporated to give methyl 4- [5-amino-1- (3-methylbut-2-enyl) indol-3-ylmethyl] -3-methoxybenzoate ( F) (0.14 g, 69%) as an oil; NMR: 1.68 (s, 3H, = C-CH _3, 1.76 (s, 3H, = C-CH _3), 3.82 (s, 3 H, CO · OCH _3), 3.89 ( s, 2H, CH ₂ -Ar), 3.91 (s, 3H, OCH ₃ ), 4.57 (d, 2H, CH ₂ N), 5.27 (t, 1H, CH ₂ CH), 6.48 (m, 2H), 6.91 (s, 1H), 7.04 (d, 1H), 7.08 (d, 1H), 7.46 (m, 2H).

Examples 24 and 25

Using a similar procedure to Example 9 but starting with the corresponding methyl ester, the following acids were obtained with Formula 1:

Example 24: 4- [5- (Zyklopentyloxykarbonyl) amino-1-zyklopropylmethylindol-3-ylmethyl] -3-methoxybenzoic acid in a yield of 72% as a solid, melting point 177 -179 C ^{0 0} C;

Example 25: 4- [5- (Cyclopentyloxycarbonyl) amino-1- (3-methylbut-2-enyl) indol-3-ylmethyl] -3-methoxybenzoic acid in 52% yield as a solid, mp 179 ° C to 18 ° C ⁰ C.

Example 26 Methyl 4- (6-hexanamido-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl) -3-methoxybenzoate Hexanoyl chloride (0.084g) was added to a stirred solution of methyl ^ -fen-amino ^^ - Dichydrobenz-i ^ -oxazin ^ -ylmethyO-S-methoxybenzoate (L) (0.2g) in dichloromethane (20ml) was added under a nitrogen atmosphere. The mixture was stirred for one hour and then diluted with dichloromethane (40 ml). This mixture was washed with water, dried (MgSO ₄ ) and evaporated. The remaining oil was dissolved in 3: 7v / v ethyl acetate: hexane and the resulting solution was filtered by passing through a short silica gel column and washed with a column volume of the same solvent mixture. Evaporation of the column eluate gave the title compound (0.212 g, 82%) as a foam; NMR (250MHz, CDCI _3): 0.9 (t, 3H, CH ₂ CH _3), 1.3 (m, 4H, CH ₃ · CH ₂ · CH _2), 1.6 (m, 2H, CH ₂ CH ₂ .CON), 2,2 (t, 2H, CH ₂ .CON), 3,35 (t, 2H-, OC _- H ₂ CH ₂ N), 3,9 (br s, 6H, OCH ₃ + CO.OCH ₃ ), 4.2 (t, 2H, OCH ₂ CH ₂ N), 4.5 (s, 2H, CH ₂ -Ar-), 6.8 (m, 3H), 6.9 (br s, 1H, NH), 7.2 (m, 1H), 7.5 (m, 2H)

 The starting aminoester (L) itself was obtained as follows:

(a) A mixture of 6-nitro-2,3-dihydrobenz-1,4-oxazine (0.45g), methyl 4-bromomethyl-3-methoxybenzoate (B) (0.65g), anhydrous potassium carbonate (0, 35g), sodium iodide (0.38g) and acetone (25ml) was stirred at reflux for 48 hours and heated, under a nitrogen atmosphere. The cooled reaction mixture was then separated by filtering. The residue was washed with acetone and the filtrate and washings were evaporated. The resulting oil was dissolved in dichloromethane and the residual solid was removed by filing. The filtrate was evaporated. The product was purified by flash chromatography on silica gel (3cm column diameter) eluting with 1: 10v / v ethyl acetate: toluene to give methyl 3-methoxy-4- (6-nitro-2,3-dihydrobenz-1,4-oxazine). 4-ylmethyl) benzoate (G) (0.75 g, 84%), mp 130 ⁰ C to 132 ⁰ C; NMR (80MHZ, CDCl ₃ ): 3.0 (t, 2H, OCH ₂ .CH ₂ N), 3.8 (s, 3H, OCH ₃ ), 3.95 (s, 3H, OCH), 4.3 (t, 2H, OCH ₂ .CH ₂ N), 4.5 (s, 2H, CH ₂ Ar), 6.8 (d, 1H), 7.5 (m, 5H).

(b) Palladium on carbon (10% w / w, 0.2g) was added to a solution of (G) (0.69g) in ethyl acetate (50ml) in a hydrogenation flask and the mixture was pressurized to 3.17 Bar Hydrogenated. After hydrogen uptake ceased, the catalyst was removed by filtering through diatomaceous earth. The filter pad was washed with ethyl acetate and the filtrate and washings were evaporated to give methyl 4- (6-amino-2,3-dihydrobenz-1,4-oxaziin-4-ylmethyl) -3-methoxybenzoate (0.625 g, 91 %) as a foam; NMR: 3.1 (br s, 2H, NH ₂ ), 3.3 (t 2H, OCH ₂ CH ₂ N), 3.85 (m, 6H, OCH ₃ + CO ₂ CH ₃ ), 4.2 ( t, 2H, OCH ₂ , CH ₂ N), 4.45 (s, 2H, CH ₂ -Ar), 6.0 (m, 2H), 6.55 (d, 1H), 7.3 (i.e. , 1H), 7.55 (m, 2H).

Example 27 Methyl 4- [6- (2-ethylhexanamido) -2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoate Using the same procedure as in Example 26 but starting with 2- Ethylhexanoyl chloride, the title compound was recovered in 95% yield as a viscous oil; partial NMR: 0.89 (m, 6H, 2X CH ₃ ), 1.97 (m, 1H, CNCON), 3.91 (s, 6H, OCH ₃ + CO x OCH ₃ ), 4.47 (s, 2H, CH ₂ -Ar).

Example 28 Methyl 4- [6- (cyclopentyloxy-carbonyl) amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoate Cyclopedotyl chloroformate (0.5 g) was dissolved in a single portion of a stirred solution of methyl -4- (6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl) -3-methoxybenzoate (L) (1.0g) and N-methylmorpholine (0.314g) in dichloromethane (30ml) a nitrogen atmosphere added. After 1 h, the mixture was diluted with dichloromethane and washed successively with 1M hydrochloric acid, 5% w / v sodium bicarbonate solution and saturated brine and then dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography on silica gel (4cm column diameter), eluted with dichloromethane to give the title compound (0.7g, 52%) as an oil; NMR (80MHz, CDCl ₃ ): 1.69 [m, 8H, (CH ₂ I ₄ ], 3.39 (t, 2H, OCH ₂ CH ₂ N), 3.90 (s, 3H, OCH ₃ ), 3.91 (s, 3H, OCH ₃ ) 4.23 (t, 2H, OCH ₂ CH ₂ N), 4.45 (s, 2H, CH ₂ .Ar), 5.10 (m, 1 H, -COO-), 6.2 (br s, 1 H, NHCO), 6.59-7.62 (m, 6H).

Example 29 4- [6- (Cyclopentyloxycarbonyl) amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoic acid Lithium hydroxide monohydrate (0.267 g) was added as a solid to a stirred solution of methyl 4- [6 - (cyclopentyloxycarbonyl) -amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoate (0.7g) in methanol (15m) and water (2ml). The mixture was stirred for 12 hours, then diluted with water and acidified to pH 3.35 with 3M hydrochloric acid. The precipitate was isolated by filtration, washed with water and crystallized from methanol to give the title compound as a solid (0.457 g, 67%), mp 221 ° C-222 ^C C. Calcd: C ₂₃ H ₂₆ N ₂ O _6: C-64.78; H-6,14; N-6,57 Determines: C - 64.77; H - 5.97; N - 6,57

Examples 30 and 31

Using a similar procedure as in Example 29 but starting from the corresponding methyl esters, the following compounds were obtained:

Example 30: 4- [6-Hexanamido-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoic acid with a yield of 77% as a solid semihydrate, m.p. 20 ⁷ -208 ° C;

Example 31: 4- [6- (2-Ethylhexanamido) -2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoic acid with a yield of 88% as a solid, mp 190 ° C-192 ° C.

Example 32 N- [4- [6- (Cyclopentyloxycarbonyl) amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxyenzoyl] benzenesulfonamide Benzenesulfonamide (0.037g) was added to a stirred solution of 4- [ 6- (cyclopentyloxycarbonyl) amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoic acid (0.1 g), 10-dimethylaminopropyl-S-ethylcarbodiimide hydrochloride (0.046 g) and 4- (dimethylamino ) pyridine (0.029 g) in dichloromethane (5 ml) under a nitrogen atmosphere. The mixture was stirred for 21 hours and then diluted with dichloromethane. This mixture was washed successively with 1 M hydrochloric acid (2 × 10 ml), 5% w / v sodium bicarbonate solution (2 × 10 ml) and saturated brine (20 ml). Then it was dried and evaporated. The residue was purified by flash chromatography on silica gel (3 cm column diameter) eluting with 1: 1 v / v ethyl acetate: hexane. The recovered solid was crystallized from ethyl acetate to give the title compound as a white powder (0.071 g, 54%), m.p. 186 ° C-187 ° C. Analysis calculated for: C ₂₉ H ₃₁ N ₃ O ₇ S: C, -61.58; H -5.52; N-7,43 Determined: C-61.18; H -5.18; N -7.00

Example 33 Methyl 4- (5-hexanamidobenzo [b] thien-3-ylmethyl) -3-methoxybenzoate

Hexanoyl chloride (0.024g) was added to a stirred solution of methyl 4- (5-aminobenzo [b] thien-3-ylmethyl) -3-methoxybenzoate (H) (0.06g) and N-methylmorpholine (0.1ml). in dichloromethane (3 ml). The mixture was stirred for one hour and then poured into water (20 ml). The aqueous mixture was extracted with dichloromethane (2χ20 L). The combined extracts were dried (MgSO ₄ ) and evaporated. The mixture was recrystallized from a mixture of ethyl acetate and hexane to give the title compound (0.05g, 75%) as a colorless solid; NMR (250MHz, DMSO-d ₆ ): 0.87 (t, 3H, CH ₂ CH ₃ ), 1.28 (m, 4H, CH ₂ .CH ₂ , CH ₃ ), 1.59 (quintet, 2H, CH ₂ CH ₂ CON), 2,29 (t, 2H, CH ₂ CON), 3,8 (fe, 3H, OCH ₃ ), 3,91 (s, 3H, OCH ₃ ), 4,11 (s, 2H, CH ₂ -Ar), 7.14 (d, 1H), 7.34 (s, 1H), 7.94 (m, 3H), 7.86 (d, 1H), 8.11 (d, 1H), 9.95 (s, 1H). The aminoester (H) was obtained as follows:

(a) Tin (IV) chloride (0.41g) was added to a stirred solution of 5-nitrobenzo [b] thiophene (0.28g) and methyl 4-bromomethyl-S-methoxybenzoate (B) (0.61g ) in dichloromethane (5 ml). The mixture was heated at reflux for 18 hours. The cooled mixture was poured into water (10ml) and extracted with dichloromethane (2 x 20ml). The combined extracts were dried (MgSO ₄ ) and evaporated. The oil was purified by flash chromatography on silica gel (100ml) and elution with 1: 9v / v ethyl acetate: hexane. The recovered solid was crystallized from hexane to give methyl 3-methoxy-4- (5-nitrobenzo [b] thien-3-ylmethyl) benzoate (I) as a solid (0.16 g, 30%); NMR (250MHz, CDCl ₃ ): 3.92) s, 3H, OCH ₃ ), 3.98 (s, 3H, OCH ₃ ), 4.28 (s, 2H, CH ₂ -Ar), 7.15 (d, 1H), 7.22 (s, 1H), 7.56 (m, 2H), 7.93 (d, 1H), 8.19 (dd, 1H), 8.73 ( d, 1H). (b) Tin (II) chloride dihydrate (0.38g) was added to a stirred solution of (I) (0.12g) in ethanol (5ml) under a nitrogen atmosphere. The mixture was heated at reflux for 2 hours. The cooled mixture was basified with saturated aqueous sodium bicarbonate (15 ml) and extracted with ethyl acetate (2 × 25 ml). The extracts were dried (MgSO ₄ ) and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml), eluted with 3: 7v / v ethyl acetate: hexane, to give methyl 4- (5-aminobenzo [b] thien-3-ylmethyl) -3-methoxybenzoate (0) , 06g, 54%) as an oil; NMR (80MHz, DMSO-d ₆ ): 3.84 (s, 3H, OCH ₃ ), 3.91 (s, 3H, OCH ₃ ), 4.03 (s, 2H, CH ₂ -Ar), 5, 0 (br s, 2H, NH ₂ ), 6.80 (m, 2H), 7.14 (m, 2H), 7.52 (m, 3H).

Example 34 4- (5-Hexanamidobenzo [b] thien-3-ylmethyl) -3-methoxybenzoic acid

Using a similar procedure to Example 29, the title compound was recovered in 70% yield as a powder, mp 234-235 ° C (after recrystallization from a mixture of tetrahydrofuran, hexane and ethyl acetate).

Analysis calculated for:

C ₂₃ H ₂₅ NSO ₄ = C-67.13; H-6,12; N -3.40

Determined -67.05; H -6.20; N -3.17

Example 35 Methyl 4- [6- (cyclopentyloxycarbonyl) aminobenzimidazol-1-ylmethyl] -3-methoxybenzoate A solution of methyl 4- (6-aminobenzimidazol-1-ylmethyl) -3-methoxybenzoate (J) (0.63g) and 2,6-lutidine (0.36 ml) in dichloromethane (10 ml) was treated with cyclopentyl chloroformate (0.33 g). After the solution was stirred for 24 hours, it was diluted with dichloromethane. The mixture was washed successively with 20% w / v sodium hydroxide, water and brine, then dried (MgSO ₄ ) and evaporated. The resulting residue was purified by flash chromatography on a 6 × 20 cm silica gel column using 1: 3 v / v hexane: ethyl acetate as eluent to give the title compound (0.57 g, 93%); NMR: 1.7 [m, 8H, (CH ₂ I ₄ ], 3.8 fs, (3 H, OCH ₃ ), 3.9 (s, 3 H, OCH ₃ ), 5.2 (m, 1H , CHO), 6.17-7.0 (br m, 3H), 7.5-7.8 (br m, 4H)

 The starting ester (J) was obtained as follows:

(a) A solution of 6-nitrobenzimidazole (2.0g) and methyl 4-bromomethyl-3-methoxybenzoate (B) (3.5g) in methyl ethyl ketone (61ml) was treated with potassium carbonate (1.9g) and then added Rewind heated for 24 hours. Thereafter, the solvent was evaporated. The residue was extracted with ethyl acetate and the inorganic material removed by filtering. The filtrate was evaporated. The resulting residue was purified by flash chromatography on a 6 × 30 cm silica gel column using 1: 1 v / v hexane: ethyl acetate as eluent to give methyl 3-methoxy-4- (6-nitrobenzimidazol-1-ylmethyl) benzoate (K. ) (1,07g, 26%), NMR: 3.9 (s, 3H, OCH _3), 4.0 (s, 3H, OCH _3), 5.7 (s, 2H, NCH _2), 7, 4 (d, 1 H, Ar), 7.8 (d, 1 H, H ⁴ -benzimidazole), 8.1 (dd, 1 H, H ⁵ -benzimidazole), 8.6 (br s, 2H, H ²⁷ benzimidazole).

(B) A solution of (K) (0.77 g) in anhydrous ethanol (23 ml) was treated with stannous chloride dihydrate (2.6 g). The mixture was stirred for 18 hours at 80 ⁰ C and then diluted with ethyl acetate. This mixture was washed successively with saturated sodium bicarbonate solution, water and brine, since dried (MgSO ₄ ) and evaporated to give methyl 4- (6-aminobenzimidazol-1-ylmethyl) -3-methoxybenzoate (J) (0.63 g, 90%). ); partial NMR: 3.4 (br s, 2H, NH ₂ ), 5.2 (s, 2H, NCH ₂ ).

Example 36 4- [6- (2-Cyclohexylcarbonyl) aminobenzimidazol-1-ylmethyl] -3-methoxybenzoic acid A stirred solution of methyl 4- [6- (cyclopentyloxy-carbonyl) aminobenzimidazol-1-ylmethyl] -3-methoxybenzoate in 1: 1 v / v / v Tetrahydrofuran: Methanol (7 mL) was treated with water (1.4 mL) and lithium hydroxide monohydrate (0.3 g). Stirring was continued for an additional 4 hours at ambient temperature. Then the solvent was evaporated. The resulting residue was dissolved in water. The recovered solution was acidified with 10% v / v hydrochloric acid. The resulting precipitate was collected by filtration to give the title compound (0.43 g, 78%). An analytical sample was recovered as a white powder by recrystallization from aqueous ethanol; Melting point 241-242 ⁰ C. Analysis calculated for:

C ₂₂ H ₂₃ N ₃ O ₅ · 0.6H ₂ O: C - 62.87; H - 5.80; N-10.0 Determined: C-62.87; H -5.55; N-9.63

Example 37 Methyl 4- [6- (butoxycarbonyl) aminobenzimidazol-1-ylmethyl] -3-methoxybenzoate Using a similar procedure as in Example 35 but using butyl chloroformate and (J), the title compound was obtained as a solid in a yield gained by 34%; partial NMR: 0.9 (t, 3 H, CH ₃ CH _2), 1.4 (m, 2 H, CH ₃ CH _2), 1.6 (m, 2 H, CH ₂ CH ₂ O), 4 , 1 (t, 2H, CH ₂ O).

Example 38 Methyl 3-methoxy-4- [6- (2-phenylbutanamide) benzimidazol-1-ylmethyl] benzoate A solution of 1,1'-carbonyldiimidazole (0.24 g) and 2-phenylbutyric acid (0.22 g ) in dichloromethane (3 ml) was heated at reflux for 30 min and then treated with a solution of (J) (0.41 g) in dichloromethane (3 ml). The mixture was heated at reflux for a further 10 min and then diluted with dichloromethyne. This mixture was washed successively with 10% v / v hydrochloric acid, water and brine, then dried (MgSO ₄ ) and evaporated. The resulting residue was purified by flash chromatography on a 5 x 25 cm silica gel column using 3:97 v / v methanol: dichloromethane as the eluent to give the title compound (0.15 g, 25%); partial NMR: 2.0 (brm, 2H, CH ₃ CH _2), 3.4 (t, 1 H, CH ₂ CH), 7.3 (s, 5H, Ar).

Examples 39 and 40

Using the same procedure as in Example 36, the following compounds of Formula I were obtained by the hydrolysis of the corresponding methyl esters.

Example 39: 4- [6- (Butoxy carbonyl) aminobenzimidazol-1-ylmethyl] -3-methoxybenzoic acid in a yield of 22% as a hemihydrate, m.p. 184 ° C-185 ° C; and

Example 40: 3-Methoxy-4- [6- (2-phenylbutanamido) benzimidazol-1-ylmethyl] benzoic acid in 31% yield as a solid, mp 256 ° C-257 ° C. (d-decomposition).

Example 41 Methyl 4- [5- (cyclopentyloxycarbonyl) amino-1- (2-methoxy) indol-3-ylmethyl] -3-methoxybenzoate Using a similar procedure as in Example 8 (see also Example 22), the title compound was dissolved in a yield of 78% recovered as an oil; partial NMR (250MHz, DMSO-de): 1.4-1.9 [m, 8H, (CH ₂ U], 3.19 (s, 3H, CH ₂ OMe); 3.59 (t, 2H ₁ CH ₂ OMe), 3.82 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.96 (s, 2H, _ArCH2); 4.22 (t, 2H, CH ₂ N) 5.08 (m, 1 H, -CHO-); 9.20 (br s, 1 H, NH) The compound was prepared from the starting materials methyl 4- [5-amino-1- (2-methoxyethyl ) in dol-3-ylmethyl] -3-methoxybenzoate (which in turn was prepared analogously to (D) in Example 4, ie, by the reaction of the nitroindole derivative

(C) with t-bromo-2-methoxyethane in Ν, Ν-dimethylformamide in the presence of sodium hydride, followed by catalytic hydrogenation of the product).

Example 42 Methyl 4- [1- (N -ethylcarbamoylmethyl) -5- {cyclopentyloxycarbonyl) aminoindol-3-ylmethyl] -3-methoxybenzoate Using a similar procedure to Example 8 (see also Example 22), the title compound was added as a obtained white powder in a yield of 73%; Melting point 192 ° C-194 ° C; partial NMR (250MHz, DMSO-d ₆ ): 1.01 (t, J = 7.15Hz, 3H, CH ₂ CH ₃ ); 1.5 - [1.9 m, 8H, (CH ₂ J ₄ ], 3.10 (m, 2H, NHCH ₂ ), 3.83 (s, 3H, OMe), 3.92 (s, 3H, OMe); 3.97 (s, 2H, ArCH ₂ ); 4.67 (s, 2H, -NCH ₂ ); 5.10 (m, 1H, -CHO-); 9.25 (br s, 1 H, ArNH) The compound was prepared starting from 4- [1- (N-ethylcarbamoylmethyl) -5-aminoindol-3-ylmethyl-3-methoxybenzoate (which in turn was prepared analogously to (D) in Example 4, ie Reaction of the nitroindole derivative (C) with 2-chloro-N-ethylacetamide in N, N-dimethylformamide in the presence of sodium hydride, followed by catalytic hydrogenation of the product).

Example 43 Methyl 4- [1-cyclopentyl-5- (2-cyclopentyloxycarbonyl) aminoindol-3-ylmethyl] -3-methoxybenzoate Using a similar procedure to Example 8 (see also Example 22), the title compound was obtained in 75% yield. recovered as a foam; partial NMR (250MHz, DMSO-d _e ): 1.4-2.15 [m, 16H, 2x (CH ₂ J ₄ ]; 3.82 (s, 3H, OMe); 3.92 (s, 3H 3.96 (s, 2H, ArCH ₂ ), 4.80 (m, 1H, -NCH), 5.10 (m, 1H, -CHO-), 9.20 (br 1 H, NH) The compound was prepared starting from methyl 4- [5-amino-1-cyclopentylindol-3-ylmethyl] -3-methoxybenzoate (which in turn was prepared analogously to (D) in Example 4, ie by the reaction of Nidroindolderivat (C) with Bromozyklopentan in N, N-dimethylformamide at 50 ⁰ C in the presence of sodium hydride, followed by catalytic hydrogenation of the product).

Example 44 Methyl 4- [5- (cyclopentyloxycarbonyl) amino-1-propylindol-3-ylmethyl] -3-methoxybenzoate Using a similar procedure to Example 8 (see also Example 22), the title compound was obtained in 86% yield. recovered as a foam; partial NMR (250MHz, DMSO-d ₆ ): 0.80 (t, J = 7.30Hz, 3H, CH ₂ CH ₃ ), 1.4-1.9 [m, 10H, (CH ₂ J ₄ and CH ₂ CH ₃ ], 3.83 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.96 (s, 2H, ArCH ₂ ), 4.02 (t, J = 7, 30Hz, 2H, NCH ₂ ); 5.05 (m, 1H, -CHO-); 9.25 (br s, 1H, NH). The compound was prepared starting from methyl 4- [5-amino- 1-propylindol-3-ylmethyl] -3-methoxybenzoate (which in turn was prepared analogously to (D) in Example 4, ie by the reaction of nitroindole derivative (C) with allyl bromide in the presence of sodium hydride followed by catalytic hydrogenation of the product, resulting in the reaction of both the nitro and the ally substituent).

Example 45 Methyl 4- [5- (cyclopentyloxycarbonyl) amino-1- (3-methylbutyl) -indol-3-ylmethyl] -3-methoxybenzoate Using a similar procedure to Example 8 (see also Example 22) the title compound was obtained recovered in a yield of 71% as a white solid; partial NMR (250MHz, DMSO-d ₆ ): 0.90 (d, J = 6.38Hz, 6H, 2 χ CH ₃ ); 1.35-2.0 [m, 11 h (CH ₂ J ₄ and NCH ₂ CH ₂ CH]; 3.82 (s, 3H, OMe); 3.91 (s, 3H, OMe); 3.96 (s, 2H, ArCH ₂ ); 4.08 (t, 2H, NCH ₂ ); 5.10 (m, 1H, -CHO-); 9.20 (br s, 1H, NH). The compound was prepared starting from methyl 4- [5-amino-1- (3-methylbutyl) -indol-3-ylmethyl-3-methoxybenzoate (which in turn was prepared analogously to (D) in Example 4, ie, by the reaction of Nitroindole derivative (C) with 4-bromo-2-methyl-but-2-ene in Ν, Ν-dimethylformamide in the presence of sodium hydride, followed by catalytic hydrogenation of the product resulting in the reduction of both the nitro and the 2-methylbutyl 2-enyl substituent leads).

Example 46 Methyl 4- [5- (cyclopentyloxycarbonyl) amino-1-hexylindol-3-ylmethyl] -3-methoxybenzoate Using a similar procedure to Example 6 except that sodium hydride was the base and a mixture of Ν, Ν-dimethylformamide and Ν, Ν'-dimethylpropyleneurea (80:20 v / v) were used as solvents, the title compound was recovered in 44% yield as an oil; partial NMR (250MHz, DMSO-d _e ): 0.81 (t, J = 6.70Hz, 3H, CH ₂ CH ₃ ); 1.21 (m, 6H); 1.4-2.0 (m, 10H); 3.83 (s, 3H, OMe); 3.92 (s, 3H, OMe); 3.96 (s, 2H, ArCH ₂ ); 4.05 (t, J = 6.85Hz, 2H, NCH ₂ ); 5.04 (m, 1H, -CHO-); 9.20 (br s, 1 H, NH); starting from methyl 4- [5- (cyclopentyloxycarbonyl) aminoindol-3-ylmethyl] -3-methoxybenzoate.

Example 47 Methyl 4- [5- (2-cyclopentylacetamido) -1-methylindol-3-ylmethyl] -3-methoxybenzoate A mixture of methyl 4- (5-amino-1-methylindol-3-ylmethyl) -3- Methoxybenzoate (D) (0.57g), cyclopentylacetic acid (0.23g), 4- (dimethylamino) pyridine (0.22g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.343g) was dissolved in dichloromethane (25ml). dissolved under a nitrogen atmosphere and stirred at room temperature for 18 hours. The mixture was poured into 1M hydrochloric acid (25 ml), the separated aqueous layers extracted with dichloromethane (3 × 25 ml), the combined organic extracts washed with water, brine, dried (MgSO ₄ ) and evaporated. The residual oil was crystallized from ethyl acetate to give the title compound (0.555 g, 73%) as a white powder; Melting point 180 ° C-181 ⁰ C; partielleNMR (250MHz, _DMS0-d6): 1.17 (m, 2H); 1.4-1.8 (m, 6H); 2.25 (m, 3H); 3.70 (s, 3H, NMe); 3.82 (s, 3H, OMe); 3.92 (s, 3H, OMe); 3.97 (s, 2H, ArCH ₂ ); 9.62 (br s, 1H, NH).

Example 48 A Methyl 4- [5- (2-cyclopentylazetamido) -1-propylindol-3-ylmethyl] -3-methoxybenzoate Using a similar procedure to Example 47, the title compound was recovered in 76% yield as a foam ; partial NMR (250 MHz, DMSO-d ₆ ): 0.81 (t, J = 7.30 Hz, 3H, CH ₂ CH ₃ ); 1.15 (m, 2H); 1.4-1.7 (m, 8H); 2.24 (m, 3H); 3.82 (s, 3H, OMe); 3.92 (2.3H, OMe); 3.97 (s, 2H, ArCH ₂ ); 4.04 (t, 2H, NCH ₂ ); 9.61 (br s, 1H, NH). The compound was prepared starting from methyl 4- [5-amino-1-propylindol-3-ylmethyl] -3-methoxybenzoate.

Examples 48 B to 56

Using a similar procedure as in Example 9, the following acids were obtained with the formula I in which W is oxy for Examples 48 B to 54 and a direct bond to R ¹ for Examples 55 and 56:

Formula I

Ex.

R ¹

Rd

Melting point ( ⁰ C)

Yield (%)

Cyclopentyl cyclopentyl cyclopentyl cyclopentyl

Cyclopentyl cyclopentyl cyclopentyl

Cyclopentylmethyl cyclopentylmethyl

propyl 157-158 allyl 171-172 hexyl 152-153 2-meth 158-159 oxy methyl N-ethyl 228-231 karbamoylmethyl 3-methyl 160-161 butyl Cyclo 189-191 pentyl methyl 238-241 ProDvl 196-197

Example 57 N- [4- [5- (Cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl] -benzenesulfonamide A mixture of [5- (cyclopentyloxy-carbonyl) amino-1-methyl-indole-3 -ylmethyl] -3-methoxybenzoic acid (6.0g), benzenesulfonamide (2.34g), 4- (dimethylamino) pyridine (1.84g) and 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (2.86g) were added under a vacuum Nitrogen atmosphere dissolved in dichloromethane (250 ml) and the mixture stirred at room temperature for 18 hours. The mixture was poured into 1 M hydrochloric acid (100 ml), the separated aqueous layer extracted with dichloromethane (2 x 100 ml), the combined organic extracts washed with water and brine, dried (MgSO ₄ ) and evaporated. The residual oil was purified by flash chromatography on silica gel (700 ml) using 45: 50: 5 v / v / v hexane: dichloromethane: ethyl acetate as eluent to give a product which was precipitated by water from hot methanol and the title compound (m.p. 7.82 g, 98%) as a white powder; Melting point 125 ° C-130 ° C (melting point 220 ° C-223 ° C after recrystallization from methanol). Analysis calculated for C ₃₀ H ₃₁ N ₃ O ₆ S: C, -64.15; H -5.56; N -7.48 Determined: C -64.24; H -5.66; N-7.54

Examples 58 to 66

Using a similar procedure to that of Example 57, the following sulfonamides of formula 2 were obtained in which W is oxo in Examples 58-65 and is a direct bond to R ¹ in Example 66:

R'.W.CO.ITH 1 _N

Formula 2

Ex.

R ¹

Rd

Melting point CC)

yield

58 Zyklopentyi propyl 109-115 84 59 cyclopentyl allyl 116-119 76 60 cyclopentyl hexyl 97-100 58 61 cyclopentyl hydrogen 244-245 30 62 cyclopentyl 3-methylbutyl 125-135 83 63 cyclopentyl 2-methoxyethyl 107-117 65 64 * cyclopentyl N-Ethylkarba- 132-140 60 moylmethyl 65 cyclopentyl cyclopentyl 179-181 89 66 cyclopentyl methyl 132-137 86 methyl

»Example 64:

Analysis calculated for:

C ₃₃ H ₃₆ N ₄ O ₇ S: C, -62.64; H -5.73; N -8.85

Determined: C -62.22; H - 5.77; N -8.78

Example 67 Methyl 4- [6- (2-cyclopentylacetamido) -2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoate Using a similar procedure as in Example 47 but starting from benzoxazineamine ( L) (and avoiding the use of excess hydrochloric acid during work-up), the title compound was recovered in 80% yield as a white powder; M.p. 152-153 ⁰ C; partial NMR (250MHz, DMSO-d ₆ ): 1.10-1.68 [m, 8H, (CH ₂ I ₄ ]; 2.14 [m, 3H, -CHCH ₂ ]; 3.41 (t, 2H, NCH ₂ CH ₂ ); 3.84 (s, 3H, OMe); 3.92 (s, 3H, OMe); 4.18 (t, 2H, OCH ₂ ); 4.41 (s, 2H, ArCH ₂ ), 9.40 (br s, 1 H, NH).

Example 68 4- [6- [2-Cyclopentylazetamido) -2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoic acid Using a similar procedure as in Example 29, the title compound was obtained in 97% yield % recovered as a yellow powder; Melting point 224 ° C-225 ^O C.

Example 69 N- [4- [6- (2-Cyclopentylazetamido) -2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide Using a similar procedure as in Example 32, the title compound recovered with a yield of 61% as a white powder; Melting point 190 ° C-192 ° C.

Example 70 Methyl 4- [5- (cyclopentoxyloxycarbonyl) aminobenzo [b] thien-3-ylmethy] -3-methoxybenzoate Starting from the amine (H) and following the same procedure as in Example 8, the title compound was obtained in a yield of 78% recovered as a white powder; M.p. 163 ⁰ C-164 ° C; partial NMR (250MHz, DMSO-d ₆ ): 1.57-1.87 [m, 8H, (CH ₂ J ₄ ]; 3.84 (s, 3H, OMe); 3.92 (s, 3H, OMe 4.11 (s, 2H, ArCH ₂ ), 5.07 (m, 1 H, -CHO-), 9.61 (br s, 1 H, NH).

Example 71 4- [5- (Cyclopentyloxycarbonyl) aminobenzo [b] thien-3-ylmethyl] -3-methoxybenzoic acid Using a similar method to Example 9, the title compound was obtained in a yield of 95% as a white powder; Melting point 259 ° C-261 ⁰ C.

Example 72. -

N- [4- [5- (Zyklopentyloxykarbonyl) aminobenzo [b] thien-3-yl-methyl] -3-methoxybenzoyl] benzenesulfonamide

Using a similar procedure to Example 57, the title compound was recovered in a yield of 51% as a white powder; Melting point 253 ° C-254 ° C.

Example 73 Methyl 4- [6- (2-cyclopentylacetamido) benzimidazol-1-ylmethyl] -3-methoxybenzoate Starting from the amine (J) and using a similar procedure as in Example 47, the title compound was recovered with an yield of 84% as a pink powder; partial NMR (80MHz, DMSO-d ₆ ): 1.57 [br m, 8H, (CH ₂ ) ₄ ]; 2.26 (br s, 3H, -CHCH ₂ ); 3.83 (s, 3H, OMe); 3.94 (s, 3H, OMe); 5.42 (s, 2H, NCH ₂ ); 9.81 (s, 1H, NH).

Example 74 4- [6- (2-Cyclopentylazetamido) benzimidiazol-1-ylmethyl] -3-methoxybenzoic acid Using a similar procedure to Example 9, the title compound was obtained in 62% yield as white crystalline needles; Melting point 280 ° C-281 ⁰ C. (d - decomposition).

Example 75 and 76

Using a similar procedure to Example 57, the following sulfonamides were obtained:

Example 75: N- [4- [6- (cyclopentyloxycarbonyl) aminobenzimidazol-1-ylmethyl] -3-methoxybenzoyl] benzene sulfonamide with a yield of 7% as a white powder; Melting point 24 ° C to 243 ° C; and

Example 76: N- [4- [6- (2-cyclopentylazetamido) benzimidazol-1-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide in 61% yield as a white powder; Melting point 220 ^° C. to 222 ^° C. (monohydrate)

Example 77 Methyl 4- [6- (cyclopentyloxycarbonyl) aminobenzotriazol-1-ylmethyl] -3-methoxybenzoate Using methyl 4- [6-aminobenzotriazol-1-ylmethyl) -3-methoxybenzoate (M) and using Using a similar procedure to Example 3 (see also Example 35), the title compound was recovered in 40% yield as a solid; Melting point 142 ° C-143 ° C.

The starting aminoester (M) was recovered from methyl 3-methoxy-4- (6-nitrobenzotriazol-1-ylmethyl) benzoate (N) by the same method as in Example 1 (b).

The methyl 3-methoxy-4- (6-nitrobenzotriazol-1-ylmethyl) benzoate, in turn, was recovered from 5-nitrobenzotrianzene using a similar procedure to Example 35 (a) with a yield of 26% as a white solid; Melting point 165 ° C-166 ° C

Example 78 4- [6- (Cyclopentyloxycarbonyl) aminobenzotriazol-1-ylmethyl] -3-methoxybenzoic acid Using a similar procedure as in Example 9, the title compound was obtained in a yield of 24% as a pink solid; Melting point: 237 ° C to 239 ^C C (partial hydrate).

Example 79

Methyl 4- [1- (2-carbethoxyethyl) -5- (cyclopentyloxycarbonyl) -aminoindol-3-ylmethyl] -3-methoxybenzoate _c

Using a similar procedure to Example 1 (see also Example 22), the title compound was recovered in 85% yield as a foam. Partial NMR (250MHz, DMSO-d ₆ ): 1.07 (t, 3H, -OCH ₂ CH ₃ ); 1.7 [m, 8 H, (CH ₂ I ₄ ); 2.76 (t, 2H, -CH ₂ CO ₂ Et); 3.82 (s, 3H, OCH ₃ ); 3.91 (s, 3H OCH ₃ ); 3.93 (s, 2H, ArCH ₂ Ar); 3.94 (1,2H, -OCH ₂ CH ₃ ); 4.32 (t, 2H, -CH ₂ N); 5.10 (m, 1H, -OCH-). The compound was prepared starting from methyl 4- [5-amino-1- (2-carboxyethoxyethyl) indol-3-ylmethyl] -3-methoxybenzoate (which in turn was recovered analogously to (D) in Example 4, ie Reaction of the nitroindole derivative (C) with ethyl acrylate in the presence of sodium hydride, followed by catalytic hydrogenation of the product).

Example 80 Methyl 4- [5- (2-cyclopentylacetamido) -1-ethylindol-3-ylmethyl] -3-methoxybenzoate. Using a similar procedure to Example 47, the title compound was recovered in 90% yield as a solid; Melting point 144 ° C-146 ° C; partial NMR (250MHz, DMSO-d ₆ ): 1.18 (m, 2H, cyclopentyl ring); 1.31 (t, 3H, -CH ₂ CH ₃ ); 1.59 (m, 6H, cyclopentyl ring); 2.24 (m, 3H); 3.82 (s, 3H, OCH ₃ ); 3.92 (s, 3H, OCH ₃ ); 3.97 (s, 2H, ArCH ₂ Ar); 4.09 (q, 2H, -CH ₂ CH ₃ ). The compound was prepared starting from methyl 4- (5-amino-1-ethylindol-3-ylmethyl) -3-methoxybenzoate (which in turn was prepared by an analogous procedure to (D) in Example 4 except that iodoethane was used instead of Iodomethane was used).

Examples 81 and 82

Using a similar procedure to Example 9, the following acids were obtained with Formula 1:

Ex. R ¹ ; W Rd Melting point ( ⁰ C) Yield (%) 81 82 Cyclopentyl cyclopentylmethyl 0 2-carboxyethyl ethyl 109-119 219-220 84 83

Direct binding to R ¹

Example 83 {±) Methyl 4 - [5- (2-cyclopentylazetamido) -1-ethyl-2,3-dihydroindol-3-ylmethyl] -3-methoxybenzoate Palladium on carbon (10% w / w, 0.5g) was added to a mixture of methyl 4- [5- (2-cyclopentylacetamido) -1-ethylindol-3-ylmethyl] -3-methoxybenzate (0.5 g, prepared as in Example 80) and formic acid (99%, 20 ml) a nitrogen atmosphere added. The mixture was stirred vigorously and heated at 8O C for one hour ^0th The cooled mixture was filtered through a pad of diatomaceous earth, the filter cake washed with methanol, and the filtrate evaporated. The resulting oil was dissolved in ethyl acetate (30 ml), washed with water and brine, then dried (MgSO ₄ ) and evaporated. The product was purified by flash chromatography on silica gel (4cm column diameter) eluting with 2: 3v / v ethyl acetate: hexane to give the title compound (0.37g, 80%) as a foam; NMR (250 MHz, DMSO-d ₆ ): 1.04 (t, 3 H, -CH ₂ CH ₃ ); 1.15 (m, 2H, cyclopentyl ring); 1.4-1.8 (m, 6H, cyclopentyl ring); 2.2 (m, 3H); 2.7 (dd, 1H); 2.85-3.2 (m, 5H); 3.45 (m, 1H); 3.86 (s, 3H, OCH ₃ ); 3.87 (s, 3H, OCH ₃ ); 6.43 (d, 1H); 7.20 (m, 2H); 7.30 (d, 1H); 7.50 (m, 2H); 9.47 (s, 1H, NH).

Example 84 (±) -4-t5- {2-cyclopentylazetamido) -1-ethyl-2,3-dihydroindol-3-ylmethyl] -3-methoxybenzoic acid Using a similar procedure to Example 29 (see also Example 9), with with the exception that the ester described in Example was used, the title compound was obtained in 84% yield, mp 183-186 ° C, as a partial hydrate.

Example 85 N- [4- [6- (2-Cyclopentylazetamido) -2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxy) ε-ωoyl] -2-methylbenzenesulfonamide Using a similar procedure as described in Example 32 (see also Example 69), with the exception that o-toluenesulfonamide was used, the title compound was obtained in a yield of 45%, mp 207 ⁰ C-208 ° C (monohydrate).

Example 86 Methyl 4- [5- (cyclopentyloxycarbonyl) amino-1-methylindazol-3-ylmethyl] -3-methoxybenzoate Methyl 4- [2- (azetoxyimino) -2- [5- (cyclopentyloxycarbonyl) -amino-2- (methylamino ) Phenyl] ethyl] -3-methoxybenzoate (0) (1.3 g) was placed in a round bottom stirred flask of 100 ml capacity with a stir bar and the bottle held under vacuum with a vacuum pump. The bottle was immersed in a preheated (17O ⁰ C) oil bath until the solid melted, then more

10 min. The cooled product was purified by flash chromatography on silica gel (5 cm column diameter) (compound was added to the column by dissolution in a small amount of dichloromethane), eluted with 2: 3 v / v ethyl acetate: hexane to give the title compound (1.1 g, 96 %) as a foam, NMR (250MHz, DMSOd ₆ ): 1.5-1.9 [m, 8H, (CHs) ₄ ]; 3.83 (s, 3H, CH _3); 3.92 (s, 3H, CH _3); 3.93 (s, 3H, 6 H _3); 4.19 (s, 2H, ArCH ₂ Ar); 5.07 (m, 1H, -OCH-); 7.14 (d, 1H); 7.35 (d, 1H); 7.45-7.49 (m, 3H); 7.78 (brs, 1H); 9.46 (brs, 1H, NH).

The oxime acetate ester (0) was obtained as follows starting from 4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoate (P), which in turn was prepared as in Example 8:

(a) Rose Bengal (0.025g) was added to a solution of methyl 4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoate (P) (2.0g) in dry methanol ( 200 ml) was added. The resulting red solution, along with a magnetic stir bar, was introduced into a quartz photolysis apparatus equipped with bubbler, drying tube, and a water-cooled dip tube containing a tungsten halogen lamp (type DVY, 650W). The stirred solution was bubbled with purified, dry oxygen gas while the solution was irradiated. After one and one half hours (TLC monitoring), the methanol solution was removed from the apparatus, evaporated and filtered through a silica gel column (6 cm column diameter) eluting with 3: 2 to 100: 0 v / v ethyl acetate: hexane to give methyl 4- [2- [5- (cyclopentyloxycarbonyl) amino-2-formyl) (methyl) aminophenyl] -2-oxoethyl] -3-methoxybenzoate (Q) (2.12 g, 98.5%) as a foam; NMR (250MHz, DMSO-d ₆ ): 1-5- [1.9m, 8H, (CH ₂ J ₄ ]; 3.04 (s, 2.25H, N-Me, isomer A); 3.24 ( s, 0.75H, N-Me, isomer B); 3,79,3,82,3,86 (singlets, 6H, 2 χ OMe); 4,12 (s, 0,5H, ArCH ₂ CO, isomer B); 4.17 (s, 1.5H, ArCH ₂ CO, isomer A); 5.11 (m, 1H, -OCH-); 7.27-8.15 (2m, 7H); 9, 85 (br s, 0.25H, NH, isomer B); 9.91 (br s, 0.75H, NH, isomer A).

(b) A solution of the ketoformanilide (Q) (1.0g, prepared as in [a] above) and hydroxylamine hydrochloride (0.84g) in freshly distilled pyridine (100ml) was heated at reflux for 18 hours under a nitrogen atmosphere and stirred. The cooled solution was concentrated, the residue dissolved in ethyl acetate (100ml), washed with water (3x25ml), dried (MgSO ₄ ) and evaporated. The product was purified by flash chromatography on silica gel (4 cm column diameter) using 1: 1 v / v ethyl acetate: hexane as eluent to give methyl 4- [2- [5- (cyclopentyloxycarbonyl) amino-2-methylaminophenyl] -2- (hydroxyimino) ethyl] -3-methoxybenzoate (R) (0.57g, 95%) as an off-white solid; NMR (DMSO-d _e ): 1.4-1.9 [m, 8H, (CH ₂ J ₄ ]; 2.81 (distorted doublet, 3 H, NMe); 3.83 (s, 3H, OMe) 3.92 (s, 3H, OMe), 4.04 (s, 2H, ArCH ₂ CO), 4.98 (m, 1 H, -CHO-), 6.57 (d, 1 H), 6 , 93 (d, 1H), 7.24 (br m, 2H), 7.46 (m, 4H), 8.92 (br s, 1H, NHCO).

(c) Essine hydride (0.27 ml, 0.29 g) was added to a solution of aminooxime (R) (1.3 g, prepared as described above under (b)) and 4- (dimethylamino) pyridine (0.35 g) in Dichloromethane (120ml) was added under a nitrogen atmosphere. After 18 hours the mixture was evaporated, the yellow residue was dissolved in ethyl acetate (50ml), washed with hydrochloric acid (0.05N, 15ml), water (15ml) and brine, dried (MgSO ₄ ) and evaporated. Crystallization from ethyl acetate / hexane at -20 ⁰ C gave methyl 4- [2- (azetoxyimino) -2- [5- (zyklopentyloxykarbonyl) amino-2-methylaminophenyl] ethyl] -3-methoxybenzoate (0) (1.36 g , 96%) as a powder, mp 124X-126 ° C; NMR (250MHz, DMSO-d ₆ ): 1.5-1.9 [m, 8H, (CH ₂ ) ₄ ]; 2,12 (s, 3H, OCOMe); 2.83 (distorted doublet, 3H, NMe); 3.83 (s, 3H, OMe); 3.88 (s, 3H, OMe); 4.17 (s, 2H, ArCH ₂ C = N); 5.00 (m, 1H, -OCH-); 6.24 (d, aH); 7.01 (d, 1H); 7.3-7.5 (m, 5H); 9.1 (br s, 1 H, NHCO).

Example 87 4- [5- (Cyclopentyloxycarbonyl) amino-1-methylindazol-3-ylmethyl] -3-methoxybenzoic acid Using a similar procedure to Example 9 except that 4- [5- (cyclopentyloxycarbonyl) amino- 1-methylindazol-3-ylmethyl] -3-methoxybenzoate, the title compound was obtained in 95% yield as a white solid, mp 216 ° C-217 ° C.

Example 88 IM- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindazol-3-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide Using a similar procedure to that of Example 57, except that of Example 87, the title compound was obtained in 63% yield as a white powder, mp 145 ^° C (hemihydrate).

Analysis calculated for:

C ₂₉ H ₃₀ N ₄ O ₆ S · O · 5H ₂ O: C-60.93; H - 5.46; N - 9,80

Determined: C-60.83; H -5.30; N -9.79 λ

Example 89 Sodium N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide Sodium hydroxide solution (1N, 10.69ml) was added to a stirred solution of N- Added [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide (6.0 g) in 1: 1 v / v tetrahydrofuran: methanol (100 ml) under a nitrogen atmosphere. After 0.5 h the organic solvents were removed in vacuo and the resulting organic solution lyophilized to give the title compound (6.1 g, 95%) as a white powder, melting point 168 ⁰ C-175 ° C (monohydrate).

Analysis calculated for:

C ₃₀ H ₃₀ N ₃ O ₆ SNa · H ₂ O: C-59.89; H -5.36; N -6.98

Determined: C - 59.74; H - 5.24; N - 6,90

Example 90 Methyl 4- [6- (cyclopentyloxycarbonyl) amino-3-methoxyindazol-1-ylmethyl] -3-methoxybenzoate Cyclo-pentyl chloroformate (0.17 ml) was added to a cooled solution (-2O ⁰ C) of methyl 4- [6 -amino-3-methoxyindazol-1-ylmethyl] -3-methoxybenzoate (S) (0.381 g) and pyridine (0.11 ml) in dichloromethane (3.0 ml). After warming to ambient temperature, the mixture was diluted with ethyl acetate and washed with hydrochloric acid (1N), water and brine, dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography on silica gel (56g) eluting with 5: 95v / v ethyl acetate: dichloromethane to give the title compound (0.365g, 75%) as an oil with satisfactory NMR spectral data.

The aminoester (S) was obtained as follows:

(a) 6-NitroindazoloI (0.206g) was added to a solution of sodium (0.026g) in methanol (1.5ml) and the mixture was heated at 50 ° C for 10min. A solution of methyl 4-bromomethyl-3-methoxybenzoate (B) (0.327g) in methanol (3.75ml) was added and Ν, Ν -dimethylformamide (DMF) (1.25ml) added followed by the mixture was refluxed for 18 hours. The cooled mixture was diluted with ethyl acetate and DMF and washed with water and brine, then dried (MgSO ₄ ) and evaporated. The residue was triturated with 1: 1 v / v ethyl acetate: ether to give methyl 4- [3-hydroxy-6-nitroindazol-1-ylmethyl] -3-methoxybenzoate (T) (0.158g, 38%) as a yellow Solid, mp 231 "C-235 ° C.

(b) Indazole (T) (1.68g) was added to a solution of sodium (0.108g) in methanol (1.0ml). After stirring for 5 minutes, iodomethane (0.32 ml) was added and stirring was continued for a further 18 hours. The mixture was diluted with ethyl acetate, washed with water and brine, then dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography on silica gel (130g) eluting with 2:98 v / v ethyl acetate: dichloromethane to give methyl 4- [3-methoxy-6-nitroindazol-1-ylmethyl] -3-methoxybenzoate (U) (0.481 g, 28%) as a yellow solid with satisfactory NMR spectral data.

(c) Palladium on carbon (5% w / w, 0.24 g) was added to a solution of indazole (U) (0.48 g) in ethyl acetate (25 mL). The mixture was hydrogenated at 1.1 bar for 3 hours. The catalyst was removed by filtering through diatomaceous earth and the filtrate was evaporated. The residue was recrystallized from a hot ethyl acetate-petroleum ether mixture to give methyl 4- (6-amino-3-methoxyindazol-1-ylmethyl) -3-methoxybenzoate (S) (0.15 g, 34%) as a pale yellow solid , 188 ° C-193 ° C.

Example 91 4- [6- (Cyclopentyloxycarbonyl) amino-3-methoxyindazol-1-ylmethyl] -3-methoxybenzoic acid Using a similar procedure as in Example 9 except that of methyl 4- [6- (cyclopentoxyloxycarbonyl) amino -3-methoxyindazole-1-ylmethyl] -3-methoxybenzoate assumed, the title compound was obtained in a yield of 54% as a solid, melting point 199 ° C to 200.5 ⁰ C.

Example 92 N- [4- [6- (Cyclopenoxyloxycarbonyl) amino-3-methoxyindazol-1-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide Using a similar procedure to Example 57 except that described in Example 91 Acid, the title compound was obtained in 53% yield as a solid, mp 246 ° C-247.5 ° C.

Example 93 5- (2-Cyclopentylacetamido) -1-methyl-3- [4- (1-H-tetrazol-5-yl) -2-methoxybenzyl] indole Sodium hydroxide solution (1M, 1.9ml) and second palladium on carbon (10% w / w, 0.05g) were added to a solution of nitrotetrazole (V) (0.69g) in methanol (50ml) and the mixture hydrogenated at an initial pressure of 3.3 bar. After two hours, the catalyst was filtered off, washed with methanol and the combined filtrate evaporated. The residue was dissolved in water (30 ml), excess of saturated aqueous dihydrogen sodium phosphate added, and the precipitate collected and dissolved in tetrahydrofuran (20 ml). Charcoal was added, the solution heated and filtered through diatomaceous earth, and the filter cake washed with tetrahydrofuran. The combined filtrate (containing crude 5-amino-1-methyl-3- [2-methoxy-4- (1-H-tetrazol-5-yl) benzyl] indole) was added to a solution of 4- (dimethylamino) pyridine (0.244g), iO-dimethylaminopropyl-S-ethylcarbodiimide hydrochloride (0.384g) and cyclopentylacetic acid (0.256g) in dichloromethane (30ml). The mixture was stirred at ambient temperature for two days, the solvents evaporated, the residue partitioned between chloroform and water, the chloroform layer washed with water, dried (MgSO ₄ ) and evaporated. The product was purified by flash chromatography on silica gel (using a 3 cm diameter column), eluting with 70: 30: 4v / v / v toluene: ethyl acetate: acetic acid to give a product which was recrystallised from a mixture of methanol and water to give the product Title compound (hydrate) (0.064g, 7.6%) as an off-white solid. Melting point 242 ° C-243 ⁰ C. The Ausgangsnitrotetrazol (V) was in turn prepared as follows:

(a) A solution of chlorosulfonyl isocyanate (5.35 ml) in dichloromethane (3 ml) was added over 45 min to a stirred suspension of 3-methoxy-4-methylbenzoic acid (9.97 g) in dichloromethane (18 ml) under reflux under a nitrogen atmosphere. The resulting bright red, homogeneous solution was heated at reflux for 45 min, quenched in an ice-bath and treated dropwise over 15 min with Ν, Ν-dimethylformamide (9.5 ml). After stirring for 30 min at ⁰ ° C, the orange solution was poured onto ice. The organic layer was separated, washed with water (5x20ml), dried (MgSO ₄ ) and evaporated. The residue was purified by preparative HPLC (SiO ₂ , 10:90 v / v Hexafr.Toluen) to give 3-methoxy-4-methylbenzonitrile (5.28 g, 60%) as a white solid, mp 51 ° C-52 , 5 ° C. '

(b) N-Bormosuccinimide (3.2g) and benzoyl peroxide (0.005g) were added to a solution of 3-methoxy-4-methylbenzonitrile (2.65g) in dry carbon tetrachloride (90ml). The mixture was heated under reflux for 15 minutes with a 250W tungsten lamp. The cooled reaction mixture was diluted with petroleum ether (b.p. 60-80 ⁰ C, 90 mL), insoluble material removed by filtration and the filtrate evaporated. The solid residue was recrystallized from a mixture of dichloromethane and petroleum ether to give 4-bromomethyl-3-methoxybenzonitrile (W) (2.64 g, 65%) as a white solid, mp 87 ° C-91 ° C.

(c) An efficiently stirred mixture of 5-nitroindole (3,24g), bromide (W) (4,57g) and silver (I) oxide (4,87g) in dry dioxane (90ml) was 5 hours at 100 ⁰ C heated. Additional silver oxide (2g) was added and heating continued for an additional hour. The cooled mixture was evaporated, the residue diluted with dichloromethane, filtered, the filter cake washed with dichloromethane until the washings were colorless, and the combined filtrate evaporated. The product was purified by flash chromatography on silica gel, eluting with 3: 7 v / v ethyl acetate: hexane to give a product that was recrystallized from a mixture of ethyl acetate and hexane and 3- (4-cyano-2-methoxybenzyl) -5- nitroindole (1.87 g, 30%) as a yellow powder. Melting point 204 ° C-206 ° C; partial NMR (80 MHz, DMSO-d ₆ ): 3.92 (s, 3H, OMe); 4.12 (s, 2H, ArCH ₂ ).

(d) Sodium hydride (60% w / w dispersion in mineral oil, 0.12 g) was added to a stirred solution of 3- (4-cyano-2-methoxybenzyl-5-nitroindole (0.85 g) in dry Ν, Ν- After about one hour, iodomethane (0.645 g) was added dropwise and stirring continued at ambient temperature for 5 hours, poured onto saturated aqueous ammonium chloride solution, extracted with ethyl acetate (2 × 20 ml), The extract was washed with water and brine, dried (MgSO ₄ ) and evaporated The residue was crystallized from acetonitrile to give 3- (4-cyano-2-methoxybenzyl) -1-methyl-5-nitroindole (0.72 g, 81%). ) as a yellow solid, melting point 200 ⁰ C-201 ° C; partial NMR (250MHz, DMSO-d _6): 3.82 (s, 3H, NMe); 3.92 (s, 3H, OMe); 4, 12 (s, 2H, ArCH ₂ ).

(e) Mixture of 3- (4-cyano-2-methoxybenzyl) -1-methyl-5-nitroindole (0.458 g), sodium azide (0.741 g) and triethylamine hydrochloride (0.785 g) in dry N-methyl-2-pyrrolidinone ( 6 ml) under nitrogen was stirred for 1.5 hours and heated to 150 ° C. The mixture was cooled to ambient temperature and cautious hydrochloric acid (25 ml) was added with stirring, the precipitated solid was isolated by filtration, washed with water and dried in vacuo to give 3- [2-methoxy-4- (1-H-tetrazole). 5-yl) benzyl] -1-methyl-5-nitroindole (V) (0.484g, 94%) as a yellow powder, mp 249 ° C-250 ° C; partial NMR (250MHz, DMSO-d ₆ ): 3.82 (s, 3H, NMe); 3.97 (s, 3H, OMe); 4.13 (s, 2H, ArCH ₂ ).

Example 94 Methyl 4- [5- (N'-cyclopentylureido) -1-methylindol-3-ylmethyl] methoxybenzoate A solution of trichloromethyl chloroformate (0.66 g) in dry dioxane (1 OmI) was stirred for 10 min Methyl 4- (5-amino-1-methylindol-3-ylmethyl) -3-methoxybenzoate (D) (1.09g) in dry dioxane (15ml) at ambient temperature. The reaction vessel was purged continuously with nitrogen gas, and the effluent was bubbled through aqueous potassium hydroxide solution to destroy excess phosgene. The in situ formation of the isocyanate of (D) was followed by TLC. Zyklopentylamin (0,574g) was added after 30 min, the mixture was stirred for a period of 20 min at 70 ⁰ C is heated, then cooled and diluted with water (100 mL). The precipitate which formed was dissolved by filtering with 95: 5v / v dichloromethane / methanol (100ml) and the solution washed with water and brine, dried (MgSO ₄ ) and evaporated to give a solid which was recrystallized from acetonitrile to give the solution Title compound (0.75 g, 56%) as a white solid, mp 210 ° C-212 ° C; partial NMR (250MHz, DMSO-d ₆ ): 1.25-1.80 (3m, 8H, cyclopentyl ring); 3.68 (s, 3H, NMe); 3.83 (s, 3H, OMe); 3.90-4.0 (2s + m, 6H, 0Me, ArCH ₂ , -CHNH-); 5.93 (d, 1H, -CH.NH-).

Example 95 4- [5- (N'-Cyclopentylureido) -1-methylindol-3-ylmethyl] -3-methoxybenzoic acid Using a similar procedure to Example 9 but starting from the ester described in Example 94, the title compound was used a yield of 74% recovered as a white powder. Melting point 203 ° C-206 ° C.

Example 96 N- [4- [5- (N'-cyclopentylureido) -1-methylindol-3-ylmethyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide Using a similar procedure to Example 57 but using ortho Toluene sulfonamide and the acid described in Example 95, the title compound was obtained in 58% yield as a white solid, mp 212 ° C-215 ° C (monohydrate).

Example 97 Methyl 4- [5- (2-cyclopentylazetamino) -1- (N, N-dimethylcarbamoylmethyl) indol-3-ylmethyl] -3-methoxybenzoate Using the same procedures as in Examples 47, 48 (see also Example 42), the title compound was recovered in 89% yield as a white powder. Melting point 129 ° C-132 ° C; partial NMR (250MHz, DMSO-d ₆ ): 1.15-1.30 (m, 2H, cyclopentyl ring); 1.45-1.80 (2m, 6H, Zyklopentylring); 2.25 (rh, 3H, CH ₂ CONH and -CHCH ₂ ); 2.83 (s, 3H, NME); 3.06 (s, 3H, NMe); 3.83 (s, 3H, OMe); 3.92 (s, 3H, OMe); 3.98 (s, 2H, ArCH ₂ ) 5.03 (s, 2H, NCH ₂ ); 9.61 (s, 1H, NH). The compound was prepared starting from methyl 4- [5-amino-1- (N, N-dimethylcarbamoylmethyl) indol-3-ylmethyl] -3-methoxybenzoate (which in turn was prepared analogously to (D) in Example 4, ie by the reaction of the nitroindole derivative (C) with 2-chloro-N, N-dimethylazeamide in Ν, Ν-dimethylformamide in the presence of sodium hydride, followed by catalytic hydrogenation of the product).

Example 98 Methyl 4- [1- (tert-butoxycarbonylmethyl) -5- (2-cyclopentylazetamido) indol-3-ylmethyl] -3-methoxybenzoate Using a similar procedure as in Example 4 but starting from cyclopentylacetyl chloride, the title compound became recovered as a foam with a yield of 47%; partial NMR (DMSO-d ₆ ): 1.1-1.3 (m, 2H, cyclopentyl ring); 1,40s, 9H, C (Me) ₃ ; 1.45-1.8 (2m, 6H, cyclopentyl ring); 2.25 (m, 3H, CH ₂ CONH and -CHCH ₂ ); 3.83 (s, 3H, OMe); 3.92 (s, 3H, OMe); 3.98 (s, 2H, ArCH ₂ ); 4.90 (s, 2H, NCH ₂ ); 9.63 (s, 1H, NH). The compound was prepared starting from methyl 4- [5-amino-1- (tert-butoxycarbonylmethyl) indol-3-ylmethyl] -3-methoxybenzoate (which in turn was prepared analogously to [D] in Example 4, ie Reaction of the nitroindole derivative (C) with tert-butyl bromoacetate in Ν, Ν-dimethylformamide in the presence of sodium hydride followed by catalytic hydrogenation of the product).

Example 99 Methyl 4- [1- (3-cyanophenylmethyl) -5- (2-cyclopentylazetamido) -indol-3-ylmethyl] -3-methoxybenzoate Using a similar procedure as in Example 4 but using cyclopentylacetyl chloride the title compound was recovered as a yellow foam in a yield of 30%; partial NMR (DMSO-d ₆ ): 1.05-1.3 (m, 2H, cyclopentyl ring); 1.4-1.8 (2m, 6H, cyclopentyl ring); 2.24 (m, 3H, CH ₂ CO and -CHCH ₂ ); 3.83 (s, 3H, OMe); 3.91 (s, 3H, OMe); 4.0 (s, 2H, ArCH ₂ ); 5.40 (s, 2H, NCH ₂ ); 9.63 (s, 1H, NH). The compound was prepared starting from methyl 4- [5-amino-1- (3-cyanophenylmethyl) indol-3-ylmethyl] -3-methylbenzoate (which in turn was prepared analogously to [D] in Example 4, ie Reaction of the nitroindole derivative (C) with 3-cyanobenzyl bromide in Ν, Ν-dimethylformamide in the presence of sodium hydride, followed by catalytic hydrogenation (but using 5% w / w palladium on carbon as catalyst in a 4: 1 solvent v / v tetrahydrofuran: methanol under atmospheric pressure) of the product).

Example 100 Methyl 4- [5- (2-cyclopentylazetamido) -1-propargylindol-3-ylmethyl] -3-methoxybenzoate Using the same procedures as in Examples 4 and 23, the title compound was recovered with a yield of 60% as a white solid. Melting point 160 ⁰ C to 161 ° C; partial NMR (250MHz, DMSO-d _e ): 1.1-1.3 (m, 2H, cyclopentyl ring); 1.45-1.8 (2m, 6H, cyclopentyl ring); 2.26 (m, 3H, CH ₂ CO and -CHCH ₂ ); 3.37 (t, 1H, ^ CH); 3.83 (s, 3H, OMe); 3.92 (s, 3H, OMe); 3.98 (s, 2H, ArCH ₂ ); 4.99 (d, 2H, NCH ₂ ); 9.66 (s, 1H, NH). The title compound was prepared starting from methyl 4- (5-amino-1-propargylindol-3-ylmethyl) -3-methoxybenzoate (which in turn was prepared analogously to [F] in Example 23, ie by the reaction of the nitroindole derivative [C]. with propyl bromide in Ν, Ν-dimethylformamide in the presence of sodium hydride followed by tin tetrachloride reduction of the product.)

Examples 101 to 104

Using a procedure similar to that of Example 9 but using the esters described in Examples 97-100, the following acids of formula 1 were prepared in which W is a direct bond to R ¹ , the hydrolysis of the corresponding Methyl ester carried out:

Ex. R ¹ Rd Mp. yield ( ⁰ o (%) 101 cyclopentylmethyl N, N-dimethyl 223-226 * 54 karbamoylmethyl 102 cyclopentylmethyl Carboxymethyl ? £ 256-258 74 103 cyclopentylmethyl 3-Zyanophenylmethyl 130-132 * 89 104 cyclopentylmethyl propargyl 226-227 * 87

* Isolated as a partial hydrate.

Φ Hydrolysis of methyl and tert-butyl esters.

Example 105 N- [4- [5- (Cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide Using a similar method to Example 57 but using ortho-toluenesulfonamide and the obtained in Example 9, the title compound was obtained in 69% yield as a white solid, mp 138 ° C-140 ° C

Analysis calculated for: C ₃₁ H ₃₃ N ₃ O ₆ S: C, -64.68; H - 5.78; N-7.30. Found: C-64.49; H - 5.78; N-7,21

Example 106 4- (6-Hexanamido-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl) -3-hydroxybenzoic acid Lithium thioethoxide was prepared by the dropwise addition of n-butyllithium (4 ml of a 1.53 mol solution in Hexane) to a stirred solution of ethyl mercaptan (0.5 ml) in dry N, N'-dimethylpropyleneurea (DMPU) (9 ml) under a nitrogen atmosphere. A solution of methyl 4- (6-hexanamido-2,3-dihydrobenz-1,4-pxazin-4-ylmethyl) -3-methoxybenzoate (prepared as in Example 26) (0.35 g) in DMPU (3 ml ), the mixture was stirred at ambient temperature for 15 minutes, then heated to 130 ° C and held at this temperature for 4 hours. The cooled mixture was diluted with water, acidified with acetic acid, extracted with ethyl acetate, the extracts washed with water, dried (MgSO ₄ ) and evaporated. The product was purified by flash chromatography on silica gel, eluting with 80: 20: 2 v / v / v toluene: ethyl acetate: acetic acid to give a white solid which was washed with hexane and dried to give the title compound (0.114g, 36%) gave a white solid. Melting point 183 ° C to 184 ° C.

Example 107 Methyl 3- (6-hexanamido-2,3-dihydrozone-1,4-oxazin-4-ylmethyl) benzoate

Hexanoyl chloride (0.135g) was added dropwise to a stirred solution of methyl 3- (6-amino-2,3-dihydrobenz-1,4-oxazins-4-ylmethylbenzoate (X) (0.3g) and N-methylmorpholine (0.101g) After 0.5 hours, the mixture was diluted with dichloromethane, washed with water, dried (MgSO ₄ ) and evaporated to give an oil which was passed through a short silica gel column using 35: 63v / v ethyl acetate / hexane Partial NMR (80MHz, CDCl ₃ ): 0.8-1.9 [complex m, 9H, CH ₃ (CH ₂ J ₃ ], 2.2 (m, 2) was added to give the title compound as a syrup H, CH ₂ CONH), 3.3 (m, 2 H, N-CH ₂ - CH ₂ O); 3.9 (s, 3H, OMe); 4.3 (m, 2H, N-CH ₂ - CH ₂ ); 4.5 (s, 2H, N · CH ₂ Ar) The aminoester (X) was obtained as follows: ^Λ

(a) A mixture of 6-nitro-2,3-dihydrobenz-1,4-oxazine (0.45g, methyl 3-bromomethylbenzoate * (Y) (0.58g), potassium carbonate (0.35g) and sodium iodide ( 0.38g) in dry 2-butanone (25ml) was stirred and heated at reflux for 48 hours, the cooled reaction mixture was filtered, the filter cake was washed with 2-butanone, and the combined filtrate evaporated The product was purified by flash chromatography on silica gel, with 5: 95v / v ethyl acetate: toluene eluted to give methyl 3- (6-nitro-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl) benzoate (0.7 g, 85%) as a yellow oil; partial NMR (80MHz, CDCl ₃ ): 3.5 (m, 2H, N x CH ₂ x CH ₂ O), 3.9 (s, 3H, OMe), 4.3 (m, 2H, N x CH ₂ CH ₂ O); 4.6 (s, 2H, NCH ₂ Ar).

(b) A mixture of methyl 3- (6-nitro-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl) benzoate (0.65g) and palladium on carbon (10% w / w, 0.025 g) in ethyl acetate (40 ml) was hydrogenated at an initial pressure of 2.9 bar. The catalyst was removed by filtering through diatomaceous earth, the filter cake washed with ethyl acetate, and the filtrate evaporated to give methyl 3- (6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl) benzoate (X). (0.3 g, 51%) as a gum; partial NMR (80 MHz, CDCl ₃ ): 3.3 (m, 2H, N x CH ₂ CH ₂ .O); 3.9 (s, 3H, OMe); 4.15 (m, 2H, N-CH ₂ -CH ₂ .O); 4.5 (s, 2H, NCH ₂ Ar).

Example 108 3- (6-Hexanamido-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl) benzoic acid

Lithium hydroxide monohydrate (0.2g) in water (5ml) was added to a stirred solution of methyl 3- (6-hexanamido-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl) benzoate (ca 400mg) in 1 Add 1 v / v methanol-tetrahydrofuran (10 mL). When the TLC (solvent system 80: 20: 2 v / v / v toluene: ethyl acetate: acetic acid) indicated complete disappearance of the ester, the mixture was diluted with water, filtered to remove any solids present, and acidified carefully with 1N hydrochloric acid. The precipitate was isolated by filtration and crystallized from a mixture of methanol and water to give the title compound (0,176g, 46% overall yield from amino ester *) as a white solid, melting point 167 ⁰ C to 171 ⁰ C (hemihydrate).

Example 109 N- [4-T5- (2-Zyklopentylazetamido) -1- (N, IM-dimethylkarbamoylmethyl) indol-3-ylmethyl] -3-methoxybenzoyl] -2-

methylbenzenesulfonamide

Using a similar procedure as in Example 57 but using ortho-toluenesulfonamide and the acid described in Example 101, the title compound was recovered in 79% yield as a white solid.

Melting point 215 ° C-217.5 "C (hemihydrate).

Analysis calculated for:

C ₃₆ H ₄₀ N ₄ O ₆ S 0.5H ₂ O: C, -64.30; H -6.32; N -8.57

Determined: C -64.38; 6.28; N-8.55

Example 110 4- [1-Acetyl-5- (2-cyclopentylazetamido) indol-3-ylmethyl] -3-methoxybenzoic acid A solution of 4- (1-acetyl-5-aminoindol-3-ylmethyl) -3-methoxybenzoic acid (Z ) (0.31 g), cyclopentylacetic acid (0.117 g), 4- (dimethylamino) pyridine (0.233 g) and 1- (3-dimethylarninopropyl) -3-ethylcarbodiimide hydrochloride (0.35 g) in dichloromethane (20 ml) under a nitrogen atmosphere was stirred at ambient temperature for two hours. The mixture was acidified with hydrochloric acid (1N, 30ml), extracted with ethyl acetate (3x50ml) and the combined extracts dried (MgSO ₄ ) and evaporated. The residual oil was purified by flash chromatography on silica gel (100 ml), eluted with 50: 45: 5v / v / v hexane: dichloromethane: ethyl acetate, to give a product which recrystallized from a mixture of tetrahydrofuran and ether and then from a mixture of Ethanol and water to give the title compound (0.055g, 14%) as a white solid, mp 245 ° C-247 ° C. The starting amino acid (Z), in turn, was prepared from the nitroester (C) as follows:

(a) A solution of lithium hydroxide monohydrate (1.2 g) in water (20 ml) was added to a suspension of nitro ester (C) (2.0 g) in methanol (30 ml). The mixture was stirred at ambient temperature for 18 hours and then acidified with hydrochloric acid (1N, 50 ml). The yellow precipitate was isolated by filtration, washed with water and dried to give 4- (5-nitroindol-3-ylmethyl) -3-methoxybenzoic acid; partial NMR (250MHz, DMSO-d ₆ ): 3.92 (s, 3H, OMe) 4.12 (s, 2H, ArCH ₂ ); 11.64 (br s, 1H, NH). , ,

(b) A solution of 4- (5-nitroindol-3-ylmethyl) -3-methoxybenzoic acid (0.6g) in Ν, Ν-dimethylformamide (DMF) (3ml) was added to an oil-free, stirred sodium hydride suspension (0.088g) in DMF (8 ml) under a nitrogen atmosphere at ambient temperature. The red solution was stirred for 20 minutes and acetic anhydride (0.187 g) was added. After 1 h, the mixture was poured into hydrochloric acid (1 N, 30 mL), extracted with ethyl acetate (3 x 50 mL), the combined extracts washed with water (2 x 20 mL) and brine, dried (MgSO ₄ ) and evaporated. The product was crystallized from a mixture of tetrahydrofuran and ether to give 4- (1-acetyl-5-nitroindol-3-ylmethyl) -3-methoxybenzoic acid (0.455 g, 67%) as a yellow powder; partial NMR (250MHz, DMSO-d ₆ ): 2.68 (s, 3H, NCOCH ₃ ); 3.95 (s, 3H, OMe); 4.13 (s, 2H, ArCH ₃ ).

(c) Palladium on carbon (10% w / w, 0.1 g) was added to a solution of 4- (1-acetyl-5-nitroindol-3-ylmethyl) -3-methoxybenzoic acid (0.35 g) in a mixture of 1: 1 v / v MethanohTetrahydrofuran (50ml) was added, which had been deoxygenated in that had been passed through a stream of nitrogen gas, and the mixture hydrogenated at an initial pressure of 50 psi (35.155 x 10 ~ ² kgf / cm ^2). After 24 hours, the catalyst was removed by filtering through diatomaceous earth and the filtrate was evaporated to give 4- (1-acetyl-5-aminoindol-3-ylmethyl) -3-methoxybenzoic acid (Z) (0.31 g, 91%) ; partial NMR (250MHz, CD ₃ OH): 2.53 (s, 3H, NCOCH ₃ ); 3.94 (s, 3H, OMe); 4.00 (s, 2H, ArCH ₂ ).

* Methyl 3-bromomethylbenzoate (Y) was prepared from methyl 3-methylbenzoate by bromination using N-bromosuccinimide in a manner analogous to that of 4-bromomethyl-3-methoxybenzonitrile (W) in part (b) of Example 93 ,

Example 111 Calcium N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide Calcium oxide (0.0487 g) and distilled water (10 ml) were successively added to a solution of N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol] -3-ylmethyl-3-methoxybenzoyl] -2-methylbenzenesulfonamide (1.0g) in tetrahydrofuran (THF) (8mL). The cloudy solution was heated C for 20 to 25 minutes at 5O ⁰ and the cooled, clear, consisting of two phase mixture evaporated (at about 50 ⁰ C). The residue was redissolved in THF (20 mL), the solution filtered through a pad of diatomaceous earth, the filtercake washed with a little THF, the filtrate added dropwise to a stirred ether (175 mL) and the resulting solution again dropwise stirred in ether (300 mL ) was added. The precipitate was collected by filtering. The filtrate was evaporated, redissolved in THF (3.5 mL) and added dropwise to stirred ether (150 mL). The precipitate was collected, combined with the first precipitate and dried to give the title compound (0,865g, 84%) as a white solid, and a partial hydrate, mp 220 ⁰ C (approximate)

 Analysis calculated for:

C ₆₂ H ₈₄ N ₆ Oi ₂ S ₂ Ca. 0.75H ₂ O: C-61.91; H -5.49; N -6.99 Determines: C - 61.83; H - 5.49; N - 6,87

Example 112 Methyl 4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoate A solution of 5- (cyclopentyloxy-carbonyl) amino-1-methylindole (AA) (1.3g) and methyl 4-bromoemethyl-3-methoxybenzoate (B) (1.3 g) in Ν, Ν-dimethylformamide (25 ml) was stirred at 100 ⁰ C and heated under a nitrogen atmosphere, wherein the reaction vessel with an aluminum foil was protected from light, duration 24 hours. The cooled mixture was poured onto saturated aqueous sodium bicarbonate solution (300mL), extracted with ethyl acetate (3x100mL), the combined extracts washed with brine (50mL), dried (MgSO ₄ ) and evaporated. The product was isolated by flash chromatography on silica gel (3.5 cm column diameter) to give the title compound (P) (0.98 g, 45%) identical to that obtained in Example 8.

The starting cyclopentyl urethane (AA) was prepared from 5-nitroindole by methylation (using sodium hydride in Ν, Ν-dimethylformamide) followed by the catalytic reduction of the nitro compound to the corresponding amino compound and the acylation of the amino compound using cyclopentyl chloroformate (using similar methods) Methods as in Example 1, part (b), and in Example 3).

Example 113 Methyl 4- [6- (2-cyclopentylazetamido) benzotriazol-1-ylmethyl] -3-methoxybenzoate Using a similar procedure as in Example 47 but starting from the aminoester (M), the title compound was obtained in 58% yield % recovered as a white powder, mp 206 ° C-208 ° C.

Example 114. - -

4- [6- (2-Cyclopentylazematido) benzotriazol-1-ylmethyl] -3-methoxybenzoic acid Using a similar procedure as in Example 29 but starting from the ester described in Example 113, the title compound became a white powder in a yield recovered from 98%, mp 235 ° C-238 ° C, in the form of a partial hydrochloride salt.

Example 115 N- [4- [6- (2-Cyclopentylazetamido) benzotriazol-1-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide Using a similar procedure as in Example 32 but starting from the acid described in Example 114 and recrystallizing from Methanol and water, the title compound was recovered in 95% yield as a white powder, mp 211 ° C-213 ° C, as a partial hydrate.

Example 116 Methyl 4- [6- (2-cyclopentylacetamido) -3-hydroxyindazol-1-ylmethyl] -3-methoxybenzoate A mixture of methyl 4- [3-benzyloxy-6- (2-cyclopentylacetamido) indazole-1 ylmethyl] 3-methoxybenzoate (BB) (5.0 g) and palladium-on-carbon (5% ² Ii, 1.25 g) in ethyl acetate (190ml) was hydrogenated for 7.5 hours at 1.1 bar. The catalyst was removed by filtering through diatomaceous earth, washing the filter cake with ethanol, the filtrate was teilweie evaporated and the residue allowed to crystallize to give the title compound (2,56g, 62%) as a solid, melting point 242 ⁰ C-245 ⁰ C.

The ester (BB) was obtained as follows:

(A). Methyl 4- (3-hydroxy-6-nitroindazol-1-ylmethyl) -3-methoxybenzoate (T) (35.7g) was added to a mixture of sodium (2.3g) and methanol (200ml). The mixture was stirred for 18 hours and evaporated. The residue was dissolved in Ν, Ν-dimethylformamide (100 ml), cooled to 0 ⁰ C, and there was added benzyl bromide (15,5ml) was added. After 18 hours at ambient temperature, ethyl acetate and 1N sodium hydroxide solution were added. The precipitate was isolated by filtration, washed with ether and chromatographed on silica gel by HPLC, eluting with dichloromethane, to give methyl 4- (3-benzyloxy-6-nitroindazol-1-ylmethyl) -3-methoxybenzoate (CC) ( 27g, 60%) as a solid; NMR (250MHz, DMSO-d ₆ ): 3.84 (s, 3H, OMe); 3.86 (s, 3H, OMe); 5.38 (s, 2H, NCH ₂ ); 5.65 (s, 2H, OCH ₂ ); 6.95 (d, 1H); 7.36 (m, 3H); 7.46 (m, 5H); 7.86 (m, 2H); 8.66 (s, 1H).

(b) Zinc dust (0.065g) was added to a stirred mixture of methyl 4- (3-benzyloxy-6-nitroindazol-1-ylmethyl) -3-methoxybenzoate (CC) (0.043g) and acetic acid (0.9ml).

The mixture was stirred for 2 hours, diluted with ether and filtered. The filtrate was washed with water and brine, dried (MgSO ₄ ) and evaporated to give 4- (6-amino-3-benzyloxyindazol-1-ylmethyl) -3-methoxybenzoate (DD) (0.034g, 85%) as a brown Oil and was used without further purification in the manner described below.

(c) Using a similar procedure to Example 47 but starting from the aminoester (DD), methyl 4- [3-benzyloxy-6- (2-cyclopentylacetamido) indazol-1-ylmethyl] -3-methoxybenzoate (BB ) with a yield of 32% as a solid, mp 139 ° C-140 ° C.

Example 117 4- [6- (2-Cyclopentylazetamido) -3-hydroxyindazol-1-ylmethyl] -3-methoxybenzoic acid Using a similar procedure to Example 9 but starting from methyl 4- [6- (2-cyclopentylacetamido) 3-hydroxyindazol-1-ylmethyl] -3-methoxybenzoate, a crude product was obtained which was purified by flash chromatography on silica gel (40g) and eluted with 3: 7 v / v methanol: dichloromethane. The chromatographed product was added to the suspension in a mixture of ethyl acetate and tetrahydrofuran and washed with 1N hydrochloric acid, water and brine, dried (MgSO 4), evaporated and recrystallized from a mixture of methanol, dichloromethane and petroleum ether to give the title compound in a yield of 16% as a solid, m.p. 269 ° C-272 ° C, as a partial hydrate.

Example 118 Methyl 4- [6- (2-cyclopentylacetamido) -3- (N-ethylcarbamoylmethoxy) indazol-1-ylmethyl] -3-methoxybenzoate Using a similar procedure as in Example 42 but starting from methyl 4- [ 6- (2-cyclopentylacetamido) -3-hydroxyindazol-1-ylmethyl] -3-methoxybenzoate (that is, reaction of this compound with 2-chloro-N-ethylacetamide in N, N-dimethylformamide in the presence of sodium hydride) and flash chromatography of the crude product on silica gel (75 g) and eluting with 1: 1 v / v ethyl acetate: dichloromethane, the title compound was obtained in 34% yield as a solid. Melting point 178 ° C-181 ⁰ C.

Example 119 4- [6- (2-Cyclopentylazetamido) -3- (N-ethylcarbamoylmethoxy) -indazol-1-ylmethyl] -3-methoxybenzoic Acid Using a similar procedure to Example 9 but using the ester of Example 118, The title compound was obtained in 80% yield as a solid, mp 219 ° C-221 ° C.

Example 120 Methyl 4- [5- (hexanamido) -1- (methoxykarbonylmethyl) indol-3-ylmethyl] -3-methoxybenzoate

Using a similar procedure to Example 4 (see also Example 98), the title compound was isolated in 86% yield as an oil; partial NMR (250MHz, DMSO-d ₆ ): 0.87 (t, 3H, CH ₂ -CH ₃ ); 1.26-1.30 (m, 4H); 1.50-1.60 (m, 2H); 2.25 (t, 2H, CH ₂ CON); 3.66 (s, 3H, OMe); 3.83 (s, 3H, OMe); 3.92 (s, 3H, OMe); 3.98 (s, 2H, ArCH ₂ Ar); 5.05 (s, 2H, NCH ₂ ); 9.66 (s, 1H, NH); starting from 4- [5-amino-1- (methoxycarbonylmethyl) indol-3-ylmethyl] -3-methoxybenzoate (which in turn was prepared analogously to [D] in Example 4, ie, by the reaction of the nitroindole derivative [C] with methyl bromacetate but in tetrahydrofuran, in the presence of sodium hydride, followed by catalytic hydrogenation of the product).

Example 121 4- [1-Carboxymethyl-5- (hexanamido) indol-3-ylmethyl] -3-methoxybenzoic acid Using a similar procedure as in Example 9 but starting from the ester described in Example 120, the title compound was obtained in a yield recovered from 59% as a white solid, mp 235 ° C-240 ° C.

Example 122 N- [4- [6- (2-Zyklopentylazetamido) -3- (N-ethylkarbamoylmethoxy) -indazole-1-ylmethyl] -3-methoxybenzoyl] -2-

methylbenzenesulfonamide

Using a similar procedure as in Example 57 but using ortho-toluenesulfonamide and the acid described in Example 119, the title compound was recovered in 32% yield as a partial hydrate and solid. Melting point 222 ° C-223.5 ° C.

Analysis calculated for:

C34H39N5O7S • 0.75 _H2 O: C - 60.47; H - 6.04; N - 10.37

Determined: C-60.41; H -5.83; N -10.31

Example 123 Methyl 4- [5- (2-cyclopentylazetamido) indol-3-ylmethyl] -3-methoxybenzoate

Starting from the aminoester (A) and using the same procedure as in Example 4 but using cyclopentylacetyl chloride (see also Example 98), the title compound was obtained in a quantitative yield as a foam; partial NMR (250MHz, DMSO-d ₆ ): 1.2-1.8 (3m, 8H, cyclopentyl ring); 2.24 (m; 3H, CH ₂ CONH and -CHCH ₂ ); 3.83 (s, 3H, OMe); 3.93 (s, 3H, OMe); 3.99 (br s, 2H, CH ₂ Ar); 9.57 (brs, 1H, NMCO); 10.79 (br d, 1H, -NH-).

Example 124 4- [5- (2-Cyclopentylazetamido) indol-3-ylmethyl] -3-methoxybenzoic acid

Using a similar procedure as in Example 9 but starting from the ester described in Example 123, the title compound was recovered in 83% yield as a white solid, mp 218 ° C-219 ° C.

Example 125 N- [4- [5- (2-Cyclopentylazetamido) indol-3-ylmethyl] -3-methoxy-benzoyl] -2-methylbenzenesulfonamide Using a similar procedure to Example 57 but starting from ortho-toluenesulfonamide and described in Example 124, the title compound was obtained in 56% yield as a white powder, mp 248 ° C-250 ° C.

Example 126 Methyl 4- [6- (2-cyclopentylacetamido) -3-oxo-2-propyl-2H, 3H-indazol-1-ylmethyl] -3-methoxybenzoate Palladium on carbon (5% w / w, 0.095 g) was added to a solution of methyl 4- [2-allyl-6- (2-cyclopentylacetamido) -3-oxo-2H, 3H-indazol-1-ylmethyl] -3-methoxybenzoate (0.462 g) in ethyl acetate (20 ml). added. This mixture was hydrogenated at 1.1 bar for hours. The catalyst was removed by filtering through diatomaceous earth, the filtrate was evaporated and the residue was purified by flash chromatography on silica gel (40g) eluting with 1: 3: 7 v / v / v acetic acid: ethyl acetate: dichloromethane. The chromatographed product was dissolved in acetone and toluene and the solution was evaporated to give the title compound in a yield of 84 "C as a solid glass, mp 74.5 ° C-77 ° C.

The starting methyl 4- [2-allyl-6- (2-cyclopentylazetamido) -3-oxo-2H, 3H-indazol-1-ylmethyl] -3-methoxybenzoate itself was prepared as follows. Using a similar procedure as in Example 42, but starting from methyl 4- [6- (2-cyclopentylacetamido) -3-hydroxyindazol-1-ylmethyl] -3-methoxybenzoate (ie, reaction of this compound with allyl bromide in Ν, Ν Dimethylformamide in the presence of sodium hydride), a mixture of methyl 4- [2-allyl-6- (2-cyclopentylacetamido) -3-oxo-2H, 3H-indazol-1-ylmethyl] -3-methoxybenzoate and methyl 4- [3-allyloxy-6- (2-cyclopentylazetamido) indazol-1-ylmethyl] -3-methoxybenzate. The compound mixture was heated for 18 hours at approximately 200 ⁰ C and the product by flash chromatography on silica gel (60 g) was isolated, has been wherein EssigsäurerEthylazetatiDichlormethaneluiert with 1:30:70 v / v / v, to give methyl 4- [2-allyl-6 To give (2-cyclopentylacetamido) -3-oxo-2H, 3H-indazol-1-ylmethyl] -3-methoxybenzoate in 81% yield as an oil with satisfactory NMR spectral data.

Example 127 4- [6- (2-Cyclopentylazetamido) -3-oxo-2-propyl-2H, 3H-indazol-1-ylmethyl] -3-methoxybenzoic Acid Using a similar procedure to Example 9 but starting from methyl 4- [6- (2-Cyclopentylacetamido) -3-oxo-2-propyl-2H, 3H-indazol-1-ylmethyl] -3-methoxybenzoate, the title compound was obtained in 83% yield as a solid, mp 122 , 5 ° C-125 ° C.

Example 128 Tablet 1 mg / tablet Connection X 100 Representative representative pharmaceutical dosage forms that are useful for the therapeutic or lactose 182.75 Prophylactic administration of an acid compound of Formula I (i.e., M is an acid group as defined above Kroskarmellosenatrium 12.0 or a corresponding pharmaceutically acceptable salt (hereinafter referred to as "compound X"). Strength 2.25 can be applied: magnesium stearate 3.0 (I) Tablet 2 mg / tablet Connection X 20 Microcrystalline cellulose 420 polyvinylpyrrolidone 14.0 Strength 43.0 magnesium stearate 3.0 (G) capsule mg / capsule Connection X 10 lactose 488.5 magnesium stearate 1.5 Injection 1 (10 mg / ml) Compound X (free acid form) 1.0% w / v (Iii) sodium phosphate 3.6% w / v 0.1 M sodium hydroxide solution 15.0% w / v Injecting water ... up to 100% Injection 2 (buffered to pH 6) 1 mg / ml (Iv) Compound X (free acid form) 0.1% w / v sodium phosphate 2.26% w / v citric acid 0.38% w / v polyethylene glycol 400 3.5 w / v Injecting water ... up to 100% (V) aerosol mg / ml Connection X 0.2 trioleate 0.27 trichlorofluoromethane 70.0 Dichloridfluormethan 280.0 Dichlorotetrafluormethan 1 094,0 (Vi)

It will be understood that the above-mentioned pharmaceutical compositions can be varied according to known pharmaceutical methods to include different amounts and types of active ingredient Compound X. The aerosol (vi) can be used in conjunction with a standard nebulizer with dosing device.

Claims (12)

1. Process for the preparation of a compound of the formula IR ² A ¹ .QA ² .M wherein the group> X-Y-Z- is selected from the group consisting of (a)> CRc-CRaRb-NRd (b)> C = N-Za (c)> C = CRa-Zb (d)> N-CRa = N- (e)> N-CRbRe-CRcRf-Zb- (f)> N-N = N- (g)> N-NRg-CO- (h)> N-N = CORdworin Ra is hydrogen or (1-4C) -alkyl; Rb and Rc are each hydrogen or form an unsaturated bond with the existing carbon-carbon bond; Rd is hydrogen or (1-10C) alkyl, optionally with one or two double or triple bonds, and wherein each carbon atom may optionally be replaced by oxygen or sulfur, each of said (1-10C) alkyls optionally additionally containing one or more Substituents selected from the group consisting of (1-4C) alkoxy, cyano, carboxy, 1H-tetrazol-5-yl, carbamoyl, N- (1-4C) -carbamoyl, N, N-di- [( 1-4C-) alkyl] -carbamoyl and (1-4C) -alkoxycarbonyl, or Rd is selected from the group consisting of (3-8C) -cycloalkyl, (3-8C) -cycloalkyl- (1-4C) -alkyl, ( 2-6C-) alkanoyl and phenyl (1-4C) alkyl, wherein the phenyl moiety may optionally bear a substituent selected from the group consisting of cyano, halo, (1-4C) alkyl, (1- 4C-) alkoxy and trifluoromethyl group was selected; Re and Rf are independently hydrogen or (1-4C) alkyl; Rg is (1-4C) alkyl; Za is oxy, thio or substituted imino of the formula -N (Rd) - where Rd is as defined above;
For example, oxy or thio is; the group R ¹ .L- represents amidic radicals of the formula R ¹ .W.CO.NH- or R ¹ .W.CS.NH-, wherein R ^{1 is} selected from the group of (a) (2-10C-) ) Alkyl optionally containing one or more fluoro substituents; (b) phenyl (1-6C) alkyl wherein the (1-6C) alkyl moiety may optionally carry a fluoro or (1-4C) alkoxy substituent and the phenyl moiety may optionally bear a substituent selected from the group consisting of halogeno, (1-4C) alkyl, (1-4C) alkoxy and trifluoromethyl, and (c) (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-6C) alkyl, wherein the cyclic component of each of these values optionally contain an unsaturated bond and can optionally carry 1 or 2 (1-4C) alkyl substituents; W is oxy, thio, imino or a direct bond to R ¹ ;
R ^{2 is} hydrogen, halo, (1-4C) alkyl or (1-4C) alkoxy; Q is phenylene optionally bearing one or more substituents optionally selected from the group halo, hydroxy, (1-4C) alkyl, (1-4C) alkoxy and trifluoromethyl; A is ¹ (1-2C) -alkylene or vinylene; A ^{2 is} methylene, vinylene or a direct bond to M and M is an acidic group selected from carboxy, 1 H -tetrazol-5-yl and an acylsulfonamide radical having the formula -CO.NH.SOmR ³ , where m is the is integer 1 or 2 and R ^{3 has been} selected from (1-6C) alkyl, (3-8C-) cycloalkyl, (6-12C) -aryl, heteroaryl of 5 to 12 atoms, at least one of which is carbon and at least one selected from the group consisting of oxygen, sulfur and nitrogen, and (6-12 C-) aryl- (1-4C) -alkyl, wherein in each case the aromatic or heteroaromatic component can carry one or two substituents selected from those of halogeno, (1-4C) -alkyl, (1-4C) -alkoxy, trifluoromethyl Nitro and amino formed group were selected; or their pharmaceutically acceptable salt, characterized in that they are prepared by a method selected from the following (A) For compounds in which M is a carboxylic acid group, decomposition of a suitable ester of formula I IN THE (B) Azylation of an amine of formula IV IV however, T is selected from the values defined for M; (C) for a compound of formula I, wherein> XYZ- has the value> CRc-CRaRb-NRd- or> C = N-Za, but where Za is a substituted imino of formula -N (Rd) -, reaction an imino compound of the formula V A ¹ .QA ² . T wherein> DEG- is a group having the formula> CRc-CRbRa-NH- or> C = N-NH-, but T is selected from the values defined for M, with an alkylating agent having the formula Rd.U, wherein U is selected is selected from the group of chloro, bromo, iodo, methanesulfonyloxy and p-toluenesulfonyloxy; (D) for a compound of formula I wherein> X-Y-Z-> CRc-CRaRb NRd-, but where Rb and Rc together with the existing carbon-carbon bond form an unsaturated bond, the reaction of an indole of formula VI Vl with an alkylating agent of the formula UA ¹ .QA ² .M in the presence of a suitable Lewis acid, where U has the meaning defined under (C) and the Lewis acid is selected from the group of silver oxide, silver carbonate, silver fluoroborate, silver trifluoroacetate, Silver trifluoromethanesulfonate, zinc chloride, iron trichloride and tin tetrachloride; (E) for a compound of formula I wherein M is a 1H-tetrazol-5-yl radical, reaction of a cyano derivative of formula VII VII ... A ¹ .Q. A ² . CW with an alkali metal azide;
(F) for a compound of formula I wherein R ^{1 is} .L- for a group of the formula R ¹ .Wa.CO.NH- or R ¹ .Wa.CS.NH-, where Wa is oxy, imino or thio , Reaction of an isocyanate or isothiocyanate of the formula VIII Q ^VIN a'.q.ast but where T is taken from the values selected for M and wherein Xb is oxygen or sulfur, with an amine of the formula R ¹ .NH ₂ , an alcohol of the formula R ¹ .OH or a thiol of the formula R ¹ .SH; (G) for a compound of formula I wherein M is a group of the formula CO.NH.SO _m .R ³ , the reaction of a compound of the formula I wherein M is carboxy with a sulfonamide derivative of the formula R ³ . SO _m .NH ₂ in the presence of a dehydrating agent; (H) for a compound of formula I, wherein>XYZ-> CRc-CRaRb-NRd, but wherein Rb and Rc together with the carbon-carbon bond present form an unsaturated bond, reaction of an indole of formula VI with an alkylating agent having the formula UA ¹ .QA ² .M, wherein U has the meaning defined in (C); (I) For a compound of formula I, wherein> X-Y-Z-> C = N-Za, but Za is a substituted imino of formula -N (Rd) -, dehydrogenating an aminooxime of formula IX Rd
R ² IX ι 'M ^0B f? i _ a'.Q.JT.T but where Taus is selected from the values defined for M; (J) for a compound of formula I, wherein> X-Y-Z-> C = CRa-Zb, but where Zb is oxy, dehydrogenating a hydroxy compound of formula XI 1 2 A '.Q.A but where T is selected from the values defined for M; (K) for a compound of formula I, wherein> X-Y-Z-> C = N-Za, but where Za is oxy, dehydrogenating a hydroxy-amine of formula XIII OH
R'.Ir-KMl _Έ ΧΙ " a 2 A ¹ .QA .T but where Taus was selected to be the values defined for M; (L) for a compound of formula I, wherein> X-Y-Z> C = CRa-Zb but where Zb is oxy or thio, reaction of a benzofuran or a benzothiophene of formula XV with an alkylating agent having the formula UA ¹ .QA ² .M, wherein U has the values defined above in (C). (M) for a compound of formula I, wherein> XYZ-> CRc-CRaRb-NRd, but where Rb and Rc are hydrogen, catalytically hydrogenating an indole of formula I, wherein> XYZ> CRc-CRaRb-NRd, but Rb and Rc together with the carbon-carbon bond present form an unsaturated bond; (N) for a compound of formula I wherein>XYZ-> C = N-Za, but where Za is -N (Rd) - and A ^{1 is} methylene, a modified version of processes (A) or ( E), characterized by the cross-linking of an indazole with the formula XVI XVI wherein Hal is chloro, bromo or iodo, with a compound having the formula Hal.CH ₂ .QA ² .T, but T is COORh or CN and in which Hal is chloro, bromo or iodo, to the corresponding Compound III or VII wherein> XYZ is> C = N-Za, but where Za is -N (Rd) - and A ^{1 is} methylene, followed by the COORh or CN group in one of values defined above for M by the application of method (A) or (E), and (O) for a compound of formula I, wherein> X- represents the group> N-, alkylating an amino compound of formula XVII
, 2 - --- :: - XVII with an alkylating agent of the formula UA ¹ .QA ² .M, wherein U has the meaning defined above in (C), in the presence of a suitable base. 2. The method according to item 1, characterized in that a compound of formula I is prepared wherein R ^{1 is} selected from the group ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 1-ethylpropyl , Hexyl, heptyl, 1-ethylphenyl, nonyl, heptafluoropropyl, benzyl, 4-chlorobenzyl, 4-trifluoromethylbenzyl, 4-methylbenzyl, 1-phenylethyl, 2-phenylethyl, 1-methylphenylethyl, 1-phenylpropyl, 1-phenylpentyl, Alpha-fluorobenzyl, alpha-methoxybenzyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 1-cyclopentylbutyl, 1-cyclohexylpropyl, 1-cyclohexylbutyl, 5-methyl-2- (1-methylethyl) cyclohexyl and 1-cyclohexene -4-yl;
R ^{2 is} selected from the group consisting of hydrogen, fluoro, chromo, bromo, methyl and methoxy; R ^{3 is} selected from the group methyl, isopropyl, butyl, cyclopentyl, phenyl, 4-chlorophenyl, 4-methylphenyl, 2-methylphenyl, naphthyl, thien-2-yl and 6-chloropyrid-3-yl; Ra is selected from hydrogen and methyl; Rb and Rc are selected to each be hydrogen or Rb and Rc together form an unsaturated bond with the carbon-carbon bond present; Rd is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, allyl, propargyl, 3-methylbutyl, 3-methylbut-2-enyl, 2-carbamoylethyl, carboxymethyl, carboxyethyl, N-ethylcarbamoylmethyl, Ν, Ν-dimethylcarbamoylmethyl, 2-carbonylvinyl, 2- (methoxycarbonyl) vinyl, 2-methoxyethyl, 3-methoxypropyl, cyclopentyl, cyclopropylmethyl, acetyl, benzyl, 3-cyanobenzyl and 4-chlorobenzyl; Each of Re and Rf is independently selected from the group consisting of hydrogen, methyl and ethyl; Rg is selected from the group methyl, ethyl and propyl A ^{1 is} selected from methylene and ethylene; A ^{2 is} selected from a direct bond and methylene; Q is selected from the group consisting of m-methylene and p-phenylene, each of which optionally carries a fluoro, chloro-hydroxy, methyl, methoxy or trifluoromethyl substituent can and
W is selected from the group oxy, imino, thio and a direct bond. 3. The method according to point ^, characterized in that a compound is prepared according to point 2, wherein R ^{1 is} selected from the group butyl, pentyl, 1-ethylpentyl, i-phenylpropyl-LAlpha Fluorobenzyl, alpha-methoxybenzyl, cyclopentyl and cyclopentylmethyl; R ^{2 is} hydrogen;
R ^{3 is} phenyl or 2-methylphenyl;
Ra is hydrogen; · Rb and Rc are selected so that they are each hydrogen or Rb and Rc taken together and form an unsaturated bond with the existing carbon-carbon bond; Rd is selected from the group consisting of hydrogen, methyl, ethyl, propyl, hexyl, allyl, propargyl, 3-methylbutyl, 3-methyl-but-2-enyl, carboxymethyl, carboxyethyl, N-ethylcarbamoylmethyl, Ν, Ν-dimethylcarbamoylmethyl, 2- Methoxyethylcyclopentyl, cyclopropylmethyl, acetyl, benzyl and 3-cyanobenzyl;
Re and Rf are each hydrogen;
Rg is propyl;
A ^{1 is} methylene;
A ^{2 is} a direct bond; Q is selected from the group m-phenylene and p-phenylene, each of which may be optionally substituted by a hydroxy or methoxy substituent and W is selected from the group oxy, imino and direct bond. 4. The method according to item 1, characterized in that a compound of formula I is prepared, selected from the group formed by (i) indoles and indolines of the formula I a la (ii) benzisoxazoles, benzisothiazoles and indazoles of the formula I b A ¹ . QA ² .M (iii) benzo [b] furans and benzo [b] thiophenes of formula I c, 2 Benzimidazoles of the formula I d ', 2 1,4-benzoxazines and 1,4-benzothiazines of the formula le ί-Ηο; Benzotriazoles of the formula I f ' -s _. _τ I ¹ ^ M ² - ¹ (vii) indazolones of the formula Ig R-Rg ! -ι ρ A ¹ .QA.] (viii) indazoles of the formula I h lc ld le If lh • A ¹ . QA ² . M 5. A method according to item I, characterized in that a compound according to item 4 is prepared, selected from the group consisting of (i) indoles and indolines of the formula la; (ii) indazoles of the formula I b; (iii) benzo [bithiophene of formula Ic; (iv) benzimidazoles of the formula I d; (v) 1,4-benzoxazines of the formula Ie; (vii) indazolones of the formula Ig; (vi) benzotriazoles of the formula I f and (viii) indazoles of the formula Ih. 6. The method according to item!, Characterized in that a compound according to item 4 is prepared, selected from the group of (a) compounds of formula Ia wherein Rb and Rc together with the carbon-carbon bond present form an unsaturated bond, and (b) Compounds of the formula Ie in which Zb is oxy or thio and Rb and Rc are each hydrogen. 7. A method according to item!, Characterized in that compounds are prepared according to one of the items 4, 5 or 6, wherein A ^{1 is} methylene; A ^{2 is} a direct bond to M; Q is p-phenylene, optionally substituted by methoxy; M is selected from the group of carboxy, 1H-tetrazol-5-yl and a radical of the formula -CO-NH-SO ₂ R ⁴ , wherein R ^{4 is} phenyl, optionally substituted as defined for R ³ . 8. Method according to item!, Characterized in that compounds according to one of the points! to 3 where R ¹ .L- is associated with the benzene moiety of Formula I to have a meta relationship to the X group but no ortho to the Z group. 9. A method according to item!, Characterized in that compounds of formula I are prepared, selected from the group of (a) Indole derivatives of the formula IIa Ra " N / A .0.A ² M (b) Indazole derivatives of the formula II b Nb (c) benzothiophene derivatives of the formula Mc lic (d) imidazole derivatives of the formula II d lld R ¹ .WXO.NH ^^ / ^% Η _ο .0.Α ² .Μ (e) 2,3-Dihydrobenz-1,4-oxazine derivatives of the formula lie He R ¹ .W, CQ. MH (f) benzotriazole derivatives of the formula II f R ¹ . W. CO. NH Hf CH ₂ .QA »Μ (g) Indazole derivatives of the formula II g , OR d , 2 I R ¹ .W.CO.NH hg 10. The method according to item 1, characterized in that compounds are prepared according to item 9, selected from the group of (a) compounds with the form! IIa and IIb, wherein M is carboxy and Rd is selected from the group of methyl, propyl, 2-methoxyethyl, N-ethylcarbamoylmethyl and cyclopentyl; (b) Compounds of the formulas IIa and Ilb, wherein M is a radical of the formula -CO-NH-SO ₂ R ⁴ , where R ^{4 is} phenyl and Rd is selected from the group of hydrogen, methyl, 2- Methoxyethyl and N-ethylcarbamoylmethyl; (c) Compounds of the formulas IIa and Ilb, wherein M is a radical of the formula! -CO-NH-SO ₂ -R ⁴ wherein R ^{4 is} 2-methylphenyl and R d is selected from the group of methyl and N / N Dimethylkarbamoylmethyl; (d) compounds of the formula Hg, wherein R ^{1 is} .W-cyclopentyloxy, M is caroboxy or -CO.NH.SO ₂ .R ⁴ wherein R ^{4 is} phenyl and R d is methyl, and (e) Compounds of the formula Hg, wherein R ^{1 is} cyclopentylmethyl, W is a direct bond, M is carboxy or -CO-NH-SO ₂ R ⁴ , wherein R ^{4 is} 2-methylphenyl and Rd is N-ethylcarbamoylmethyl , 11. The method according to item 1, characterized in that compounds are prepared according to item 1, which are selected from the group of (a) N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl] -benzenesulfonamide, (b) N- [4- [5- (cyclopentyloxycarbonyl) amino-1- (N-ethylcarbamoylmethyl) indol-3-yl-methyl] -3-methoxybenzoyl] -benzenesulfonamide; (c) N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindazol-3-ylmethyl] -3-methoxybenzoyl] -benzenesulfonamide, (d) N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide, (e) N- [4- [5- (cyclopentylazetamido) -1- (N, N-dimethylcarbamoylmethyl) indol-3-ylmethyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide, (f) N - [- 4 [6- (cyclopentyloxycarbonyl) amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide, (g) N- [4- [6- (2-cyclopentylazetamido) -2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3-methoxybenzoyl-benzenesulfonamide; (h) N- [4- [5- (cyclopentyloxycarbonyl) aminobenzo [b] thien-3-ylmethyl] -3-methoxybenzoyl] - benzenesulfonamide,
(i) N- [4- [6- (2-cyclopentylanzetetamido) benzimidazol-1-ylmethyl] -3- methoxybenzoyl] benzenesulfonamide,
(j) N- [4- [6- (2-cyclopentylazetamido) -2,3-dihydrobenz-1,4-oxazin-4-ylmethyl] -3- methoxybenzoyl] -2-methylbenzenesulfonamide,
(k) N- [4- [6- (cyclopentyloxycarbonyl) amino-3-methoxyindazol-1-ylmethyl] - methoxybenzoyl] benzenesulfonamide,
(I) N- [4- [5- (N'-cyclopentylureido) -1-methylindol-3-ylmethyl] -3-methoxybenzoyl] -2- methylbenzenesulfonamide,
(m) N- [4- [6- (2-cyclopentylazetamido) benzotriazol-1-ylmethyl] -3-methoxybenzoyl] benzenesulfonamide,
(n) N- [4- [5- (cyclopentyloxycarbonyl) aminoindol-3-ylmethyl] -3-methoxybenzoyl] - benzenesulfonamide,
(o) N- [4-t5- (cyclopentyloxycarbonyl) amino-1- (2-methoxyethyl) indol-3-ylmethyl] -3- methoxybenzoyl] benzenesulfonamide,
(p) N- [4- [5- (2-cyclopentylazetamido) -1-methylindol-3-ylmethyl] -3-methoxybenzoyl] - benzenesulfonamide,
(q) N- [4-t6- (2-cyclopentylazetamido) -3- (N-ethylcarbamoylmethoxy) indazol-1-ylmethyl] -3- methoxybenzoyl] -2-methylbenzensulfonamidund
(r) N- [4- [6- (cyclopentyloxycarbonyl) aminobenzimidazol-1-ylmethyl] -3-methoxybenzoyl] - benzenesulfonamide,
wherein each of these compounds is in the form of a free acid or the corresponding pharmaceutically acceptable salt. 12. The method according to item!, Characterized in that a salt of a compound having the formula! I is prepared according to any one of items 1 to 11, which is selected from alkali metal, j Alkaline earth metal, aluminum and ammonium salts and salts with organic bases, i which give physiologically acceptable cations.