CZ474199A3 - 4,5-diarylimidazoles substituted in position 2, process of their preparation and pharmaceutical preparations containing thereof - Google Patents

Abstract

2-substituted 4,5-diarylimidazoles wherein: i) an atom nitrogen at the 1-position is substituted with a substituent containing a trialkylsilyl group, or (ii) a substituent at position 2 is arylalkyl, arylsulfonyl, aiylthio, arylselen, aiyltellur, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, amino or hydrazino, or mono- or a bicyclic N-heterocyclyl group wherein the ring containing the nitrogen atom has 6 ring members, especially the compounds of formula I, wherein R 1, R 2, R 3 and R 4 are specifically defined in the free form or in the form of a pharmaceutically acceptable acid addition salt or in the form of a physiologically cleavable ester thereof p38 MAPkinase inhibitory activity (mitogen activated protein kinase). the compounds are used as medicaments for the treatment of TNFα and IL-1 mediated diseases, such as is rheumatoid arthritis and bone metabolism diseases for example osteoporosis.

Description

4,5-diarylimidazoles substituted in the 2-position, processes for their preparation and pharmaceutical compositions containing them

Technical field

The present invention relates to 4,5-diarylimidazoles substituted at the 2-position and their use for the treatment of diseases mediated by TNFα and IL-1, such as rheumatoid arthritis and bone metabolism diseases such as osteoporosis.

* Summary of the Invention

The present invention provides novel 4,5-diarylimidazoles substituted in the 2-position wherein:

(i) the 1-nitrogen atom is substituted with a trialkylsilyl-containing substituent; or (ii) the 2-substituent is arylalkyl, arylsulfonyl, arylthio, arylselio, aryltelluro, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, hydroxycycloalkenyl, or cycloalkenyl, a mono- or bicyclic N-heterocyclyl group wherein the nitrogen-containing ring has 6 ring members, provided that the substituent at the 2-position is not piperidin-4-yl, 1-tert-butoxycarbonyl-4-benzyl-piperidin-4-yl, A 4-dimethyl-piperidin-4-yl group, a 4-benzyl-piperidin-4-yl group or a piperidinyl group which is further substituted only on the nitrogen atom and further provided that neither the 4- nor the 5-aryl substituent is a phenyl group substituted with a radical selected from an alkylsulfonyl group or an aminosulfonyl group; · · · · · Φ .φφ · · ·. And their pharmaceutically acceptable acid addition salts and their physiologically cleavable esters.

The 4- or 5-aryl substituents may be any substituents known to those skilled in the art; for example those described in WO 95/03297 and WO 97/12876. For example, they can be a 4- or 5-aryl substituents are the same as mentioned below for R and R ₂ in formula I and include heteroaryl "substituents.

A When the nitrogen atom in the 1-position is substituted with a trialkylsilyl group, the substituent is preferably a trialkylsilylalkoxyalkyl substituent.

When the substituent at the 2-position is an arylalkyl group, it is usually a phenylalkyl group.

When the substituent at the 2-position is an arylalkyl, arylsulfonyl, arylthio, arylselio, aryltelluro, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, amino or hydrazino group, or a mono- or bicyclic N-heterocyclyl group, for example up to six substituents selected from the group consisting of halogen, hydroxyl group, alkyl group containing from 1 to 4. carbon atoms, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, nitro, amino, C 1 -C 4 alkylsulfinyl, (C 1 -C 4) alkylsulfonyl, carboxylate, or ester.

 3

Above and elsewhere in the present specification, the terms halo or halogen means iodine, bromine, chlorine or fluorine, preferably fluorine.

In a particular embodiment, the present invention provides compounds of formula I

N \

N where

R 1 is 4-pyridyl, pyrimidinyl, quinazolin-4-yl, quinolyl, isoquinolyl, 1-imidazolyl or 1-benzamidazolyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyl (C 1 -C 4) -halo, halogen, (C 1 -C 4) -alkoxy, (C 1 -C 4) alkylthio, NR ₅ R ₆ , or N-heterocyclyl (C 5 -C 7) ring and optionally containing other heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen atom, wherein R ₅ and _R are independently alkyl of 1 to 4 carbon atoms;

R ₂ is phenyl, naphth-l-yl or naphth-2-yl, which is optionally substituted with up to five substituents;

R ₃ is a hydrogen atom, a heterocyclyl group, ····

heterocyclylalkyl having 1 to 10 carbon atoms in the alkyl moiety, trialkylsilylalkoxyalkyl having 1 to 4 carbon atoms in each alkyl moiety and 1 to 10 carbon atoms in the alkoxy moiety, optionally halogen-substituted alkyl having 1 to 10 carbon atoms, alkenyl C 2 -C 10 alkynyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 10 cycloalkylalkyl, C 5 -C 7 cycloalkenyl, aryl, arylalkyl a (C 1 -C 10) alkyl group, a heteroaryl group, or a (C 1 -C 10) heteroarylalkyl group, or a C 1 -C 4 mono- or dialkyl group substituted with an C 1 -C 4 alkyl group yloxycarbonyl or oxythiocarbonyl containing from 0 to 10 carbon atoms in the alkyl moiety optionally substituted by from 1 to 10 carbon atoms, cycloalkyl containing from 3 to 7 carbon atoms, heterocyclyl, heterocyclylalkyl containing from 1 to 10 carbon atoms in the alkyl moiety alkyl, arylalkyl having 1 to 10 carbon atoms in the alkyl moiety, heteroaryl, heteroaryl having 1 to 10 carbon atoms in the alkyl moiety, or a mono- or dialkyl having 1 to 4 carbon atoms in each alkyl moiety containing 1 to 10 carbon atoms optionally substituted

4444 44 44 cyano, nitro, hydroxyl, C 1 -C 10 alkoxy, C 3 -C 3 cycloalkoxy. 7 carbon atoms, heterocycloxy, heterocyclylalkoxy having 1 to 10 carbon atoms in the alkoxy moiety, aryloxy, arylalkoxy having 1 to 10 carbon atoms in the alkoxy moiety, heteroaryloxy, heteroarylalkoxy having 1 to 10 carbon atoms in the alkoxy moiety, optionally substituted with 1 to 10 carbon atoms, thiocarboxylate, carbonyl or thiocarbonyl, sulfinyl or sulfonyl;

R ₄ is mono- or dicykloalkylalkylová radicals in which each cycloalkyl part of 3-7 carbon atoms and alkyl 0-4 carbon atoms optionally substituted by halogen, hydroxyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon C 1 -C 4 thioalkoxy, nitro, amino, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, carboxylate, or ester,

- NR ₇ R ₈ , NHNHR ₈ , wherein independently R ₇ , R ₈ or R ₉ is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 6 alkynyl, 0 000 0 0 0- 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 «υ ·· · ······· ·· ··

X-aryl containing from 5 to 10 carbon atoms in the aryl portion (including heteroaryl) wherein X is sulfur, SO ₂ , selenium, tellurium or C 1 -C 4 alkyl, mono- or bicyclic N -heterocyclyl, wherein the nitrogen-containing ring has six members, or an aryl or heteroaryl group optionally substituted with up to 4 substituents, provided that when R ₃ is not a trialkylsilylalkoxyalkyl group containing from 1 to 4 carbon atoms in each alkyl moiety and an alkoxy moiety 1 up to 10 carbon atoms,

R ₄ is not an aryl or heteroaryl group optionally substituted with up to three substituents, except when R ₄ is a mono- or bicyclic N-heterocyclyl group wherein the nitrogen-containing ring has six members;

provided that:

R ₄ is not piperidin-4-yl, 1-tert-butoxycarbonyl-4-benzyl-piperidin-4-yl, 1,4-dimethyl-piperidin-4-. yl, 4-benzyl-piperidin-4-yl or piperidinyl which is further substituted only on nitrogen and *

further provided that R ₂ is not phenyl substituted with a radical selected from the group consisting of alkylsulfonyl or aminosulfonyl, and their pharmaceutically acceptable acid addition salts and physiologically cleavable esters.

• · ··· ·

R ₂ is substituted with up to five substituents which may be any substituents known to those skilled in the art; for example as described for R ₄ in WO 95/03297 and for the R substituent in WO 97/12876.

When R ₄ is -X-aryl of 5 to 10 carbon atoms, aryl of 5 to 10 carbon atoms, or X, when it is C 1 -C 4 alkyl, may be substituted with up to six substituents selected from the group consisting of halogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, nitro, amino, C 1 -C 4 alkylsulfinyl a (C1-C4) alkylsulfonyl group, a carboxylate group or an ester group.

When R ₄ is a mono bicyclic N-heterocyclyl group wherein the nitrogen-containing ring has six members, it may be saturated or unsaturated, for example, an aromatic group, a heterocyclyl group.

When R _{4 is an} aryl or heteroaryl group optionally substituted with up to four substituents, R ₄ may contain one of the usual aryl or heteroaryl substituents which may be substituted. are used in this area; for example, as defined for the substituent R ₃ in WO 93/032297.

Imidazoles with a substituent at the 2- position, for example R ₄ as defined above, as well as aryl substituents at both the 4 and 5 positions, for example as defined for R 1 and R ₂ above, wherein the 1-position nitrogen is substituted with a trialkylsilyl containing substituent group are brand new.

Accordingly, in a further aspect, the present invention provides compounds of Formula I '.

8 ··· ·, ^R 3 ' ^R i Jn

I / X-R

R, N

R ₃ 'is a trialkylsilylalkoxyalkyl group containing from 1 to 4 carbon atoms in each alkyl moiety and from 1 to 10 carbon atoms in the alkoxy moiety, and R 1, R ₂ and R ₄ are as defined above and their pharmaceutically acceptable acid addition salts and their physiologically cleavable esters.

Compounds of formula I 'wherein R ₄ is hydrogen and R ₂ , R ₃ ' and R ₄ are as defined above are key intermediates for the synthesis of other compounds of formula I wherein R ₃ is not a trialkylsilylalkoxyalkyl group containing in each C 1 -C 4 alkyl and C 1 -C 10 alkoxy as described below.

The substituents R ₃ , R ₂ , R ₃ , R ₃ 'have the following meanings.

have independently

Preferably Rx is 4-pyridyl or pyrimidinyl, especially 4-pyridyl.

R ₂ is preferably phenyl, including substituted phenyl.

Most preferably, R _{3 is a} trimethylsilylethoxymethyl group.

When R ₃ trialkylsilylalkoxyalkylová radicals in which each alkyl moiety with 1 to 4 carbon atoms in the alkoxy moiety 1 to 10 carbon atoms, R ₂ is preferably 4-pyridyl skuDina. '

If it is. R _{3 is a} trialkylsilylalkoxyalkyl group containing from 1 to 4 carbon atoms in each alkyl moiety and in an alkoxy group;

444 444

4 4

4

4 4

* 444 4

4 4

4

4

4

4444 46 44 parts of 1 to 10 carbon atoms, group.

R ₂ is preferably 4 - fluorophenyl

When R ₃ is a group containing at trialkylsilylalkoxyalkylová. Alkylov.é each part _(1-4 carbon atoms in the alkoxy moiety 1-10 carbon atoms, R ₄ is preferably hydrogen.

In another preferred aspect of the present invention, R _{4 is an} X-aryl group containing 5 to 10 carbon atoms in the aryl portion, preferably a phenyl group wherein X is as defined above, for example a compound of formula III

Wherein R _{1 (} R ₂ , R ₃ and X are as defined above and R ₂₁ are 1 to 4 substituents independently selected from the group consisting of hydrogen, halogen, hydroxyl, (C 1 -C 4) alkyl, (C 1 -C 4) -alkoxy (C 1 -C 4), (C 1 -C 4) thioalkoxy, nitro, amino, (C 1 -C 4) alkylsulfinyl, (C 1 -C 4) alkylsulfonyl, carboxylate or ester group, and pharmaceutically acceptable acid addition salts thereof; and their physiologically cleavable esters.

According to another preferred aspect of the present invention, R _{4 is a} cycloalkyl group, a cycloalkenyl group, an alkylcycloalkyl group, an alkylcycloalkenyl group or a mono- or bicyclic N-heterocyclyl group wherein the nitrogen-containing ring has 6 members, for example a compound of formula IV. · · ♦ ·· • · 9 99 9 9 9 9 9 9

9 9 9 9 9 9

9999 99 999 999

9 9 9 9 9 pQt · · 99 9 99 9 9 9 9 9 9

IV wherein R _1; R ₂ and R ₃ are as defined above, D is a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkenyl group having 3 to 7 carbon atoms, or a mono- or bicyclic N-heterocyclyl group wherein the nitrogen-containing ring has 6 members and X is a direct bond or CR ₁₂ R ₁₃ where R ₁₂ is hydrogen or C 1 -C 4 alkyl and R ₁₃ is hydrogen or C 1 -C 4 alkyl optionally substituted with C 3 -C 7 cycloalkyl or cycloalkenyl a group having 3 to 7 carbon atoms, with the proviso that X is a direct bond when D is a mono- or bicyclic N-heterocyclyl group wherein the nitrogen-containing ring has 6 members, and their pharmaceutically acceptable acid addition salts and their physiologically cleavable esters.

In formula IV, X 'and D may be further substituted, for example with up to 6 substituents selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkoxy of 1 to 4 carbon atoms C 4 -C 4 alkyl, nitro, amino, C 1 -C 4 alkyl sulfinyl, C 1 -C 4 alkylsulfonyl, carboxylate or ester.

• ·

-I η · · · · ··

-L-i- ···· · ··· ··········

D is preferably cyclohexyl, cyclohexenyl, cyclopropyl, pyridinyl (e.g. 4-pyridinyl), piperidinyl (e.g. piperidin-4-yl), piperidinyl (e.g. piperidin-4-yl), azabicyclo [3.2] 1] octanyl, azabicyclo [3,3,1] honyl or tropanyl bicyclic N-heterocyclic group (and enyl analogues of such a bicyclic N-heterocyclic group, for example 8-azabicyclo {3.2.1} oct-2-en-3 -yl group). In a particularly preferred embodiment, -X'-D is 1-hydroxycyclohexyl, laminocyclohexyl, 1-cyclohexenyl, cyclopropylmethyl, 1,2-dicyclopropylethyl, 2,3,5,6-tetrafluoropyridinyl, 2-amino -3,5,6-trifluoropyridinyl, 2,6-diamino-3,5-difluoropyridinyl, tropa-3-olyl, 4-hydroxy-1-methylpiperidinyl, 4alkoxy-1-methylpiperidiriyl having 1 to β carbon atoms in the alkoxy moiety 4-n-butyloxy-1-methylpiperidinyl, 8-methyl-8-azabicyclo (3.2.1} oct-2-en-3-yl), 1-methyl-4-piperidinyl.

When R _{4 is} -X-aryl or -X'-D, R ₂ is preferably 4-pyridyl.

When R _{4 is} -X-aryl or -X'-D, R ₂ is preferably a halogen-substituted phenyl group, especially a 4-fluorophenyl group.

When R _{4 is} -X-aryl or -X'-D, R ₃ is preferably hydrogen.

Particularly preferred compounds of formula IV are those wherein X 1 is a direct bond and D is an optionally substituted pyridinyl group, for example a 4-pyridinyl group or a piperidinyl group, for example a piperidin-4-yl group.

· · »· · · · · · · · ·

The novel 4,5-diarylimidazoles substituted in the 2-position of the present invention, in particular the compounds of formulas I to IV and the specific compounds of Examples 1 to 19 are hereinafter referred to as "compounds of the present invention."

Compounds of the present invention that contain free hydroxyl groups may also exist in the form of pharmaceutically acceptable, physiologically cleavable esters, and as such form part of the present invention. Such pharmaceutically acceptable esters are preferably ester derivative prodrugs that can be converted by solvolysis or cleavage under physiological conditions to the corresponding compounds of the present invention that contain free amino groups. Suitable pharmaceutically acceptable ester prodrugs are those derived from carboxylic acids, monoesters of carbonic acid or carbamic acid, preferably esters derived from optionally substituted lower alkanoic acids or arylcarboxylic acids.

The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts and as such form part of the present invention. Pharmaceutically acceptable salts include acid addition salts with common acids, for example mineral acids, for example hydrochloric, sulfuric or phosphoric acid, or with organic acids, for example aliphatic or aromatic carboxylic acids or sulfonic acids, for example acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, hydroxymaleic acid, pyruvic acid, pamoic acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylsulfamic acid; also with amino acids, 4 ♦, c, c

4,444 such as arginine and lysine. For compounds of the present invention containing acidic groups, for example free carboxyl groups, pharmaceutically acceptable salts are also metal salts and ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts as well. ammonium salts formed with ammonia or with suitable organic amines.

The compounds of the present invention of formulas III and IV as defined above can be prepared by reacting a compound of formula VIII

R "

-N

CH, \. Si · .CH,

R, ch;

CH, // CH, ‘CH,

VIII wherein R 1 and -R ₂ are as defined above, with the corresponding aldehyde, ketone, disulfonamine, disulfide, diselenide, ditelluride or halide and, if appropriate, introducing the desired substituent R ₃ or further transforming the product obtained and optionally converting it into the free form or a salt form. Thus, for example, a compound of formula VIII is reacted with the corresponding aldehyde, ketone, disulfonamine, disulfide, diselenide, ditelluride or halide in the presence of n-butyllithium, for example in a cold (e.g. -40 ° C) tetrahydrofuran solution.

When the compound of formula VIII is reacted with the corresponding aldehyde or ketone, the initial product obtained is substituted with a hydroxyl group at the 1-position of the substituent R ₄ , for example a 1-hydroxycyclohexyl group when the ketone is cyclohexanone. The corresponding dehydrated compound, for example R ₄ ', is 1Λ 4 ♦ 4

4 · 4 ·

4,444,444

The cyclohexenyl group can be obtained, for example, by reaction with pTsOH under reflux in toluene solution.

The present invention includes a process for preparing a compound of the present invention or a salt of formula III and IV as defined above, which comprises reacting a compound of formula VIII

CH '

where Rj. and R ₂ are as defined above, with the corresponding aldehyde, ketone, disulfonamine, disulfide, diselenide, ditelluride or halide and, where appropriate, introducing the desired substituent R ₃ or further transforming the product obtained and optionally converting the compound of the present invention to the free or salt form.

Compounds of formula VIII may be prepared by reaction of the corresponding 1H-imidazole, i. corresponding compounds of formula I wherein R ₄ is hydrogen with 5- (trimethylsilyl) ethoxymethyl halide (e.g. chloride), for example in the presence of potassium bis (trimethylsilyl) amide in a cold (e.g. -78 ° C) dimethylformamide / tetrahydrofuran solution. This procedure yields a mixture of the corresponding 1-2- (trimethylsilyl) ethoxymethylimidazoles of formulas VIII and IX.

Φ Φ φ φ φ Φ φφφ

CH \ Υ

CH,

wherein R _x and R ₂ are as defined above.

Compounds of formula VIII are novel intermediates for the preparation of other compounds of the present invention and as such form part of the present invention. Compounds of formula (IX) are compounds of the present invention.

In an alternative preferred embodiment, a nitrogen-protecting alkoxyalkyl group, for example a nitrogen-protecting dialkoxyalkyl group, in particular a diethoxymethyl protecting group, is used instead of a trimethylsilylethoxymethyl protecting group. This alkoxyalkyl protecting group may be introduced by reaction of the corresponding 1H-imidazole of formula I, i. the corresponding compounds of formula (I). wherein R ₄ is a hydrogen atom with a trialkyl orthoformate, for example triethyl orthoformate, for example as described in the examples.

The synthesis of the compounds of the present invention is further described by way of examples.

DETAILED DESCRIPTION OF THE INVENTION

Examples 1 and 2

- (4-fluorophenyl) -5- (4-pyridyl) -1- (2- (trimethylsilyl) ethoxymethyl) imidazole and 4- (4-pyridyl) -5- (4-fluorophenyl) -1- (2- ( trimethylsilyl) ethoxymethyl) imidazole 9 9 9 9 9 9 9 9 9 9 9 9 9 ·

4- (4-Fluorophenyl) -5- (4-pyridyl) -4-imidazole (3) (1 g 4.18 mmol) was dissolved in dimethylformamide / tetrahydrofuran (50 mL / 20 mL) and cooled to -78. Deň: 32 ° C. Potassium bis- (trimethylsilyl) -amide (15% in toluene, 6.7 ml, 5 mmol) was added at -78 ° C and the mixture was stirred for 30 minutes, then 2- (trimethylsilyl) ethoxymethyl chloride and the reaction mixture were added. After 2 hours, it is poured into water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, evaporated to dryness and purified by chromatography (silica gel acetone / hexane 4/6 to 6/4) to give 1- (2- (trimethylsilyl) ethoxymethyl) -4- (4-fluorophenyl) -5- (4-pyridyl) imidazole, which eluted first as white

crystals (218 mg 1.4%) and then 4- (4-pyridyl) -5- (4-fluorophenyl) 1- (2- (trimethylsilyl) ethoxymethyl) imidazole as white crystals (590 mg -38%). determined by ROESY, HSQC and HMBC spectrometry.

1 H-NMR (360MHz, CDCl 3) 1- (2- (trimethylsilyl) ethoxymethyl) -4- (4-fluorophenyl) -5- (4-pyridyl) imidazole (Example 1): 0.00 (s, 9H) ; 0.92 (t, 2H); 3.55 (t, 2H); 5.15 (s. 2H); 6.95 (t, 2 H); 7.36 (d, 2 H); 7.42 (dd, 2 H); 7.72 (s, 1H); 8.68 (d, 2 H); 4- (4-pyridyl) -5- (4-fluorophenyl) -1- (2- (trimethylsilyl) ethoxymethyl) imidazole (Example 2): 0.00 (s, 9H); 0.90 (t, 2 H);

3.48 (t, 2 H); 5.10 (s. 2H); 7.20 (t, 2 H); 7.35-7.45 (m, 4H);

7.7 δ (s, 1H); 8.4 (d, 2H).

• ·

► 9 ·

I · · · · · ·

Alternatively, the 1H-imidazole starting material can be converted to the corresponding 4- (4-fluorophenyl) -5- (4-pyridyl) -1- (1,1-diethoxymethyl) imidazole product and 4- (4-pyridyl) -5- (4-fluorophenyl) -1 (1,1-diethoxymethyl) imidazole product.

1- (1,1-Diethoxymethyl) -4- (4-fluorophenyl) -5- (4-pyridinyl) imidazole and 1- (1,1-diethoxymethyl-5- (4-fluorophenyl) -4- (4-pyridinyl) ) imidazole

- (4-Fluorophenyl) -5- (4-pyridinyl) imidazole (72.7 g; 0.304 mol) and pTsOH.H ₂ O (1.1 g; 5 mmol) were dissolved in hot triethyl orthoformate (77 ml) and the mixture is heated to boiling until about 300 ml of triethyl orthoformate and ethanol are slowly distilled off. After 2 hours, the reaction mixture was evaporated to dryness and taken up in tert-butyl methyl ether (500 mL). Hexane (51) was added slowly, the precipitate was filtered off and washed with tert-butyl methyl ether / hexane (1: 9). The filtrate was washed with 1 N sodium carbonate, dried over sodium sulfate and evaporated. Add xylene twice and evaporate again to give the title compound as a tan viscous oil (79.3 g; 76%; about 1: 1 mixture) which is used without further purification.

Example 3

4- (4-Fluorophenyl) -2 - ((RS) -1-hydroxy-4'-fluorobenzyl) -5- (4-pyridyl) imidazole

1) BuLi-40C 4-F-benzacyl

2) Bu4NF

• 449 4

1.6-η-BuLi in hexane (0.085 mL, 0.13 mmol) was added at rt. -40 ° C add 1- (2- (trimethylsilyl) ethoxymethyl) -4- (4-fluorophenyl) • 0 00 00 • 0 0 9 0 · 0 0 · 00

0 0 · 0 0 0 0 0 4 9 4 4: 9 000000

0 0 0 · 0 000 000 0 000 0000 00 00

5- (4-pyridyl) imidazole (example 2; 50 mg, 0.13 mmol) in tetra- hydrofuran (1.4 mL). After 15 minutes at -40 ° C se to reaction mixture 4-fluorobenzaldehyde (0.018 ml, 0.18 mmol) in tetra-

hydrofuran (0.4 mL), warmed to room temperature and after 10 minutes poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, evaporated to dryness to give the desired N-protected compound (64 mg). In order to remove the SEM, the obtained compound was dissolved in 2 ml of tetrahydrofuran, treated with Bu ₄ NF (4.3 ml; 1M in tetrahydrofuran) for 1 hour at 60 ° C, poured into saturated sodium bicarbonate solution and washed three times with ethyl acetate. extract with ethyl acetate. The combined organic layers were dried over sodium sulfate, evaporated to dryness and purified by chromatography (silica gel; toluene / ethanol / conc. Ammonia 90/10 / 0.6) to give the title compound as white crystals (32 mg 67). % after two steps).

1 H-NMR (360 MHz perdeuterodimethylsulfoxide): 5.80 (s, 1H); 6.30 (bs, OH); 7.15 '(t, 2H); 7.20-7.30 (bs, 1H); 7.37. (d, 2H); 7.42-7.48 (m, 2 H); 7.52-7.58 (m, 2 H); 8.38-8.51 (bs, 2H); 12.50-12.60 (bps, NH)

Alternatively, a mixture of 1- (1,1-diethoxymethyl) -4- (4-fluorophenyl) -5- (4-pyridinyl) imidazole and 3- (1,1-diethoxymethyl) -4- (4-fluorophenyl) may be used. -5- (4-pyridinyl) imidazole, prepared as above, instead of 1- (2- (trimethylsilyl) ethoxymethyl) -4- (4-fluorophenyl) -5- (4-pyridyl) imidazole; for example, as described below for the preparation of 4- (4-fluorophenyl) -5- (4-pyridyl) -2- (2,3,5,6-tetrafluoropyridinyl) imidazole.

4- (4-Fluorophenyl) -5- (4-pyridyl) -2- (2,3,5,6-tetrafluoropyridinyl) imidazole

444444 4 44 ·· ··· 4 · 4 · 4 · · 4

4 4 ·· '··· «· 4 4 4 * 444444 4 4 4 4 4

444 «4,444 44 · 4,444 44

1,6-n-BuLi (66 ml; 45 mmol) is added to 1: 1 1- (1,1-diethoxymethyl) -4- (4-fluorophenyl) -5- (4-pyridinyl) at -45 ° C 1-Imidazole and 1- (1,1-diethoxyethyl) -5- (4-fluorophenyl) -4- (4-pyridinyl) imidazole (15 g; 43 mmol) in tetrahydrofuran (210 mL). After 15 minutes at -45 ° C, the reaction mixture was cooled to -55 ° C and pentafluoropyridine (5.1 mL; 47 µmol) was added rapidly. Remove the cooling bath, allow the reaction mixture to warm to -15 ° C and pour into water (1 L), which is then acidified with 2N hydrochloric acid (100 mL). After stirring for 5 minutes, the mixture was combined with saturated sodium carbonate solution and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness to afford the title compound as brown crystals (16.3 g). Purification by chromatography (silica gel; acetone / hexane 1: 1) affords the title compound together with unreacted and unprotected imidazole starting material, which can be removed by washing with acetone to give the title compound (8.7 g; 52%). , 4%).

¹ H-NMR (360 MHz, CDCl 3): 7.30-7.40 (bt, 2H); 7.45 (d, 2 H); 7.58 (bq, 2H); 8.52 (bs, 2H).

and

MS (m / z): 388.9 (MH < + >)

Using very similar procedures as described in Example 3 and suitable. The following compounds of the formula .X shown in Table 1 are prepared from the starting materials:

♦ «· ** ·

Table 1

Example X ” D ' .......................... 1 --- NMR data and the like 4 -so ₂ - Ό 1 H-NMR (360 MHz DMSO-d 6): 7.28 (t, 2H); 7.35 (d. 2H); 7.49 (m. 2H); 7.67-7.80 (m, 3 H); 8.05 (d. 2H); 8.50 (b, 2H) 5 -with- Ό 1 H-NMR (360 MHz DMSO-d 6): 7.20-7.45 (m, 9H); 7.55 (dd, 2 H); 8.40-8.60 (m, 2H). 6 -Se- 1 H-NMR (360 MHz DMSO-d 6): 7.25-7.36 (5H); 7.40 (d, 2 H); 7.48-7.55 (m. 4H); 8.48 (d, 2H) 7 direct custody ° O 1 H-NMR (360 MHz DMSO-d 6), 7/3 mixture.  NH tautomers: 1.20-1.40 (bs, 1H); 1.51 (bs, 3 H); 1.60-1.72 (m, 2 H); 1.72-1.85 2H); 1.90-2.05 (M, 2 H); 5.60 (s, 0.7H); 5.67 (s, 0.3H); 7.12-7.21 (bt, 0.3 H); 7.30 (bt, 0.7H); 7.40 (d, 2 H); 7.48 (bt, 2 H); 8.40 (bd, 1.4H); 8.48 (bd, 0.6H); 12.25 (s, IH) 8 direct custody X ch ₂ 1 ² .CH v 1 H-NMR (360 MHz DMSO-d 6): 0.00 (bs, IH); 0.20-0.30 (m, 2 H); 0.32-0.43 (m. 2H); 0.50-0.60 (m, 1H); 0.65-0.75 (m, 1H); 1Ό5- 1.15 (m, 1H); 1.60-1.70 (m, 1H); 1.81-3.91 (m, 1H); 2.10-2.20 (m, 1H); 7.15-7.40 m 4H); 7.50 (dd, 2 H); 8.40 (bs, 1 H); 8.45 (bs, IH); 12.20 (bs, lH) MS (m / z): 348 (MH < + >)

• · · ·

00 «00«

9 -CH _r 1 H-NMR (360 MHz CDCl ₃ ): 0.48 (q, 2H); 0.68 (q. 2H); 1.20 (m, IH); 2.84 (d, 2 H); 7.10 (t. 2H); 7.45 (dd, 2 H); 7.55 (d. 2H); 8.45 (d, 2H). MS (m / z): 294 (MH &lt; + &gt;) 10 direct custody F in SS ^F , N F F 1 H-NMR (360 MHz CDCl 3): 7.30-7.40 (bt, 2H); 7.45 (d. 2H); 7.58 (bq, 2H); 8.52 (bs, 2H). MS (m / z): 388.9 (MH &lt; + &gt;) 11 direct custody 1 H-NMR (360 MHz DMSO): 1.83 (bd; 2H); 1.90 (bs, 2 H); 2.13 (bd, 2 H); 2.25 (bs, 2 H); 2.40 (bd, 2 H); 3.12 (bs, 3 H); 5.15 (bs, 1 H); 7.20-7.30 (bs, 2 H); 7.46 (d. 2H); 7.45 (dd, 2H); 8.35-8.50 (s, 2 H); 12.25 (s, 1 H). MS (m / z): 377.1 (MH &lt; - &gt;) 12 direct custody <- ⁿ 'ch ₂ 1 H-NMR (360 MHz DMSO, 120 C): 2.3 8 (bt, 1 H); 2.21 (bt, IH); 2.40-2.50 (m, 2 H); 2.78 (s. 3H); 2.7-2.95 (bm. 4H); 5.45 (bs, 1H); 7.21 (dd, 2 H); 7.42 (dd, 2 H); 7.51 (dd, 2H); 8.45 (dd, 2 H). MS (m / z): 352 (M &lt; + &gt;)

b means "wide q means" quartet

0000

00 0 · 0 0 • t

0 ·· 000 ····

Example 13

2- (1-Cyclohexenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) imidazole

The product of the example. 7, 2 - ((1-hydroxy) cyclohexyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole (50 mg 0.15 mmol) was dissolved in toluene (100 mL) and heat to boiling with pTsOH (100 mg) for 15 minutes. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, evaporated to dryness, and purified by chromatography (silica gel; acetone / hexane 4/6) to give the title compound as white crystals (38 mg; 81%).

1 H-NMR (360 MHz perdeuterodimethylsulfoxide), 8/2 NH-tautomers: 1.60 (m, 2H); 1.68 (m, 2 H); 2.18 (bs, 2H); 2.50 (bs, 2H); 6.55 (bs, 0.8H); 6.62 (bs, 0.2H); 7.15-7.60 (m, 6H); 8.40 (d, 1.6H); 8.52 (d, 0.4H); 12.25. (bs, 0.2H); 12.37 (bs, 0.8H)

Using very similar procedures to those described in Example 13 and the appropriate starting materials, the following compounds of formula X are shown in Table 2:

Ύ >> - x - ^D '___ / ~~ N

X · · • * * * * * * * * • • • X • • • • • · · ·· ···· ·· ··

Table 2

Example X ” D ' NMR data and the like 14 direct custody limb,. 1 H-NMR (360 MHz DMSO, 120 C): 1.55-1.65 (m, 2H); 1.72 (dt, 2 H); 2.00-2.18 (m, 2 H); 2.22 (d, 1 H); 2.35 (s. 3H); 3.35 (bt, 1H) 3.42 (bt, 1H); 6.68 (bs, 1 H); 7.10-7.30 (bd, 2 H); 7.40 (d, 2 H); 7.50 (dd, 2 H); 8.35-8.55 (bd, 2 H); 12.00 (bs, 1 H). MS (m / z): 361.1 (M + H &lt; + &gt;). 15, direct custody 1 H-NMR (360 MHz, DMSO, 120 C): 2.35 (s, 3H); 2.65 (s, 4 H); 3.10 (s. 2H); 6.55 (bs, 1 H); 7.10-7.30 (bd, 2 H); 7.42 (bs, 2 H); 7.52 (bt, 2 H); 8.35-8.55 (bd, 2 H); 11.90-12.10 (bs, 1 H). MS (m / z): 334 (M &lt; + &gt;).

1-SO ₂ Cl in pyridine is used instead of pTsOH in toluene b means "wide."

Examples 16 and 17

4- (4-Fluorophenyl) -5- (4-pyridyl) -2- (2-amino-3,5,6-trifluoropyridinyl) imidazole and 4- (4-fluorophenyl) -5- (4-pyridyl) -2 - (2,6-diamino-3,5'-difluoropyridinyl) imidazole

The product of Example 10, 4- (4-fluorophenyl) -5- (4-pyridyl) -2 (2,3,5,6-tetrafluoropyridinyl) imidazole (2g; 5.15 mmol), was suspended in concentrated ammonia (25g). %, 200 ml) and heated to 150 ° C in a sealed steel vessel for 5 hours. The water was evaporated and the residue was purified by chromatography (silica gel; T3ME / methanol / conc. Ammonia 98/2 / 0.2) to give the title compounds 4- (4-fluorophenyl) -5- ( 4-pyridyl) -2- (2-amino-3,5,6-trifluoropyridinyl) imidazole (880 mg; 44.4%) and 4- (4-fluorophenyl) -5- (4-pyridyl) -2- ( 2,6-diamino-3,5-difluoropyridinyl) imidazole (650 mg; 33%) as light colored crystals.

4- (4-Fluorophenyl) -5- (4-pyridyl) -2- (2-amino-3,5,6-trifluoropyridinyl) imidazole: ¹ H-NMR (400 MHz, piperidine dimethyl sulfoxide) tautomer mixture: 6.80 ( s, 2H); 7.25 (bt, 0.6H); 7.38 (t, 1.4H);

7.45 (d, 2 H); 7.58 (t, 2 H); 8.49 (d, 1.4H) -; 8.62 (bd, 0.6H);

MS (m / z): 385 (M &lt; + &gt;)

- (4-Fluorophenyl) -5- (4-pyridyl) -2- (2,6-diamino-3,5'-difluoropyridinyl) imidazole: ¹ H-NMR (400MHz, perdeuterodimethylsulfoxide) mixture. tautomers: 5.75 (s, 2H); 7.22 (t, 0.6H); 7.33 (t, 1.4H);

7.41-7.47 (m, 2 H); 7.52-7.58 (m, 2 H); 8.47 (d, 1.4H); 8.58 (d,

0.6H); MS (m / z): 382 (M &lt; + &gt;)

Example 18

- (4-Fluorophenyl) -2 - ((1-amino) cyclohexyl) -5- (4-pyridyl) imidazole

(a) Bydrobromide

1- (4-Fluorophenyl) -2-bromo-2- (4-pyridyl) ethanone

Bromine (74.4 g; 0.46 mol) in acetic acid (160 mL) was added to a solution of 4-fluorophenyl-4-pyridylmethylketone (I.Lantos et al. J. Med. Chem. 1984, 27, 72-75) (100 g; 0.46 mol) in acetic acid (800 mL). The yellow crystals are filtered off, washed with acetic acid, ether, hexane and then dried under reduced pressure to give the hydrobromide of the title compound (250 g; 72%).

Φ Φ φ φ φ φ φ φ · · · · · · · · · · · ·

(b) 4- (4-Fluorophenyl) -2- (1-N-carbobenzyloxycyclohexyl) -5- (4-pyridyl) imidazole;

1-N-carbobenzyloxy-1-cyclohexanecarboxylic acid (E. Didier et al. Tetrahedron 1992, 48 (39), 8471) (13.9 g; 50 mmol) and ammonium carbonate (Fluka; 4.8 g; 50 mmol) Dissolve in dimethylformamide (50 mL) and heat at 110 ° C for 10 min before stopping gas evolution. The reaction vessel is cooled to 60 ° C and 1- (4-fluorophenyl) - hydrobromide is added as a solid.

2-bromo-2- (4-pyridyl) ethanone (3.75 g; 10 mmol) and the mixture was heated at 125 ° C for -2.5 hours. The reaction mixture was poured into 1M sodium carbonate solution and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, evaporated to dryness to give the crude title compound (4.8 g) which was purified by chromatography (silica gel; ethyl acetate) to give the pure title compound yellow crystals (1.4 g; 30%).

1 H-NMR (400 MHz; CDCl 3) 1.25-2.40 (m, 10H); 5.12 (s. 2H); 7.08-7.16 (m, 2 H); 7,30-7,50. (m, 9H); 8.50 (d, 2 H);

MS (m / z): 471.2 (MH &lt; + &gt;)

99

4 4 ·

9 4 ·

499 444 ·

44 r · * · •

• 9

4499 • · ····

c) 4- (4-Fluorophenyl) -2- (1-aminocyclohexyl) -5- (4-pyridyl) imidazole (243-653)

- (4-Fluorophenyl) -2 - ((1-N-carbobenzyloxy) cyclohexyl) -5- (4-pyridyl) imidazole; (1.6 g; 4 mmol) was dissolved in ethanol (140 mL) and hydrogenated at 100 kPa in the presence of palladium on charcoal (10%; 0.7 g) for 2 hours at room temperature. Filtration, evaporation of the solvent and recrystallization from ethyl acetate / ether gave the desired amine as white crystals (0.63 g; 47 °).

δ-NMR (400 MHz; perdeuterodimethylsulfoxide): 1.25-1.78 (m,

8H); 1.95-2.10 (bt, 2H); 7.25-7.34 (bt, 2H); 7.40 (d, 2 H);

7.47-7.52 (m, 2H); 8.43 (d, 2 H); MS (m / z): 336 (M &lt; + &gt;)

Example 19

4- (4-Fluorophenyl) -5- (4-pyridyl) -2- (4-n-butyloxy-1-methylpiperidin-4-yl) imidazole

F ··· · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 4 4 4 4 4 4 4 4

Ζ / «· · · · · · · ·

The product of Example 12, 4- (4-fluorophenyl) -5- (4-pyridyl) -2- (4-hydroxy-1-methylpiperidin-4-yl) imidazole (22.2 g; 63 mmol), was heated to 40 ° C. ° C, dissolved in 1-butanol (1 L). Concentrated sulfuric acid (27.8 g; 283 mmol) was added dropwise and the resulting suspension was heated to boiling for 3.5 hours while distilling about 200 mL of 1-butanol. The reaction mixture was cooled to room temperature and poured into saturated sodium carbonate solution (500 mL). The aqueous layer was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. Purification by chromatography (silica gel; TBME / methanol / concentrated ammonia 96/4 / 0.4 to 70/30/1) gave the title compound as yellow crystals (15.5 g, 60.3%). The sample was recrystallized from dichloromethane (TBME) to give colorless crystals of m.p. 177 ° C.

¹ H-NMR (400MHz; perdeuterodimethylsulfoxide): mixture of tautomers that doubled aromatic signals: 0.80 (bt, 3H); 1.25-1.35 (m, 2 H); 1.38-1.48 (m, 2 H); 2.12 (bs, 4H); 2.18 (s, 3H); 2.35 (m, 2 H); 2.42 (m, 2 H); 3.12 (t. 2H); 7.18 (t, 0.5H); 7.32 (t, 1.5H); 7.40 (m, 2 H); 7.48 (m. 2H); 8.40 (d, 1.5H); 8.53 (d, 0.5H); MS (m / z): 408 (M &lt; + &gt;,20%); 351 (100%); 335 (95%).

The compounds of the present invention in free form or in the form of pharmaceutically acceptable acid addition salts or in the form of physiologically cleavable esters which exhibit pharmacological activity and are useful as medicaments, for example for the treatment of the diseases and conditions mentioned herein are called agents according to the invention. according to the invention.

In particular, the agents of the invention have inhibitory activity with respect to p38 MAP kinase (mitogen-activated protein kinase). The agents of the invention act to inhibit the production of inflammatory cytokines such as TNF-α and IL-1 and also potentially block the effect of these cytokines on their target cells. These and more • · · · · ·

QC · · · · ···

The pharmacological activities of the agents of the present invention can be demonstrated using standard testing procedures, as described, for example, below: 9999 9 999 9999 99 99

p38 MAP kinase assay

Substrate (GST-ATF-2; fusion protein containing amino acids 1109 ATF-2 and GST 'protein obtained by E. coli expression) is plated in microtiter plate wells (50 μϊ / well; 1 μ9 / ΓηΓ in PBS (0.02% Na azide) and left overnight at 4 [deg.] C. The next day the microtiter plates are washed four times with PBS / 0.5% Tween 20 / 0.02% Na azide and blocked with PBS / 2% BSA / 0.02% Na azide 1. The plates are washed four times with PBS / 0.5% Tween 20 / 0.02% Na azide and the cascade kinase reaction is then started by adding the following reactants in 10 µl aliquots to a final reaction volume of 50 µΐ.

1. Reagents of the present invention are titrated from 10 to 0.001 μΜ in 10-fold dilutions or solvents (DMSO) or water.

2. Kinase buffer (5x); pH 7.4; 125 mM Hepes (stock at 1M;

Gibco # 15630-056), 125 mM β-glycerophosphate (Sigma # G6251): 125 mM MgCl ₂ (Merck # 5833); 0.5 mM sodium orthovanadate (Sigma # 5-6508), 10 mM DTT (Boehringer Mannheim # 708992). Kinase buffer (5x) must be prepared fresh on the day of the assay from 5x alkaline solutions maintained at room temperature. The DTT is maintained at -20 ° C and added as the last reagent.

3. His-p38 MAP kinase (10 ng / well; Novartis - fusion protein containing full-length murine p38 MAP kinase and His tag obtained by expression in E. coli)

4. Cold ATP (final concentration 120 μΜ; Sigma # A-9187)

5. Water

After 1 hour at 37 ° C, the reaction is terminated by washing the plates four times as described above. Phosphorylated GST-ATF-2 is then detected by adding:

1. PhosphoPlus ATF-2 (Thr71) antibody (50 μΐ / well; 1/1000 final dilution in PBS / 2% BSA / 0.02% Na Azide; New England. Biolabs # 9221L) 90 minutes at room temperature.

2. Biotin-labeled goat-anti-rabbit, IgG (50 μΐ / well; 1/3000 final dilution in PBS / 2% BSA / 0.02% Na Azide; Sigma # B-9642) for 90 minutes at room temperature.

3. Streptavidin-alkaline phosphatase (50 μ 50 / well; 1/5000 dilution in PBS / 2% BSA / 0.02% Na Azide; Jackson Immunoresearch # 016-050-084) for 30 minutes at room temperature.

4. Substrate (100 μΐ / well; Sigma 104 phosphatase substrate tablets, 5 mg / tablet; # 104 105; 1 mg / ml in substrate buffer, diethanolamine (97 ml / 1; Merck # 803116) + MgCl ₂ .6H ₂ O (100 mg / l; Merck # 5833) + Na Azide (0.2 g / l) + HCl 1M to pH

9.8) 30 minutes at room temperature.

After steps 1, 2 and 3, the microtiter plates are washed four times

PBS / 0.5% Tween 20 / 0.02% Na azide. After step 4, the plates are read on a BioRad microplate reader in dual wavelength mode (measuring filter 405 nm and reference filter 490 nm). Subtract the baseline value (without ATP) and calculate the IC ₅₀ value using the Origin computer program (4 parameter logistic function).

When tested according to the above procedure, the agents of the present invention typically have an IC ₅₀ value for inhibition of p38 MAP kinase in the range of 1 µΜ to 10 nM or less. For example, compound 17 has an IC _{50 of} 10 nM in this assay.

• · 9.: ..

TNF-α release inhibition assay from hPBMC

9 9 9 9

989 99 9

Human peripheral blood mononuclear cells (hPBMC) are prepared from peripheral blood of healthy volunteers using ficoll-hypaque density gradient separation according to the method described by Hansell et al., J. Immun. Methods (1991) 145: 105 and used at 10 ⁵ cells / well in RPMI 1640 plus 10% FCS. Cells are incubated in serial dilutions of test compounds for 30 minutes at 37 ° C before addition of IFNg (100 U / ml) and LPS (5 mg / ml) and then incubated for 3 hours. Incubation is terminated by centrifugation at 1400 rpm for 10 minutes. TNFα in the supernatant is measured using a commercial ELISA (Innotest hTNFα, available from Innogenetics NV, Zwijnaarde, Belgium). The agents of the present invention are tested at concentrations of 0 to 10 mM. Tested. agents of the present invention typically suppress TNF release in this assay at an IC _{50 of} 1 µΜ to 10 nM or less. For example, when testing the compound of Example 17 with this assay, it has an IC _{50 of} 90 nM.

TNF-α production inhibition assay in LPS-stimulated mice

Injection of lipopolysaccharide (LPS) induces rapid release of soluble tumor necrosis factor (TNF-α) into the periphery. This model is used to analyze potential TNF release blocking agents in vivo.

LPS (20 mg / kg) is injected I.v. To 0F1 mice (female, 8 weeks old). After one hour (1), animals are bled and the plasma TNF level is analyzed by ELISA using the TNF-α antibody. Usage of 20 mg / kg LPS usually induces up to 15 ng of TNF-α / ml plasma. The compounds to be tested using this assay are administered orally or s.c. 1-4 hours before LPS injection. Inhibition of LPS-induced TNF release is considered a reference value.

4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 ·

4444 44 444 444

44 44 44 X 44444 444444 4. 4 4 4 4

The agents of the present invention typically inhibit TNF production in the range of 50% to -90% or more when administered p.o. at 10 mg / kg. For example, the compound of Example 1.7 inhibits TNF production by about 80% in this assay.

As can be seen from the above assays, the agents of the present invention are potent inhibitors of TNF-α release. Thus, the novel compounds of the present invention have the following pharmaceutical utility:

The agents of the present invention are useful for the prophylaxis and treatment of cytokine-mediated diseases or pathologies such as TNFα and IL-1, for example, inflammatory conditions, autoimmune diseases, severe infections and organ or tissue transplant rejection, e.g. treatment of recipients of heart, lung, heart and lung transplants simultaneously,. liver, kidney, pancreas, skin or cornea and to prevent graft versus host disease following bone marrow transplantation.

The agents of the present invention are particularly suitable for the treatment, prevention or amelioration of autoimmune diseases and inflammatory conditions, particularly inflammatory conditions. with an ethiology including an autoimmune component such as arthritis (e.g. rheumatoid arthritis, progressive chronic arthritis and deformative arthritis), and rheumatoid disease. Specific autoimmune diseases for which agents of the present invention can be used include autoimmune hematological diseases (including, for example, haemolytic anemia, aplastic anemia, pure red blood cell anemia and idiopathic thrombocytopenia), systemic, lupus erythematosus, polychondritis, scleroderma, Wegener dermatomatosuide , chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic maladsorption syndrome, autoimmune inflammatory bowel diseases (including • 6 · · · ·

4 β · ··

4 · 4 4 4 4 4 4 4 4

4. 6 4 · · · · · · · · 4 4 4 6 6 ·

4 4 4 4 4 νΖ 4444 4 444 ··· 46 44 ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, youthful diabetes (type I diabetes mellitus), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glornerulonephritis (with or without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy).

The agents of the present invention are also useful for treating, preventing or ameliorating asthma, bronchitis, pneumoconiosis, pulmonary emphysema, and other obstructive or inflammatory airway diseases.

The agents of the present invention are useful in the treatment of unwanted acute and hyperacute inflammatory reactions that are mediated by TNF, particularly TNFα, for example, acute infections such as septic shock (e.g. endotoxic shock and adult respiratory distress syndrome), meningitis, pneumonia; and severe burns; and for the treatment of cachexia or sagging syndrome associated with the pathological release of TNF resulting from infection, cancer or organ dysfunction, particularly AIDS-related cachexia, for example, associated with or following HIV infection.

The agents of the present invention are particularly useful for treating diseases of bone metabolism including osteoarthritis, osteoporosis and other inflammatory arthritis.

Of course, for the above indications, appropriate dosages will vary depending upon, for example, the particular agent of the present invention employed, the patient being treated, the route of administration, and the nature and severity of the condition being treated. In general, however, satisfactory results were obtained in animals at a daily dose of 1 to 10 mg / kg / day p.o. In higher mammals, for example

0 0.0 0 ·

0 0 0 * 0 0 0 0 0

0 0 0 0 0 0 0

0 0 0 0 0 000 * 0 0

0 00 0 0 0 0000 0 000 ··· 00 00 In humans, the daily dose will be in the range of 50 to 750 mg of an agent of the present invention administered orally in a single dose or, more preferably, in two to four doses per dose. day.

The agents of the present invention may be administered by any suitable route, for example orally, for example in the form of a drinking solution, tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions. Oral dosage forms are normally suitable for systemic administration, although, in some indications, the agents of the present invention may be administered topically or dermally, for example, in the form of a skin cream or gel or the like, for application to the eye, eye cream, gel. or eye drops; or may be administered by inhalation, for example in the treatment of asthma. Suitable unit dosage forms for oral administration contain, for example, 25 to 250 mg of the novel compound per dose.

In accordance with the foregoing description, the present invention also provides another series of embodiments:

A. A method of inhibiting soluble TNF1 production. in particular TNFα, or suppressing inflammation in patients (i.e., mammals, especially humans) in need thereof, the method comprising administering to said patient an effective amount of an agent of the invention, or a method of treating any of the above conditions, particularly a method of treating inflammatory or autoimmune diseases or conditions, for example rheumatoid arthritis or amelioration of one or more symptoms of any of the above diseases.

B. The agent of the present invention for use as a medicament, for example, for use as an immunosuppressant or anti-inflammatory agent, or 'for use' in preventing, ameliorating. · · · · · · · · · · ·

Or treating any disease or condition described above, such as an autoimmune or inflammatory disease or condition.

C. Pharmaceutical composition comprising an agent of the present invention in association with a pharmaceutically acceptable diluent or carrier, for example, for use as an immunosuppressive or anti-inflammatory agent, or for use in preventing, ameliorating or treating any of the diseases or conditions described above, e.g. an inflammatory disease or condition.

D. Use of an agent of the present invention for the preparation of a medicament for use as an immunosuppressive or anti-inflammatory agent or for use in the prevention, alleviation or treatment of any of the diseases or conditions described above, for example an autoimmune or inflammatory disease or condition.

Claims (12)

1. 4,5-Diarylimidazole substituted in position i) the nitrogen atom in the 1-position is substituted with a trialkylsilyl group; or ii) the 2-substituent is arylalkyl, arylsulfonyl, arylthio, arylselio, aryltelluro, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl or aminocycloalkenyl. a hydrazino group, or a mono- or bicyclic N-heterocyclyl group wherein the nitrogen-containing ring has 6 ring members, provided that the substituent at the 2-position is not piperidin-4-yl, 1-tert-butoxycarbonyl-4-benzyl-piperidine -4-yl, 1,4-dimethyl-piperidin-4-yl, 4-benzylpiperidin-4-yl or piperidinyl, which is further substituted on nitrogen only and further provided that neither 4 neither the 5-aryl substituent is a phenyl group substituted with a radical selected from an alkylsulfonyl group or an aminosulfonyl group, in free form or in the form of a pharmaceutically acceptable acid addition salt or in the form of a physiologically cleavable ester. 2. A compound of formula I R-. is 4-pyridyl, pyrimidinyl, quinazolin-4-yl, quinolyl, isoquinolyl, • 9 9 999 9 9 9 998 9 · 9 9 · · · · 1-imidazolyl or 1-benzamidazolyl optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4) alkyl, halogen, (C 1 -C 4) alkoxy, alkylthio containing 1 to 4 carbon atoms, NR ₅ R ₆ , or an N-heterocyclyl ring containing 5 to 7 ring atoms and optionally containing additional heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen, wherein R ₅ and R ₆ are independently C1-C4alkyl; R ₂ is phenyl, naphth-l-yl or naphth-2-yl, which is optionally substituted with up to five substituents; R ₃ . is a hydrogen atom, a heterocyclyl group, a heterocyclylalkyl group containing from 1 to 10 carbon atoms, a trialkylsilylalkoxyalkyl group containing from 1 to 4 carbon atoms in each alkyl portion and from 1 to 10 carbon atoms in the alkoxy portion, optionally substituted by a halogen atom containing from 1 to 10 carbon atoms; 10 atoms, carbon, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 1 to 10 carbon atoms, cycloalkenyl of 5 to 10 carbon atoms 7 carbon atoms, aryl group, φ • arylalkyl group containing 1 to 10 carbon atoms in the alkyl part, a heteroaryl group, or a heteroaryl group, or a heteroaryl group, or C 1 -C 10 alkyl, optionally mono- or dialkyl containing 1 to 4 carbon atoms in each alkyl moiety substituted alkyl-oxycarbonyl or -oxythiocarbonyl containing 0 to 10 carbon atoms in the alkyl moiety optionally substituted by an alkyl moiety 1 to 10 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, heterocyclyl, heterocyclylalkyl of 1 to 10 carbon atoms in the alkyl moiety, aryl, arylalkyl of 1 to 10 carbon atoms in the alkyl moiety, heteroaryl, heteroarylalkyl content group C 1 -C 10 alkyl or C 1 -C 10 mono- or dialkyl C 1 -C 10 alkyl optionally substituted by cyano, nitro, hydroxyl, C 1 -C 10 alkoxy in each C 1 -C 4 alkyl moiety 10 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, heterocycloxy, heterocyclylalkoxy of 1 to 10 carbon atoms, aryloxy, arylalkoxy of 1 to 10 carbon atoms, heteroaryloxy of 1 to 10 carbon atoms · · · · «® * * * * ® * * * ® ® ® ® ® ® ® ® ® ® ® ® Optionally, substituted amino, carboxylate, thiocarboxylate, carbonyl a thiocarbonyl group, a sulfinyl group or a sulfonyl group; R ₄ is a mono- or dicycloalkylalkyl group containing from 3 to 7 carbon atoms in each cycloalkyl moiety and from 0 to 4 carbon atoms in the alkyl moiety optionally substituted by halogen, hydroxyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 atoms atoms, thioalkoxy containing 1 to 4 carbon atoms, nitro, amino, alkylsulfinyl having 1 to 4 carbon atoms, alkylsulphonyl of 1-4 carbon atoms, carboxylate or ester groups, NH _2, NR ₇ R ₈ or a group NHNHR ₉ wherein R _7, independently, R _e · _s or R is alkyl of 1-4 carbon atoms, alkenyl of 2-4 carbon atoms, alkynyl of 2-6 carbon atoms, -X-aryl of 5 to 10 carbon atoms in the aryl part (including heteroaryl) wherein X is sulfur, SO ₂ , selenium, tellurium or C 1 -C 4 alkyl, mono- or bicyclic N- a heterocyclyl group, wherein the nitrogen-containing ring has six members, or an aryl or heteroaryl group optionally substituted with up to 4 substituents, provided that: • · when R ₃ is not trialkylsilylalkoxyalkylová radicals in which each alkyl moiety with 1 to 4 carbon atoms in the alkoxy portion and 1 to 10 carbon atoms, R ₄ is not an aryl or heteroaryl group optionally substituted with up to four substituents, except where R ₄ is a mono- or bicyclic N-heterocyclyl group wherein the nitrogen-containing ring has six members; provided that: R ₄ is not piperidin-4-yl, 1-tert-butoxycarbonyl-4benzyl-piperidin-4-yl, 1,4-dimethyl-piperidin-4-yl, 4-benzyl-piperidin-4-yl or piperidinyl, which is further substituted only on the nitrogen atom and further provided that R ₂ is not phenyl substituted with a radical selected from the group consisting of alkylsulfonyl group nebo'aminosulfonylové. A compound according to claim 2 of formula I '4 wherein R _3. ' is a trialkylsilylalkoxyalkyl group having from 1 to 4 carbon atoms in each alkyl moiety and from 1 to 10 carbon atoms in the alkoxy moiety, and R 1, R ₂ and R ₄ are the same as defined in claim 2, in free form or in pharmaceutically acceptable acidic form addition salts or in the form of a physiologically cleavable ester. Compound according to claim 2 of the general formula III III wherein R _1; R ₂ , R ₃ and X are as defined in claim 2 and R 1 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy carbon, thioalkoxy having 1 to 4 carbon atoms, nitro, amino, alkylsulfinyl having 1 to 4 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, carboxylate or ester, in free form or in the form of a pharmaceutically acceptable acid addition salt or in the form of a physiologically cleavable ester. A compound according to claim 2 of the general formula IV IV R 1, R ₂ and R ₃ are as defined in claim 2, D is a cycloalkyl group containing 3 to 7 carbon atoms, a cycloalkenyl group containing 3 to 7 carbon atoms or a mono- or bicyclic N-heterocyclyl group wherein the nitrogen-containing ring has 6 and X 'is a direct bond or a group -CR ₁₂ R ₁₃ . wherein R _i2 is hydrogen or alkyl having 1 to 4 carbon atoms and R ₁₃ is hydrogen or an alkyl group containing · '1 to 4 carbon atoms or • ···· ·· ·. 9 9 9 9 9 99 9 9 9 • · 999 9999 99 9 9 Substituted with cycloalkyl of 3 to 7 carbon atoms or cycloalkenyl of 3 to 7 carbon atoms, with the proviso that X 'is a direct bond when D is a mono- or bicyclic N-heterocyclyl group wherein the nitrogen-containing ring has 6 in the free form or in the form of a pharmaceutically acceptable acid addition salt or in the form of a physiologically cleavable ester. The compound of claim 2 selected from the group consisting of: 4- (4-fluorophenyl) -5- (4-pyridyl) -1- (2-trimethylsilylethoxymethyl) imidazole; 4- (4-fluorophenyl) -2 - ((RS) -1-hydroxy-4-fluorobenzyl) -5- (4-pyridyl) imidazole; 4- (4-fluorophenyl) -2- (phenylsulfonyl) -5- (4-pyridyl) imidazole; 4- (4-fluorophenyl) -2- (phenylthio) -5- (4-pyridyl) imidazole; 4- (4-fluorophenyl) -2- (phenylselen) -5- (4-pyridyl) imidazole; 4- (4-fluorophenyl) -2 - ((1-hydroxy) cyclohexyl) -5- (4-pyridyl) imidazole; 2- (1-cyclohexenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) imidazole; 2- (1,2-dicyclopropylethyl) -4- (4-fluorophenyl) -5- (4-pyridyl) imidazole; 2- (cyclopropylmethyl) -4- (4-fluorophenyl) -5- (4-pyridyl) imidazole; 4- (4-fluorophenyl) -5- (4-pyridyl) -2- (2,3,5,6-tetrafluoropyridinyl) imidazole; 4- (4-Fluorophenyl) -5- (4-pyridyl) -2- (tropan-3α-ol-3β-yl) imidazole; 4- (4-Fluorophenyl) -5- (4-pyridyl) -2- (4-hydroxy-1-methylpiperidin-4-yl) imidazole; +/- 4- (4-fluorophenyl) -5- (4-pyridyl) -2- (8-methyl-8-azabicyclo [3.2.1] oct-2-en-3-yl) imidazole; 4- (4-fluorophenyl) -5- (4-pyridyl) -2- (2-amino-3,5,6-trifluoropyridinyl) imidazole; • β · φ φ · · φ φ φ φ φ φ φ · · · · · · · · · 4- (4-fluorophenyl) -5- (4-pyridyl) -2- (2,6-diamino-3,5-difluoropyridinyl) imidazole; 4- (4-fluorophenyl) -2 - ((1-amino) cyclohexyl) -5- (4-pyridyl) imidazole; 4- (4-Fluorophenyl) -5- (4-pyridyl) -2- (4-n-butyloxy-1-methylpiperidin-4-yl) imidazole or 4- (4-fluorophenyl) -5- (4-pyridyl) -2- (1-methylpiperid-3,4-en-4-yl) imidazole, in free form or in the form of a pharmaceutically acceptable acid addition salt or in the form of a physiologically cleavable ester . 7. 4- (4-Pyridyl) -5- (4-fluorophenyl) -1- (2-trimethylsilylethoxymethyl) imidazole, in free form or in the form of a pharmaceutically acceptable acid addition salt or in the form of a physiologically cleavable ester. A process for preparing a compound of formula III as defined in claim 4 or a compound of formula IV as defined in claim 5, comprising reacting a compound of formula VIII VIII wherein R 1 and R ₂ are as defined above, with the corresponding aldehyde, ketone, disulfonamine, disulfide, diselenide, ditelluride or halide and, if appropriate, introducing the desired substituent R ₃ or further transforming the product obtained and optionally isolating the free or salt form . • · · ··· ··· · · · · · A method of inhibiting the production of soluble TNF or suppressing inflammation in a patient in need thereof, comprising administering to said patient an effective amount of a compound as defined in claim 1 or 2. The compound of claim 1 or 2 for use as a medicament, for example, for use as an immunosuppressant or anti-inflammatory agent. A pharmaceutical composition comprising a compound as defined in claim 1 or 2 together with a pharmaceutically acceptable diluent or carrier, for example, for use as an immunosuppressant or anti-inflammatory agent. Use of a compound according to claim 1 or 2 in the manufacture of a medicament for use as an immunosuppressant or anti-inflammatory agent.