CA2093290A1

CA2093290A1 - Imidazopyridines

Info

Publication number: CA2093290A1
Application number: CA002093290A
Authority: CA
Inventors: Werner Mederski; Dieter Dorsch; Norbert Beier; Pierre Schelling; Ingeborg Lues; Klaus-Otto Minck
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1992-04-06
Filing date: 1993-04-02
Publication date: 1993-10-07
Also published as: PL298392A1; SK27193A3; ZA932459B; JPH0625239A; HU9300999D0; CN1082045A; DE4211474A1; CZ58193A3; EP0564960A1; NO931302L; NO931302D0; KR930021638A; HUT64342A; AU3673193A

Abstract

Abstract Imidazopyridine derivatives of formula I:

I

wherein R1 to R4 and Y have the meaning stated in Claim 1, and their salts, exhibit antagonistic properties towards angiotensin II and have inter alia a hypotensive action.

Description

2~329V
Merck Patent Gesellschaft mit be~chrankter Haftung 6100 D a r m 9 t a d t Imidazopyridine~

The invention relates to novel imidazopyridine derivatives of formula I:

R~
N
~NR3 N ll Rl I Y f= R2 CH2~3 wherein Rl i9 H or A, 10 R2 is H, Hal, OH, OA, COOH, COOA, CONH2, CN, NOz, NH2, NHA, N(A)2, NHCoR5, NHSO2Rs or lH-5-tetra-~olyl, R3 i~ H, cyanoalkyl, ~r-alkyl, cycloalkylalkyl having 3-8 C atom~ in the cycloalkyl group, Het-al~yl, Ar'-alkyl, R6-CO-alkyl~ Ar-CO-alkyl or Het-CO-alkyl having, in each casa, 1-6 C
atom~ in the 'alkyl' moiety, it being pos~ible for an H atom in the 'alkyl' moiety to be replaced by a COOH or a COOA group, 20 R4 i~ H or Hal, Rs and R6 are ln each case alkyl having 1-6 C atoms, wherein one or more H atom~) can also be replaced by F, Y i9 O or S, 25 A is alkyl, alkenyl or alkynyl in each case having up to 6 C atom~, Ar i9 a phenyl group which i~ un~ub~tituted or mono~ubRtituted by ~al, R~, OH, OA, COO~, COOA, CN, NO2, NH2, NHA, N(A)2, NHCOR5, NHSo2R5 or 1~-5-20~2~a tetrazolyl, Ar' is a phenyl group su~stituted by Ar, Het is a five or six membered heteroaxomatic radical having 1 to 3 N , 0 and/or S atoms, S which can also be conden~ed with a benzene or pyridine ring, and Hal is F, Cl, Br or I, and their salts.
The object of the invention was to find novel compounds with valuable properties, especially compounda which can be used for the preparation of ~ruga.
It has been found that the compounds of fo~nula I and their 3alts possess ~ery valuable pharmacological properties coupled with a good tolerance. In particular, they exhibit antagonistic properties towards angiotensin II and can therefore be used as pharmaceutical active ingredient~ in human and veterinary medicine, especially for the prophylaxis and/or therapy of cardiac, circulatory and vascular diseases and in particular for the txeatment of angiotensin II-dependent hyperten~ion, aldosteronism and cardiac insufficiency, as well as disorders of the central nervous system, furthermore of hypertrophy andhyperælasY
of the blood vessels and the heart, angina pectoris, cardiac infarction, haemorrhagic stroke, restenosis after angio-plasty or by-pass surgery, arteriosclerosis, ocular hyper-tension, glaucoma, macular degeneration, hyperuricaernia, disturbances of the renal functions such as renal failure, diabetic complications such as nephropathia diabetica or ~o retinopathia diabetica, psoriasis, angiotensinII-induces disturbances in female sexual organs, cognitive disorders, f.e. dementia, amnesia, disturbances of the functions of memory, states of fear, depressions and/or epilepsy.

2~32~

The~e effect~ can be determined by conventional in vitro or in vivo method~ such as those deqcribed for example in US Patent 4 880 804 and in W0 91/14367, a~ well a~ thos2 de~cribed by A.T. Chiu et al., S J. Pharmacol. Exp. Therap. 250~, 867-874 (1989), and by P.C. Wong et al., ibid. 252, 719-725 (1990j in vivo, on rat~).
The invention relates to the compounda of formula I, their ~alts and to a process for the preparation of these compounds and their salts, characterised in that a compound of formula II:
~2 E-CH ~ II

2~32~

wherein E is Cl, Br, I, a free O~ group or an OH group which has been functionally modified to ~cquire reactivity, and 5 R2 has the meaning stated in Claim 1, is reacted with a compound of fon~ula III

III

~1 H

wherein Rl, R3, R~ and Y have the meanings ~tated in Clalm 1, or in that a compound of formula I iB liberated ~rom one of its functional derivatives by treatment with a solvolysing or hydrogenolysiny agent, and/or in that one or more radical(~) Rl, R2, R3, R~ and/or Y in a compound of formula I are converted to one or more other radicals R1, R2, R3, R4 andtor Y, and/or a base or acid of formula I is converted to one of its salt~.
Hereinabove and hereinafter, the radicals or parameters Rl to Ra, y, A, Ar, Ar', Het, ~al and E have the~ meanings stated in formulae I and II, unle~s expres~ly indicated otherwise.
In the above formulae, A i9 particularly alkyl having 1-6, preferably 1, 2, 3 or 4 C atom~, preferably methyl, or el~e ethyl, propyl, i~opropyl, butyl, isobutyl, sec-butyl or tert-butyl, or else pentyl, 1-, 2-or 3-methylbutyl, 1,1-, 1,2- or 2,2-dim~thylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl or 1~1,2- or 1~2~2-trLmethylpropyl. However, A can al~o be alkenyl or alkynyl in each ca~e having 2-6, preferably 2, 3 or 4 C atoms, in particular vinyl, 1- or 2-propenyl lallyl), 1-propen-2-yl, 1-/ 2- or 3-butenyl, ethynyl, 1- or 2-propynyl (propargyl), 1-, 2- or 3-butynyl.
Accordingly, the radical OA i9 preferably methoxy, or else ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, ~ec-butoxy, tert-butoxy, vinyloxy, allyloxy, ethynyloxy or propargyloxy. The ~roup COOA i8 preferably methoxycarbonyl or ethoxycarbonyl, or el~e propyloxy-carbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, allyloxycarbonyl, propargyloxy-carbonyl. The group NHA i~ preferably methylamino orethylamino. The group N(A)z i~ preferably dimethylamino or diethylamino.
Hal iB prefe~ably F, Cl or Br, or else I.
The radical Ar is preferably an un~ubstituted phenyl group, or else preferably a phenyl group ~ub-stituted in the p-po~ition or substituted in the o- or m-po~ition. Preferred ~ubstituents are COO~, COOA, NO2 lH-5-tetrazolyl. Accordingly, Ar is preferably phenyl, o-, m- or (e~pecially) p-carboxyphenyl, o, m- or (especially) p-methoxycarbonylphenyl, o-, m- or (especially) p-ethoxycarbonylphenyl, o-, m- or (especially) p-nitrophenyl, o-, m- or (e~pecially) p-(1~-5-tetrazolyl)-phenyl furthermore preferably, o-, m- or (especially) p-aminophenyl, o-, m- or (especially) p-climethylamino-phenyl, o-, m- or (especially) p-diethylaminophenyl, o-, m- or p-tolyl, o , m or p-trifluoromethylphenyl, o-, m- or p-hydroxyphenyl, o-, m or p-methoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-iodophenyl, o-, m- or p-cyanophenyl, o-, m- or p-methylaminophenyl, o-, m- or p-acetamidophenyl, o-, m- or p-trifluoroacetamidophenyl, o-, m- or p-methylsulfonamidophenyl, o-, m- or p-tri-fluoromethylsulfonamidophenyl.
The radical Ar' i~ preferably 4-biphenylyl, 2'-carboxy-4-biphenylyl, 2'-methoxycarbonyl-4-biphenylyl, 2'-cyano-4-biphenylyl or 2' (1~-5-tetrazolyl)-4-biphenylyl.

2~3,5 Het i~ preferably 2- or 3-ruryl, 2- or 3-thienyl, 1 , 2- or 3-pyrrolyl, 1-~, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-i~oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-i~othiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1,2,3-oxadlazol-4- or -5-yl, 1,2,~-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 2,1,5-thiadiazol-3- or -4-yl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, l-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-~ 6 or 7-benzi~oxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzi~othiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1~, 3-, 4-, 5-, 6-, 7- or 8-i~oquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolyl/ 2-, 4-, 5-, 6-, 7- or 8-quinazolyl, lH-1-, -2-, -5-, -6- or -7-imidazo[4,5-b]pyridyl, 3~-2 , -3-, -5-, -6- or -7-im.idazo[4,5-b]pyridyl, 1~-1-, -2-, -4-, -6- or -7-imidazo[4,5-c]pyridyl, 3H-2-, -3-, -4-, -6- or -7-imidazo[4,5-c]pyridyl.
The ter~ "~et" also include~ the homologous radical~ in which the heteroaromatic ring i9 substituted by one or more, prefera~ly 1 or 2, A groups, preferably methyl and/or ethyl groups, for example 3-, 4- or 5-methyl-2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,4-di-methyl-3-furyl, 3-, 4~ or 5-methyl-2-thienyl, 3-methyl-S-tert.-b~tyl-2-thienyl, 2~, 4- or 5-methyl-3-thienyl, 2-or 3-methyl-1-pyrrolyl, 1-, 3-, 4- or 5-methyl-2-pyrrolyl, 3,5-dimethyl-4-ethyl-2-pyrrolyl, 2-, 4- or 5-methyl-1-imidazolyl, 4-methyl-5-pyrazolyl, 4- or 5-methyl-3-i~oxazolyl, 3- or 5-methyl-4-i~oxazolyl, 3- or 4-methyl-5-isoxazolyl, 3,4-dimethyl-5-i~oxazolyl, 4-,or 5-methyl-2-thiazolyl, 4- or 5-ethyl-2-thiazolyl, 2- or ~ t3~ ~ ~

5-methyl-4-thiazolyl, 2- or 1-methyl-5-khiazolyl, 2,4-dimethyl-5-thiazolyl, 3~, 4-, 5- or 6-methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2- or 3-methyl-4-pyridyl,4-methyl-2-pyrimidinyl,4,6-dimethyl-2-pyrimidinyl, 2-, 5- or 6-methyl-4-pyrimidinyl, 2,6-dimethyl-4-pyrimidinyl, 3-, 4-, 5-, 6 or 7-methyl-2-benzofuryl, 2-ethyl-3-benzofuryl, 3-, 4-, 5-, 6~ or 7-methyl-2-benzothienyl, 3-ethyl-2-benzothienyl, 1-, 2~, 4-, 5-, 6- or 7-methyl-3-indolyl, 1-methyl-5- or 6-benzimidazolyl, l-ethyl-5- or 6-benzimidazolyl.
The radical Y i9 preferably 0.
The radical Rl i9 preferably A, in particular butyl, furthermore preferably propyl, pentyl or hexyl.
The radical R2 i8 preferably COOH, f~rthermore preferably 1~-5-tetrazolyl, COOCH3, COOC2Hs, CON~2, CN or NO2 .
Th~ "alkyl" moiety in the radical R3 is in the individual groups preferably -C~2~ or -CH2C~2-, furthermore preferably -CH(CH3)-, -(C~2)3-, -(CH2) 4- ~
-(CH2)5- or -(C~2)B-' Specifically, R3 i9 preferably ~;
Ar-alkyl such as benzyl, 1- or 2-phenylethyl, o~, m- or (especially) p-carboxybenzyl, o-, m- or (eqpecially) p-methoxycarbonylbenzyl, o-, m- or (especially) p-ethoxycarbonylbenzyl, o-, m- or (especially) p nitro-benzyl, o-, m- or ~especially) p~aminobenzyl, o-, m- or (especially) p-cyanobenzyl; cycloalkylalkyl such a~
cyclopropylmethyl, cyclobutyl-methyl, cyclopentylmethyl, cyclohexylmethyl, 1- or 2-cyclohexylethyl, cycloheptyl-methyl, cyclooctylmethyl; ~et-alkyl such a~
(especially) 2- or 3-thienylmethyl, 1~ or 2-(2-thienyl)-ethyl; Ar'-alkyl such a~ 4-biphenylyl-methyl, 2'-carboxy-4-biphenylylmethyl, 2'-methoxy~arbonyl-4-biphenylyl~
methyl, 2'-ethoxycarbonyl-4-biphenylylmethyl, 2'-cyano-4-biphenylylmethyl, 2'-(lH-5-tetrazolyl)-4-biphenylyl-methyl; RB-CO-alkyl such as 2-oxopropyl, 2-oxobutyl, 3-methyl-2-oxobutyl,3,3-dimethyl-2-oxobutyl;Ar-CO-alkyl such as benzoyl-methyl, o-, m- or p-carboxybenzoylmethyl, o-, m- or p-methoxycarbonylbenzoylmethyl, o-, m- or 2 0 ~

p-ethoxy carbonylbenzoylmethyl, o-, m~ or p-cyanobenzoyl-methyl, o-, m- or p-nitrobenzoylmethyl, o-, m- or p-aminobenzoylmethyl; Het-CO-alkyl such a~ 2-thlenyl-carbonyl-methyl. If an H atom in the "alkyl" moiety of 5 the radical R3 i~ replaced by COO~ or COOA, the ~aid radical i9 preferably, for example, c~-ethoxycarbonylbenzyll ~-cyclo-hexyl-~-ethoxycarbonyl-methyl, 1-ethoxycarbonyl-2-phenyl-ethyl.
The radical R4 i~ preferably E3.
10 The radicals R5 and R6 are each preferably A such as methyl or ethyl, and trifluoromethyl, furthennore preferably fluoromethyl, difluoromethyl, pentafluoroethyl or haptafluoropropyl.
The compoundR of formula I can posses~3 one or 15 more chiral centres and can therefore exi~t in different form~ (optically active or optically inactive). Formula I includes all these forms.
Accordingly, the invention relates e~pecially to those compound~3 of formula I in which at least one of 20 said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following partial formulae Ia to Id which correspond to the formula ï and wherein the radical4 not described more precis~ly have the meaning~
25 stated for forrnula I but wherein:
in Ia Rl i9 alkyl ha~ring 1-6 C atoms;
in Ib R2 is COOI~, COOCE13, COOC2E~5, CN, CON~2, NO2 or lH-5-tetrazolyl;
in Ic R2 COOH, COOCH3, COOC2Hs, CN, CONE~2, NO2 or lH-5-tetrazolyl and i~ in the p position;
in Id R2 is alkyl having 1-6 C a~om~ and R2 i4 COOH, COOCH3, (~OOC2H5, CN, CON~12, N02 or lH-S-tetrazolyl.
Compounds which are furthermore preferred are 35 those of the formulae:
Ie and Iae, Ibe, Ice and Ide, ~hich corre~pond to the formulae I and Ia, Ib, Ic and Id but wherein additionally R3 is H;

~3~

If and Iaf, Ibf, Icf and Idf, which corre~pond to the formulae I and Ia, Ib, Ic and Id but wherein additionally R3 is Ar-alkyl;
Ig and Iag, Ibg, Icg and Idg which correspond to the formulae I and Ia, Ib, Ic and Id but wherein additionally R3 is benzyl, carboxybenzyl, methoxycarbonylbenzyl, cyanobenzyl, nitrobenzyl or aminobenzyl;
Ih and Iah, Ibh, Ich and Idh which correspond to the formulae I and Ia, Ib, Ic and Id, but wherein additionally R3 i~ cycloalkylalkyl having 3-8 C atoms in the cycloakyl group;
Ii and Iai, Ihi, Ici and Idi which correspond to the formulae I and Ia, Ib, Ic and Id but wherein additionally R3 is ~et-alkyl;
Ij and Iaj, Ibj, Icj and ~dj which corre~pond to the formulae I and Ia, Ib, Ic and Id but wherein additionally R3 is Ar'-alkyl;
Ik and Iak, Ibk, Ick and Idk which correspond to the formulae I and Ia, Ib, Ic and Id but wherein additionally R3 i9 R6-CO-alkyl;
Il and Ial, Ibl, Icl and Idl which correspond to the formulae I and Ia, Ib, Ic ~nd Id b~t wherein additionally R~ is Ar-CO-alkyl;
Im and Iam, Ibm, Icm and Idm which correspond to the formulae I and Ia, Ib, Ic and Id but wherein additionally ~3 i~ ~et-C~-alkyl;
In and Ian, Ibn, Icn and Idn which correspond to the formulae I and Ia, Ib, Ic and Id, but wherein additionally R3 is ~, benzyl, carboxybenzyl, methoxycarbonylbenzyl, cyanobenzyl, nitrobenzyl, aminobenzyl/ -carboxy-~-cyclohexylmethyl, ~-cyclohexyl-~-methoxycarbonylmethyl, thienylmethyl, carboxy-4-blphenylylmethyl, methoxy-carbonyl-4-biphenylylmethyl, (lH-S-tetrazolyl)-4-bi-phenylylmethyl or 3,3-dimethyl-2-oxobutyl;
Io and Iao, Ibo, Ico and Ido which correspond to the formulae I and Ia, Ib, Ic and Id but wherein additionally 2 ~

_ 9 R3 is H, benzyl, p-carboxybenzyl, ~-carboxybenzyl, p-methoxycarbonylbenzyl, ~-methoxycarbonylbenzyl, p-cyanobenzyl, p-nitrobenzyl, p-aminobenzyl, ~-carboxy-~-cyclohexylmethyl, u-cyclohexy~ methoxycarbollymethylr 2-thienylmethyl, 2'-carboxy-4-biphenylylmethyl, 2'-methoxycarbonyl-4-biphenylylmethyl, 2' l1~-5-tetrazolyl)-4-biphenylylmethyl or 3,3-dimethyl-2-oxo-butyl.
Particularly preferred cornpounds are all tho~e of the abovementioned formulae in which additionally Y i~ O
and/or R~ is H.
The compounds of formula I and also the ~tarting materials for their preparation ara moreover prepared by methods known per se, such a~ those de~cribed in the literature (for example in the standard work~ like Houben-Weyl, Methoden der organischen Chemie ~Method~ of Organic Chemistry~, Georg-Thieme-Verlag, Stuttgart, but especially in European Patent Application A2-0 430 709 and US Patent 4 880 804), under reaction condition~ which are known and suitable for ~aid reactions, it also being possible to make use of variants known per ~e, which are not mentioned in greater detail here.
If desired, the starting materials can al80 be formed in situ, so that they are not isolated from the reaction mixture but in~ediately reacted further to give the compound~ of formula I.
The compounds of for~ula I can preferably be obtained by reacting compounds of formula II with compounds of formula III.
In the compound~ of formula II, ~ i8 preferably Cl, ~r, I or an 0~ group which ha~ been functionally modified to acquire reactivity, such a~ alkyl~ulfonyloxy having 1-6 C atoms (preferably methyl~ulfonyloxy) or arylsulfonyloxy having 6-10 C atom~ (prefera~ly phenyl-or p-tolyl-sulfonyloxy).
The reaction of II with III i~ convenlently carried out by f irst converting III to a ~alt by treatment with a base, for example with an alkali metal alcoholate such a~ CH~ONa or potassium tert-butylat2 in an alcohol such as CH30H or in an amide such a~ dimethyl-formamide (DMF), or with an alkali metal hydride such a~
NaH or an alkali metal alcoholate in DMF, and then reacting said salt with II in an inert solvent, for example an amide such as DMF or dlmethylacetamide, or a sulfoxide such as dimethyl sulfoxlde (DMSO), conveniently at temperatures of between -20 and 100, preferably of between 10 and 30. Other suitable bases are alkali metal carbonate~ such as Na2CO3 or K2CO3, or alkali metal hydro-gen carbonates ~uch a~ NaHCO3 or KHCO3.
Some of the starting material~, especially those of formula II, are known. If they are not known, they can be prepared by known method~ in analogy to known substances. Compounds of the formula III (R3 ~ ~) can be obtained for example by condensation of 3,4-diamino-6--R~-1,2-dihydro-2-oxo- (or -2-thioxo-)-pyridine~ or of 3,4-diamino-2-chloro-6-R4-pyridines with carboxylic acid~ of the formula Rl-COOH in the presence of polyphosphoric acid.
A compound of formula I can also be liberated from one of its functional derivatives by treatment with a solvolysing (for example hydroly~ing) or hydrogenolyYing agent.
Thus it i~ possible, using one of the methods indicated, to prepare a compound which has formula I but in which a 5 tetrazolyl ~roup is replaced with a 5-tetrazolyl group functionally modified in the 1- position (protected by a protecting group)~ Examples of ~uitable protecting groups are triphenylmethyl, which can be eliminated with HCl or formic acid in an inert solvent or solvent mixture, for exampl~ methanol or ether/dichloromethane/methanol; 2-cyanoethyl, which can be eliminated with NaO~ in water/THF; and p-nitro-benzyl, which can be eliminated with H2/Raney nickel in ethanol (compare European Patent Application A2-0 291 969).
It is also possihle to convert one compound of formula I to another compound of formula I by converting ~3~

one or more of the radical~ Rl, R2, R3, R4 and/or Y to other radicals Rlt R2, R3, R4 and/or Y, for ex~nple by reducing nitro groups to amino groups (for example by hydrogenation on Raney nickel or Pd/charcoal in an inert ~olvent ~uch a3 methanol or ethanol), and/or functionally modifying free amino and/or hydroxyl group~, and/or freeing functionally modified amino and/or hydroxyl groups by ~olvolysis or hydrogenoly~ia, and/or replacing halogen atoms with CN groups (for example by reaction with copper(I) cyanide), and/or hydrolysing nitrile groups to cooa group~ or to CON~2 groups, or converting nitrile groups to tetrazolyl groups w1th hydrazoic acid derivatives, for example 30dium azide in N-methyl-pyrrolidone or trimethyltin azide in toluene.
Thu~, for ex~nple, free amino groups can be acylated in conventional manner with an acid chloride or anhydride, or free hydroxyl and/or NR groups can be alkylated with an unsubstituted or substituted alkyl or Ar-alkyl halide or with aldehyde~ ~uch a~ formaldehyde, in the presence of a reducing agent ~uch a~ NaBH~ or formic acid, conveniently in an inert solvent such as methylene chloride or THF, and/or in the presence of a base such as triethylamine or pyridina, at temperatures of between -60 and +30.
If desired, a functionally modified ~nino and/ or hyclroxyl group in a compound of forlnula I can be freed by ~olvolysis or hydrogenolysis u~ing conventional methods.
Thus, for example, a compound of formula I containing an NHCoR5 or COOA qroup can be converted to the corre~ponding compound of formula I containing an NM2 or COOH group insteadO E~ter group~ can be hydroly~ed for example with NaOH or KO~ in water, water/THF or water/dioxane, at temperature~ of between Q and 100.
The reaction of nitriles of formula I (R2 = CN or R3 = cyanoalkyl) with hydrazoic acid deri~ative~ lead~ to tetrazole~ of formula I (R2 ~ lH-5-tetrazolyl and/or R3 = 1H-5-tetrazolylalkyl~. It i~ pra~era~le to use trialkyltin azides such a~ trimethyltin azide, in an ~3~

inert ~olvent, for example an aromatic hydrocarbon such a~ toluene, at temperatures of betw~en 20 and 150, preferably of between 80 and 140, or sodium azide in N-methylpyrrolidone at temperature~ of between about 100 and 200.
A base of formula I can be converted with an acid to the corresponding acid addition salt. Possible acida for this reaction are e~pecially those which yield physiologically acceptable salts. Thus it is pos3ible to u~e inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric . acid~ such a~
orthophosphoric acid, and ~ulfamic acid, a~ well a~
organic acids, especially aliphatic, alicyclic, ~raliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, Rucclnic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethane~ulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono~ulfonic and -disulfonic acids and lauryl sul~Euric acid. Salts with physiologically unacceptable acids, for example picrates, : can be used for i301ating and/or purifying the compounds of f ormula I.
On the other hand, compounds of formula containing COO~ or tetrazolyl groups can be converted with bases lfor example sodiu~ or pota~sium hydroxide or carbonate) to the corresponding metal salt~, especially alkali metal or alkaline earth metal salt~, or to the corre~ponding ammonium salt3. The potassium ~alts are particularly preferred.
The novel compounds of formula I and their physiologically acceptable salts can be used for the preparation of pharmaceutical formulation~ by 2~!932~

incorporation into a suitable do~age form together with at least one excipient or adjunct and, if desired, together with one or more other active ingredients. The resulting formulations can be used as drug~ in human or veterinary medicine. Possible excipient~ are organic or inorganic substance~ which are ~uitable for enteral (for example oral or rectal) or parenteral admini~tration or for administration in the form of an inhalation spray, and which do not react with tlle novel compound~, example~
being water, vegetable oils, benzyl alcohol~, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates such a3 lactose or starch, magnesium stearate, talc and cellulose. Tablets, coated tablets, capsules, ~yrups, juices or drops, in particular, are used for oral administration; lacquered tablets and capsules with coatings or shells resistant to gastric juice~ are of special intere~t. Suppo~itories are used for rectal administration, and Dlutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants, are used for parenteral administration. For administration aa inhalation spray~, it is possible to use ~pray~ containing the active ingredient either di~solved or suspended in a propellant or propellant mixture (for example hydrocarbons such as propane or butane, or fluorocarbons such as heptafluoropropane). It is convenient here to u~e the active ingredient in micronised form, it being possible for one or more additional physloloqically compatible ~olvents r for example ethanol, to be pre~ent. Inhalation solutions can be administered with the aid of conventional inhaler~.
The novel compounds can al~o be lyophili~ed and the resulting lyophilisates used for example for the manufacture of injectable preparations. The indicated formulations can be starilised and/or can contain adjuncts such as preservatives, stabilisera and/or wetting agents, emulsifiers, salt~ for influencing the osmotic pressure, buffer substances and colours and/or 2~32~

flavourings. If de~ired, they can al80 contain one or more other active ingxedient~, for example one or more vitamins, diureticq or antiinflammatory agent~.
The sub~tance~ according to the invention are normally administered in analogy to other known, commercially a~ailahle preparations, but in paxticular in analogy to the compollnd~ de~cribed in US Patent 4 880 804, preferably in dose~ of between about 1 mg and 1 g, especially of between 50 and 500 mg per dQsage unit.
The daily dose i5 preferably between about 0.1 and 100 mg/kg, especially between 1 and 50 mg/kg of body weight. However, the particular dose for each individual patient depend~ on a very wide variety of factor , for example on the efficacy of the particular compound u~ed, age, body weight, general ~tate of health, ~ex, diet, time and mode of admini~qtration, rate of excretion, drug combination and severity of the particular di~ea~e to which the therapy is applied. Oral admini~tration i8 preferred.
~ereinbefore and hereinafter, all temperature~
are given in C. In the following Examples, "conventional working-up" mean~: Water i5 added if nece~sary, the pH i~
adjuated to between 2 and 10 if neces~ary, depending on the con~titution of the end product, extractlon i~
carried out with ethyl acetate or methylene chloride, and the organic pha~e i~ ~eparated off, dried over aodium ~ulfate, evaporated and purified by chromatography on silica gel and/or by cry~tallisation. Rf = Rf on ~ilica gel (by thin layer chromatography; eluent: ethyl 30 ac0tate/methanol 9:1). DOI - -4,5-dihydro-4-oxo-3~-imidazo[4,5-c]pyridine.

~a~3~

Example l 19.1 g of 2-butyl-4,5-dihydro-4-oxo-l(or 3)H-imidazo~4,5-c]pyridine (mOp. 285-290; obtainable by heating 3,4-diamino-2-chloropyridine and valeric acid in polypho~phoric acid at 1~0-140, then 170-180) ~re di~solved in 500 ml of DMF, 16.6 g of K2CO3 are added, the mixture is stirred for 45 min, a solution of 27.45 g of methyl p-bromomethylbenzoate i8 added dropwi~e, the mixture i9 stirred at 20 for 16 h, and water iR added.
The precipitate which ha~ ~eparated out i8 filtered off, wa~hed with water, dried and chromatographed on ~ilica gel. Uqing ethyl acetate and then ethyl acetate/methanol, first 2-butyl-3,5 bi~-p-methoxycarbonylbenzyl-DOI ~m.p.
124) i~ obtained, and then 2-butyl-3-p-methoxycarbonyl-benzyl-DOI Im.p. 219).
Obtained analogously ~ing p-bromomethylbenzo-nitrile are 2-butyl-3,5-biq-p-cyanobenzyl-DOI (m.p.
12~.5~ and 2-butyl-3-p-cyanobenzyl-DOI (m.p. 201).
Obtained analogou~ly from 4,5-dihydro-4-oxo-20 2-propyl-l(or 3)H-imidazo[4,5-c]pyridine (m.p. 258;
obtainable from 3,4-diamino-2-chloropyridine and butyric acid in polyphosphorlc acid) are 3,5-bis-p-methoxy-carbonylbenzyl-2-propyl DOI (oily; Rf 0.51 in ethyl acetate) and 3-p-methoxycarbonylbenzyl-2-propyl-DOI, m.p.
25 235.
Example 2 Obtained in analogy to Example 1 from 2-butyl-5-(~-cyclohexyl-~-methoxycarbonylmethyl)-DOI(obtainableby benzylation of 2-butyl~4,5-dihydro-4-oxo-l(or 3)~-imidazo[4,5-c~pyridine to give the 3-benzyl-3~-compound, reaction with methyl ~-bromo-~-cyclohexylacetate to give 2-butyl-3-benzyl 5-l~-cyclohexyl-~-methoxycarbonyl-methyl)-DOI and elimination of the benzyl group by hydrogenolysis) and methyl p-bromomethylbenzoate i~
2-butyl-5-(~-cyclohexyl-~-methoxycarbonylmethyl)-3-p-methoxycarbonylbenzyl-DOI, Rf 0.63.

2~32~

Example 3 1.34 g of K tert.-butylata are added under N2 to a solution of 3.39 g of 2-butyl-3-p-methoxyca~bonyl-benzyl-DOI (m.p. 218-219) in 85 ml of DMF, the mixture i8 stirred at 20 for 10 min, a solution of 2.16 g o p-nitrobenzyl bromide in 35 ml of DMF i8 added, and the mixture is stirred at 20 for 2.5 h. Conventional working-up (chromatography on ~ilica gel, ethyl acetate) results in 2-butyl-3-p-methoxycarbonylben7yl-5-p-nitro-benzyl-DOI, m.p. 142.
Obtained analogou~ly uaing 2-thlenylmethyl chloride is 2-butyl-3-p-methoxycarbonylbenzyl-5-(2-thienylmethyl)-DOI.
Obtained analogously using methyl ~-bromo-~-lS cyclohexylacetate i9 2-butyl-5-(~-cyclohexyl-~-methoxy-carbonylmethyl)-3-p-methoxycarbonylbenzyl-DOI, ~f. 063.
Obtained analogously u~ing methyl ~-bromo-~-phenylacetate iB 2-butyl-3-p-methoxycarbonylbenzyl-5-~-methoxycarbonylbenzyl-DOI, ~f 0.47 (ethyl acetate/hexane 9~
Obtained analogously u~ing methyl 2-bromo-3-phenylpropionate i9 2-butyl-3-p-methoxycarbonylbenzyl 5-(1-methoxycarbonyl-2-phenylethyl)-DOI, Rf 0~64.
Obtained analogously from 3-p-methoxycarbonyl-benzyl-2-propyl-DOI are the following 3-p-methoxycar-bonylbenzyl-2-propyl-DOI;
5-Benzyl-S-p-Nitrobenzyl-5-(3!3-Dimethyl-2-oxo~butyl)-.
Obtained analogou~ly from 2-butyl-3-p-cyano-benzyl-DOI u~ing methyl 4'-bromomethylbiphenyl-2-car-boxylate i9 2-butyl-3-p-cyanobenzyl-5-(2'-methoxy-carbonylbiphenylyl-4-methyl)-DOI, m.p. 65.
Obtained analogously from 2-butyl-3-p-cyano-benzyl-DOI u~ing chloroacetonitrile i~ 2-butyl-3-p-cyanobenzyl-5-cyanomethyl-DOI, m.p. 197.

~32~

Example 4 3 g of 2-butyl-4,5-dihydro-4-oxo-l(or 3)H-imidazo[4,5-c~pyridine are di~olved in 75 ml of ~ethanol and, while stirring at 20, a solution of 0.4 g of Na in 10 ml of methanol i8 added dropwise. The mixture i8 ~tirred for 45 min and then evaporated, the residue i~
di~olved in 30 ml of DMF and cooled to 0, and, at thi~
temperature, a solution of 3.7 g of p-nitrobenzyl bromide i~ added, and the mixture is ~tirred at 20 for 16 h.
Evaporation and conventional working-up re~ult~, after chromatography (silica gel; ethyl acetate/toluene 7:3), first in 2-butyl-3,5-bi~-p-nitrobenzyl-DOI (m.p~ 142-143) and then 2-butyl-3-p nitrobenzyl-DOI (m.p. 193-194) Example 5 1 g of 2-butyl-3-p-methoxycarbonylbenzyl-5-p-nitrobenzyl-DOI iq di~olved in 50 ml of methanol and hydrogenated on 0.5 g of Pd-c (5~) at 20 and under 1 bar until the H2 uptake cea~e~, and the mixture i~ filt~red and, after evaporation and chromatography on silica gel (ethyl acetate/methanol 9:1), re~ults in 5-p-aminobenzyl-2-butyl-3-p-methoxycarbonylbenzyl-DOI, m.p. 59-60.
Example 6 A mixture of 1 g of 2~utyl-3-p-methoxycarbonyl-benzyl-5-p-nitrobenzyl DOI, 20 ml of 1 N ~odium hydroxide solution, 6 ml of methanol and 18 ml of T~F i8 ~tirred ~t 20 for 16 h and is acidified with hydrochlori~ acid, and con~entlonal workîng-up result~ in 2-butyl-3-p-carboxy-benzyl-5-p-nitrobenzyl-DOI, m.p. 170.
The follo~ing DOI are obtained analogously by hydroly~is of the corre~ponding methyl e~ters-5-p-~ninobenzyl-2-butyl-3-p-carboxybenzyl-, m.p. 130 2-Butyl-3-p-carboxybenzyl-, m.p. 249 2-Butyl-3,5-bi~-p-carboxybenzyl, m.p. 150 3-p-Carboxybenzyl-2-propyl-, m.p. 2~9 3,5-Bis-p-c~rboxybenzyl-2-propyl-, m.,p. 209 5-Benzyl-3-p-carboxybenzyl-2-butyl-, m.p. 212, K salt, m.p. ~ 300 3-p-Carboxybenzyl~5-p-nitrobenzyl-2-propyl-, m.p. 300 2-~utyl-3-p-carboxybenzyl-5-t2-thienylmethyl)-,m.p.201 3-p-Carboxybenzyl-5-(3,3-dimethyl-2-oxo-butyl)-2-propyl-, m.p. 195 2-Butyl-3-p-carboxybenzyl~5-~-carboxy-u-cyclohexyl-methyl-, m.p. 195 2-Butyl-3-p-carboxybenzyl-5-~-carboxybenzyl-, se~quihydrate, m.p. 234 2-Butyl-3-p-carboxybenzyl-5-(1-carboxy-2-phenyl-ethyl)-, 10 m.p. 253.
Example 7 ~eaction of 2-butyl-3-p-cyanobenzyl-5-(2'-methoxycarbonylbiphenyl-4-methyl)-DOI in analogy to Example 6 with ~odiu~ hydro~ide ~olution/methanol/T~F
15 re3ult~ in 2-butyl-3-p-carbamoylbenzyl-5-(2'-carboxy-biphenylyl-4-methyl)-DOI~ m.p. 241, a~ main product.
Example 8 a) A mixture of 4.21 g of 2-butyl-3,5-bis-p-cyano-benzyl-DOI, 41.2 g of trimethyltin azide and 300 ml of toluene ~ 8 boiled for 72 h and evaporated. The residue i~ ~tirred with 100 ml o~ methanolic hydrochloric acid at 20 for 2 h, and conventional working-up ~aturated NaCl solution/dichloromethane) re~ult~ in 2-butyl-3,5-bii-~p~ 5-tetrazolyl)-benzyl]-DOI, m.p. 272.

Obtained analogouily from 2-butyl-3-p-cyanobenzyl-DOI i~ 2-butyl-3-[p~ 5-tetrazolyl)b~nzyl]-DOI.

Obtained analogously fro~ 2-butyl-3-p-cyanobenzyl-5-(2'-methoxycarbonylbiphenylyl-4-methyl)-DQI i~
2-butyl-5-(2'-methoxycarbonylbiphenylyl-4-methyl)-3-[p-(1~-5-tetrazolyl)benzyl]-DOI, m.p. 154.

Obtained analogou~ly from 2-~utyl-3-p-cyanobenzyl-5-cyanomethyl-DOI i3 2-butyl-~-[p-(1~-5-tetrazolyl)-benzyl]-5-(1~-5-tetra201yl~ethyl)-DOI, m.p. 276 (decompo~ition~.

2~3~

The following Examples relate to pharmaceutical formulations containi.ng active ingredient~ of formula I
or their salts.

E mple A: TabletR and coated kablet~
Tablet~ of the following composition are produced by compres~ion in conventional manner and, where required~ are provided with a conventional 3ucro~e-based coating:

Active ingredient o~ formula I 100 mg 10 Microcrystalline cellulose278.8 mg Lactose 110 mg Maize ~tarch 11 mg Magne~ium ~tearate 5 mg Finely divided silicon dioxide 0.2 mg Example B: Hard gelatin capsules Conven-tional two-piece haxd gelatin capsules are each filled with Active ingredient of formula I 100 mg Lactose 150 mg 20 Cellulose 50 mg Magnes1um stearate 6 mg Example C: Soft gelatin cap~ules Conventional soft gelatin cap~ule~ are filled with a mixture of 50 mg of active ingredient and 250 mg of olive oil in each case.

Example D: Ampoules A solution of 200 g of active ingredient in 2 kg of 1,2-propanediol is made up to 10 1 with water and filled into ampoule~ so that each ampoule contains 20 mg of active ingredient.

~ ~9 3 2 e63i 0 ~ ~0 ~
~alllpl.Q_~: Aqlleoul luF~p~ll310n for oral a~miniatratiQn An aqu~ou~ Huspen~lon i8 prepared in conventional manner. The Ull.i.t dose (5 ml) cQntains 100 m~ c~f active i.n~r~cli.~nt, 1001llg o~ aodium ca~boxylnethylcellulos~, 5 I~J
S o~ 1od.~m b~nzoat~ and 100 mg of aorbitol.

Claims

1. An imidazopyridine derivative of formula I:

I

wherein R1 is H or A, R2 is H, Hal, OH, OA, COOH, COOA, CONH2, CN, NO2, NH2, NHA, N(A)2, NHCOR5, NHSO2R5 or 1H-5-tetrazolyl, R3 is H, cyanoalkyl, Ar-alkyl, cycloalkylalkyl having 3-8 C atoms in the cycloalkyl group, Het-alkyl, Ar'-alkyl, R6-CO-alkyl, Ar-CO-alkyl or Het-CO-alkyl having, in each case, 1-6 C
atoms in the 'alkyl' moiety, it being possible for an H atom in the 'alkyl' moiety to be replaced by a COOH or a COOA group, R4 is H or Hal, R5 and R6 are in each case alkyl having 1-6 C atoms, wherein one or more H atom(s) can also be replaced by F, Y is O or S, A is alkyl, alkenyl or alkynyl in each case having up to 6 C atoms, Ar is a phenyl group which is unsubstituted or monosubstituted by Hal, R5, OH, OA, COOH, COOA, CN, NO2, NH2, NHA, N(A)2, NHCOR5, NHSO2R5 or 1H-5-tetrazolyl, Ar' is a phenyl group substituted by Ar, Het is a five or six-membered heteroaromatic radical having 1 to 3 N, O and/or S atoms, which can also be condensed with a benzene or pyridine ring, and Hal is F, C1, Br or I, and their salts.

2. a) 2-Butyl-5-benzyl-3-p-carboxybenzyl-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine and its salts;

b) 2-Butyl-3-p-carboxybenzyl-5-(2-thienylmethyl)-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine and its salts;

c) 5-p-Aminobenzyl-2-butyl-3-p-carboxybenzyl-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine and its salts.

3. Process for the preparation of imidazopyridines of formula I according to Claim 1, and their salts, characterised in that a compound of formula II

II

wherein E is C1, Br, I, a free OH group or an OH group which has been functionally modified to acquire reactivity, and R2 has the meaning stated in Claim 1, is reacted with a compound of formula III

III
wherein R1, R3, R4 and Y have the meanings stated in Claim 1, or in that a compound of formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent, and/or in that one or more radical(s) R`, R2, R3, R4 and/or Y in a compound of formula I are converted to one or more other radicals R1, R2, R3, R4 and/or Y, and/or a base or acid of formula I is converted to one of its salts.

4. 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 semi-liquid excipient or adjunct.

5. 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. 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.