ZA200206642B - Pyridinylimidazoles. - Google Patents

Description

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PYRIDINYLIMIDAZOLES

This invention relates to pyridyl substituted imidazoles which are inhibitors of the . transforming growth factor, ("TGF")-B signaling pathway, in particular, the phosphorylation of smad2 or smad3 by the type I or activin-like kinase ("ALK")-5 receptor, methods for their . 5S preparation and their use in medicine, specifically in the treatment and prevention of a disease ’ state mediated by this pathway.

TGF-$1 is the prototypic member of a family of cytokines including the TGF-Bs, activins, inhibins, bone morphogenetic proteins and Miillerian-inhibiting substance, that signal through a family of single transmembrane serine/threonine kinase receptors. These receptors can be divided in two classes, the type I or activin like kinase (ALK) receptors and type II receptors.

The ALK receptors are distinguished from the type II receptors in that the ALK receptors (2) lack the serine/threonine rich intracellular tail, (b) possess serine/threonine kinase domains that are very homologous between type I receptors, and (c) share a common sequence motif called the GS domain, consisting of a region rich in glycine and serine residues. The GS domain is at the amino terminal end of the intracellular kinase domain and is critical for activation by the type II receptor. Several studies have shown that TGF- signaling requires both the ALK and type II receptors. Specifically, the type II receptor phosphorylates the GS domain of the type I receptor for TGF-B, ALKS, in the presence of TGF-B. The ALKS, in turn, phosphorylates the cytoplasmic proteins smad2 and smad3 at two carboxy terminal serines. Generally it is believed that in many species, the type II receptors regulate cell proliferation and the type I receptors regulate matrix production. Therefore, preferred compounds of this invention are selective in that they inhibit the type I receptor and thus matrix production, and not the type II receptor mediated proliferation.

Activation of the TGF-B1 axis and expansion of extracellular matrix are early and persistent contributors to the development and progression of chronic renal disease and vascular disease. Border W.A., Noble N.A., N. Engl. J. Med., Nov. 10, 1994; 331(19):1286-92. Further,

TGF-B1 plays a role in the formation of fibronectin and plasminogen activator inhibitor-1, components of sclerotic deposits, through the action of smad3 phosphorylation by the TGF-31 receptor ALKS5. Zhang Y., Feng X.H., Derynck R., Nature, Aug. 27, 1998; 394(6696):909-13;

Usui T., Takase M., Kaji Y., Suzuki K., Ishida K., Tsuru T., Miyata K., Kawabata M., Yamashita

H., Invest. Ophthalmol. Vis. Sci., Oct. 1998; 39(11):1981-9.

Progressive fibrosis in the kidney and cardiovascular system is a major cause of suffering and death and an important contributor to the cost of health care. TGF-PB1 has been implicated in many renal fibrotic disorders. Border W.A_, Noble N.A_ N. Engl J. Med., Nov 10, 1994, 331(19):1286-92. TGF-B1 is elevated in acute and chronic glomerulonephritis, Yoshioka K.,

Takemura T., Murakami K., Okada M., Hino S., Miyamoto H., Maki S., Lab. Invest., Feb. 1993; : 68(2):154-63, diabetic nephropathy, Yamamoto, T., Nakamura, T., Noble, N.A_, Ruoslahti, E.,

Border, W.A., (1993) PNAS 90:1814-1818, allograft rejection, HIV nephropathy and . angiotensin-induced nephropathy, Border W.A., Noble N.A., N. Engl. J. Med., Nov. 10, 1994; 40 331(19):1286-92. In these diseases the levels of TGF-f1 expression coincide with the production of extracellular matrix.- Three lines of evidence suggest a causal relationship between TGF-p1 and the production of matrix. First, normal glomeruli, mesangial cells and non-renal cells can be induced to produce extracellular-matrix protein and inhibit protease activity by exogenous TGF- :

¥ Y

B1 in vitro. Second, neutralizing anti-bodies against TGF-B1 can prevent the accumulation of extracellular matrix in nephritic rats. Third, TGF-B1 transgenic mice or in vivo transfection of the TGF-B1 gene into normal rat kidneys resulted in the rapid development of glomerulosclerosis.

Kopp I.B., Factor V.M., Mozes M., Nagy P., Sanderson N., Bottinger E.P., Klotman P.E., : 5 Thorgeirsson S.S., Lab Invest, June 1996; 74(6):991-1003. Thus, inhibition of TGF-B1 activity is indicated as a therapeutic intervention in chronic renal disease. . TGF-B1 and its receptors are increased in injured blood vessels and are indicated in neointima formation following balloon angioplasty, Saltis J., Agrotis A., Bobik A., Clin Exp

Pharmacol Physiol, Mar. 1996; 23(3):193-200. In addition TGF-B1 is a potent stimulator of smooth muscle cell ("SMC") migration in vitro and migration of SMC in the arterial wall is a contributing factor in the pathogenesis of atherosclerosis and restenosis. Moreover, in multivariate analysis of the endothelial cell products against total cholesterol, TGF- receptor

ALKS5 correlated with total cholesterol (P < 0.001) Blann A.D., Wang J.M., Wilson P.B., Kumar

S., Atherosclerosis, Feb. 1996; 120(1-2):221-6. Furthermore, SMC derived from human atherosclerotic lesions have an increased ALK5/TGF-f type II receptor ratio. Because TGF-B1 is over-expressed in fibroproliferative vascular lesions, receptor-variant cells would be allowed to grow in a slow, but uncontrolled fashion, while overproducing extracellular matrix components

McCaffrey T.A., Consigli S., Du B., Falcone D.J., Sanborn T.A., Spokojny A.M., Bush H.L., Jr.,

J Clin Invest, Dec. 1995; 96(6):2667-75. TGF-B1 was immunoiocalized to non-foamy macrophages in atherosclerotic lesions where active matrix synthesis occurs, suggesting that non- foamy macrophages may participate in modulating matrix gene expression in atherosclerotic remodeling via a TGF-B-dependent mechanism. Therefore, inhibiting the action of TGF-B1 on

ALKS is also indicated in atherosclerosis and restenosis.

TGF-B is also indicated in wound repair. Neutralizing antibodies to TGF-31 have been used in a number of models to illustrate that inhibition of TGF-B1 signaling 1s beneficial in restoring function after injury by limiting excessive scar formation during the healing process.

For example, neutralizing antibodies to TGF-PB1 and TGF-B2 reduced scar formation and improved the cytoarchitecture of the neodermis by reducing the number of monocytes and macrophages as well as decreasing dermal fibronectin and collagen deposition in rats Shah M., J.

Cell Sci., 1995, 108, 985-1002. Moreover, TGF-f antibodies also improve healing of corneal wounds in rabbits Moller-Pedersen T., Curr. Eye Res., 1998, 17, 736-747, and accelerate wound healing of gastric uicers in the rat, Ernst H., Gut, 1996, 39, 172-175. These data strongly suggest that limiting the activity of TGF-B would be beneficial in many tissues and suggest that any disease with chronic elevation of TGF-f would benefit by inhibiting smad2 and smad3 signaling pathways.

TGF- is also implicated in peritoneal adhesions Saed GM. et al, Wound Repair

Regeneration, 1999 Nov-Dec, 7(6), 504-510. Therefore, inhibitors of ALKS would be beneficial in preventing peritoneal and sub-dermal fibrotic adhesions following surgical procedures.

TGFP1-antibodies prevent transplanted renal tumor growth in nude mice through what is 40 thought to be an anti-angiogenic mechanism Ananth S, et al, Journal Of The American Society Of ) Nephrology Abstracts, 9: 433A(Abstract). While the tumor itself is not responsive to TGF-B, the

IES surrounding tissue is responsive and supports tumor growth by neovascularization of the TGF-B

’ h secreting tumor. Thus, antagonism of the TGF-B pathway should prevent metastasis growth and reduce cancer burden.

Bioorg. Med. Chem. Lett., 1995, 5(6), 543 discloses 2-[5-(2-methylphenyl)-2-propyl-1H- imidazol-4-yl]pyridine as an inhibitor of gastric HY/K* ATPase. ’ 5 DE 2221546 discloses the following compounds as antiinflammatory, analgesic or antipyretic agents: . 2-[2-(1,1-dimethylethyl)-5-(4-methoxyphenyl)- 1 H-imidazol-4-yl]pyridine, 2-[2~(1,1-dimethylethyl)-5-phenyi- 1 H-imidazol-4-yl]pyridine.

Japanese Patent No. 09124640 discloses the following compounds as agrochemical fungicides: 2-[5-(3,5-dichlorophenyl)-2-methyl- 1H-imidazol-4-yl]pyridine, 2-[5-(3,5-dimethylphenyl)-2-methyl-1H-imidazol-4-yl]pyridine, 2-[5-(3,5-dimethylphenyl)-2-ethyl-1H-imidazol-4-yl]pyridine, 2-[5-(3,5-dimethylphenyl)-2-amino- 1H-imidazol-4-yl]pyridine, 2-[5-(3,5-dimethylphenyl)-2-isopropyl-1H-imidazol-4-yl]pyridine, 2-[5-(3,5-dimethylpheny!)-2-propyl- 1 H-imidazo}-4-yl]pyridine, 2-[5-(3,5-dimethylphenyl)-2-carboxamide-1H-imidazol-4-yl]pyridine.

Surprisingly, it has now been discovered that a class of 2-pyridyl substituted imidazoles of formula (I), function as potent and selective non-peptide inhibitors of ALKS5 kinase and therefore, have utility in the treatment and prevention of various disease states mediated by ALKS kinase mechanisms, such as chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers, ocular disorders, corneal wounds, diabetic nephropathy, impaired neurological function, Alzheimer's disease, trophic conditions, atherosclerosis, peritoneal and sub-dermal adhesion, any disease wherein fibrosis is 2 major component, including, but not limited to lung fibrosis and liver fibrosis, and restenosis.

According to the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

R, X

JR

~~ %2

Lon

RJ

@ wherein Rj is naphthyl, anthracenyl, or phenyl optionally substituted with one or more substituents selected from the group consisting of halo, C1_galkoxy, C1-galkylthio, C}_galkyl,

C1-ghaloalkyl, O-(CHy)m-Ph, S{(CHy)m-Ph, cyano, phenyl, and COR, wherein R is hydrogen . or Cj_galkyl and m is 0-3; or Rj is phenyl or pyridyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to three heteroatoms, } 35 independently selected from N, O and S, and is optionally substituted by =O;

Ry represents hydrogen, Cj.galkyl, Ci.galkoxy, phenyl, C|.ghaloalkyl, halo, NHp, NH-

C1-6alkyl or NH(CH)p-Ph wherein n is 0-3;

Rg3 represents C_galkyl, -(CH2)p-CN, -(CH2)p-COOH, -(CH2)p-CONHR4R5,

¢ h ~(CH2)pCORy, -(CH2)4(OR6)2, (CH2)pOR4, -(CHp)q-CH=CH-CN, «(CH2)q-CH=CH-CO2H, ~(CH)p-CH=CH-CONHR4R3, -(CH2)pNHCOR7 or -(CH2)pNRgRo,

R4 and Rs are independently hydrogen or C1_galkyl;

Rg is Cy galkyl; ’ 5 R7 is Cj.7alkyl, or optionally substituted aryl, heteroaryl, arylC}_galky! or heteroarylC1.- alkyl; . Rg and Rg are independently selected from hydrogen, C1.galkyl, aryl and arylC1.galkyl; pis 0-4; q is 1-4; one of Xj and X7 is N and the other is NR | o; and

Rj is hydrogen, Cj_galkyl, or C3.7cycloalkyl; provided that the compound is not: i) 2-[5-(2-methylpheny!)-2-propyl-1H-imidazol-4-yl]pyridine, if) 2-[2-(1,1-dimethylethyl)-5-(4-methoxyphenyl)- 1H-imidazol-4-yl]pyridine, ii) 2-[2~(1,1-dimethylethyl)-5-phenyl-1H-imidazol-4-yl]pyridine, iv) 2-[5-(3,5-dichlorophenyl)-2-methyl- 1 H-imidazol-4-yljpyridine, v) 2-[5-(3,5-dimethylphenyl)-2-methyl- 1H-imidazol-4-yl]pyridine, vi) 2-[5-(3,5-dimethylphenyl)-2-ethyl- 1H-imidazol-4-yl]pyridine, vii) 2-[5-(3,5-dimethylphenyi)-2-amino- 1 H-imidazol-4-yl]pyridine, : viii) 2-[5-(3,5-dimethylphenyl)-2-isopropyl-1H-imidazol-4-yl]pyridine, ix) 2-[5-(3,5-dimethylphenyl)-2-propyl-1H-imidazol-4-yl]pyridine, or

X) 2-[5-(3,5-dimethylphenyl)-2-carboxamide-1H-imidazol-4-yl}pyridine.

As used herein, the double bond indicated by the dotted lines of formula (I), represent the possible tautomeric ring forms of the compounds falling within the scope of this mvention, the double bond being to the unsubstituted nitrogen.

In a preferred group of compounds R is optionally substituted naphthyl or phenyl.

Preferably R; is phenyl optionally substituted with one or more substituents selected from the group consisting of halo, Cj.galkoxy, C}.galkylthio, and phenyl; more preferably Rj is phenyl optionally substituted with one or more substituents selected from the group consisting of halo,

Cji-galkoxy, Ci_galkylthio, and cyano; or Rj is phenyl or pyridyl (notably phenyl) fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to three heteroatoms, independently selected from N, O and S, and is optionally substituted by =O; for example R represents benzo[1,3]dioxolyl, 2,3-dihydrobenzo[ 1,4]dioxinyl, benzoxazolyl, benzothiazolyl, quinoxalinyl, benzo[1,2,5]oxadiazolyl, benzo[1,2,5}thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridyl, dihydrobenzofuranyl, benzo[1,4]oxazinyi-3-one or benzoxazolyl-2- one.

Preferably Ry is other than hydrogen. When R> is other than hydrogen it is preferably . positioned ortho to the nitrogen of the pyridyl ring.

Preferably R3 is C1. alkyl or (CH2)pNHCOR7 wherein Ry is Cj.7alkyl, or optionally 40 substituted aryl, heteroaryl, arylC1.galkyl or heteroarylCj_galkyl.

Preferably one of Xj and X3 is N and the other is NR, wherein Rj is hydrogen or Cj. galkyl.

R10 is preferably hydrogen. :

¢ A}

The compounds for use in the methods of the invention preferably have a molecular weight of less than 800, more preferably less than 600.

Specific compounds of the invention which may be mentioned include those described in the examples. ) 5 Suitable, pharmaceutically acceptable salts of the compounds of formula (I) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, . diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate, and stearate.

Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.

Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably at least 10% of a compound of formula (I) or pharmaceutically = acceptable derivative thereof. : The terms "Cj _galkyl" and "Cy_7alkyl" as used herein whether on its own or as part of a larger group e.g. C1_galkoxy, means a straight or branched chain radical of 1to 6 and 1 to 7 carbon atoms respectively, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl and tert-butyl.

C1-6 haloalkyl groups may contain one or more halo atoms, a particular Cj.¢ haloalkyl group that may be mentioned in CF3.

The terms "halo" or "halogen" are used interchangeably herein to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.

The term "C3_jcycloalkyl” as used herein means cyclic radicals of 3 to 7 carbons, including but not limited to cyclopropyl, cyclopentyl and cyclohexyl. . The term "aryl" as used herein means 5- to 14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, including, but not 40 limited to pheny! and naphthyl.

The term "ALKS inhibitor” as used herein means a compound, other than inhibitory smads, e.g. smadé6 and smad7, which selectively inhibits the ALKS5 receptor preferentially over p38 or type II receptors. r - 5 -

The term "ALKS mediated disease state" as used herein means any disease state which is mediated (or modulated) by ALKS, for example a disease which is modulated by the inhibition of the phosphorylation of smad 2/3 in the TGF-18 signaling pathway.

The term "ulcers" as used herein includes, but is not limited to, diabetic ulcers, chronic ’ 5 ulcers, gastric ulcers, and duodenal ulcers.

The compounds of formula (I) can be prepared by art-recognized procedures from known . or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.

Specifically, compounds of formula (I) where one of X and X3 is NH may be prepared according to Scheme 1. The ketone may be oxidised to a diketone with HBr in DMSO. This diketone can then be condensed with a suitably substituted aldehyde or protected aldehyde derivative and ammonium acetate to give the imidazole according to the method outlined in WO 98/56788. Alternatively the ketone may be treated with sodium nitrite in HCI to afford an o—oximinoketone which can then be condensed with a suitably substituted aldehyde or protected aldehyde derivative and ammonium acetate to give the N-hydroxyimidazole. Treatment of this with triethylphosphite affords the imidazole according to the method outlined in US Pat. 3,656,644.

Schemel

Ri © R, 0] R, N

N nd HBr na R,CHO nal

LN TT = TT H 4 DMSO \ _N NH, OAC \ N

Re RS Rf

NY Ring?® Agen e

NOH

R;

Compounds of formula (I) where one of X} and X7 is NH may also be prepared according to

Scheme 2. A suitable bromide is coupled with trimethylsilylacetylene using palladium catalysis.

The trimethylsilyl group can be removed by treatment with potassium carbonate and the terminal ) acetylene coupled with 6-bromo-2-methylpyridine again using palladium catalysis. The acetylene may then be oxidised to the diketone using palladium chloride in DMSO. Formation of the - imidazole is then carried out with a suitable aldehyde as described in Scheme 1.

Scheme 2

R, 1) Pde, TMS—== oe

RiBr Sm ES 2) K,CO, ' Ros ZN

Ll xX Me ' PdCl,

DMSO

R, N Ry ©

Na ~ N R,CHO EN 0

YP NH,OAc Lyn

RY R

Non-selective alkylation of the imidazole nitrogen (using one of the procedures outlined in N. J. Liverton et al; J. Med. Chem., 1999, 42, 2180-2190) with a compound of formula L-R1¢ wherein L is a leaving group, e.g. halo, sulfonate or triflate, will yield both isomers of the compounds where Xj or Xp is NRjg in which Rj is other than hydrogen, the isomers can be separated by chromatographic methods (Scheme 3).

Scheme 3

R, N hi Vs, =~ N \ UN Rio

R;

R, N + [ >= 7 \ Je

VP ~* y Rs

Ry N =~

Re

Compounds of formula (I) where R3 is -CH;NHCOR?7 may be prepared according to . Scheme 4. The appropriate dione is condensed with (1,3-dioxo-1,3-dihydro-isomdol-2-yI)- acetaldehyde and ammonium acetate to form the imidazole. This product is treated with hydrazine to unmask the free amine which can then be coupled to an appropriate carboxylic acid using standard amide bond formation conditions.

Scheme 4

H O

R,~_.0 aves Ris N or | or M0

ANS 0) —_ a x N N ‘_N Ammonium acetate | _N 0

Hydrazine

Ri~_ _N Rine—N > R, R,CO,H Dam

NN N= BE ——— Hh N NH, =N HOBT =N

R{ Rr

During the synthesis of the compounds of formula (T) labile functional groups in the intermediate compounds, e.g. hydroxy, carboxy and amino groups, may be protected. A comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in for example Protective

Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts, (Wiley-Interscience, New York, 2nd edition, 1991).

Further details for the preparation of compounds of formula (I) are found in the examples.

The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds of formula (I). Libraries of compounds of formula (T) may be prepared by a combinatorial ‘split and mix’ approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skiiled in the art. .

Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of formula (I) or pharmaceutically acceptable salts thereof.

The invention further provides the use of a compound of formula (IT), but without provisos i) to x), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease mediated by the ALKS5 receptor in mammals.

The invention further provides a method of treatment of a disease mediated by the ALK5 receptor in mammals, comprising administering to a mammal in need of such treatment, a ) therapeutically effective amount of a compound of formula (I), but without provisos i) to x), or a pharmaceutically acceptable salt thereof.

ALKS-mediated disease states, include, but are not limited to, chronic renal disease, acute ) renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers, ocular disorders, corneal wounds, diabetic nephropathy, impaired neurological function,

Alzheimer's disease, trophic conditions, atherosclerosis, any disease wherein fibrosis is a major component, including, but not limited to peritoneal and sub-dermal adhesion, lung fibrosis and liver fibrosis, and restenosis. :

By the term "treating" is meant either prophylactic or therapeutic therapy.

The invention further provides a method of inhibiting the TGF-f signaling pathway in mammals, for example, inhibiting the phosphorylation of smad2 or smad3 by the type I or activin- like kinase ALKS receptor, which method comprises administering to 2 mammal in need of such : treatment, a therapeutically effective amount of a compound of formula (I), but without provisos i) to x), or a pharmaceutically acceptable salt thereof.

The invention further provides the use of a compound of formula (I,) but without provisos i) to x), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the TGF- signaling pathway in mammals.

The invention further provides a method of inhibiting matrix formation in mammals, for example, by inhibiting the phosphorylation of smad?2 or smad3 by the type I or activin-like kinase

ALKS receptor, which method comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of formula (I), but without provisos i) to x), or a pharmaceutically acceptable salt thereof.

The invention further provides the use of a compound of formula (I), but without provisos i) to x), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting matrix formation in mammals.

The compounds of formula (I) and pharmaceutically acceptable salts thereof, may be administered in conventional dosage forms prepared by combining a compound of formula (I), but without provisos i) to x), with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I), but without provisos iv) to x), or a oo pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.

The compositions may be formulated for administration by any route. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to } assist drug penetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, such as cream or 40 ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, } 5 talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well . known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient.

The dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of admmistration. . Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day. i. 40 It will be recognized by one of skill in the art that the optimal quantity and spacing of ) individual dosages of a compound of formula (I), but without provisos i) to x), will be determined - by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by

Claims (10)

Claims:

1. A compound of formula (T) or a pharmaceutically acceptable salt thereof: . R, X, Dan R, . ~ % LN Rj ty) wherein Ry is naphthyl, anthracenyl, or phenyl optionally substituted with one or more substituents selected from the group consisting of halo, C1.galkoxy, C1.galkylthio, C{_galkyl, Cj-ghaloalkyl, O-(CH2)mp-Ph, S-(CH2)m-Ph, cyano, phenyl. and CO2R, wherein R is hydrogen or Cj_galkyl and m is 0-3; or Rj is phenyl or pyridyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to three heteroatoms, independently selected from N, O and S, and is optionally substituted by =O; Ry represents hydrogen, C;_galkyl. C;_galkoxy, phenyl. C;.ghaloalkyl, halo. NH3. NH- C1-6alkyl or NH(CHj)p-Ph wherein n is 0-3; R3 represents Cj_galkyl, -(CH2)p-CN, «(CH)p-COOH, -(CHp)p-CONHR4Rs3, ~(CH2)pCORy, -(CH2)q(ORé)2, (CH2)pOR4, -(CH2)q-CH=CH-CN, -(CH3)q-CH=CH-CO2H, -(CH2)p-CH=CH-CONHR4R3, -(CH2)pNHCOR7 or (CH2)pNRgR9, R4 and Rs are independently hydrogen or C_galkyl; Rg is Cj-galkyl; oo R7 is Cy.7alkyl, or optionally substituted aryl, heteroaryl, arylC_galkyl or heteroarylC1. alkyl; Rg and Rg are independently selected from hydrogen, C_galkyl, aryl and arylC;_galkyl; pis 0-4; qis 1-4; one of X and X3 is N and the other is NR; and R10 is hydrogen, C1_galkyl, or C3.7cycloalkyl; provided that the compound is not: i) 2-[5-(2-methylphenyi)-2-propyl-1H-imidazol-4-yl]pyridine, it) 2-[2+(1,1-dimethylethyl)-5-(4-methoxyphenyl)- 1 H-imidazol-4-yl]pyridine, iif) 2-[2<(1,1-dimethylethyl)-5-phenyl-1H-imidazol-4-yl]pyridine, iv) 2-[5-3,5-dichlorophenyl)-2-methyl- 1 H-imidazol-4-yl]pyridine, v) 2-[5+3,5-dimethylphenyl)-2-methyl- 1H-imidazol-4-yl]pyridine,

. vi) 2-[5~(3,5-dimethylphenyl)-2-ethyi- 1 H-imidazol-4-yl]pyridine, vii) 2-[5<3,5-dimethyliphenyl)-2-amino-1H-imidazol-4-yljpyridine, vili) 2-[5+3,5-dimethylphenyl)-2-isopropyl-1H-imidazol-4-yl]pyridine, ix) 2-[5+(3,5-dimethylphenyl)-2-propyl-1H-imidazol-4-yl]pyridine, or x) 2-[5-(3,5-dimethylphenyi)-2-carboxamide- 1 H-imidazol-4-yl]pyridine.

2. A compound according to claim 1 wherein R; is phenyl optionally substituted with one or more substituents selected from the group consisting of halo, Cj.galkoxy, C1_galkylthio, and cyano; or Ry is phenyl or pyridyl! fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to three heteroatoms, independently : selected from N, O and S, and is optionally substituted by =O.

3. A compound according to claim 1 or 2 wherein Ry is positioned ortho to the nitrogen of the pyridyl ring.

4. A compound according to any one of the preceding claims wherein R3 is C}_g alkyl or (CH2)pNHCOR?7 wherein R7 is Cj.7alkyl, or optionally substituted aryl, heteroaryl, arylCj. galkyl or heteroarylC1.galkyl.

5. A compound according to any one of the preceding claims wherein R1( is hydrogen.

6. A compound according to claim 1 as definede in any one of Examples | to 71. ora pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound according to any one of the preceding claims, but without provisos iv) to x), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

8. A method of inhibiting the TGF-B signaling pathway in mammals, comprising administering to 2 mammal, comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound according to any one of claims 1 to 6, but without provisos 1) to x), or a pharmaceutically acceptable salt thereof.

9. A method for treating a disease selected from chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers, ocular disorders, corneal wounds, diabetic nephropathy, impaired neurological function, Alzheimer's disease, trophic conditions, atherosclerosis, peritoneal and sub-dermal adhesion, any disease wherein fibrosis is a major component, and restenosis, comprising administering to 2a mammal in need of such treatment, a therapeutically effective amount of a compound according to any one of claims 1 to 6, but without provisos i) to x), or a pharmaceutically acceptable salt thereof.

10. A method for inhibiting matrix formation in mammals, comprising administering to a mammal, a therapeutically effective amount of a compound according to any one of claims 1 to 6, . but without provisos i) to x), or a pharmaceutically acceptable salt thereof.