CA2084736A1

CA2084736A1 - Benzofuranes

Info

Publication number: CA2084736A1
Application number: CA002084736A
Authority: CA
Inventors: Werner Mederski; Horst Juraszyk; Norbert Beier; Pierre Schelling; Ingeborg Lues; Klaus-Otto Minck
Original assignee: Individual
Current assignee: Merck Patent GmbH
Priority date: 1991-12-09
Filing date: 1992-12-07
Publication date: 1993-06-10
Also published as: NO924745D0; ZA929513B; NO924745L; AU2993792A; EP0546449A3; MX9207070A; HU9203893D0; DE4140519A1; EP0546449A2; PL296865A2; JPH05262768A

Abstract

Abstract of the Disclosure Novel benzofurans of formula I:
I

wherein R is the radical

Description

- 2 - 2 0 ~ ~43 ~3 Merck Patent Gesell~chaft mit beschrankter Haftung 6100- D a r m ~ t a d t Benzofuran~

S The invention relates to novel benzofuran~ of formula I:

wherein R in the radical R3~

10 R1 is ~, ~al, COO~, COM~2, C~O, CN, NH2 or tetra-zol-S-yl, R2 is ~, CooR3, CN~ NO2~ NH2~ NHCOCF3~ NHSO2CF3 or tetrazol-5-yl, R3 i ~ or alkyl, alkenyl or alkynyl eac~ having up to 6 C atom~, R~ , alkyl having 1-6 C atom~ or cyanoal~yl, R300C-alkyl, tetrazol-5-ylalkyl orAr alkyl each having 1-6 C atom~ in the Naikyl~ ty, ~A-B-C~D- i~ one of the groups -C~sC~-C~ , -C~=CH-N-C~ C~sM-CH=CH-, -N~C~-C~=C~ C~=C~-CO-NR~-, -C~QC~-NR~--CO-, -CO-NR~-C~=C~- or -~R4-CO-C~-C~-, wher~in the H atom~ of the C~
group~ can be ~ub~tituted by alkyl having 1-6 C atoms 9 ~al, CooR3, CN and/or tetrazol-5-yl, 208~736 ~r i3 phenyl which i~ un~ubstituted or mono-~ub~tituted or di~ub~tituted by ~al, R3, CF3, - CooR3, CN~ oR3, N02, NH2, NHCOCF3, NHS02CF3 or tetrazol-5-yl, and 5 ~al i~ F, Cl, ~r or I, and their ~alts.
SLmilar co~pounds are known from European patent application A2-0 430 70g, but they contain a benzothio-phene ring in place of the benzofuran ring and a sub-stituted or unsubstituted Lmidazolyl group in place ofthe radical R.
The object of the invention was to find novel compounds with valuable properties, e~pecially compounds which can be used for ~he preparation of dru~.
It has been found that the compounds of formula I and their salts possess very valuable pharmacological properties coupled with a good tolerance. In particu-lar, they exhibit antagoni~tic propertie~ towards angiotensin II and can therefore be u~ed for the treatment of angiotensin II-dep,endent hypertension, aldo~teronism and cardiac in~uff:iciency, as well as disorders of the central nervous s~y~tem. ~he~e effPcts can be determined by conventional in vitro or in vivo methods such as those de~crib~d for example in US patent 4 880 804 and in international patent application 91/14367, a8 w~ll a~ those de~cribed by A.T. Chiu et al., J~ Pharmacol. Exp~ Therap~ 250, 867-874 tl989), and by POC. Wong et al~, ibid. 252t 719-725 (1990; in vivo, on rat~).
The compound~ of formula ~ can b~ u~d a~ phar-maceutical active ingredients in human and veterinary med.ici~e, e~pecially for the prophylaxi~ and/or therapy of cardiac, circulatory and vascular di~ea~es and in particular of hypertonia, cardiac insufficiency and 208~73~
- 3a -hyperaldosteronism, furthermore of hypertrophy and hyperplasy of the blood vessels and the heart, angina p~ctoris, cardiac infarction, haemorrhagjc stroke, restinosis after angioplasty or by-pass surgery, arteriosclerosis, ocular hypertension, glaucoma, macular degeneration, hyperuricaemia, disturbances of the renal functions such as renal failure/diabetic complications such as nephropathia diabetica or retinopathia diabetica, psoriasis, angiotensinII- induced disturDances in female sexual organs, cognitive disorders, f.e. dementia~amnesia, disturbances of the function of memory, states of fear, depr~ssions and/or epilepsy.
The invention relates to the compounds o~ formula I and their salt~ and to a process for the preparation of the~e compounds and their salts, characteri~ed in that a compound of formula II:

E-CH~ II

wherein E i~ Cl, Br, I9 a free OH group or an OH group which has been functionally modified to acquire reacti-vity, and R~ and R2 are as defined in ClaLm 1, is reacted with a compound of ~ormula III:

H-R III

wherein R iQ as def ined in Claim 1, or in that a compound o~ formula I is free~ from one of its functional derivative~ by treatment with a solvo-ly~ing or hydrogenoly~ing agent, and/ox i~ that one or more radical~ R1, R2 and/or R in a compound of for~ula I are converted to one or more other radicals R1, R2 and/or R, and/or a ba~e or ~cid of ~ormula I i~ coh~rted to o~e of it~ salts.
Abo~e and below, the radicals or parameters R, Rl to R~ -A-B-C-D-, Ar, ~l and E are as defined in formulae I and II unl~s exprss~ly indicated otherwi~e.
1~ the above formulae, ~alkyl~ has 1-6, pre-ferably 1, 2, 3 or 4 C atoms. ~lkyln i~ preferably methyl, nr el~a ethyl, propyl, i~opropyl, butyl~ iso-b~tyl, sec-butyl or tert-butyl, or elsa pentyl, 1-, 2- or 3-methylbutyl~ 1, 20 or 292~dLmethylpropyl, 1-ethylpropyl, hexyl, 1~, 2-, 3- or 4-methylpentyl, 1,l-o 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dLmethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methyl-propyl or 1,1,2- or 1,2,2-trlmethylpropyl. Alke~yl i~

7 3 ~

preferably vinyll prop-1-enyl, prop-2-enyl or but-l enyl, or el~e pent-1-enyl or hex-l~enyl~ Alkynyl i preferably ethynyl, prop-1-ynyl or prop-2-ynyl, or el~e but-1-ynyl, pent-1-ynyl or hex-1-ynyl.
Hal is preferably F, Cl or Br, or else I.
R i3 a radical derived from lH- or 3~-imidazo-[4,5-b]pyridine or a radical derived from 1~- or 3H
imidazo[4,5-c]pyridine or, more precisely:
(a) 2-R3-3~-imidazo[4,5-b]pyridin-3-yl (if -A-B-C-D- =
-C~-C~-C~=N-), (b) 2-R3-3~-imidazo[4~5-c]pyridin-3-yl (if -A-B-C-D- =
-C~-C~ N-CH ), (c) 2-R3-l~-imidazo[4,5 c]pyridin-1-yl (if -A-B-C-D- =
-C~=N-CH=C~-), lS (d) 2-R3~ imidazo[4,5-b]pyridin-l-yl (if -A-B-C-D- =
-~=CH-CH=C~-), (e) 2-R3-4-~4-4,5-dihydro-5-oxo-~-imidazo[4,5-b~pyri-din-3-yl (if -A-B~C-D- = -C~=CH-Co-NR4-), (f) 2-R3-5-R4-4~5odihydro-4-oxo-3~-imidazo[4,5-c]pyri-din-3-yl (if -A~B-C-D- = -C~-:CH-NR4-Co~
(g) 2 -R3- 5 -R4-4,5-dihydro-4-oxo-].~-imidazo[4,5-c]pyri-din-3-yl (if -A-B-C-D- - -CO-NR~-C~=C~
(h) ~-R3-4-R4-4,5-dihydro-S-oxo-l~-Lmidazo[4,5-b]pyri-din-3-yl (if -A-B-C-D- - -NR4-co-~
In the radical~ A-~-C-~- here, the ~ atoms located on the C atomh can be ~ub~tituted by alkyl (preferably met~yl), ~al (preferably F or Cl), CoOR3 (preferably COO~, COOc~3 or COOC2~5), CN and/or t~tra-zol-S-yl. Preferred sub~titue~ts are C~3 and CO~.
Preferably only o~ or two of the~e ~ atoms are sub-~tituted by one of the ~ubstitu~nt~ indicated~
Accordingly, the co~pounds of formula I i~clude tho~e of formulae Ia to Ih~ wherein R i~ a~ defined in each case under (a) to ~h). The compound~ of f ormulae Ia and If are preferred.
The radical Rl i8 prefera~ly ~ or Br.
The radical R2 i~ preferably CN, or el~e pre-ferably tetrazol-5-yl, COO~, COOCH3, COOC2~5 or N~SO2CF3.

20~73~

The radical R3 (if it i~ not H) i8 preferably linear and i8 preferably alkyl or alkenyl each having 2-6 C atoms, especially butyl, or el~e ethyl or propyl, or else pentyl, hexyl, allyl or pxop-l-enyl, or else but-1-enyl, pent-l-enyl, hex-1-enyl, ethynyl, prop-l-ynyl, but-l-ynyl, pent-1-ynyl or hex-1-ynyl.
The radical R4 i8 preferably ~, or else preferably alkyl (especially CH3), cyanoalkyl (e~pecially cyano-methyl, 2~cyanoethyl, 3-cyanopropyl), AOOC-alkyl ~especially methoxycarbonylmethyl, ethoxycarbonyl methyl, 2-methoxycarbonylethyl, 2-ethoxycarbo~ylethyl), carboxy-alkyl (especially carboxymethyl, 2-carboxyethyl, 3-carboxypropyl) or tetrazol-5-ylalkyl [especially tetrazol-5-ylmethyl, 2-(tetrazol-5-yl)ethyl, 3-(tetra-zol-5-yl)propyl], it being possible for all these radicals preferably to contain a total of up t3 6 C atoms in each case. Also, the radical R4 iS preferably Ar-alkyl having 7-11 C atom~, especially benzyl, 1- or 2-phenyl~
ethyl, 1-, 2- or 3-phenylpropyl, 1-, 2-, 3- or 4-phenyl-butyl, o-, m- or p-fluorobenzyl, (preferably) o-, m- or p-chlorobenæyl, o-, m- or p-bromobenzyl, o-, m- or p-methylbenzyl, o-, m- or p-tri~luoromethyl benzyl, o-, m- or p-methoxycarbonylbenzyl, o-, m- or p-ethoxy-carbonylbenzyl~ (preferably) o-~ m-- or p-cyanobenzyl, o-, m or p-carboxybenzyl, o-, m- or p-nitrobenzyl, (prefer-ably) o-, m- or p~aminobenzyl or (pr~ferably) o-, m- or p-(tetrazol-5-yl)benzyl.
The compounds of formula I can pnsse~ one or more chiral centres and ca~ therefore exist in different form~ (optically active or optica~ly inactive)~ Formula I include~ all the~e fo~ms.
Accordingly, the inventio~ relate~ especlally to those compounds of forml?la I in which at lea~t one of said radicals ha3 one of the preferred meanings indicated above. Some preferred groups of compounds can be expres~ed by the following partial formulae Ii, Ij, Iai to Ihi and Iaj to Ihj, which correspond to formulae I and Ia to Ih and wherein the radicals not described more _ 7 _ 2-6~74~2~6 precisely are ac defined in formulae I and Ia to Ih~
compound~ of formulae Ii and Iai, Ibi, Ici, Idi, Iei, Ifi, Igi and Ihi, which correspond to formula~ I and Ia to Ih except that in addition R1 is ~ therein; and S compound~ of formulae Ij and Iaj, Ibj, Icj, Idj, Iej, If3, Igj, Ihj, Iij, Iaij, Ibij, Icij, Idij, Ieij, Ifij, Igij and Ihij, which correspond to formulae I, Ia to Ii and Iai to Ihi except that in addition R2 is CN or (preferably) tetrazol-5-yl therein.
Another sel~cted group of preferred compounds has formula I wherein Rl is ~, R2 is tetrazol-5-yl, R3 is alkyl having 2-4 C atom~ and -A-B-C-D- is -C(C~3) e C~-C~=N-,-C(CH3)=C~-C( CH3)=N-,-C~=C~-N(o-~OOC-C6H4-CH2)--CO-, ~CH=CH-NH-CO- or -CH=CH-N(CH2COOH)-CO-.
The compounds of fo~mula I and also the starting mat~rial~ for th~ir preparation are moreover prepared by methods known per qe, such a~ those de~cribed in the litexature (for example in the ctandard works like Houben-Weyl, Methoden der organischen Chemie (Methods of ~0 Organic Chemistry), Georg-Thieme-V~rlag, Stuttgart, but e~pecially in European patent application A2-0 430 709 and US patent 4 880 804)~ under reaction condition~ which are known and uitable for ~aid reactions~ it al~o being pos~ible to make use of variant~ ~lown per ~e, which are not mentioned in greater detail here.
If desired, the st~rting l~aterials can also be formed i~ ~itu, so that they are not i~olated from the reaction mixture but Lmm~diately reacted further to give the compounds of f ormula I.
~ The compounds of for~ula I can preferably be obtained by rea~ting compound~ of formula TI with com-pound~ of formula IIIo In the compound~ of formula II, ~ is preferably Cl, Br, I or an 0~ group which ha~ bee~ functionally modified to acguire reactivity, ~uch as alkyl~ulfonyloxy having 1-6 C atoms ~preferably methyl~ulfonyloxy) or arylaulfonyloxy having 6-10 C atoms ~preferably phenyl-or p-tolyl-sulfonyloxy).

20~4~3~

The reaction of II with III i8 conveniently carried out by fir~t converting III to a salt by treatment with a base, ~or ex~mple with an alkali metal alcoholate such as CH30Na or pota~ium t~rt-~utylate in an alcohol such as C~30~, or with an alkali metal hydride gUCh a8 ~aH or an alkali metal alcoholate in dimethyl-formamide (DMF), and then reacting said salt with II in an inert solvent, for example an amide such as DMF or dimethylacet~mide, or a 3ulfoxide such a~ dimethyl sulfoxide (DMSO), conveniently at temperatures of between -20 and 100, pref~rably of between 10 and 30. Other suitable ba~es are alkali metal carbonate~ such as ~a2CO3 or ~2CO3, or alkali metal hydrogen carbonates such as NaHCO3 or ~03.
Some of the starting materials, especially those of formula III, are known. If they are not known, they can be prepared by known method~ analogously to known substances.
Compounds of formula II are novel. Compourlds of formula II lE = Br~ can be obtained for example by reaction of 5-methylsalicylaldehyde with an ~-R1-2-R2-benzyl bromide of formula IV to glve an ~-Rl-2-R2-benzyl ether of formula V:

R~ H3C CHO
Br~C~ ~ ~ CHR

IV V

2S cycli~ation with the eliml~ation of water ~for example with ~/DMF) ~o give the corresponding 3-Rl-2-(2-R2-phenyl)-5-methylbenzofuran ~formula II with ~ in place of E) and bromination (for ~xample with N-bromo~uccinLmide~.
A compound of formula I can also be freed from one of it~ functional derivative~ by treatment with a solvolysing (for example hydrolysing) or hydrogenolysing 2~3~73~

agent.
Thu~ it i~ po~ible, usins one of the methods indi~ated, to prepare a compound which has formula I but in which a tetrazol-S-yl group is replaced with a S tetrazol~S-yl group functionally modified in the 1-position (protected by a protecting group). Example~ of suitable protecting groups are: triphenylmethyl, which can be cleaved with ~Cl or formic acid in an inert solvent or solvent mixture, for example ether/methylene chloride/methanol; 2-cyanoethyl, which can be cleaved with NaO~ in water/~F; and p-nitrobenzyl, which can be cleaved with H2/Raney nickel in ethanol (compare European patent application A2-0 291 969~
It is also possible to convert one compound of formula I to another compound of formula I by converting one or more of the radicals R~, R2 and/or R to other radicals Rl, R2 ~nd/or R, for example by reducing nitro groups to amlno groups (for example by hydrogenation on Raney nickel in an inert solvent such as methanol or ethanol), and/or functionally modifying free amino and/or hydroxyl groups, and/or freeing functionally modified amlno and/or hydroxyl groups by solvolysis or hydro-genoly~is, and/or replacing halogen atom~ with C~ groups (for example by reaction with copper(I3 cyanide), and/or 2g hydrolysing nitrile group8 to COO~ groups, or co~verting nitrile group~ to tetrazolyl group~ with hydrazoic acid derivatives, for e~ample ~odium azide in N-methyl-pyrrolidone ~r trimethyltin a~ide in toluene.
Thus, for e~ample, free amino group~ can be acylated in conventional ~an~er wi~h an acid chloride or anhydride, or free hydro~yl and/or N~ groups ca~ be alkylated with an u~ub~titu~ed or ~ub~tituted alkyl or Ar alkyl halide, conveniently in an inert ~olv~nt ~uch a~
methylene chloride or T~E', and/or in the pre~ence of a 35 base such a~ triethylamine or pyridine, at temperature~
of between -60 and +30. The conver~ion of a radical R
wherein R~ = ~ to another radical R wherein R4 i~ other than H i8 Lmportant. Thi~ reaction i~ preferably carried 2~7~

out in an acid amide ~uch a~ D~F, N methylpyrrolido~e, 1,3-dimethyl~2-oxohexahydropyrimi dine or h~xametbyl-phosphorotriamide, an alcohol such a~ m thanol or tert-butanol, an ether such a~ THF, or a halogenated S hydrocarbon such a~ methylene chloride, or mixtures thereof, a the solvent, and/or in the pressnce of an alkali metal alcoholate such as sodium methylate or potassium tert-butylate, an alkali metal hydride such as odium or potassium hydride, an alkali metal carbonate such a~ sodium or potassium carbonat0, an alkali metal bicar~onate such as ~odium or pota~sium bicar~onate, or a tertiary amine such a~ triethylamine or ethyldii~o propylamine, at temperature~ of between about -30 and 200, preferably of between 20 and 60.
1~ If desired, a functionally modified amino and/or hydroxyl group in a compound of formula I can be freed by solvolysi~ or hydrogenolysi~ using conventional method~.
Thu~, for example, a compound of for~ula I containing an N~COCF3 or CoOR3 group (wherein R3 i3 other than ~) can be conv~rted to the corre~ponding compound of formula I
containing an N~2 or ~OOC group instead. Ester groups can be saponified for example with NaO~ or KO~ in water, watèr~T~F or water/dioxane, at temperatures of between 0 and 100.
The reaction of nitrile~ of formula T (R1 and/or R2 - C~) with hydrazoic acid derivatives leads to t~trazoles o~ formula I (R1 and/or ~2 = tetrazol-5-yl).
It iB preferable to U8~ trialkyltin azide~ such as trLm~thyltin azide, in an inert ~olvent, for example a~
aro~atic hydr~carbo~ su~h a~ toluene, at temperatures of between 20 and 150, preferably of b~tween 80 and 140, or 30dium azide in ~-methylpyrrolidone at temperatures of between abol1t 100 and 200.
A ba~e of formula I can be converted with an acid to the corre~ponding acid addition ~alt. Po~ible acids ~or this reaction are especially tho~e which yield physiologically acceptable salts. Thus it i~ possible to use inor~anic acids, for example sulfuric acid, nitric 2~8~ 736 acid, hydrohalic acid3 such a~ hydrochloric acid or hydrobromic acid, phosphoru~ acids such as ortho-phosphoric acid, and sulfamic acid, a~ well as organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monoba6ic or polyba~ic carboxylic, Rulfonic or sulfuric acids, for example formi c acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic asid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid~ nicot~nic acid, i~onicotinic aeid, methane- or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene~mono~ulfonic and -disulfonic acids and laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be nsed for isolating and/or purifying the compounds of formula I.
On the other hand, compounds of formula I con-taining COOH or tetrazolyl groups can be converted withbase~ t~or example ~odium or potas~ium hydroxide or carbonate) to the corresponding ~tal salts, e~pecially alkali metal or alkaline earth ~3tal salts, or to the corre~ponding ammonium salt~. ~he potas~ium ~alt4 of the 2S tetrazolyl derivative~ are particularly preferred.
The novel co~pound~ of formula I and their phy~iologically acceptable salt~ can be used for the manufaoture of pharmaceuti~al preparation~ by incor-poratio~ into a suitable dosage form together with at lea~t one excipient or ad~unct and, if desired, togPther with one or ~ore other active ingredi~t~O The resulting fo~mulations can be u~ed a~ drug~ in hu~an or veterinary medicine. Pos3ible excipient~ are organic or inorganic sub~tance~ which are ~litable for e~teral (for example oral or rectal) or parenteral administration or for administration in the form of a~ inhalation ~pray, and which do not react with ~he novel compoundY, examples being water, vegetable oil~, benzyl alcohol~, 208~736 polyethylene glycols, glycerol triacetate and other fatty acid glyceride~, gelatin, soya lecithin, carbohydrat~s such as lactose or ~tarchf magne~ium stearate, talc and cellulos0. Tablets, coat~d tablet~, cap~ule~, ~yrups, S juices or drops~ in particular, are used for oral administration; lacquered tablets and capsules with coatings or shells resistant to gastric juices are of special interest. Suppositories are used for rectal administration and solutions, prefer~bly oily or aqueous solutions, as well as suspensions, emulsions or implants, are used for parenteral administration. For admini~-tration as inha~ation sprays, it i~ possible to use sprays containing the active ingredient either dissolved or suspended in a propellant mixture (for example fluoro-chlorohydrocarbon~j. It i~ convenient here to use theactive ingredient in micronised form, it being possible for one or more additional physiologically compatible solvents, for example ethanol, to be present. Inhalation solutions can be administered with the aid of conven-~0 tional inhalers. The novel compounds can also be lyo-philised and the resulting lyophili~ates used for example for the manufacture of injectable preparations. The indicated formulation~ can be st:erilised and/or can contain adjun~t~ such as preservative~, stabilisers and/or wetting agent3, emulsifier~, ~alts for influencing the o~motic pre~sure, buffer 3ub~tance~ and colours and/or flavouring~ de~ired~ they can al~o contain one or more other active ingredien~ or ex~ple one or more vitsmin3, diuretic~ or antiphlogistic~.
. 30 The ~ub~tances according to the invention are normally admini~tered analogously to other known, com-mercially available preparations, but in particular analogou~ly to the compounds described in US patent 4 880 804, preferably in dose3 of between about 1 m~ and 35 1 g, especially of between 50 and 500 mg per dosage unit.
The daily do~e i8 preferably between abollt 0.1 and 50 mg/kg, e~pecially between 1 and 100 mg/~g of body weight. However, the particular dose for each individual 2~73~

patient depends on a ve~y wide variety of factor~, for example on the efficacy of the particular compound u8ed, age, body weight, general ~tate of health, sex, diet~
time and mode of administration, rate of excretion, d~ug combination and ~everity of the particular disease to which the therapy i~ applied. Oral administration is preferred.
Above and below, all temperatures are given in C. In the following Examples, ~conventional working-upl~ means: Water is added if necessary, the p~ isadjusted to between 2 and 10 if nece~sary, depending on the constitution of the end product, extraction is carried out with ethyl acetate or methylene chloride and the organic phase i~ ~eparated off, dried over sodi~m sulfate/ evaporated and purified by chromatography on silica gel and/or by cry tallisation. MS (FAB) = mass spectrum (obtained by the fast atom bo~bardment method).

A solution of 0.23 g of Na in 20 ml of methanol i~ added dropwise over 15 min to a solution of 3.2 g of 2-butyl-1(or 3)~-Lmidazo[4,5-b]pyr}.dine in 75 ml of methanol. The mixture i8 ~tirred for a further 30 min at 20 and evaporated, the re~idue $~ dis~olved in 20 ml of ~MF, a~d ~ ~olution o 3.45 g of 5-bromomethyl-2-(2~methoxycarbonylphenyl)ben~ofuran in 10 ml of DMF i8 added dropwise at 0, with ~irring. The mixture is ~tirred for 16 hour~ at 20, evaporated, worked up ~n conventional mann~r a~d chromatographed on silica ~el to give 2-~utyl-3-(2-(2-methoxqcarbonylphenyl)benzo-furan 5-ylm~thyl) 3H-imidazo[4,5-b3pyridine.

xamDl~ 2 ~a) l-e9 g f 2-butyl-7-methyl-3H-Lmidazot4,5-b~-pyridine (m.p. 75-76) are di~olved in 60 ml o~
DMF, 1.44 g of potas3ium carbonate are added at ~10 to -14, the mixture i~ ~tirred for 40 min at -14 and a ~olution of 5.97 g of 5-hromomethyl-2-(2~

2~8~73~ `

triphenylmethyl- lH-tetrazol-5-yl)phenyl~benæofuran ("A") in 120 ml of DMF i~ added dropwise. The mixture is then stirred for a further 2 hour~ at -14 and 16 hours at 20, evaporated and worked up with water/ethyl acetate. After chromatography first with methylene chloride/methanol ~8:2 and then with toluene/ethyl acetate 8:2, 2-butyl-7-methyl-3-(2-(2-(1-triphenylmethyl-1~-tetrazol-5-yl)phenyl)-benzofuran-5-ylmethyl)-3~-Lmidazo[4,5 b]pyridine is obtained: Rf 0.61 (methylene chloride/methanol 97:3); MS ~FAB) 70~.
The starting material "A" i~ obtained as follows:
The bromlnation of o-tol~onitrile in carbon tetrachloride ( W irradiation~ gives o-bromomethyl-benzonitrile (m.p. 69). This is rea~ted with 5-methylsalicylaldehyde in acetone, in the presence of potassium carbonatel to give 2-(o-cyanobenzyloxy)-5-methylbenzaldehyde (m.p. 99). Cyclisation with Na~ in DMF under argon at 20 give~ 2-o-cyanophenyl-5-methyl-benzofuran (mOp. 112-113), which i9 converted to 2-o-(1-trimethyl~tannyl-1~-tetrazol-S-yl)phenyl-5-methylbenzofuran ~m.p. 289 (decomposition)] with trimethyltin azide in boiling toluene. Cleavage of the protecting group with ~Cl in methanol/ether gives 2-~2 (1~-tetrazol-5-yl)phenyl~-5-methylbenzofuran, which i~ converted in ~he crude ~tate to 2-~2~ triphenyl-methyl~lH-tetrazol-S-yl)phenyl]-5-methylbenzofuran (m.p.
167~ with triphenylchloromethane in methylene chloride, in the pre3e~ce of triethylAmine. Bromination with M-bromo3uccini~;de gives ~A~ ~m.p. 169)~
(b) The product obtained according to (a) (Rf 0.61;
1 g) i~ dissolved in 60 ml of 4 n ~Cl i~ dioxane and th~ solution i~ ~tirred for 16 hours at 20. After evaporatio~ and conventional working-up, 2-butyl-7 . 35 methyl-3-(2-t2-(lH-tetrazol-5-yl)phenyl)-benzof uran-S-ylmethyl ) - 3~-imidazo t 4, 5 -b ] pyridine is obtained: m.p. 250 (decompo~ition); MS (FAB) 464.
The following are obtained analogously:

2~736 from 2-ethyl-5,7-dLmethyl~3~ imidazo[4,5-b]pyridine and "A": 2~ethyl-5,7~dimethyl-3-(2-(2 (l-triphenylmethyl-1~-tetrazol-5 yl~phenyl~benzofuran-5-ylmethyl)-3~-imidazo[4,5-b3pyridine, and from the latter with ~Cl/dioxane 2-ethyl-5,7-dim~thyl-3-(2-(2-(lH-tetrazol-5-yl)phenyl)benzofuran-5-ylmethyl)-3H-imidazo[4,5-b]
pyridine, m.p. 256;
from 2-butyl~5-(2-carboxybenzyl)-4,5-dihydro-4-oxo-3~-imidazo[4,5-c]pyridine t"C"; obtainable by the hydro-genolysi~ of 3-benzyl-5-(2-benzyloxycarbonylbenzyl)-2-~utyl-4,5-dihydro-4-oxo-3~-imidazo[4,5-c]pyridine) and "A": 2-butyl-5-(2-carboxybenzyl)-4,5-dihydro-4-oxo-3-(2-(2-(1-triphenylmethyl-lH-tetrazol-5-yl)phenyl)-benzofuran-5-ylmethyl)-3~-Lmldazo[4,5-c~pyridine, and from the latter with ~Cl/dioxane: 2-butyl-5-(2-carboxy-benzyl)-4,5-dihydro-4-oxo-3-(2-(2-(lH-tetrazol-5-yl)-phenyl)benzofuran-5-ylmethyl)-3B-imidazo[4,5-c]pyridine;
from 2-butyl-4,5-dihydro-4-oxo-3~-imidazo r 4,5-c]pyridine and "A"- 2-butyl-4,5-dihydro-4-oxoo3-(2-(2-(1-triphenylmethyl-1~-tetra~ol-5-yl)phenyl)benzofuran-5-ylmethyl)-3~-imidazo[4,5-c]pyridine, and from the latter with ~Cl/dioxane: 2-butyl-4,5-dihydro-4-oxo-3-t2-(2-(1~-tetrazol-5-yl)phenyl) benzo f uran-5 -ylmethyl)~
3~-imidazo~4,5-c~pyridine;
f rom 2-bu~yl-5-carboxymethyl-4,5 dihydro-4-oxo-3~-Lmidazo[4,5-c]pyridine tobtainable by the hydrogenoly~is of 3-benzyl-5-benzyloxycarbonylmethyl-2-butyl-4,5-dihydro-4-oxo-3~imidazot4,5-c3pyridine) and "A":
2-butyl-5-carboxymethyl-4~5-dihydro 4-oxo-3~(2-(2~
triphenylmethyl-1~-tetrazol-5-yl)phenyl)benzofuran-5-ylmethyl3-3H-Lmidazo~4,5-c]pyridine, and from the latter with HCl/dioxane: 2-butyl-5-carboxymethyl-4,5-dihydro-4-oxo-3-(2-t2-(1~-tetrazol-5-yl)phenyl)benzo furan-5-ylmethyl ) -3~-imidazo[4,5-c]pyridine.

35 ~3xample 3 The following are obtained analogously to Example 2a) with 5-bromomethyl-2-(2-cyanophenyl)benzofuran :

2~8~73~

2-butyl-3-(2-(2-cyanophenyl)benzofuran-5-ylmethyl)-7-methyl-3~-imidazo[4~5-b]pyridine;
3-(2-(2-cyanophenyl)benzofuran-5-ylmethyl)-2-ethyl-5,7-dimethyl-3~-imidaza[4,5-b]pyridine;
2-butyl-5-(2-carboxyb~nzyl)-3-(2-(2-cyanophenyl)benzo-furan 5-ylmethyl)-4,5-dihydro-4-oxo-3H-imidazo~4,5-c]pyridine;
2-butyl-3-(2-(2-cyanophenyl)benzofuran-5-ylmethyl)-4,5-dihydro-4-oxo-3~-imidazo~4,5-c]pyridine;
2-butyl-5-carboxymethyl-3-(2-(2-cyanophenyl)benzofuran-5-ylmethyl)-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine.

Example 4 The following are obtained analogously to Example 2 from the starting materials of formula III given therein with 3-bromo-5-bromomethyl-2-(2-(1-tri-- phenylmethyl~ tetrazol-5-ylphenyl)benzofuran:
3-(3-bromo~2-~2-(1-triphenylmethyl-lH-tetrazol-5-yl) phenyl)benzofuran-S-ylmethyl)-2-butyl-7-methyl-3H-imidazot4,5 b]pyridine, and from the latter: 3-~3-bromo-2-(2-(1~-tetrazol-5-yl)phenyl)benzofuran-5-yl methyl)-2-butyl-7-methyl-3~-imidazo r 4,5-b]pyridine;
3-(3-bromo-2-(2~ triphenylmeth~yl-1~-tetrazol-5-yl) phenyl~be~zofura~-5-ylmethyl)-2-ethyl-5,7-dimethyl-3~-LmidazoL4,5-b~pyridine, and from the latter: 3-(3-bromo-2-(2~ tetrazol-5-yl~phenyl)benzofuran-5~yl-methyl)-2-ethyl-5,7-dimethyl-3~-Lmidazo[4,5-b~pyridine;
3-(3-bromo 2~ triphenylmethyl~ tetrazol-5-yl)-phenyl)benzofuran-5-ylmethyl)-2-butyl-5-(2-~arboxy-benzylj-4,5-dih~dro-4-oxo-3~-imidazo[4,5-~]pyridine, and from the latter: 3-(3-bromo-2-(2-tlH-tetrazol-5-yl)phenyl)benzofuran-5-ylmethyl)-2-butyl-5-(2-carboxy-benzyl)-4,~ dihydro 4-oxo-3~-imidazo[4,5-c]pyridine;
3-(3-bromo-2-(2-(1-triphenylmethyl~ tetrazol-S-yl)-phenyl ) benzofurarl-5-ylmethyl ) ~2-butyl-4, 5-dihydro-4-oxo-3E~-imidazot4,5-c]pyridine, and from the latter: 3-(3-bromo-2-(2-(1~-tetrazol-5-yl)ph~nyl)benzofuran-5-ylmethyl)-2-butyl-4,5-dihydro-4-oxo-3~-imidazo~4,5-c]-2~73~

pyridine;
3-(3-bromo-2-(2-(1-triphenylmethyl-1~-tetrazol-5-yl)-phenyl)benzofuran-5-ylmethyl)-2-butyl-5-carboxymethyl-4,5-dihydro-4-oxo-3H-Lmidazo[4,5-c~pyridine, andfromthe latter: 3 (3-bromo-2-(2~ tetrazol-5-yl~phenyl)-benzofuran-5 ylmethyl3-2-methyl-5-carboxymethyl-4,5-dihydxo-4-oxo-3H-imidazo[4,5-c]pyridine.

Example 5 The following are obtained analogously to Example 2a) from 2-butyl-l(or 3)~-imidazo[4,5-b]pyridine:
with 5-bromomethyl-2-(2-~itrophenyl)benzofuran: 2-butyl-3-(2-(2-nitrophenyl)benzofuran-5-ylmethyl)-3H-imidazo[4,5-b]pyridine;
with S~bromomethyl-2-(2-trifluoroacetamidophenyl)-benzofuran: 2-butyl-3-(2-(2-trifluoroacetamldophenyl)-benzofuran-5-ylmethyl) 3H imidazo[4,5-b]pyridine;
with 5-bromomethyl-2-(2-cyanophenyl)-3-fluorobenzofuran:
2-butyl-3-(2-(2-cyanophenyl~-3-fluorobenzofuran-5-ylmethyl)-3H-imldazot4,5-b~pyridine;
with 5-bromomethyl-3-chloro-2-(2-ethoxycarbonylphenyl)-benzofuran: 2 butyl-3-(3-chloro-2-(2-ethoxycarbonyl-phenyl)benzofuran-5-ylmethyl)-3~-Lmidazo[4,5-b3pyridine~

:~x~.
A mixture of 1 g of 2-butyl-3-(2-(2-methoxy-carbo~ylphenyl)benzofura~-5-ylmethyl)-3H-imidazo[4,5-b]pyridîne, 12 ml of 2 n aqueou~ NaO~ solution and 48 ml of etha~ol i~ boiled for 2 hour~ and then evaporated.
Acidification to p~ 3 with HCl give~ 2-butyl-3-(2-(2-carboxyphenyl)benzofuran~5~ylmethyl)~3~-imidazo ~0 t4,5-b]pyridine, which i8 filtered off, washed with water and dri~d.

Exa~ple 7 A mixture of 420 mg of 2-butyl-3-(2-(2-cyano-phenyl)benzofuran-5-ylmethyl)-7-methyl-3~-imidazo-[4,5b]pyridine, 206 mg of trimethyltin azide and 15 ml of - 18 - 2~ 7~ ~
xylene i~ boiled for 96 hour~. After 48 hours, a further O.2 g of trLmethyltin azide is added. The mixture i8 cooled, treated with et~ereal hydrochloric ac.id and evaporated. Conventional working-up give~ 2-butyl-7-methyl-3 (2-(2~ tetrazol-5-yl)phenyl)benzo-furan-5 ylmethyl)-3~Lmidazo[4,5-b]pyridine, mOp. 250 (decomposition).
The corresponding K salt is prepared therefrom in conventional manner.

~xam~le 8 A solution of 1 g of 2-butyl-3-(2-(2-nitro-phenyl)benzofuran-5-ylmethyl)-3~-im~dazot4,5-b]pyridine in 30 ml of ethanol i~ hydrogenated on 1 g of Raney Ni at 20 and normal pressure until the uptake of H2 ha~ ceased~
The m1xture is filtered and evaporated to give 3-(2-(2-aminophenyl)benzofuran-5-ylmethyl)-2-butyl-3~-imidazo[4,5-b]pyridine.

~xample 9 A solution of 2.82 g of trifluoromethanesulfonic anhydride in 10 ml of methylene chloride is added dropwi~e at -50 to -60 to a ~olution of 3.96 g of 3-(2-(2 aminophenyl)benzofuran-5-ylmethyl) 2-butyl-3~-Lmidazot4,5-b]pyridine and 1.01 g of triethylamine in 30 ml of methylene chloride. The mixture is left to warm up to 20 and poured into dilu~e acetic acid to give 2-butyl 3-(2-(2-trifluoromethan~sulfonamidophenyl)-benzofuran-5-ylmethyl)~3~-Lmidazol4,5-b~pyridine after conventional working-up.

xample 10 A qolution of 0.79 g of chloroacetonitrile in 5 ml of DMF i~ added dropwise at 20 to a ~olution of 7.07 g of 2 butyl-3-(2-(2-tl-triphenylmethyl 1~-tetra-zol-5-yl3phenyl)be~zofuran-s-ylmethyl)-4~5-dihydro-4-oxo-3~-Lmidazot4,s-c]pyridine and 1.17 g of potassi~m tert-butylate in 25 ml of DMF, with stirring. The 2~73~

mixture iB stirred for a further 30 min at 20 and poured on to ice, hydrochloric acid i5 added to pH 6 and the mixture ic worked up in conventional manner to give 2-butyl-5-cyanomethyl-3~ (2~ triphenylmethyl-lH-S tetrazol-5-yl)phenyl)benzofuran-5-ylmethyl)-4,5-di-hydro-4-oxo-3~-imidazo[4,5-c]pyridine.
The following 2-butyl-3-l2-(2-(1-triphenyl-methyl-l~-tetrazol-5-yl)phenyl)benzofuran-5-ylmethyl)-4,5-dihydro-4-oxo-5-R4-3~-imidazo[4,5-c]pyridines are 10 obtained analogously:
with methyl iodide: 5-methyl-with ethyl iodide: 5-ethyl~
with isopropyl iodide~ S-isopropyl-with butyl bromide: 5-butyl-15 with tert-butyl bromide: 5-tert-butyl-with 3-bromopropionitrile: 5-(2-cyanoethyl)-with 4-bromobutyronitrile: 5-(3-cyanopropyl)-with methyl bromoaeetate: 5-methoxycarbonylmethyl with ethyl 3-bromopropionate: 5-(2-ethoxycarbonylethyl)-with benzyl bromide: 5-benzyl-with o-fluorobenzyl bromide: 5-to-fluorobenzyl)-with m-fluorobenzyl bromlde: 5-(m-fluorobenzyl)-with p-fluorobenzyl bromlde: 5-(p-fluorobenzyl)-with o-chlorobenzyl bromide~ 5-(o-chloro~enzyl)-~5 with m-chlorobenzyl bromide: 5-(m-chlorobenzyl)-with p-chlorobenæyl bromide: 5~(p-chlorobenzyl)-with o-bromobenxyl bromide: 5-(o-bromobenzyl)-with m-bro~ob zyl bromide: 5-(m-bromobenzyl)-with p-bromobe~zyl brom1de: 5~-(p-b~omobenzyl)-with p-~ethylbenzyl bromide: 5-(p-m~thylbenzyl~-with o-trifluoromethylbenzyl bromide: 5-(o-trifluoroMethyl-ber~zyl ) -with m-trifluoromethylbenzyl bromide: 5 (m-trifluoromethyl-benzyl)-with p-trifluoromethylbenzyl bromide: 5-(p-trifluoromethyl-benzyl)-with o-methoxycarbonylbenzyl brom1de: 5-(o-methoxycarbonyl-benzyl)-with m-methoxycar~onylbenzyl bromide: 5-(m-methoxycarbonyl-benzyl)-with p-methoxycarbonylbe~yl bromide: 5-(p-m~thoxycarbonyl-benzyl)-with o-cyanobenzyl brcmide: 5-~o-cyanobenzyl)-with m-cyanobenzyl bromide: 5-(m-cya~ob nzyl)-with p-cyanobenzyl bromlde: 5-(p-cyanobenzyl)-with o-nitrobenzyl chloride: S-(o-nitrobenzyl)-with m-nitrobenzyl chloride: 5-(m-nitro~enzyl)-with p-nitrobenzyl chloride: 5-(p-nitrobenzyl)-with o-trifluoroacetamido-benzyl bromideo 5-(o-trifluoroacetamido-benzyl)-with m-trifluoroacetamido-benzyl bromlde: S-(m~trifluoroacetamldo-benzyl)-with p-trifluoroacetamido benzyl bromide: 5-(p-trifluoroacetamido~
benzyl)~
with o-trifluoromethyl~ul-fo~amidobenzyl bromide: 5-~o-trifluoromethylsul-fon~midobenzyl)-with m-trifluoro~ethylsul-fonamidobenzyl bromide: 5-(m-trifluoromethylsul-fonamldobenzyl)-with p-trifluoromethyl~ul~
fonamidobenzyl bromide: 5-(p~trifluoromethyl~ul-fonamidobenzyl)-.

2~8~73~

~am~le 11 The following 2-butyl-4,5-dihydro-4-oxo-3-(2-~2-(1~-tetrazol-5-yl)phenyl)benzofuran-5~ylmethyl)-5-R4-3H-imidazo[4,5-c]pyridines are obtained analogously to Example 2b) ~rom the compounds described in Example 10:
5-cyanomethyl-5-methyl-5-ethyl-5-isopropyl-5-butyl-5-tert-butyl-5-(2-cyanoethyl)-5-(3-cyanopropyl)-5-methoxycarbonylmethyl- (alRo 5-carboxymethyl-) 5-(2-ethoxycarbonylethyl)- [also 5-52-carboxyethyl)-]
5-benzyl-5-(o-fluorobenzyl)-5-(m-fluorobenzyl)-S-(p-fluoroben~yll-5-(o-chlorobenzyl)-5-(m-chlorobenzyl)-5-(p-chlorobenzyl)-5-(o~bromobenzyl)-5-(m-bromobenzyl)-5-(p-bromobenzyl)-5-(p-methylbenzyl)-5-(o-trifluoromethylbenzyl)-5-(m-trifluoromethylbenzyl)-5-(p-trifluoromethylbenzyl)-5-(o-methoxycarbonylbenzyl)- [al~o 5-(o-~arboxy benzyl)]
s-~m-methoxycarbonylbenzyl)- tal~o 5-tm-carboxy benzyl)]
5-(p-methoxycarbonylbenzyl)- [ al80 5-(p-carbo~y benzyl)]
5-(o-cyanobenzyl)-5-(m-cyanobenzyl)-5-(p-cyanobenzyl)-2~8~73~

5-(o-nitrobenzyl)-5-(m-nitrobenzyl) 5-(p-nitrobenzyl)-S-(o-trifluoroacetamidobenzyl)-S-(m-trifluoroacetamidobenzyl)-5-(p-trifluoroacetamidobenzyl)-S-(o-trifluoro~ethylsulfonamidobenzyl)-5-(m-trifluoromethylsulfonamidohenzyl)-5-(p-trifluoromethylsulfonamidobenzyl)-.

xample 12 Tha following 3-(3-bromo-2-(2-(1-triphenyl-methyl~ tetrazol-5-yl)phenyl)benæofuran-5-ylmethyl)-2-butyl-4,5-dihydro-4-oxo-5-R4-3~-imidazo[4,5-c]pyridines are obtained analogously to Example 10 by reaction of 3-(3-bro~o-2-(2-(1-triphenylmethyl-1~-tetrazol-S-yl)phenyl)benzofuran-5-ylmethyl)-2-butyl-4,5-dihydro-4-oxo-3~-imidazo[4,S-c]pyridine with chloroacetonitrile or with the other alkylating agents indicated in said ~xample-5-cyanomethyl-S-methyl-S-ethyl-5-i~opropyl-5-tert-butyl-5~ cyanoethyl)-5-(3 cyanopropyl)- .
S-metho~ycarbo~ylmethyl-5-(2-ethoxycarbonylethyl)-S-benzyl-5-(o-fluorobenzyl)-S-(m-fluorobenzyl)-S-(p-fluorobenzyl~-S~(o-chlorobenzyl)-5-(m-chlorob~nzyl)-5-(p-chlorobenzyl)-5-(o-bromobenzyl)-5-(m-bromobenzyl)-S-(p~bromobenzyl)-5~(p-methylbenzyl)-5-(o-trifluoromethylbenzyl)-5-(m-trifluoromethylb~nzyl)-5-(p-trifluoromethylbenzyl)-5~(o-methoxycarbonylbenzyl)-5-(m-methoxycarbonylbenzyl)-5-(p-methoxycarbonylbenzyl)-5-(o-cya~obenzyl)-5-(m-cyanobenzyl)-5-(p-cyanobenzyl)-5-(o-nitrobenzyl)-5-~m-nitrobenzyl)-5-(p-nitrobeazyl)-5-(o-trifluoroacetammdobenzyl)-5-(m-trifluoroacetamidobenzyl)-5-(p-trifluoroacetamidob~nzyl)-5-(o-trifluoromethylsulfonamidobenzyl)-5-(m-trifluoromethylsulfonamidobenzyl)-5-(p-trifluoromethylsulfonamidobenæyl)-.

The followi~g 3-(3-bromo-2-(2-(1~-tetrazol-5-yl)phenyl)benzofuran-S-ylmethyl)-2-butyl-4,5-dihydro-4-oxo-5-Rs-3~-imidazot4,5 c~pyridine~ are obtained analo-~ously to Exa~ple 2b~ fr3m the compounds de~c~ibed in~xample 12:
5-cyallomethyl-5-me~hyl-3 0 S -ethyl -5 -i80propyl -5-tert-butyl 5-(2~cyanoethyl~
5O(3-cya~opropyl)-5-methoxycarhonylmethyl- (al~o 5-carboxymethyl-) 5-(2-ethoxycarbonylethyl~- talso 5~(2-carboxyethyl.)-]
5-benzyl-2~8~73~

5-(o fluorobenzyl~-5-(m-fluorobenzyl)-5~(p-fluorobenzyl)-5 (o-chlorobenzyl)-5-(m-chlorobenzyl)-5-(p-chlorobenzyl)-5-(o-bromobenzyl)-5-(m-bromobenzyl)-5-(p-bromobenzyl)-5-(p-methylbenzyl)-5-(o-trifluoromethylbenzyl)-5-(m~trifluoromethylbenzyl)-5-(p-trifluoromethylbenzyl)-5-(o-methoxycarbonylbenzyl)- [al~o 5-(o-carboxy benzyl~]
5-(m-methoxycarbonylben~yl)- [also 5-(m-carboxy benzyl)]
5-(p-methoxycarbonylbenzyl)- ~also 5 (p carboxy benzyl)]
5-(o-cyanobenzyl)-S-(m-cyanobenzyl)- ~ -5-(p-cyanobenzyl) 5-~o nitrobenzyl)-5-(m-nitrobenzyl)- ~-5-(p-nitrobenzyl)-5- ~ o-trif luoroacetamidobenzyl)-5~ trifluoroacetamldobenzyl)-5-(p trifluoroacetamldobenzyl)-5-(o-trifluoro~ethyl~ulfona~idobenzyl)-5-(m-trifluoro~ethyl~ulfonamidoben2yl)-5-(p-trifluoromethylsulfonamidobenzyl)-.

E~ample 14 A ~olution of 1 g of 2-butyl-4,5-dihydro-5-(o-nitrobenzyl)-4-oxo-3-(2-(2~ -tetrazol-5-yl)phenyl)-benzofuran-5-ylmethyl)-3~-Lmidazol4,5-c]pyridine in 20 ml of methanol is hydrogenated on 0.3 g of 5% Pd-on-charcoal at 20 and normal pres~ure until the calculated 2~8~7~6 a~ount f ~2 ha~ been taken up. The catalyst is filtered off and the filtrate i8 evaporated to give 5-~o amino-benzyl) 2-butyl 4,5-dihydro-4-oxo-3-(2-(2~
tetrazol-5 yl)phenyl)benzofura~-5-ylmethyl)-3B-imidazo-[4~5-c]pyridine~
The following 2-butyl-4,5-dihydro-4-oxo~3-(2-~2-(1~-tetrazol-5-yl)phenyl)benzofuran-5-ylmethyl)-3~-imidazo[4,5-c]pyridines:
.5-(m-aminobenzyl) 5-(p-aminobenzyl)-, or the followiny 3-t3-bromo-2-(2~ -tetrazol-5-yl)-phenyl)benzofuran-5-ylmethyl)-2-butyl-4,5-dihydro-4-oxo-4~ imidazo[4,5-c]pyridine~:
5-(o-aminobenzyl)-5-(m-aminobenzyl)-5-(p-aminobenzyl)-, are obtained analogously by hydxoqenation of the cor-responding nitro compounds mentioned in Example 11 or 13 re~pectively.
The following Examples relate to pharmaceutical formulations containing active ingredients of formula I
or their salts.

~xa~le As Tablet~ and coated tablets Tablet3 of the following composition are produced by compression in conve~tional manner and, where required, are provided with a co~ventional sucrose based co~ting:
Active i~gredient of formula ~100 mg ~icrocrystalline cellulose 278.8 mg 30 Lacto~e 110 mg M~ize ~tarch 11 mg Magne~ium stearate 5 mg Fi~ely divided silicon dioxide0.2 mg ~x~Epl~ B: ~ard gelati~ cap~ules Co~ventional two-part hard gelatin cap~ules are each filled with 2~8~ 7~6 Active ingrsdient of formula I100 mg Lactose 150 mg Cellulose 50 mg Magne~ium stearate 6 mg ~xam~le C: 5Oft gelatin sap~ule~
Conventional ~oft gelatin capsule~ are filled with a mixture of 50 mg of active ingredient and 250 mg of olive oil in each case~

~ample D: ampoules A solution of 200 g of active ingredient in 2 kg of propane-1,2-diol i~ made up to 10 l with water and filled into ampoules so that each ampoule contains 20 mg of active ingredient.

~xa~ple ~: Aqueou~ ~uspen~ion for oral adm;ni~tration An aqueou~ suspension is prepared in conventional manner. The unit dose (5 ml) contains 100 mg of active ingredient, 100 mg of ~odium carboxymethyl cellulose, S ml of sodium benzo~te and 100 mg of sorbitol.

Claims

1. A benzofuran of formula I:
I

wherein R is the radical , R1 is H, Hal, COOH, CONH2, CHO, CN, NH2 or tetrazol-5-yl, R2 is H, COOR3 , CN, NO2, NH2, NHCOCF3, NHSO2CF3 or tetrazol-5-yl, R3 is H, or alkyl, alkenyl or alkynyl each having up to 6 C atoms, R4 i3 H, alkyl having 1-6 C atoms or cyanoalkyl, R3OOC-alkyl, tetrazol-5-ylalkyl or Ar-alkyl each having 1-5 C atoms in the "alkyl" moiety, -A-B-C-D- is one of the groups -CH=CH=CH=N- , -CH=CH-N=CH-, CH=N-CH=CH-, -NH=CH-CH=CH-, -CH=CH-CO- NR4-, -CH=CH-NR4-CO-, -CO-NR4-CH=CH-or -NR4- CO-CH=CH-, wherein the H atoms of the -CH groups can be substituted by alkyl having 1-6 C atoms, Hal, COOR3, CN and/or tetra-zol-5-yl, Ar is phenyl which is unsubstituted or monosub-stituted or disubstituted by Hal, R3, CF3, COOR3, CN, OR3, NO2, NH2, NHCOCF3, NHSO2CF3 or tetrazol-5-yl, and Hal is F, Cl, Br or I, and its salts.

2. a) 2-Butyl-7-methyl-3-(2-(2-(1H-tetrazol-5-yl)-phenyl)benzofuran-5-ylmethyl)-3H-imidazo[4,5-b]-pyridine.
b) 2-Ethyl-5,7-dimethyl-3-(2-(2-(1H-tetrazol-5-yl)-phenyl)benzofuran-5-ylmethyl)-3H-imidazo[4,5-b]-pyridine.
c) 2-Butyl-5-(2-carboxybenzyl)-4,5-dihydro-4-oxo-3-(2-(2-(1H-tetrazol-5-yl)phenyl)benzofuran-5-yl-methyl)-3H-imidazo[4,5-c]pyridine.
d) 2-Butyl-4,5-dihydro-4-oxo-3-(2-(2-(1H-tetrazol-5-yl)phenyl)benzofuran-5-ylmethyl)-3H-imidazo[4,5-c]pyridine.
e) 2-Butyl-5-carboxymethyl-4,5-dihydro-4-oxo-3-(2-(2-(1H-tetrazol-5-yl)phenyl)benzofuran-5-yl-methyl)-3H-imidazo[4,5-c]pyridine.

3. A process for the preparation of benzofurans of formula I according to CLaim 1, and their salts, cha-racterised in that a compound of formula II:
II

wherein E is Cl, Br, I, a free OH group or an OH group which has been functionally modified to acquire reactivity, and R1 and R2 are as defined in Claim 1, is reacted with a compound of formula III:

H-R III

wherein R is as defined in Claim 1, or in that a compound of formula I is freed from one of its functional derivatives by treatment with a solvo-lysing or hydrogenolysing agent, and/or in that one or more radicals R1, R2 and/or R in a compound of formula I are converted to one or more other radicals R1, R2 and/or R, and/or a base or acid of formula I is converted to one of its salts.

4. A process for the preparation of pharmaceutical formulations, characterised in that a compound of formula I according to Claim 1, and/or one of its physiologically acceptable acid addition salts, are incorporated into a suitable dosage form together with at least one solid, liquid or semiliquid excipient or adjunct.

5. A pharmaceutical formulation, characterised in that it contains at least one compound of formula I
according to Claim 1, and/or one of its physiologically acceptable acid addition salts.

6. A compound of formula I according to claim 1, and its physiologically acceptable acid addition salts, for the control of diseases.

7. Use of compounds of formula I according to Claim 1, and/or their physiologically acceptable acid addition salts, for the preparation of a drug.

8. Use of compounds of formula I according to Claim 1, and/or their physiologically acceptable acid addition salts, in the control of diseases.