WO2000026209A1

WO2000026209A1 - Anti-inflammatory 4-phenyl-5-pyrimidinyl-imidazoles

Info

Publication number: WO2000026209A1
Application number: PCT/EP1999/008358
Authority: WO
Inventors: Laszlo Revesz
Original assignee: Novartis Ag; Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.
Priority date: 1998-11-03
Filing date: 1999-11-02
Publication date: 2000-05-11
Also published as: AU6476599A

Abstract

Novel 4- phenyl- 5-(2- aryl-X)- 4-pyrimidinyl-, 4- phenyl-5- (2-cycloalkyl- X)-4-pyrimidinyl-, 4- phenyl-5- (-aralkyl-X)-4- pyrimidinyl- or 4-phenyl- 5-(2-cycloalkylalkyl- X)-4-pyrimidinyl- imidazoles, in which the 5- pyrimidinyl substituent is aryl, cycloalkyl, aralkyl or cycloalkylalkyl substituted directly via a heteroatom X selected from N, O or S, and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof are provided, in particular compounds of formula (I), wherein the symbols are as defined, which are MAP kinase inhibitors, useful pharmaceutically for treating TNFα and IL-1 mediated diseases such as rheumatoid arthritis and diseases of bone metabolism, e.g. osteoporosis.

Description

ANTI-INFLAMMATORY 4-PHENYL-5-PYRIMIDINYL-IMIDAZOLES

This invention relates to 4-phenyl-5-[(2-substituted)-4-pyrirmdinyl]-l-H-irnidazoles which are the tautomeres of 5-phenyl-4-[(2-substituted)-4-pyrirnidinyl]-l-H-imidazoles and to their use for treating TNFα and IL-1 mediated diseases such as rheumatoid arthritis and diseases of bone metabolism, e.g. osteoporosis. Both tautomers represent the same structure; their nomenclature may be used interchangeably.

Accordingly the present invention provides novel 4-phenyl-5-[(2-aryl-X)-4-pyrimidinyl]-, 4- phenyl-5-[(2-cycloalkyl-X)-4-pyrimidinyl]-, 4-phenyl-5-(2-aralkyl-X)-4-pyrimidinyl- or 4-phenyl- 5-[(2-cycloal ylalkyl-X)-4-pyrimidinyl] -imidazoles, in which X is a heteroatom selected from N, O or S, and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.

The 5-pyrimidinyl substituent is aryl-, cycloalkyl-, aralkyl- or cycloalkylalkyl-substituted directly via a heteroatom selected from N, O or S, i.e. the aryl, cycloalkyl, aralkyl or cycloalkylalkyl substituent and the pyrimidinyl ring are linked by a single atom which is N, O or S. Preferably the heteroatom is optionally substituted N, more preferably -NH-.

The aryl or aralkyl substituent may comprise a carboaryl substituent or a heteroaryl substituent; for instance, phenyl, benzyl, phenylethyl, 4-pyridylmethyl, naphthyl (e.g. naphth-1-yl or naphth-2-yl), pyridyl (e.g. 4-pyridyl), pyrimidinyl, quinazolinyl (e.g. quinazolin-4-yl), quinolinyl, isoquinolinyl, imidazolinyl (e.g. 2- or 3-imidazolyl) or benzamidazolinyl (e.g. 2- benzamidazolyl). The cycloalkyl or cycloalkylalkyl substituent may comprise a C₃ to ₂ cycloalkyl ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl ring. The aryl, cycloalkyl, aralkyl and cycloalkylalkyl substituents may be optionally substituted, e.g. by up to 3 substituents selected from alkyl, halogen, halo-substitued-alkyl, hydroxy, alkoxy, alkylthio, optionally substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom (e.g. O, S or N). Preferably the aryl or aralkyl substituent on the 5-pyrimidinyl substituent is benzyl, phenylethyl, 4-pyridylmethyl or phenyl, optionally substituted, preferably in the meta and/or para positions, by halogen, Cι.ι₀alkyl, Ci. ι₀alkoxy, hydroxy, halo-substitued Ci-ioalkyl (e.g. trifluoromethyl), or optionally substituted amino.

The 4-phenyl substituent may be unsubstituted, though is preferably substituted by one or more substituents, each of which may be independently selected from halo, cyano, amido, thioamido, carboxylate (including thiocarboxylate and esters of both of these), optionally substiutedCo-i alkyl optionally substituted carbonyl or thiocarbonyl (i.e. both aldehyde and ketone), alkoxy or thioalkoxy, optionally substituted alkyl, optionally substituted oxycarbonyl or amino- carbonyl (including thio analogues thereof), (optionally substituted)-amino or -aminomethyl, optionally substituted alkylamino-carbonyl or -thiocarbonyl, optionally substituted amino- sulphinyl or -sulphonyl optionally substituted by amino. Preferably the 4-phenyl has up to 3 substituents and preferably these are halo or halo-containing substituents, e.g. the 4-phenyl substituent is 2, 4, 5 trihalo-substituted phen-1-yl or especially 4-halo-, 3 -trifluoromethyl, 3- chloro, or 3,4-difluoro substituted.

The C-2 and Nl atoms of the of the imidazole ring may also be substituted, conveniently by substituents such as those described at equivalent positions in WO 95/03297, WO 97/25048, WO 97/12876 or WO 99/01499. The numbering of the atoms of the imidazole ring is shown below in Figure I.

Above and elsewhere in the present description the terms halo or halogen denote I, Br, Cl or F, preferably F.

In particular embodiments the invention provides a compound of formula I

wherein Ri is pyrimidinyl;

X is -NRe-Y-, -O- or -S-, where R is H, C_Malkyl, C₃-₈cycloalkyl, C₃-₈cycloalkylCι.₃alkyl, C₆-Cι₈aryl, C₃-C₁₈heteroaryl, C₇-Cι₉aralkyl or C -C₁₉heteroaralkyl, and -Y- is . ₄alkylene or a direct bond ;

R₂ is phenyl, optionally substituted by one or more substituents, each of which is independently selected from halo, CF₃, cyano, a ido or thioamido which is optionally mono- or di-N-substituted by C_Malkyl or the N atom of which forms a 5-7 membered heterocyclic ring optionally containing an additional hetero atom selected from O, S or N which N is optionally C_Malkyl C_1-4alkylcarbonyl or C alkylthiocarbonyl substitued, carboxylate or thiocarboxylate optionally in the form of an optionally halo- substituted Ci-ioalkoxy, C_2-!0alkenoxy, C_2-ι₀alkynoxy, C_3-7cyclalkoxy, C_5- ₇cycloalkenoxy, aryloxy, arylalkoxy, heteroaryloxy or heteroarylalkoxy ester, optionally mono- or di-Ci^alkyl-substituted-Co-ialkyl optionally CMalkyl- or C₃.₅ cycloalkyl-substituted-carbonyl or -thiocarbonyl, optionally halo-substituted-C alkoxy, C^alkenoxy, C₂^alkynoxy, C₃.₅cycloalkoxy or C_3-5cyclothioalkoxy, optionally halo substituted C alkyl, oxycarbonyl or optionally N-Ci^alkyl-substituted aminocarbonyl both of which are optionally C_Malkyl or C₃.₅cycloalkyl substituted (including thiocarbonyl analogues thereof), optionally mono- or di-Ci^alkyl-substituted-Co-i alkylamine which is optionally mono-or di-N-C_]- alkyl substituted, optionally mono- or

substituted amino-carbonyl or -thiocarbonyl, optionally N-C_Malkyl-substituted amino-sulphinyl or -sulphonyl optionally substituted by optionally mono- or

amino, a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C alkyl Cι- alkylcarbonyl or

substitued, or sulphinyl or sulphonyl optionally substituted by optionally halo-substituted-C_Malkyl, C_2- alkenyl, C_2- alkynyl, optionally mono- or

amino, a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C_Malkyl

or C_Malkylthiocarbonyl substitued; R₃ is hydrogen, heterocyclyl, heterocyclylC i .i ₀alkyl, optionally halo substituted Ci-ioalkyl, C_2-ι₀ alkenyl, C_2-ι₀ alkynyl, C₃.₇ cycloalkyl, C_3-7 cycloalkylCi-ioalkyl, C_5-7 cycloalkenyl, aryl, arylCι.ι₀alkyl, heteroaryl, or heteroarylCuioalkyl, optionally mono-or di-C alkyl-substitutedCo-ioalkyl-oxycarbonyl or oxythiocarbonyl optionally substituted by Cι.ι₀alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclylC i.ioalkyl, aryl, arylCi-ioalkyl, heteroaryl, heteroarylCι..₀alkyl, or optionally mono-or di-Cι^alkyl-substitutedCι-ι₀alkyl -cyano, -nitro,

-hydroxy, -Cι.ι₀alkoxy, -C_3-7cycloalkoxy, -heterocycloxy, -heterocyclylCi. ι₀alkoxy, -aryloxy, -arylCi.i₀alkoxy, -heteroaryloxy, -heteroarylCi-ioalkoxy (and thio oxy analogues thereof), optionally substituted amino, carboxylate, thiocarboxylate, carbonyl or thiocarbonyl, sulphinyl or sulphonyl; ΕU is H, or Ci.ioalkyl, C_3-ι₀cycloalkyl, C_3-ι₈heterocycloalkyl, C₆.ι₈aryl, or C_3-ι₈heteroaryl all optionally substituted by up to 4 substituents separately selected from alkyl, halogen, halo- substitued-alkyl, hydroxy, alkoxy, alkylthio, or optionally substituted amino; R₅ is C₆-C_]8aryl, C₃-Cι₈heteroaryl, or C₃-Cι₂cycloalkyl optionally substituted by up to 3 substituents separately selected from alkyl, halogen, halo-substitued-alkyl, hydroxy, alkoxy, alkylthio, optionally substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof .

Ri is preferably 4-pyrimidinyl.

When R» is alkyl it is Cι-Cι₀alkyl, preferably C C₆alkyl, optionally substituted, preferably with one or two substituents separately selected from hydroxy, -βalkoxy or amino.

When is aryl or heteroaryl either of which is optionally substituted by up to 4 substituents, i may comprise one of the customary aryl or heteroaryl substituents in the art and may be substituted as is customary in the art; for instance as defined for the substituent R₃ of of WO 93/03297.

When t is cycloalkyl it is preferably C₃-C₈, especially Cs- cycloalkyl (e.g. cyclohexyl), optionally substituted, preferably with up to 2 substituents separately selected from alkyl, halogen, hydroxy, alkoxy, or amino.

When R» is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, optionally substituted, e.g. by up to 2 substituents, selected from halogen, hydroxy, alkoxy, or amino.

When R₅ is aryl it is preferably phenyl. When R₅ is cycloalkyl, it is preferably C₃-C₇ cycloalkyl, e.g. cyclopropyl, cyclopently, cyclohexyl or cycloheptyl. R₅ may be unsubstituted or substituted, preferably mono-substituted, e.g. phenyl conveniently meta or para substituted, by halogen, Cι.ι₀alkyl, halo-substitued Cι-ι₀alkyl, Cι.ι.₀alkoxy, hydroxy or -NR₇R₈, where R₇ and R₈ are idependently H,

C₆-ιoaryl, C_6-ιoheteroaryl, C₇.n aralkyl or C_7-πheteroaralkyl.

When -Y- is C C₄ alkylene, it is preferably Cι-C₂ alkylene, and is optionally substituted, e.g. by C C₄alkyl (e.g. methyl), halogen, hydroxy, alkoxy, or amino. Preferably R₂ is phenyl substituted, preferably mono-substituted, by halogen, e.g. 4- fluorophen-1-yl, or 3-CF₃, 3-C1, or 3,4-difluoro substituted.

Preferably R₃ is H.

Preferably R is H or ^ lower alkyl, l-hydroxyCι.ι₀alkyl, l-Cι^alkoxyCι.ι₀alkyl, 1- aminoCi-ioalkyl, 1 -hydro xyC_3-ι₀cycloalkyl,

l-aminoC_3-10cycloalkyl, 1- hydroxyC_3-i₈heterocycloalkyl, or l-C_1-6alkoxyC₃.i8heterocycloalkyl.

Preferably X is -NH-Y'-, -O- or -S-, where Y' is -CH₂-, -CH₂-CH₂-, -CH(CH₃)- or a direct bond

Thus in preferred embodiments the invention provides a compound of formula I'

wherein

R₅' is phenyl or C₃-C₇cycloalkyl each of which is optionally mono-substituted by halogen, Ci.ioalkyl, Cι-ι₀alkoxy, hydroxy, trihalomethyl or -NR₇R₈, where R₇ and R₈ are idependently H, C₆.ιoaryl, .ioheteroaryl, .πaralkyl or C_7-nheteroaralkyl; Rio is halogen, cyano, amido, thioamido, amino or

Rt' is H,

1-hydroxyCj.ιoalkyl,

l-aminoC _Oa]kyl, 1- hydroxyC₃.i₀cycloalkyl, l-Cι-6alkoxyC -ιocycloalkyl, l-aminoC_3-ιocycloalkyl, l-hydroxyC_3- igheterocycloalkyl, or l-Cι^alkoxyC₃.ι₈heterocycloalkyl, and

X' is -NH-Y'-, -O- or -S-, where Y' is -CH₂-, -CH₂-CH₂-, -CH(CH₃)- or a direct bond, and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof . In the present description the terms such as "C_3-ι₈heteroaryl, C_4-ι₉heteroaralkyl and C_3- isheterocycloalkyl" denote heteroaryl, heteroaralkyl or heterocycloalkyl substituents comprising at least 3 ring atoms, at least one of which is a hetero atom, e.g.N, O or S, and which in the case of C₄.i₉hetero aralkyl groups are attached via an alkylene moiety comprising at least 1 carbon atom.

Preferably R₅' is monosubstituted by halogen,

(e.g. methoxy), hydroxy or CF₃. For instance, when R₅' is C_3-i8heterocycloalkyl, eg. piperidinyl, it may be substituted, preferably at the hetero atom thereof, e.g. as N-C alkyl-piperidinyl

Preferably Rio is halogen.

Preferably X' is -NH-, -NH-Y'- or -O-.

The Invention includes the following compounds:

4-(4-Fluorophenyl)-5-(2-(3-fluorophenylanτino)-4-pyrirr dinyl)imidazole;

4-(4-Fluorophenyl)-5-(2-(3-bromophenylan ino)-4-pyrimidinyl)imidazole;

4-(4-Ruorophenyl)-5-(2-(3-hydroxyphenylamino)-4-pyrirnidinyl)imidazole;

4-(4-Huorophenyl)-5-(2-(4-bromophenylamino)-4-pyrimidinyl)imidazole;

4-(4-Huorophenyl)-5-(2-(3-methoxyphenylanτ o)-4-pyrinτidinyl)imidazole;

4-(4-Fluorophenyl)-5-(2-(3-methylphenylanτino)-4-pyrin idinyl)irnidazole;

4-(4-Huorophenyl)-5-(2-(3-trifluoromethylphenylanτino)-4-pyrin idinyl)irnidazole;

4-(4-Huorophenyl)-5-(2-(3-fluorophenylamino)-4-pyrimidinyl)-2-tert.butylirnidazole;

4-(4-Ruorophenyl)-5-(2-(3-fluorophenyloxy)-4-pyrimidinyl)imidazole;

2-( 1 -Arninocyclohexyl)-4-(4-fluorophenyl)-5-(2-(R- 1 -phenylethylamino)-4-pyrimidinyl)- 1 -

H-imidazole;

5-(4-Fluorophenyl)-2-( 1 -hydroxy-4-methylpiperidinyl)-4-(2-(R)- 1 -phenylethylamino-4- pyrimidinyl)-l-H- imidazole;

5-(4-Fluorophenyl)-2-( 1 -aminocyclohexyl)-4-(2-(3-methylphenyl- 1 -amino)-4-pyrimidinyl)-

1 -H-imidazole;

5-(4-Fluorophenyl)-2-[( 1 -amino- 1 -methyl)-ethyl]-4-(2-(R )- 1 -phenylethyl amino-4- pyrimidinyl)- 1 -H-imidazole; 5-(4-Fluorophenyl)-2-[( 1 -amino- 1 -methyl)ethyl]-4-(2-(S)- 1 -phenylethylarnino-4- pyrirnidinyl)- 1 -H-imidazole;

5-(4-Fluorophenyl)-2-[( 1 -amino- 1 -methyl)-ethyl]-4-(2-cyclohexylamino-4-pyrirnidinyl)- 1 -

H-imidazole;

5-(4-Fluorophenyi)-2-[( 1 -amino- 1 -methyl)-ethyl]-4-(2-cyclopropyl methylamino-4- pyrimidinyl)- 1 -H-imidazole;

5-(4-Fluorophenyl)-2-( 1 -hydro xy-4-methylpiperidinyl)-4-(2-(S)- 1 -phenylethylamino-4- pyrirnidinyl)-l-H- imidazole;

5-(4-Huorophenyl)-2-(l-hydroxy-4-methylpiperidinyl)-4-(2-cyclohexylamino-4- pyrirnidinyl)-l-H- imidazole;

5-(4-Fluorophenyl)-2-(l-hydroxy-4-methylpiperidinyl)-4-(2-cyclopropylmethylamino-4- pyrimidinyl) -1-H- imidazole;

5-(4-Huorophenyl)-2-(l-hydroxy-4-methylpiperidinyl)-4-(2-cycloheptylamino-4- pyrimidinyl)-l-H- imidazole;

5-(4-Ruorophenyl)-2-(l-hydroxy-4-methylpiperidinyl)-4-(2-cyclopropylarnino-4- pyrimidinyl)-l-H- imidazole;

5-(4-Fluorophenyl)-2-(l-hydroxy-4-methylpiperidinyl)-4-(2-cyclopentylarnino-4- pyrimidinyl)-l-H- imidazole;

5-(4-Fluorophenyl)-2-( 1 -hydroxy-4-ethylpiperidinyl)-4-(2-(S)- 1 -phenylethyl amino-4- pyrimidinyl)-l-H- imidazole;

5-(4-Huorophenyl)-2-(l-hydroxy-4-ethylpiperidinyl)-4-(2-cyclohexylamino-4-pyrirnidinyl)-

1-H- imidazole;

5-(4-Fluorophenyl)-2-( 1 -hydro xy-4-ethylpiperidinyl)-4-(2-cyclpropylmethyl amino-4- pyrimidinyl)-l-H- imidazole;

5-(4-Fluorophenyl)-2-( 1 -n-butyloxy-4-methylpiperidinyl)-4-(2-(R)- 1 -phenylethylamino-4- pyrimidinyl)-l-H- imidazole, and

5-(4-Fluorophenyl)-2-( 1 -n-butyloxy-4-methylpiperidinyl)-4-(2-(S)- 1 -phenylethylamino-4- pyrimidinyl)-l-H- imidazole.

The novel imidazoles of the invention, in particular the compounds of formulae I and V and the specific compounds listed above are hereinafter referred to "Agents of the Invention". Agents of the Invention of formula I"

wherein P^', R₅' and Rio are as previously defined and X" is -NH- or -O-, may be prepared by reacting the corresponding precursor compound of formula II

wherein R₄' and Rj₀ are as previously defined, with the corresponding R₅'-NH₂ or R₅'-OH derivative. For example, the reaction may be carried out by refluxing the reactants in an organic solvent, e.g. dichloroethane, e.g. in the presence of diethoxytrifluoroborane.

The precursor compound of formula II may be prepared by controlled oxidation of the corresponding 5(2-methylthio-4-pyrimidinyl)-4-phenylimidazole, e.g. employing an oxidising agent such as mCPBA (meta chloroperbenzoic acid), conveniently in an organic solvent such as methylene chloride. The corresponding 5(2-methylthio-4-pyrimid yl)-4-phenylimidazole compound may be prepared by contacting the corresponding acetophenone precursor compound of formula LU

wherein Rio is as defined above, with a mixture of formic acid formamide and ammonium formiate at elevated temperature, e.g. at a temperature of up to about 190°C. The compound of formula m may be prepared by bromination of the corresponding 2-(2-methylthio-4- pyrimidinyl) acetophenone. The 2-(2-methylthio-4-pyrimidinyl)acetophenone precursor may be prepared by reacting the corresponding N-methoxy-N-methylbenzamide with 4-methyl-2- (methyltWo)pyrimidine, e.g. in a THF containing organic solvent with cooling.

Thus in a further aspect the invention includes a process for the preparation of a compound of formula I"

wherein R*', R₅' and Rio are as previously defined and X" is -NH- or -O-, which comprises reacting the corresponding precursor compound of formula II

wherein R and Rio are as previously defined, with the corresponding R₅'-NH₂ or R₅'-OH derivative.

The synthesis of Agents of the Invention is further described in the following Examples. EXAMPLES

Example 1: 4-(4-FIuorophenyl)-5-(2-(3-fluorophenylamino)-4-pyrimidinyl)-l-H-imidazole

a 4-Fluoro-2-(2-methylthio-4-pyrimidinyI)acetophenone

n-BuLi (10 ml of a l.6 M solution in hexane; 12 mmol) is added at -78°C to a solution of diisopropylamine (2.48 ml; 17 mmol) in THF (15 ml) and stirred for 5 min. 4-Methyl-2- (methylthio)pyrimidine (2g; 14.5 mmol) dissolved in THF (2 ml) is added dropwise and stirred for 30 min at -78 C. 4-Fluoro-N-methoxy-N-methylbenzamide (2.66 g; 14.5 mmol) is dissolved in THF (3 ml) and added slowly to the reaction mixture. The mixture is warmed to r.t. within 45 min. and poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na₂SO₄ and evaporated to dryness to yield 2.5 g (65%) of yellow crystals after recrystallisation from tert.butyl methyl ether/hexane.

IH-NMR (200 MHz CDC1₃): 3.00 (s, 3H); 6.30 (s, IH; vinyl-H of enol); 7.00 (d, IH); 7.50 (dd, 2H); 8.20 (dd, 2H); 8.7 (d, 2H). Due to pH-dependent keto-enol tautomery, signals may be duplicated.

b) 4-FIuoro-2-bromo -2-(2-methylthio-4-pyrimidinyl)acetophenone

Bromine (1.22g; 7.6 mmol) in acetic acid (5.6 ml) is added to a solution of 4-Fluoro-2-(2- methylthio-4-pyrimidinyl)acetophenone (2g; 7.6 mmol) in acetic acid (40 ml). The initially thick precipitate is almost dissolved after 20 min., filtered and the filtrate evaporated to dryness. The residue is taken up in a saturated solution of NaHCO₃ and extracted three times with tert. butyl methyl ether. The combined organic phases are dried over Na₂SO and evaporated to dryness to yield 2.6 g (100%) of a brown oil, which is used in the next step without purification.

c) 4-(4-FIuorophenyl)-5-(2-methylthio-4-pyrimidinvI -l-H-imidazole

4-Fluoro-2-bromo -2-(2-methylthio-4-pyrimidinyl)acetophenone (0.2 g; 0.58 mmol) is dissolved in formic acid (2.6 ml), formamide (2.1 ml) and ammonium formate (2.6g) added and heated at 190 C for 20 min. The mixture is poured on water (100 ml), filtered, and the filtrate adjusted to pH -10 with a saturated solution of Na₂CO₃. A yellow precipitate is formed and yielded after washing with water and drying at high vacuum the title compound (63 mg; 38%). IH-NMR (360 MHz DMSO-d6): 2.18 (s, 3H); 7.28 (dd, 2H); 7.45-7.55 (bs, IH); 7.65 (dd, 2H); 7.90 (s, IH); 8.50 (d, IH); 12.85 (bs, IH). FAB-MS (m/z): 287 (MH+).

d) 4-(4-FIuorophenyl -5-(2-methvIsuIfinyl-4-pyrimidinyl)-l-H-imidazole

4-(4-Huorophenyl)-5-(2-methylthio-4-pyrir dinyl)imidazole (0.1 g; 0.35 mmol) in methylene chloride (1 ml) is stirred and cooled to 5-10 C and mCPBA (55%, 0.33 g; 1.4 mmol) in methylene chloride (3 ml) added. The yellow, turbid mixture clears and becomes almost colorless and is warmed up to r.t. A precipitate formed after ~1.5 hrs and is stirred for another 6 hrs. The precipitate is filtered off, washed with ether and yields the title compound (77 mg; 70%). IH-NMR (360 MHz DMSO-d6): 3.05 (s, 3H); 7.28 (dd, 2H); 7.72 (dd, 2H); 8.00 (s, IH); 8.05- 8.20 (bs, IH); 8.92 (d, 2H); 13.00 (bs, IH).

e) 4-(4-Fluorophenyl -5-(2-(3-fluorophenylamino)-4-pyrimidinyl)-l-H-imidazole

4-(4-Huorophenyl)-5-(2-methylsulf yl-4-pyrirnidinyl)imidazole (0.05 g, 0.16 mmol) is dissolved in 1,2-dichloroethane (2 ml), 3 -fluoro aniline (0.5 ml, 5.2 mmol) and BF₃.OEt₂ (0.02 ml; 0.16 mmol) added and the reaction mixture refluxed for 3.5 hrs. The mixture is taken up in IN Na₂CO₃ and extracted three times with tert. butyl methyl ether. The combined organic phases are dried over Na₂SO₄ and evaporated to dryness to yield a brown oil (520 mg), which is purified by silica gel chromatography (CH₂Cl₂/MeOH/NH₃ cone 97.5/2.5/0.25) and gives the title compound (10 mg; 18%) as off- white crystals.

IH-NMR (400 MHz DMSO-d6, 120 C): 6.32 (dt, IH); 7.02-7.08 (m, 3H); 7.15 (dd, IH); 7.22 (td, IH); 7.82 (dd, 2H); 7.88 (s, IH); 8.20 (d, IH); 9.00 (bs, IH). MS (m/z): 349 (M+).

The following compounds of Formula V identified in Table I are prepared analogously.

Table 1

Example 8: 4-(4-FluorophenvI -5-(2-(3-fluorophenylamino)-2-tert.butyl-4-pyrimidinyl) -1- H-imidazole

a) 4-(4-Fluorophenyl)-5-(2-methylthio-4-pyrimidinvI)-2-tert.butyl-l-H-imidazole

Pivalic acid (60 g, 538mmol) is melted by heating to 160 C. (NH4)₂CO₃ (5 g, 52.7 mmol) is added portionwise and after completed addition the mixture is cooled to 80 C. 4-Fluoro-2-bromo- 2-(2-methylthio-4-pyrimidinyl)acetophenone (3 g, 3.8 mmol), dissolved in ca lg of pivalic acid, is added and the reaction mixture heated to 180 C for 10 min., poured on a saturated solution of Na₂CO₃ and extracted with tert.butylmethylether. The organic phase is washed with 2N HCl and the water phase made basic with a saturated solution of Na₂CO₃ and extracted with tert.butylmethylether. Purification by silica gel chromatography (ethyl acetate/hexane 15/85 to 20/80) yields the title compound as yellow crystals (762mg, 25%).

IH-NMR (360 MHz, CDC13): 1.50 (s, 9H); 2.62 (s, 3H); 6.92 (d, IH); 7.15 (dd, 2H); 7.58 (dd, 2H); 8.27 (d, 2H), 9.91 (bs, IH). MS (m/z): 343 (MH+).

b) 4-(4-FIuorophenyl)-5-(2-methylsulfinvI-4-pyrimidinyl)-2-tert.butyl-l-H-imidazole

4-(4-Ruorophenyl)-5-(2-methylsulfinyl-4-pyrimidinyl)-2-tert.butylimidazole (0.4 g; 1.16 mmol) in methylene chloride (4 ml) is stirred and cooled to 5-10 C and mCPBA (55%, 0.48 g; 1.5 mmol) in methylene chloride (3 ml) added. After stirring at r.t. for 2 h, the reaction mixture is diluted with ethyl acetate (30 ml) and washed once with 0.5N Na₂S₂O₃ (30 ml) and then twice with IN NaOH. The organic phase is dried over Na₂SO and evaporated to dryness to yield the title compound as light yellow crystals (397 mg, 95%), which are used without further purification.

c) 4-(4-FluorophenvI)-5-(2-(3-fluorophenylamino)-4-pyrimidinvI)-2-tert.butyl-l-H- imidazole

4-(4-Fluorophenyl)-5-(2-methylsulfmyl-4-pyrirrudinyl)-2-tert.butylirnidazole (0.2 g, 0.55 mmol), 3-fluoroaniline (1 ml, 10 mmol) and BF₃.OEt₂ (0.07ml, 0.5 mmol) are heated for 20 min. at 160 C. The reaction mixture is diluted with tert.butylmethylether and washed with a solution of saturated Na₂CO₃. The organic phase is dried over Na₂SO , evaporated to dryness and the the product purified over silica gel (acetone/hexane 3/7) to yield the title compound, which is recrystallised from methanol (181 mg, 80%).

IH-NMR (400 MHz, DMSO-d6, 120 C): 1.50 (s, 9H); 6.60 (bs, IH); 7.09 (dd, 2H); 7.15-7.30 (bs, 2H); 7.30-7.50 (bs, 2H); 6.05 (bs, 2H); 8.39 (bs, 2H); 11.60-11.70 (bs, 1-2H). MS (m/z): 405 (M+), 390 (M-CH3).

Example 9 4-(4-Fluorophenyl)-5-(2-(3-fluorophenyloxy)-4-pyrimidinyl) -1-H- imidazole

3-Fluorophenol (0.074 ml, 0.8 mmol) is added to a solution of KN(TMS)₂ (0.88 ml of a 1.3 M solution in toluene; 0.66 mmol) in THF (3 ml) and is stirred for 5 min. 4-(4-Fluorophenyl)-5-(2- methylsulfmyl-4-pyrimidinyl)imidazole (0.05 g, 0.16 mmol) is dissolved in warm THF (4 ml) and added rapidly to the reaction mixture, which is then stirred over night at room temperature. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na₂SO₄, evaporated to dryness, and the product purified over silica gel (acetone/hexane 3/7 to 6/4) to yield the title compound (45 mg, 79%) as white crystals. IH-NMR (360 MHz, DMSO-d6): 6.95 (d, IH); 7.05 (dd(=t), 2H); 7.37 (dd, IH); 7.56 (d, IH); 7.58 (d, IH); 7.85 (s, IH); 8.55 (dd, IH). MS (m/z): 350 (M+), 349 (M-H).

Example 10 2-(l-AminocvcIohexyl)-4-(4-fluorophenyl -5-(2-(R-l-phenylethvIamino -4- pyrimidinvD-l-H-imidazole a) 5-(4-Fluorophenyl)-2-(l-N-carbobenzyloxycyclohexyl)-4-(2-methvIthio-4-pyrimidinvI)-l- H-imidazole

1-N-carbobenzyloxy-l-cyclohexanecarboxylic acid (E.Didier et al. Tetrahedron 1992, 48(39), 8471) (4.17g; 15mmol), and ammoniumcarbonate (Fluka; 1.46g; 15mmol) are dissolved in DMF (15ml) and heated to 110°C for 20min. until gas evolution ceases. After cooling to room temperature, 4-fluoro-2-bromo-2-(2-methylthio-4-pyrimidinyl)acetophenone (361mg; lmmol) is added as a solid and the mixture heated tol25°C for 2h. The reaction mixture is poured on 1M Na₂CO₃ and extracted with ethyl acetate three times. The combined organic phases are washed with water, dried over Na₂SO , evaporated to dryness and chromatographed (SiO2; acetone/hexane 15/85) to give the pure title compound as a yellow oil (0.26g; 51%). IH-NMR (400MHz; DMSO-d6): Mixture of tautomers: 1.30-1.65 (m, 8H); 2.06 (s, 3H); 2.15- 2.30 (m, 2H); 4.95 (bd, 2H); 5.18 (t, IH); 7.18-7.40 (m, 9H); 7.50 (d, IH); 8.48 (d, 0.8H); 8.51 (d, 0.2H). MS (m/z): 517 (M+).

b) 5-(4-Fluorophenyl)-2-(l-N-carbobenzvIoxycvcIohexyl)-4-(2-methylsulfϊnyl-4- pyrimidinvD-l-H-imidazoIe

5-(4-Fluorophenyl)-2-(l-N-carbobenzyloxycyclohexyl)-4-(2-methylthio-4-pyrimidinyl)imidazole (8.5g; 16.4mmol) is dissolved in methylene chloride (160ml) and cooled to 5°C under stirring, while mCPBA (4.46g; 21.86mmol) in methylene chloride (45ml) is added within 30min. After stirring for 15min., the reaction mixture is poured on 1M Na₂CO₃ and extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO , evaporated to dryness and purified by chromatography (SiO₂; acetone/hexane 15/85) to yield the title compound as a yellow foam (5.6g; 62%).

IH-NMR (400MHz; DMSO-d6): Mixture of tautomers: 1.30-1.70 (m, 6H); 2.00-2.30 (m, 4H); 2.62 (s, 3H); 5.00 (s, 2H); 7.20-7.45 (m, 7H); 7.65-7.77 (m, 2H); 7.90 (d, IH); 8.85 (d, 0.8H); 8.87 (d, 0.2H) MS (m z): 532.2 (M-H). c) 5-(4-FIuorophenyl)-2-(l-N-carbobenzvioxycvclohexyl)-4-(2-(R-l-phenylethylamino)-4- pyrimidinvD-1-H-imidazole

5-(4-Fluorophenyl)-2-(l-N-carbobenzyloxycyclohexyl)-4-(2-methylsulfinyl-4- pyrimidinyl)imidazole (2g; 3.75mmol) and R(+)-l-phenylethylamine (2.27ml; 18.75mmol) are dissolved in toluene (75ml) and heated to 125°C for 48h. Toluene is evaporated and the residue chromatographed (SiO₂; acetone/cycohexane 15/85) to yield the title compound as light yellow foam (1.6g; 72%).

MS (m/z): 591.3 (MH+).

d) 4-(4-FIuorophenyl)-2-(l-aminocvclohexyl)-5-(2-(R-l-phenylethvIamino -4-pyrimidinyl - 1 -H-imidazole

^^H3 CH₃

5-(4-Fluorophenyl)-2-( 1 -N-carbobenzyloxycyclohexyl)-4-(2-(R- 1 -phenylethylamino)-4- pyrirnidinyl)imidazole (lg; 1.7mmol) is dissolved in HO Ac (60ml) and HBr/HOAc (33%; 6ml) added. The reaction mixture is stirred at 35°C for 90min. and then poured on water (500ml) and washed twice with ether. The water phase is made basic with a saturated solution of Na₂CO₃ and 2N NaOH_and extracted with tert. butyl methyl ether three times. The combined organic phases are washed with water, dried over Na₂SO₄, evaporated to dryness and chromatographed (SiO₂; TBME/MeOH/NH₃conc. 96/4/0.4) to yield the title compound as a white foam, which is cystallised from ether (574mg; 75%).

IH-NMR (400MHz; DMSO-d6, 120°C): 1.42 (d, 3H); 1.50-1.80 (m, 8H); 2.10 (bt, 2H); 5.00

(dq, IH); 6.58 (d, IH); 6.85 (d, IH); 7.10-7.20 (m, 2H); 7.22-7.32 (m, 5H); 7.65-7.71 (m, 2H);

8.15 (d, IH).

MS (m/z): 457 (MH+).

Example 11 5-(4-FIuorophenvI)-2-(l-hvdroxy-4-methvIpiperidinvI)-4-(2-(R)- phenylethylamino-4-pyrimidinvI)-l-H- imidazole a) 5-(4-Fluorophenyl)-2-(l-hvdroxy-4-methylpiperidinyl)-4-(2-methvIthio-4-pyrimidinyl)-l- (trimethylsilylethvIoxymethvPimidazofe

5-(4-Fluorophenyl)- 4-(2-methylthio-4-pyrirnidinyl)- 1 -(trimethylsilylethyloxymethyl) imidazole (7.1g; 17mmol) is dissolved in THF (80ml) and cooled to -78°C. n-BuLi (12.7ml of a 1.6M solution; 20mmoι) is added and the reaction stirred for lOmin at -78°C. N-methyl-4- piperidone (2.6g; 22mmol) is added rapidly and after stirring for 5 minutes at -78°C, the reaction mixture is poured on a saturated solution of NaCl and extracted 3x with ethyl acetate. The combined organic phases are dried over Na₂SO and evaporated to dryness to render the crude product, which is purified by silica gel chromatography (tert.butyl methyl ether/methanol/NH₃ cone 97:3:0.2) to yield the title compund as yellow solid (5.35g; 59%). IH-NMR (200 MHZ; CDC13): 0.00 (s, 9H); 0.82 (dd, 2H); 1.97 (s, 3H); 1.98-2.10 (bd, 2H); 2.40 (s, 3H); 2.47-2.61 (m, 4H); 2.70-2.88 (m, 2H); 3.33 (dd, 2H); 5.30 (s, 2H); 7.20 (dd, 2H); 7.43 (dd, 2H); 7.65 (d, IH); 8.42 (d, IH).

b) 5-(4-Fluorophenyl)-2-(l-hvdroxy-4-methylpiperidin^yl⁾-4-⁽2-⁽R⁾-l-phenylethvIamino-4- pyrimidinyl)-l-(trimethylsiIvIethyloxymethyl)imidazole

5-(4-Fluorophenyl)-2-(l-hydroxy-4-methylpiperidinyl)-4-(2-methylthio-4-pyrimidinyl)-l- (trimethylsilylethyloxymethyl)imidazole (32.7 g; 0.06 mol) was dissolved in methylene chloride (200 ml), HOAc (50 ml) added and cooled to 0° C. mCPBA (19 g; 70%, 0.077 mol) in methylene chloride (120 ml) was added dropwise within 5 min. After stirring for another 5 min. the reaction mixture was poured on a saturated solution of Na2C03 and extracted with ethyl acetate three times. The combined organic phases were dried over Na2S04 and evaporated to dryness to render the crude product, which was filtered through silica gel (TBME/MeOH/NH3conc. 80/20/3). The solid product was washed with TBME and yielded pure 5-(4-Fluorophenyl)-2-(l-hydroxy-4-methylpiperidinyl)-4-(2-methylsulfιnyl-4-pyrimidinyl)-l- (trimethylsilylethyloxymethyl)imidazole (24.2 g; 72%).

5-(4-Huorophenyl)-2-(l-hydroxy-4-methylpiperidinyl)-4-(2-methylsulfinyl-4-pyrimidinyl)-l- (trimethylsilylethyloxymethyl)imidazole (2.1g; 3.8mmoι), R(+)- 1 -phenylethylamine (25ml) and toluene (25 ml) are heated to 140°C for 2h. Toluene and excess R(+)-l -phenylethylamine are distilled off at 0.1 mm Hg and the residue purified by silica gel chromatography (acetone/methanol 90/10 to 95/5) to deliver l.lg (47%) of the title compound as colorless crystals. IH-NMR (360MHZ; DMSO-d6): -0.06 (s, 9H); 0.72 (bt, 2H); 1.16 (bs, 3H); 1.93-2.03 (m, 2H); 2.20 (s, 3H); 2.16-2.28 (m, 2H); 2.36 (bt, 2H); 2.53 (bt, 2H); 3.19-3.27 (m, 2H); 4.18-4.35 (bs, IH); 5.30-5.43 (dd, 2H); 5.48 (s, IH; OH); 6.97-7.05 (bs, IH); 7.06-7.18 (m, 4H); 7.21-7.26 (t, 2H); 7.29-7.34 (t, 2H); 7.50-7.56 (t, 2H); 8.17 (d, IH). FAB-MS (m/z): 603 (MH+)

c) 5-(4-Fluorophenyl)-2-(l-hvdroxy-4-methylpiperidinyl)-4-(2-(R)-phenylethylamino-4- pyrimidinyl)-l-H- imidazole

5-(4-Fluorophenyl)-2-( 1 -hydro xy-4-methylpiperidinyl)-4-(2-(R)- 1 -phenylethylamino-4- pyrirnidinyl)-l-(trimethylsilylethyloxymethyl)imidazole (740mg, 1.23mmol) is dissolved on EtOH (10ml) and hydrochloric acid (aqueous, 37%, 10ml) and kept at room temperature for 20 minutes. The reaction mixture is then poured on a saturated solution of Na₂CO₃ and extracted with ethyl acetate. The resulting yellow foam is triturated with tert.butyl methyl ether/diethyl ether and the solid obtained is filtered off to provide the title compound (514mg; 88.7%) as yellow powder. IH-NMR (400MHz; DMSO-d6; 120°C): 1.3-1.52 (bm, 3H); 1.85 (bd, 2H); 2.15-2.30 (m, 2H); 2.25 (s, 3H); 2.43-2.61 (m, 4H); 4.5 (bs, IH); 7.10-7.45 (m, 8H); 7.66 (dd, 2H); 8.15 (d, IH). FAB-MS (m/z): 473 (MH+, 100); 453 (25); 308 (45).

The compounds of Examples 12-17 of Formula VI identified in Table 2 below are prepared by analogy with Example 10 and similarly the compounds of Examples 18-26, also of formula VI and as identified in Table 2, are prepared by analogy with Example 11.

Table 2

Example 27; 5-(4-Fluorophenyl)-2-(l-n-butyloxy-4-methylpiperidinv0-4-(2-(R)-l- phenylethylamino-4-pyrimidinyl)-l-H- imidazole

5-(4-Fluorophenyl)-2-( 1 -hydro xy-4-methylpiperidinyl)-4-(2-(R)- 1 -phenylethylamino-4- pyrimidinyl)-l-H- imidazole (Example 11) (430 mg; 0.911 mmol), 1-butanol (30 ml) and H₂SO (360 mg; 3.6 mmol) are refluxed for 4.5 h and evaporated to dryness. The residue is taken up in a saturated solution of Na₂CO₃ and extracted with ethyl acetate three times. The combined organic phases are dried over Na₂SO₄, filtered, evaporated and purified via SiO₂ chromatography (TBME/MeOH/NH₃ cone 98/2/0.2 to 96/4/0.2) to yield the title compound as colorless crystals (198 mg; 41%).

IH-NMR (400MHz; DMSO-d6). Mixture of rotamers with broad signals: 0.78-0.83 (m, 3H); 1.21-1.49 (m, 7H); 2.05-2.13 (bs, 4H); 2.17 (s, 3H); 2.25-2.48 (m, 4H); 3.05-3.16 (bq, 2H); 4.48-4.72 (bs, 0.6 H); 4.95-5.13 (bs, 0.4H); 6.90-7.10 (bs, 2H); 7.10-7.33 (m, 6H); 7.53-7.70 (m, 2H); 8.18 (d, IH); 12.00 (bs, IH, NH)); 13.00 (bs, IH, NH). MS (m/z) El: 428 (M+; 20); 471 (55); 455 (100). The compound of Example 28 is prepared by analogy with example 27 from the compound of Example 18.

Example 28; 5-(4-Fluorophenyl)-2-(l-n-butvIoxy-4-methylpiperidinyl)-4-(2-(S)-l- phenylethvIamino-4-pyrimidinyl)-l-H- imidazole

The title compound is the enantiomer of example 27. Their NMR- and MS-spectras are identical.

The Agents of the Invention, as defined above, e.g., of formula I, particularly as exemplified, in free or pharmaceutically acceptable acid addition salt form, exhibit pharmacological activity and are useful as pharmaceuticals, e.g. for therapy, in the treatment of diseases and conditions as hereinafter set forth.

In particular Agents of the Invention possess p38 MAP kinase (Mitogen Activated Protein Kinase) inhibiting activity. Thus the Agents of the Invention act to inhibit production of inflammatory cytokines, such as TNF-α and IL- 1 , and also to potentially block the effects of these cytokines on their target cells. These and other pharmacological activities of the Agents of the Invention as may be demonstrated in standard test methods for example as described below:

p38 MAP kinase Assay

The substrate (GST-ATF-2; a fusion protein comprising amino acids 1-109 of ATF-2 and the GST protein obtained by expression in E. coli) is coated onto the wells of microtiter plates (50 μl/well; 1 μg/ml in PBS/0.02% Na azide) overnight at 4 °C. The following day, the microtiter plates are washed four times with PBS/0.5% Tween 20/0.02% Na azide and are blocked with PBS/2% BSA/0.02% Na Azide for 1 h at 37 °C. Plates are washed again 4 times with PBS/0.5% Tween 20/0.02% Na azide. The kinase cascade reaction is then started by adding the following reactants in 10 μl aliquots to a final reaction volume of 50 μl. 1. Agents of the Invention titrated from 10 to 0.001 μM in 10-fold dilutions or solvent (DMSO) or H₂O.

2. Kinase buffer (5x); pH 7.4; 125 mM Hepes (Stock at 1M; Gibco #15630-056), 125 mM β- glycerophosphate (Sigma #G-6251):125 mM MgCl₂ (Merck #5833); 0.5 mM Sodium orthovanadate (Sigma #5-6508), 10 mM DTT (Boehringer Mannheim #708992). The (5x) kinase buffer must be prepared fresh the day of the assay from 5x stock solutions kept at RT. DTT is kept at -20 °C and is added as the last reagent.

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

4. cold ATP (final concentration 120 μM; Sigma #A-9187)

5. Water

After lh at 37 °C the kinase reaction is terminated by washing the plates four times as previously described. Phosphorylated GST-ATF-2 is then detected by adding:

1. the PhosphoPlus ATF-2 (Thr71) Antibody (50 μl/well; 1/1000 final dilution in PBS/2% BSA/0.02% Na Azide; New England Biolabs #9221L) for 90 min at RT.

2. Biotin labelled goat-anti-rabbit IgG (50 μl/well; 1/3000 final dilution in PBS/2% BSA/0.02% Na Azide; Sigma #B-9642) for 90 min at RT.

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

4. Substrate (100 μl/well; Sigma 104 Phosphatase substrate tablets, 5 mg tablet; #104-105; 1 mg/ml in substrate buffer, Diethanolamine (97 ml/1; Merck #8031 16) + MgCl₂.6H₂0 (100 mg/1; Merck #5833) + Na Azide (0.2 g/1) + HCl 1M to pH 9.8) 30 min at RT.

After step 1,2 and 3 the microtiter plates are washed four times with PBS/0.5% Tween 20/0.02% Na azide. After step 4, the plates are read in a Bio-Rad microplate reader in a dual wavelength mode (measurement filter 405 nm and reference filter 490 nm). The bachground value (without ATP) is subtracted and IC50 values are calculated using the Origin computer program (4 parameter logistic function).

Agents of the Invention typically have ICsoS for p38 MAP kinase inhibition in the range from about 100 nM to about 10 nM or less when tested in the above assay. Assay for Inhibition of TNF-α release from hPBMCs

Human peripheral blood mononuclear cells (hPBMCs) are prepared from the peripheral blood of healthy volunteers using ficoll-hypaque density separation according to the method of Hansell et al., J. Imm Methods (1991) 145: 105. and used at a concentration of 10⁵ cells/well in RPMI 1640 plus 10% FCS. Cells are incubated with serial dilutions of the test compounds for 30 minutes at 37°C prior to the addition of IFNg (100 U/ml) and LPS (5 mg/ ml) and subsequently further incubated for three hours. Incubation is terminated by centrifugation at 1400 RPM for 10 min. TNF-α in the supernatant is measured using a commercial ELISA (Innotest hTNFa, available from Innogenetics N.V., Zwijnaarde, Belgium). Agents of the Invention are tested at concentrations of from 0 to 10 mM. Exemplified Agents of the Ivention typically suppress TNF release in this assay with an IC₅₀ of from about 500 nM to about 50 nM or less when tested in this assay.

Assay for Inhibition of TNF-α Production in LPS stimulated mice

Injection of lipopolysaccharide (LPS) induces a rapid release of soluble tumour necrosis factor (TNF-α) into the periphery. This model is be used to analyse prospective blockers of TNF release in vivo.

LPS (20 mg/kg) is injected i.v. into OF1 mice (female, 8 week old). One (1) hour later blood is withdrawn from the animals and TNF levels are analysed in the plasma by an ELISA method using an antibody to TNF-α. Using 20 mg/kg of LPS levels of up to 15 ng of TNF-α / ml plasma are usually induced. Compounds to be evaluated are given either orally or s.c. 1 to 4 hours prior to the LPS injection. Inhibition of LPS-induced TNF-release is taken as the readout.

Agents of the Invention typically inhibit TNF production to the extent of up to about 50% or more in the above assay when administered at 10 mg/kg p.o.

As indicated in the above assays Agents of the Invention are potent inhibitors of TNF-α release. Accordingly, the Novel Compounds have pharmaceutical utility as follows:

Agents of the Invention are useful for the prophylaxis and treatment of diseases or pathological conditions mediated by cytokines such as TNFα and IL-1, e.g., inflammatory conditions, autoimmune diseases, severe infections, and organ or tissue transplant rejection, e.g. for the treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants and for the prevention of graft-versus-host disease, such as following bone marrow transplants.

Agents of the Invention are particularly useful for the treatment, prevention, or amelioration of autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases. Specific auto-immune diseases for which Agents of the Invention may be employed include autoimmune haematological disorders (including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy).

Agents of the Invention are also useful for the treatment, prevention, or amelioration of asthma, bronchitis, pneumoconiosis, pulmonary emphysema, and other obstructive or inflammatory diseases of the airways.

Agents of the Invention are useful for treating undesirable acute and hyperacute inflammatory reactions which are mediated by TNF, especially by TNFa, e.g., acute infections, for example septic shock (e.g., endotoxic shock and adult respiratory distress syndrome), meningitis, pneumonia; and severe burns; and for the treatment of cachexia or wasting syndrome associated with morbid TNF release, consequent to infection, cancer, or organ dysfunction, especially AIDS -related cachexia, e.g., associated with or consequential to HIN infection. Agents of the Invention are particularly useful for treating diseases of bone metabolism including osteoarthritis, osteoporosis and other inflammatory arthritides.

For the above indications the appropriate dosage will, of course, vary depending, for example, on the particular Agent of the Invention employed, the subject to be treated, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are obtained at daily dosages of from about 1 to about lOmg/kg/day p.o.. In larger mammals, for example humans, an indicated daily dosage is in the range of from about 50 to about 750mg of Novel Compound administered orally once or, more suitably, in divided dosages two to four times/day.

The Novel Compounds may be administered by any conventional route, e.g. orally, for example in the form of solutions for drinking, tablets or capsules or parenterally, for example in the form of injectable solutions or suspensions. Normally for systemic administration oral dosage forms are preferred, although for some indications the Novel Compounds may also be administered topically or dermally, e.g. in the form of a dermal cream or gel or like preparation or, for the purposes of application to the eye, in the form of an ocular cream, gel or eye-drop preparation; or may be administered by inhalation, e.g., for treating asthma. Suitable unit dosage forms for oral administration comprise e.g. from 25 to 250mg Novel Compound per unit dosage.

In accordance with the foregoing the present invention also provides in a further series of embodiments:

A. A method of inhibiting production of soluble TNF, especially TNFα, or of reducing inflammation in a subject (i.e., a mammal, especially a human) in need of such treatment which method comprises administering to said subject an effective amount of an Agent of the Invention, or a method of treating any of the above mentioned conditions, particularly a method of treating an inflammatory or autoimmune disease or condition, e.g. rheumatoid arthritis, or alleviating one or more symptoms of any of the above mentioned conditions.

B. An Agent of the Invention for use as a pharmaceutical, e.g. for use as an immunosuppressant or antiinflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.

C. A pharmaceutical composition comprising an Agent of the Invention in association with a pharmaceutically acceptable diluent or carrier, e.g., for use as an immunosuppressant or anti- inflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.

D. Use of an Agent of the Invention in the manufacture of a medicament for use as an immunosuppressant or anti-inflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune of inflammatory disease or condition.

Claims

1. A 4-phenyl-5-(2-aryl-X)-4-pyrimidinyl-, 4-phenyl-5-(2-cycloalkyl-X)-4-pyrimidinyl-, 4- phenyl-5-(2-aralkyl-X)-4-pyrimidinyl- or 4-phenyl-5-(2-cycloalkylalkyl-X)-4-pyrimidinyl- imidazole, in which the 5-pyrimidinyl substituent is aryl, cycloalkyl, aralkyl or cycloalkylalkyl substituted directly via a heteroatom X selected from N, O or S, and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof..

2. A compound according to claim 1 of formula I

wherein

Ri is pyrimidinyl;

X is -NRe-Y-, -O- or -S-, where Re is H, Chalky!, C₆-Cι₈aryl, C₃-Cι₈heteroaryl, C₇-Cι₉aralkyl or C₄- Cι heteroaralkyl, and -Y- is d^alkylene or a direct bond ; R₂ is phenyl, optionally substituted by one or more substituents, each of which is independently selected from halo,

CF₃, cyano, amido or thioamido which is optionally mono- or di-N-substituted by

or the N atom of which forms a 5-7 membered heterocyclic ring optionally containing an additional hetero atom selected from O, S or N which N is optionally C_halky!

C_Malkylcarbonyl or C alkylthiocarbonyl substitued, carboxylate or thiocarboxylate optionally in the form of an optionally halo- substituted Cι-ιoalkoxy, C₂.ιoalkenoxy, C₂-ιoalkynoxy, C_3-7cyclalkoxy, C_5- ₇cycloalkenoxy, aryloxy, arylalkoxy, heteroaryloxy or heteroarylalkoxy ester, optionally mono- or

optionally C_halky!- or C_3-5 cycloalkyl-substituted-carbonyl or -thiocarbonyl, optionally halo-substituted-CMalkoxy, C_2-4alkenoxy, C_2-4alkynoxy, C_3-5cycloalkoxy or C₃.5cyclothioalkoxy, optionally halo substituted

alkyl, oxycarbonyl or optionally N-O^alkyl- substituted aminocarbonyl both of which are optionally

or C_3-5cycloalkyl substituted (including thiocarbonyl analogues thereof), optionally mono- or di-C alkyl-substituted-Co-ialkylamine which is optionally mono-or di-N-Cι-4 alkyl substituted, optionally mono- or di-Ci^alkyl-substituted-Co-ialkyl optionally N-C alkyl- substituted amino-carbonyl or -thiocarbonyl, optionally

amino-sulphinyl or -sulphonyl optionally substituted by optionally mono- or di-N-Ci^alkyl-substituted amino, a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally

C alkylcarbonyl or C alkylthiocarbonyl substitued, or sulphinyl or sulphonyl optionally substituted by optionally halo-substituted-Ci^alkyl, C_2-4 alkenyl, C_2-4 alkynyl, optionally mono- or di-N-Ci^alkyl-substituted amino, a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally

C alkylcarbonyl or C alkylthiocarbonyl substitued; R₃ is hydrogen, heterocyclyl, heterocyclylCi-ioalkyl, optionally halo substituted Ci-ioalkyl, C₂.ι₀ alkenyl, C₂.ιo alkynyl, C₃.₇ cycloalkyl, C₃.₇ cycloalkylCi-ioalkyl, C_3-7 cycloalkenyl, aryl, arylCι.ι₀alkyl, heteroaryl, or hetero arylC i .1 oalkyl, optionally mono-or di-C alkyl-substitutedCo-ioalkyl-oxycarbonyl or oxythiocarbonyl optionally substituted by Ci-ioalkyl, C_3- cycloalkyl, heterocyclyl, heterocyclylCuioalkyl, aryl, arylCι_-)0alkyl, heteroaryl, heteroarylCi.ioalkyl, or optionally mono-or di-Ci^alkyl-substituted .ioalkyl -cyano, -nitro,

-hydroxy, -Ci-ioalkoxy, -C_3- cycloalkoxy, -heterocycloxy, -heterocyclylCi. _loalkoxy, -aryloxy, -arylCi.i₀alkoxy, -heteroaryloxy, -heteroarylC _Oalkoxy (and thio oxy analogues thereof), optionally substituted amino, carboxylate, thiocarboxylate, carbonyl or thiocarbonyl, sulphinyl or sulphonyl; R» is H, or Cι_-10alkyl, C_3-ι₀cycloalkyl, C_3-ι₈heterocycloalkyl, C₆-ι₈aryl, or C_3-ι₈heteroaryl all optionally substituted by up to 4 substituents separately selected from alkyl, halogen, halo- substitued-alkyl, hydroxy, alkoxy, alkylthio, or optionally substituted amino; R₅ is C₆-Cι₈aryl, C₃-Cι₈heteroaryl, or C₃-Cι₂cycloalkyl optionally substituted by up to 3 substituents separately selected from alkyl, halogen, halo-substitued-alkyl, hydroxy, alkoxy, alkylthio, optionally substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.

3. A compound according to claim 1 of formula I'

wherein

R₅' is phenyl or C₃-C₇cycloalkyl each of which is optionally mono-substituted by halogen,

Ci.ioalkyl, Ci.ioalkoxy, hydroxy, trihalomethyl or -NR₇R₈, where R₇ and R₈ are idependently

H, C_6-ιoaryl, C₆-ιoheteroaryl, C₇-nararkyl or C₇.nheteroaralkyl;

Rio is halogen, cyano, amido, thioamido, amino or Chalky!;

R_t' is H,

l-hydroxyCι.ι₀alkyl, 1-Cι.ealkoxyCι.ιoalkyl, 1-aminoCι-ιoalkyl, 1- hydroxyC_3-ιocycloalkyl, l-Cι.₆alkoxyC₃.ιocycloalkyl, l-aminoC_3-ι₀cycloalkyl, l-hydroxyC_3- isheterocycloalkyl, or l-Cι^alkoxyC₃.ι₈heterocycloalkyl, and

X' is -NH-Y'-, -O- or -S-, where Y' is -CH₂-, -CH₂-CH₂-, -CH(CH₃)- or a direct bond, and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.

4. A compound according to claim 1 as described in any one of Examples 1 to 28.

5. A method of inhibiting production of soluble TNF, especially TNFα, or of reducing inflammation in a subject (i.e., a mammal, especially a human) in need of such treatment which method comprises administering to said subject an effective amount of a compound according to claim 1.

6. A compound according to claim 1 for use as a pharmaceutical, e.g. for use as an immunosuppressant or antiinflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.

7. A pharmaceutical composition comprising a compound according to claim 1 in association with a pharmaceutically acceptable diluent or carrier, e.g., for use as an immunosuppressant or anti-inflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.

8. Use of a compound according to claim 1 in the manufacture of a medicament for use as an immunosuppressant or anti-inflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.

9. A process for the preparation of a compound of formula I"

wherein R₄', R5' and Rio are as defined in claim 3 and X" is -NH- or -O-, which comprises reacting the corresponding precursor compound of formula II

wherein R»' and R]₀ are as defined in claim 3, with the corresponding R₅'-NH₂ or R₅'-OH derivative.