WO2004024718A1 - Imidazolidinedione-derivatives and their use as metalloproteinase inhibitors - Google Patents

Abstract

The invention provides compounds of formula in which R1, G1 and G2 have the meanings defined in the specification; processes for their preparation; pharmaceutical compositions containing them; a process for preparing the pharmaceutical compositions; and their use in therapy.

Description

IMIDAZOLIDINEDIONE-DERIVATIVES AND THEIR USE AS METALLOPROTEINASE INHIBITORS.

The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified into families and subfamilies as described in N.M. Hooper (1994) FEBS Letters 354-' 1-6. Examples of metalloproteinases include the matrix metalloproteinases (MMPs) such as the collagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase (MMP12), enamelysin (MMP19), the MT-MMPs (MMP14, MMP15, MMP16, MMP17); the reprol sin or adamalysin or MDC family which includes the secretases and sheddases such as TNF converting enzymes (ADAM 10 and TACE); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloproteinases such as aggrecanase, the endothelin converting enzyme family and the angiotensin converting enzyme family.

Metalloproteinases are believed to be important in a plethora of physiological disease processes that involve tissue remodelling such as embryonic development, bone formation and uterine remodelling during menstruation. This is based on the ability of the metalloproteinases to cleave a broad range of matrix substrates such as collagen, proteoglycan and fibronectin. Metalloproteinases are also believed to be important in the processing, or secretion, of biological important cell mediators, such as tumour necrosis factor (TNF); and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (for a more complete list see N. M. Hooper et al., (1997) Biochem J. 321:265-279). Metalloproteinases have been associated with many diseases or conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these diseases or conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro-intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema, dermatitis); in tumour metastasis or invasion; in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget's disease); in diseases associated with aberrant angiogenesis; the enhanced collagen remodelling associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelinating diseases of the central and peripheral nervous systems (such as multiple sclerosis); Alzheimer's disease; extracellular matrix remodelling observed in cardiovascular diseases such as restenosis and atheroscelerosis; asthma; rhinitis; and chronic obstructive pulmonary diseases (COPD).

MMP12, also known as macrophage elastase or metalloelastase, was initially cloned in the mouse by Shapiro et al [1992, Journal of Biological Chemistry 267: 4664] and in man by the same group in 1995. MMP12 is preferentially expressed in activated macrophages, and has been shown to be secreted from alveolar macrophages from smokers [Shapiro et al, 1993, Journal of Biological Chemistry, 268: 23824] as well as in foam cells in atherosclerotic lesions [Matsumoto et al, 1998, Am J Pathol 153: 109]. A mouse model of COPD is based on challenge of mice with cigarette smoke for six months, two cigarettes a day six days a week. Wildtype mice developed pulmonary emphysema after this treatment. When MMP12 knock-out mice were tested in this model they developed no significant emphysema, strongly indicating that MMP12 is a key enzyme in the COPD pathogenesis. The role of MMPs such as MMP12 in COPD (emphysema and bronchitis) is discussed in Anderson and Shinagawa, 1999, Current Opinion in Anti-inflammatory and Immunomodulatory Investigational Drugs 1(1): 29-38. It was recently discovered that smoking increases macrophage infiltration and macrophage-derived MMP-12 expression in human carotid artery plaques Kangavari [Matetzky S, Fishbein MC et al., Circulation 102: (18). 36-39 Suppl. S, Oct 31, 2000].

MMP9 (Gelatinase B; 92kDa TypelN Collagenase; 92kDa Gelatinase) is a secreted protein which was first purified, then cloned and sequenced, in 1989 [S.M. Wilhelm et al (1989) J. Biol Che . 264 (29): 17213-17221; published erratum in J. Biol Chem. (1990) 265 (36): 22570]. A recent review of MMP9 provides an excellent source for detailed information and references on this protease: T.H. Vu & Z. Werb (1998) (In : Matrix Metalloproteinases. 1998. Edited by W.C. Parks & R.P. Mecham. ppl 15 - 148.

Academic Press. ISBN 0-12-545090-7). The following points are drawn from that review by T.H. Vu & Z. Werb (1998).

The expression of MMP9 is restricted normally to a few cell types, including trophoblasts, osteoclasts, neutrophils and macrophages. However, it's expression can be induced in these same cells and in other cell types by several mediators, including exposure of the cells to growth factors or cytokines. These are the same mediators often implicated in initiating an inflammatory response. As with other secreted MMPs, MMP9 is released as an inactive Pro-enzyme which is subsequently cleaved to form the enzymatically active enzyme. The proteases required for this activation in vivo are not known. The balance of active MMP9 versus inactive enzyme is further regulated in vivo by interaction with T P-1 (Tissue Inhibitor of Metalloproteinases -1), a naturally-occurring protein. TIMP-1 binds to the C-terminal region of MMP9, leading to inhibition of the catalytic domain of MMP9. The balance of induced expression of ProMMP9, cleavage of Pro- to active MMP9 and the presence of TIMP- 1 combine to determine the amount of catalytically active MMP9 which is present at a local site. Proteolytically active MMP9 attacks substrates which include gelatin, elastin, and native Type IN and Type V collagens; it has no activity against native Type I collagen, proteoglycans or laminins. There has been a growing body of data implicating roles for MMP9 in various physiological and pathological processes. Physiological roles include the invasion of embryonic trophoblasts through the uterine epithelium in the early stages of embryonic implantation; some role in the growth and development of bones; and migration of inflammatory cells from the vasculature into tissues.

MMP9 release, measured using enzyme immunoassay, was significantly enhanced in fluids and in AM supernantants from untreated asthmatics compared with those from other populations [Am. J. Resp. Cell & Mol. Biol., Nov 1997, 17 (5):583-5911. Also, increased MMP9 expression has been observed in certain other pathological conditions, thereby implicating MMP9 in disease processes such as COPD, arthritis, tumour metastasis, Alzheimer's, Multiple Sclerosis, and plaque rupture in atherosclerosis leading to acute coronary conditions such as Myocardial Infarction.

A number of metalloproteinase inhibitors are known (see for example the reviews of MMP inhibitors by Beckett R.P. and Whittaker M., 1998, Exp. Opin. Ther. Patents, 8(3):259-282. and by Whittaker M. et al, 1999, Chemical Reviews 99(9):2735-2776).

We have now discovered a new class of compounds that are inhibitors of metalloproteinases and are of particular interest in inhibiting MMPs such as MMP 12 and MMP9. In particular, we have discovered compounds that are potent dual MMP 12 and MMP9 inhibitors and have desirable activity profiles. The compounds of this invention have beneficial potency, selectivity and/or pharmacokinetic properties.

In accordance with the present invention, there is therefore provided a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof

wherein

.1

R represents hydrogen, or a group selected from Cj-Cg alkyl and a saturated or unsaturated 3- to 10-membered ring system which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, carboxyl, -NR²R³, -CONR⁴R⁵, - alkyl, Cι-C₆ alkoxy, Ci-C₆ alkylcarbonyl(oxy), -S(O)_mCι-C6 alkyl where m is 0, 1 or 2, Cj-Cg alkyl sulphonylamino, Cj-Cg alkoxycarbonyl(amino), benzyloxy and a saturated or unsaturated 5- to 6- membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring in turn being optionally substituted with at least one substituent selected from halogen, hydroxyl, oxo (=O), carboxyl, cyano, C1-C6 alkyl,

C]-C6 alkoxycarbonyl and Cj-Cό hydroxy alkyl;

2 3 4 5

R , R , R and R each independently represent hydrogen or C\ -C(, alkyl optionally substituted by at least one substituent selected from hydroxyl, halogen and Ci-Cg alkoxy;

2 G represents a piperidine or a tetrahydropyridine ring;

G represents a 5- or 6- membered aryl or heteroaryl monocyclic ring which may be optionally fused to a second ring to form a bicyclic ring system containing a total of 8- to

10-ring atoms, the monocyclic ring or fused bicyclic ring system being optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, nitro, -C6 alkyl (optionally substituted by one or more of cyano, halogen, hydroxyl and methoxy), C2-Cg alkenyl, C\-C alkoxy (optionally substituted by one or more halogen atoms), -S(O)_nCι-C6 alkyl where n is 0, 1 or 2 (optionally substituted by one or more halogen atoms), Ci-Cζ alkylcarbonyl(amino), -Cg alkylcarbonyloxy, phenyl, benzyloxy and

and

R and R each independently represent hydrogen or C_\ -C alkyl optionally substituted by at least one substituent selected from hydroxyl, halogen and Ci-Cβ alkoxy.

In the context of the present specification, unless otherwise stated, an alkyl or alkenyl substituent group or an alkyl moiety in a substituent group may be linear or branched. A hydroxyalkyl substituent may contain one or more hydroxyl groups but preferably contains one or two hydroxyl groups. In the definition of R , it should be understood that each of the saturated or unsaturated 3- to 10-membered ring system and the saturated or unsaturated 5- to 6-membered ring may have alicyclic or aromatic properties. An unsaturated ring system will be partially or fully unsaturated. Further, in G , the second ring in the bicyclic ring system need not be aromatic and may contain one or more ring heteroatoms selected from nitrogen, oxygen and sulphur.

In an embodiment of the invention, R represents hydrogen, or a group selected from -C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) and a saturated or unsaturated 3- to 10-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur, each group being optionally substituted with at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. chlorine, fluorine, bromine or

2 3 4 5 iodine), hydroxyl, cyano, carboxyl, -NR R , -CONR R , -Cό, preferably

C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), Cj-Cg, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), Cj-Cg, preferably C1-C4, alkylcarbonyl(oxy) (e.g. methylcarbonyl(oxy), ethylcarbonyl(oxy), n-propylcarbonyl(oxy), isopropylcarbonyl(oxy), n-butylcarbonyl(oxy), n-pentylcarbonyl(oxy) or n-hexylcarbonyl(oxy)), -S(O)_mCι-C6, preferably C1-C4, alkyl where m is 0, 1 or 2 (e.g. methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl or ethylsulphonyl), -Cό, preferably C1-C4, alkylsulphonylamino

(e.g. methylsulphonylamino, ethylsulphonylamino, n-propylsulphonylamino, isopropylsulphonylamino, n-butylsulphonylamino, n-pentylsulphonylamino or n-hexylsulphonylamino), Cj-Cg, preferably -C4, alkoxycarbonyl(amino) (e.g. methoxycarbonyl(amino), ethoxycarbonyl(amino), n-propoxycarbonyl(amino) or n-butoxycarbonyl(amino)), benzyloxy and a saturated or unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur, the ring in turn being optionally substituted with at least one substituent (e.g. one, two or three substituents independently) selected from halogen (e.g. chlorine, fluorine, bromine or iodine), hydroxyl, oxo, carboxyl, cyano, -Cg, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), Ci-Cg, preferably C1-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl) and -C^, preferably -C4, hydroxyalkyl (e.g. -CH₂OH, -CH₂CH₂OH, -CH₂CH₂CH₂OH or -CH(OH)CH₃).

Examples of saturated or unsaturated 3- to 10-membered ring systems that may be used, which may be monocyclic or polycyclic (e.g. bicyclic) in which the two or more rings are fused, include one or more (in any combination) of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diazabicyclo[2.2.1]hept-2-yl, naphthyl, benzofuranyl, benzothienyl, benzodioxolyl, quinolinyl, 2,3-dihydrobenzofuranyl, tetrahydropyranyl, pyrazolyl, pyrazinyl, thiazolidinyl, indanyl, thienyl, isoxazolyl, pyridazinyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, imidazolyl, pyrimidinyl, benzimidazolyl, triazolyl, tetrazolyl and pyridinyl. Preferred ring systems include phenyl, pyridinyl and tetrahydropyranyl.

Examples of saturated or unsaturated 5- to 6-membered ring substituents in R include cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiomorpholinyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolidinyl, thienyl, isoxazolyl, pyrimidinyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl and pyridinyl. Preferred rings include moφholinyl, pyrimidinyl, phenyl, imidazolyl, piperidinyl, tetrahydropyranyl and triazolyl.

1 .

Particular values for R include the following

CH, , _ -*CH,

H O ^{3 s}COOH

H₃C CH₃

In another embodiment of the invention, R represents hydrogen, or a group selected from C1-C4 alkyl and a saturated or unsaturated 5- to 10-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur, each group being optionally substituted with at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen, hydroxyl, cyano, carboxyl, -NR²R³, -CONR⁴R⁵, -C4 alkyl, C1-C4 alkoxy, -C4 alkylcarbonyl(oxy), -S(O)_mCι-C₄ alkyl where m is 0, 1 or 2, -C4 alkylsulphonylamino, C1-C4 alkoxycarbonyl(amino), benzyloxy and a saturated or unsaturated 5- to 6- membered ring which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur, the ring in turn being optionally substituted with at least one substituent (e.g. one, two or three substituents independently) selected from halogen, hydroxyl, oxo, carboxyl, cyano, C1-C4 alkyl, C1-C4 alkoxycarbonyl and -C4 hydroxyalkyl.

In still another embodiment, R represents hydrogen or -C4 alkyl, particularly methyl.

2 3 4 5

R , R , R and R each independently represent hydrogen or Cj-Cg, preferably

C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by at least one substituent (e.g. one, two or three substituents independently) selected from hydroxyl, halogen (e.g. chlorine, fluorine, bromine or iodine) and Cj-Cό, preferably -C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy).

2 3 4 5 In an embodiment of the invention, R , R , R and R each independently represent hydrogen or Cj-Cg, preferably C1-C4, alkyl, in particular methyl. In another embodiment,

2 3 4 5

R , R , R and R each independently represent hydrogen. 2 G represents piperidine or tetrahydropyridine such as 1 ,2,3,6-tetrahydropyridine of formula

G represents a 5- or 6- membered aryl or heteroaryl monocyclic ring which may be optionally fused to a second ring to form a bicyclic ring system containing a total of 8- to 10-ring atoms, the monocyclic ring or fused bicyclic ring system being optionally substituted with at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. chlorine, fluorine, bromine or iodine), hydroxyl, cyano, nitro, Cj-Cό, preferably C1-C4, alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl (optionally substituted by one or more, e.g. one, two or three, substituents independently selected from cyano, halogen such as chlorine, fluorine, bromine or iodine, hydroxyl and methoxy, e.g. -CF3), C2-Cg, preferably C2-C4, alkenyl (e.g. ethenyl, prop-1-enyl, prop-2-enyl, but-1-enyl, pent-1-enyl, hex-1-enyl or 2-methyl-pent-2-enyl),

Cj-Cg, preferably -C4, alkoxy such as methoxy, ethoxy, n-propoxy or n-butoxy (optionally substituted by one or more, e.g. one, two or three, halogen atoms such as chlorine, fluorine, bromine or iodine, e.g. -OCF3), -S(O)_nCι-C6, preferably C1-C4, alkyl where n is 0, 1 or 2 (optionally substituted by one or more, e.g. one, two or three, halogen atoms such as chlorine, fluorine, bromine or iodine) (e.g. methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl, ethylsulphonyl or -SCF3);

Ci-Cζ, preferably C1-C4, alkylcarbonyl(amino) (e.g. methylcarbonyl(amino), ethylcarbonyl(amino), n-propylcarbonyl(amino), isopropylcarbonyl(amino), n-butylcarbonyl(amino), n-pentylcarbonyl(amino) or n-hexylcarbonyl(amino)), Cj-Cό, preferably C1-C4, alkylcarbonyloxy (e.g. methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, n-pentylcarbonyloxy or n-hexylcarbonyloxy), phenyl, benzyloxy and

A 5- or 6-membered heteroaryl ring will comprise at least one ring heteroatom (e.g. one, two or three ring heteroatoms independently) selected from nitrogen, oxygen and sulphur.

Examples of 5- or 6- membered aryl or heteroaryl monocyclic rings include phenyl, pyridinyl, thienyl, furanyl, pyrazinyl, pyrimidinyl, pyrrolyl and thiazolyl, for instance,

If the 5- or 6- membered aryl or heteroaryl monocyclic ring is substituted, it is preferred that the substituent(s) are located in the meta and/ 'or para positions, as illustrated in the examples below:

* denotes a meta substitution position; # denotes a. para substitution position.

A preferred meta substituent is a C1-C3 alkyl group or -CH2CN.

A preferred para substituent is Br, CI, -CN, -CF3, -SCF3 or -OCF3. In an embodiment of the invention, in G , the 5- or 6- membered aryl or heteroaryl monocyclic ring is fused to a second ring to form a bicyclic ring system containing a total of 8- to 10-ring atoms such as quinolinyl, isoquinolinyl, indolyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, naphthyl or dihydroindolyl. A preferred bicyclic ring system is dihydrobenzofuranyl.

In one embodiment, G represents a 5- or 6- membered aryl or heteroaryl monocyclic ring which may be optionally fused to a second ring to form a bicyclic ring system containing a total of 8- to 10-ring atoms, the monocyclic ring or fused bicyclic ring system being optionally substituted with one, two or three substituents independently selected from halogen, hydroxyl, cyano, nitro, C1-C4 alkyl (optionally substituted by one or more, e.g. one, two or three, substituents independently selected from cyano, halogen, hydroxyl and methoxy), C2-C4 alkenyl, C1-C4 alkoxy (optionally substituted by one or more, e.g. one, two or three, halogen atoms), -S(O)_πCι-C4 alkyl where n is 0, 1 or 2 (optionally substituted by one or more, e.g. one, two or three, halogen atoms),

6 7

C1-C4 alkylcarbonyl(amino), -C4 alkylcarbonyloxy, phenyl, benzyloxy and -NR R .

In another embodiment, G represents a 6- membered aryl or heteroaryl monocyclic ring which may be optionally fused to a second ring to form a bicyclic ring system containing a total of 9- to 10-ring atoms, the monocyclic ring or fused bicyclic ring system being optionally substituted with one or two substituents independently selected from halogen, cyano and C1-C4 alkyl.

In still another embodiment, G represents phenyl, pyridinyl or dihydrobenzofuranyl, each of which is optionally substituted with one or two substituents independently selected from halogen (particularly chlorine), cyano and C1-C4 alkyl (particularly methyl).

1 2

Particular combinations of G and G include the following:

R

each independently represent hydrogen or C]-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by at least one substituent (e.g. one, two or three substituents independently) selected from hydroxyl, halogen (e.g. chlorine, fluorine, bromine or iodine) and Cj-Cό, preferably -C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy).

In an embodiment of the invention,

each independently represent hydrogen or 7

Cj-Cό, preferably -C4, alkyl, in particular methyl. In another embodiment, R and R each independently represent hydrogen.

In an embodiment of the invention: R represents -C4 alkyl; 2 G represents a piperidine or a tetrahydropyridine ring; and

G represents a 6- membered aryl or heteroaryl monocyclic ring which may be optionally fused to a second ring to form a bicyclic ring system containing a total of 9- to

10-ring atoms, the monocyclic ring or fused bicyclic ring system being optionally substituted with one or two substituents independently selected from halogen, cyano and

C!-C₄ alkyl.

In another embodiment of the invention:

R¹ represents methyl;

2 G represents a piperidine or a tetrahydropyridine ring; and

G represents phenyl, pyridinyl or dihydrobenzofuranyl, each of which is optionally substituted with one or two substituents independently selected from chlorine, cyano and methyl.

Examples of compounds of the invention include:

2-Methyl-4-[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]benzonitrile,

(5S)-5-({ [4-(2,3-Dihydro-l-benzofuran-5-yl)-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione, (5S)-5-Methyl-5-{[(4-methyl-3',6'-dihydro-2,4'-bipyridin-l'(2'H)- yl)sulfonyl]methyl } imidazolidine-2,4-dione,

(5S)-5-({ [4-(4-Chloro-3-methylphenyl)-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione,

2-Methyl-4-[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4- yl]methyl } sulfonyl)piperidin-4-yl]benzonitrile, and pharmaceutically acceptable salts and solvates thereof.

It will be appreciated that the particular substituents and number of substituents in the compounds of the invention are selected so as to avoid sterically undesirable combinations. Each exemplified compound represents a particular and independent aspect of the invention.

It will be appreciated that the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centres (chiral centres) in compounds according to the invention can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof. Racemates may be separated into individual optically active forms using known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pi 04- 107) including for example the formation of diastereomeric derivatives having convenient optically active auxiliary species followed by separation and then cleavage of the auxiliary species.

Where optically active centres exist in the compounds of the invention, we disclose all individual optically active forms and combinations of these as individual specific embodiments of the invention, as well as their corresponding racemates.

Where tautomers exist in the compounds of the invention, we disclose all individual tautomeric forms and combinations of these as individual specific embodiments of the invention.

The compounds of the invention may be provided as pharmaceutically acceptable salts or solvates. These include acid addition salts such as hydrochloride, hydrobromide, citrate, tosylate and maleate salts and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic a ine salt for example triethylamine. Examples of solvates include hydrates. The compounds of formula (I) have activity as pharmaceuticals. As previously outlined the compounds of the invention are metalloproteinase inhibitors, in particular they are dual inhibitors of MMP 12 and MMP9 and may be used in the treatment of diseases or conditions mediated by MMP 12 and/or MMP9 such as asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis (such as rheumatoid arthritis and osteoarthritis), atherosclerosis and restenosis, cancer, invasion and metastasis, diseases involving tissue destruction, loosening of hip joint replacements, periodontal disease, fibrotic disease, infarction and heart disease, liver and renal fibrosis, endometriosis, diseases related to the weakening of the extracellular matrix, heart failure, aortic aneurysms, CNS related diseases such as Alzheimer's disease and Multiple Sclerosis (MS), and hematological disorders.

In the context of the present specification, a compound is considered to be a dual inhibitor of MMP 12 and MMP9 if the potency of the compound (as measured by its IC50 value) is less than or equal to 100 nanomolar (< 100 nm) for each of MMP12 and MMP9, or, if the ratio of the potencies (MMP9:MMP12) is less than or equal to 20 (< 20).

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.

In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly. The invention further provides a method of treating a disease or condition mediated by MMP 12 and/or MMP9 which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined.

The invention also provides a method of treating an obstructive airways disease (e.g. asthma or COPD) which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula (I)/salt/solvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary.

Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.

The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w, of active ingredient, and, from 1 to 99.95 %w, more preferably from 30 to 99.90 %w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition. Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal adminstration or by inhalation. For these puφoses the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.

In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more diseases or conditions referred to hereinabove such as "Symbicort" (trade mark) product.

Preparation of the compounds of the invention

The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as defined above which comprises,

(a) reacting a compound of formula

1 2 in which G and G are as defined in formula (I), with a compound of formula

wherein L represents a leaving group (e.g. a halogen atom such as chlorine) and R is as defined in formula (I); or

(b) reacting a compound of formula

1 1 2 wherein R , G and G are as defined in formula (I), with potassium cyanide and ammonium carbonate; and optionally after (a) or (b) forming a pharmaceutically acceptable salt or solvate.

In process (a), the reaction is conveniently carried in an organic solvent such as pyridine, dimethylformamide, tetrahydrofuran, acetonitrile or dichloromethane and optionally in the presence of a base such as triethylamine, Ν-methylmoφholine, pyridine or an alkali metal carbonate. The reaction will usually be carried out over about 1 to 24 hours at elevated temperature, for example, from ambient (20°C) to reflux temperature. Compounds of formula (II) are either commercially available, are known in the literature (for example, from Wusttow et al, Synthesis, 1991, H, 993-995) or may be prepared using known techniques.

Compounds of formula (III) may be prepared as described by Mosher, J., J. Org. Chem., 2 233,, 11225577 ((11995588)),, oorr aalltteerrnnaattiivveellyy,, wwhheenn LL rreepprreessents chlorine, may be prepared by oxidative chlorination of* compounds of formula

wherein R is as defined in formula (111), for example, as described by Griffith, O.W., J. Biol. Chem., 1983, 258 (3), 1591-1598.

In process (b), the reaction is conveniently carried out in the presence of a protic solvent such as ethanol and in a sealed vessel at about 40°C to 80°C for about 4-24 hours.

Compounds of formula (IV) may conveniently be prepared by treating a compound of formula

1 2 in which G and G are as defined in formula (IN) with excess (e.g. 2-3 equivalents worth) strong base such as lithium diisopropylamide, lithium hexamethyldisilazane or butyl lithium in the presence of an organic solvent such as tetrahydrofuran, followed by reaction with a compound of formula

wherein R represents an alkyl or aryl group and R is as defined in formula (IN), in a non-protic solvent.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of the invention may involve, at various stages, the addition and removal of one or more protecting groups.

The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley- Interscience (1999).

Compounds of formulae (V), (VI) and (VU) are either commercially available, are known in the literature or may be prepared using known techniques.

The present invention will now be further explained by reference to the following illustrative examples.

General procedures

1HΝMR and ¹³CNMR were recorded on a Varian ^umty Inova 400 MHz or a Varian Mercury-YX 300 MHz instrument. The central peaks of chloroform-^ (6_H 7.27ppm), dimethylsulfoxide- t_f (5H 2.50 ppm) or methanol-^ (5_H 3.31 ppm) where used as internal references. Low-resolution mass spectra were obtained on an Agilent 100 LC-MS system equipped with an APCI ionisation chamber. Column chromatography was carried out using silica gel (0.063-0.2 mm) (Merck). Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were laboratory grade and used as received. Abbreviations:

DCM: dichloromethane

THF: tetrahydrofuran

LDA: lithium diisopropylamide

EtOAc: ethyl acetate

EtOH: ethanol

AcOH: acetic acid

Pd C: palladium on carbon catalyst

Example 1 2-Methyl-4-[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]benzonitrile

2-Methyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzonitrile; hydrochloride (60 mg, 0.26 mmol) was taken up in 2 ml of dry DCM and 2 ml of dry THF and neutralised with diisopropylethylamine (55 μl, 0.33 mmol) at room temperature. [(4S)-4-Methyl-2,5-dioxo- imidazolodin-4-yl]methanesulfonyl chloride (80 mg, 0.35 mmol) was added and after stirring for 10 min, diisopropylethylamine (55 μl, 0.33 mmol) was added and the reaction mixture was stirred at room temperature until LC-MS (APCI) indicated consumption of the amine. The reaction mixture was evaporated and the residue was purified using preparative HPLC to give the title compound (yield = 27 mg, 27%).

LC-MS (APCI) m/z 389 [MH⁺]. 1H NMR (DMSO-d₆): 6 10.76 (1H, s); 8.04 (1H, s); 7.74 (1H, d, 7=8.07 Hz); 7.56 (1H, s); 7.46 (1H, d, 7=8.07 Hz); 6.40 (1H, s); 3.90 (2H, q, 7=3.07 Hz); 3.55, 3.42 (1H each, ABq, 7=14.79 Hz); 3.39 (2H, t, 7=5.92 Hz); 2.59 (2H, bs); 2.50 (obscured by DMSO-peak) (3H, s); 1.34 (3H, s).

The starting materials were prepared as follows:

tert-Butyl 4-{ r(trifluoromethyl)sulfonyl1oxyl-3.6-dihydropyridine-l(2H)-carboxylate A solution of tert-butyl 4-oxopiperidine-l-carboxylate (5.07 g, 25mmol) in THF (50 ml) was added drop wise to a solution of LDA (2M in THF, 15 ml, 30mmol) and THF (100 ml) over 25 mins at -78 °C. After stirring for 10 mins a solution of 1,1,1-trifluoro-N -phenyl - N-[(trifluoromethyl)sulfonyl]methanesulfonamide (lOg, 28 mmol) in THF (50ml) was added and the mixture stirred at 0 °C for 3 hours. The solvent was evaporated off and the residue passed through a 20 g plug of aluminium oxide with 9: 1 heptane / ethyl acetate. The solvent was evaporated to give 7.5 g product. GC/MS m z: 331 [M ⁺] very weak.

1H NMR (CDC1₃): 6 1.47 (9H, s); 2.41-2.47 (2H, m); 3.63 (2H, t); 4.04 (2H, q); 5.76 (1H, bs).

tert-Butyl 4-(4,4,5,5-tetramethyl-l,3.2-dioxaborolan-2-ylV3,6-dihydropyridine-l(2H)- carboxylate tert-Butyl 4- { [(trifluoromethyl)sulfonyl]oxy ] -3 ,6-dihydropyridine- 1 (2H)-carboxylate (7.50g, 22.6 mmol), 4,4,4' ,4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (6.33 g, 24.9mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (55 mg, 0.7mmol), l ,l'-bis(diphenylphosphino)ferrocene (37 mg, 0.7 mmol) and potassium acetate (6.6 g, 67mmol) were mixed, reaction vessel purged with nitrogen and heated at 80 °C for 6 hours. The solvent was evaporated and the residue purified by column chromatography eluting with 9 heptane : 1 ethyl acetate to give 4.4 g product.

1H NMR (CDC1 ): δ 1.26 (12H, s); 1.46 (9H, s); 2.19-2.25 (2H, m); 3.43 (2H, t); 3.94 (2H, q); 6.44-6.48 (1H, m).

tert-Butyl 4-(4-cvano-3-methylphenyl)-3.6-dihvdropyridine-l(2H)-carboxylate 4-Bromo-2-methyl-benzonitrile (150 mg, 0.77 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-y])-3,6-dihydropyridine-l(2Η)-carboxylate (284 mg, 0.92 mmol) and PdCl₂(dpρf) (38 mg, 0.05 mmol) were dissolved in toluene (2.5 ml), EtOH (0.75 ml) and 2M aqueous Na₂CO₃. The reaction vessel was purged with nitrogen and heated at 80 °C over night. After cooling, the mixture was partitioned between EtOAc and H₂O. The organic layer was washed with brine, dried over Na₂SO₄ and purified using flash chromatography (heptane:ethylacetate 7: 1) affording 171 mg (74%) of white crystals. LC-MS m/z 199 [M⁺].

1H NMR (CDCI₃): δ 7.52 (1H, d, 7=8.09 Hz); 7.27 (1H, s); 7.23 (1H, d, 7=8.51 Hz); 6.12 (1H, bs); 4.07 (2H, q, 7=5.81 Hz); 3.61 (2H, t, 7=5.61 Hz); 2.52 (3H, s); 2.48 (2H, bs); 1.47 (9H, s).

2-Methyl-4-( 1 ,2,3,6-tetrahvdropyridin-4-yl)benzonitrile hydrochloride tert-Butyl 4-(4-cyano-3-methylphenyl)-3,6-dihydropyridine-l(2H)-carboxylate (110 mg, 0.37 mmol) was dissolved in TΗF (5 ml) and cone. ΗC1 (5 ml) and was stirred at room temperature for 30 minutes after which the solvents were removed by rotary evaporation. The residue was dissolved in EtOΗ and toluene and evaporated again twice to remove all traces of water affording 84 mg (97%) of the title product. LC-MS (APCI) m z 199 [MΗ⁺].

5-Methyl-5-{ f(phenylmethyl)thio]methylUmidazoIidine-2,4-dione A steel vessel was charged with ethanol and water (315mL/135mL). 31.7g (0.175 mol) of benzylthioacetone, 22.9g (0.351 mol) of potassium cyanide and 84.5g (0.879 mol) of ammonium carbonate was added. The closed reaction vessel was kept in an oil bath (bath temperature 90 °C) under vigorous stirring for 3h. The reaction vessel was cooled with ice-water (0.5 h), the yellowish slurry was evaporated to dryness and the solid residue partitioned between 400 mL water and 700 mL ethylacetate and separated. The water-phase was extracted with ethyl acetate (300 mL). The combined organic phases were washed with saturated brine (150 mL), dried (Na₂SO₄), filtered and evaporated to dryness. If the product did not crystallize, 300 mL of dichloromethane was added to the oil. Evaporation gave the product as a slightly yellowish powder,43.8 g (90%). LC-MS (APCI) m/z 251.1 (MH+).

1H NMR (DMSO-d₆) δ: 10.74 (lH,s); 8.00 (1H, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72,

2.62 (1H each, ABq, 7=14.0 Hz); 1.29 (3H, s).

¹³C NMR (DMSO-d₆) δ: 177.30, 156.38, 138.11, 128.74, 128.24, 126.77, 62.93, 37.96,

36.39, 23.15.

(5S)-5-Methyl-5-f r(phenylmethyl)thio1methvIlimidazolidine-2,4-dione

The title compound was prepared by chiral separation of the racemic material using a

250mm x 50mm column on a Dynamic Axial Compression Preparative HPLC system.

The stationary phase used was CHJJ ALPAK AD, eluant=Methanol, flow=89mL/min, temp=ambient, UV=220nm, sample conc=150mg/mL, injection volume=20mL.

Retention time for title compound = 6 min.

Analysis of chiral purity was made using a 250mm x 4.6mm CHIRALPAK-AD column from Daicel, flow=0.5mL/min, eluent=Ethanol, UV=220nm, temp=ambient.

Retention time for title compound = 9.27min. Purity estimated to >99% ee.

LC-MS (APCI) m/z 251.1 (MH+).

[α]_D=-30.3° (c=0.01g/mL, MeOH, T=20°C).

1H NMR (DMSO-d₆) δ: 10.74 (lH,s); 8.00 (1H, s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72,

2.62 (1H each, ABq, 7=14.0 Hz); 1.29 (3H, s). ¹³C NMR (DMSO-d₆) δ: 177.30, 156.28, 138.11, 128.74, 128.24, 126.77, 62.93, 37.96, 36.39, 23.15.

r(4S)-4-Methyl-2.5-dioxoimidazolidin-4-vnmethanesulfonyl chloride (5S)-5-Methyl-5-{ [(phenylmethyl)thio]methyl}imidazolidine-2,4-dione (42.6g; 0.17mol) was dissolved in a mixture of AcOH (450 mL) and H₂O (50 mL). The mixture was immersed in an ice/water bath, chlorine gas was bubbled through the solution, the flow of gas was adjusted so that the temperature was kept below +15 °C. After 25 minutes the solution became yellow-green in colour and a sample was withdrawn for LC MS and HPLC analysis. It showed that starting material was consumed. The yellow clear solution was stirred for 30 minutes and an opaque solution /slurry was formed. The solvent was removed on a rotary evaporator using a water-bath with temperature held at 37°C. The yellowish solid was suspended in toluene (400mL) and solvent removed on the same rotary evaporator. This was repeated once more. The crude product was then suspended in iso-hexane (400mL) and warmed to 40°C while stirring, the slurry was allowed to cool to room temperature before the insoluble product was removed by filtration, washed with iso-hexane (6xl00mL), and dried under reduced preassure at 50°C overnight. This gave the product as a slightly yellow powder. Obtained 36.9 g (95%) of the title compound. Purity by HPLC = 99%, NMR supported that purity. [α]_D=-12.4° (c=0.01g/mL, THF, T=20°C).

Η NMR (THF-d₈): δ 9.91 (1H, bs); 7.57 (1H, s); 4.53, 4.44 (1H each, ABq, 7=14.6Hz); 1.52 (s, 3H, CH₃). ¹³C NMR (THF-dg): δ 174.96; 155.86; 70.96; 61.04; 23.66.

The following compounds were prepared by methods analogous to the synthesis of 2-methyl-4-[l-({ [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl }sulfonyl)-l ,2,3,6- tetrahydropyridin-4-yl]benzonitrile and its starting materials, and purified either by preparative HPLC or precipitation from EtOH H₂O. Example 2

(5S)-5-({[4-(2,3-Dihydro-l-benzofuran-5-yl)-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)-5-methyIimidazolidine-2,4-dione

LC-MS (APCI) m/z 392 [MH⁺].

1H NMR (DMSO-d_ό): δ 10.75 (IH, s); 8.03 (IH, s); 7.33 (IH, s); 7.17 (IH, dd, 7=8.38, 2.00 Hz); 6.73 (IH, d, 7=8.39 Hz); 6.03 (IH, bs); 4.52 (2H, t, 7=8.84 Hz); 3.85-3.80 (2H, m); 3.53, 3.39 (IH each, ABq, 7=15.57 Hz); 3.17 (2H, t, 7=8.42 Hz); 1.33 (3H, s).

Example 3

(5S)-5-Methyl-5-{[(4-methyl-3^,,6'-dihydro-2,4'-bipyridin-l^,(2'H)- yl)suIfonyl]methyl}imidazolidine-2,4-dione

LC-MS (APCI) m/z 365 [MH⁺].

^]H NMR DMSO-d₆: δ 10.76 (IH, s); 8.49 (IH, d, 7=5.41 Hz); 8.05 (IH, s); 7.62 (IH, s); 7.37 (IH, d, 7=5.04 Hz); 6.76 (IH, bs); 3.98-3.92 (2H, m); 3.56, 3.44 (IH each, ABq, 7=14.98 Hz); 3.40 (2H, t, 7=5.92 Hz); 2.70-2.64 (2H, m); 2.43 (3H, s); 1.34 (3H, s). Example 4

(5S)-5-({[4-(4-ChIoro-3-methylphenyl)-3,6-dihydropyridin-l(2H)-yl]sulfonyl}methyI)-

5-methylimidazolidine-2,4-dione

LC-MS (APCI) m/z 398 [MH⁺].

1H NMR DMSO-d₆: δ 10.75 (IH, s); 8.03 (IH, s); 7.45 (IH, d, 7=1.94 Hz); 7.38 (IH, d, 7=8.30 Hz); 7.29 (IH, dd, 7=8.30, 1.94 Hz); 6.22 (IH, bs); 3.87-3.83 (2H, m); 3.54, 3.40 (IH each, ABq, 7=15.11 Hz); 3.37 (2H, t, 7=6.23 Hz); 2.58-2.52 (2H, m); 2.34 (3H, s); 1.33 (3H, s).

Example 5 2-Methyl-4-[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyI)piperidin-

4-yl]benzonitrile

LC-MS (APCI) m/z 391 [MH⁺].

1H NMR DMSO-d₆: δ 10.74 (IH, s); 8.02 (IH, s); 7.69 (IH, d, 7=7.99 Hz); 7.39 (IH, s); 7.29 (IH, d, 7=8.11 Hz); 3.69-3.55 (2H, m); 3.52, 3.34 (IH each, ABq, 7=14.61 Hz); 2.93- 2.81 (2H, m); 2.74-2.63 (IH, m); 2.46 (3H, s); 1.87-1.79 (2H, m); 1.72-1.59 (2H, m); 1.34 (3H, s).

The starting material was prepared as follows: tert-Butyl 4-(4-cvano-3-methylphenyl)piperidine-l-carboxylate tert-Butyl 4-(4-cyano-3-methylphenyl)-3,6-dihydropyridine-l(2H)-carboxylate (171 mg, 0.57 mmol) was dissolved in EtOAc (10 ml), 10% Pd/C (10 mg) added and the mixture was hydrogenated at room temperature and 1 atm for 40 mins. The catalyst was filtered off and the solvent removed by rotary evaporation affording 171 mg (99%) of the title compound as a clear oil. LC-MS (APCI) m/z 201 [MΗ⁺].

Η NMR CDC1₃: δ 7.49 (IH, d, 7=7.99 Hz); 7.12 (IH, bs); 7.07 (IH, dd, 7=8.04, 1.71 Hz); 4.22 (2H, d, 7=11.67 Hz); 2.76 (2H, t, 7=12.14 Hz); 2.49 (3H, s); 1.77 (2H, d, 7=12.71 Hz); 1.65-1.48 (2H, m); 1.45 (9H, s).

Pharmacological Example Isolated Enzyme Assays

Recombinant human MMP 12 catalytic domain may be expressed and purified as described by Parkar A.A. et al, (2000), Protein Expression and Purification, 20:152. The purified enzyme can be used to monitor inhibitors of activity as follows: MMP 12 (50 ng/ml final concentration) is incubated for 60 minutes at room temperature with the synthetic substrate Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH₂ in assay buffer (0.1M "Tris-HCl" (trade mark) buffer, pH 7.3 containing 0.1M NaCl, 20mM CaCl₂, 0.020 mM ZnCl and 0.05% (w/v) "Brij 35" (trade mark) detergent) in the presence (5 concentrations) or absence of inhibitors. Activity is determined by measuring the fluorescence at λex 320nm and λem 405nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [Fluorescence^ inhibi_tor - uoτes,ccnce_backg_round] divided by the [Fluorescence_{m nM ϊ} inhibi_tor- ^^ τescence_background).

A protocol for testing against other matrix metalloproteinases, including MMP9, using expressed and purified pro MMP is described, for instance, by C. Graham Knight et al., (1992) FEBS Lett. 296(3):263-266. The following table shows the IC₅₀ figures (in nanomolar) for the compounds of the examples when tested against MMP 12 and MMP9.

Claims

C L A I M S

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof

wherein 1

R represents hydrogen, or a group selected from Cι-C6 alkyl and a saturated or unsaturated 3- to 10-membered ring system which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano,

2 3 4 5 carboxyl, -NR R , -CONR R , Cj -CO alkyl, CJ-CO alkoxy, -Cg alkylcarbonyl(oxy),

-S(O)_mCj-C6 alkyl where m is 0, 1 or 2, Ci-Cg alkylsulphonylamino,

Cj-Cg alkoxycarbonyl(amino), benzyloxy and a saturated or unsaturated 5- to 6- membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring in turn being optionally substituted with at least one substituent selected from halogen, hydroxyl, oxo, carboxyl, cyano, Cι-C6 alkyl,

Cj-Cg alkoxycarbonyl and Ci-Cβ hydroxyalkyl;

2 3 4 5

R , R , R and R each independently represent hydrogen or Cj-C6 alkyl optionally substituted by at least one substituent selected from hydroxyl, halogen and Ci-Cg alkoxy;

2 G represents a piperidine or a tetrahydropyridine ring; G represents a 5- or 6- membered aryl or heteroaryl monocyclic ring which may be optionally fused to a second ring to form a bicyclic ring system containing a total of 8- to

10-ring atoms, the monocyclic ring or fused bicyclic ring system being optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, nitro,

C_j-Cό alkyl (optionally substituted by one or more of cyano, halogen, hydroxyl and methoxy), C₂-C6 alkenyl, C\-C(, alkoxy (optionally substituted by one or more halogen atoms), -S(O)_nC]-C6 alkyl where n is 0, 1 or 2 (optionally substituted by one or more halogen atoms), Cj-Cό alkylcarbonyl(amino), Ci-Cβ alkylcarbonyloxy, phenyl, benzyloxy and

and fx 7

R and R each independently represent hydrogen or Ci-Cό alkyl optionally substituted by at least one substituent selected from hydroxyl, halogen and Ci-Cg alkoxy.

2. A compound according to claim 1 , wherein R represents hydrogen, or a group selected from C1-C4 alkyl and a saturated or unsaturated 5- to 10-membered ring system which may comprise one, two, three or four ring heteroatoms independently selected from nitrogen, oxygen and sulphur, each group being optionally substituted with one, two, three or four substituents independently selected from halogen, hydroxyl, cyano, carboxyl, -NR²R³, -CONR⁴R⁵, C1-C4 alkyl, C]-C₄ alkoxy, C1-C4 alkylcarbonyl(oxy), -S(O)_mCι-C4 alkyl where m is 0, 1 or 2, C1-C4 alkylsulphonylamino, C]-C4 alkoxycarbonyl(amino), benzyloxy and a saturated or unsaturated 5- to 6-membered ring which may comprise one, two, three or four ring heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring in turn being optionally substituted with one, two or three substituents independently selected from halogen, hydroxyl, oxo, carboxyl, cyano, C1-C4 alkyl, C1-C4 alkoxycarbonyl and Cι-C4 hydroxyalkyl.

3. A compound according to claim 1 or claim 2, wherein R represents hydrogen or C1-C4 alkyl.

2 4. A compound according to any one of claims 1 to 3, wherein G represents a tetrahydropyridine ring.

5. A compound according to any one of claims 1 to 4, wherein G represents a 5- or 6- membered aryl or heteroaryl monocyclic ring optionally substituted in a metα and/or para position.

6. A compound according to claim 5, wherein the meta substituent is selected from C!-C₃ alkyl and -CH₂CN.

7. A compound according to claim 5, wherein the para substituent is selected from Br, CI, -CN, -CF₃, -SCF₃ and -OCF₃.

8. A compound according to any one of claims 1 to 4, wherein, in G , the bicyclic ring system is selected from quinolinyl, isoquinolinyl, indolyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, naphthyl and dihydroindolyl.

9. A compound according to claim 1 which is selected from the group consisting of:

2-Methyl-4-[ 1 -( { [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl }sulfonyl)-l ,2,3,6- tetrahydropyridin-4-y]]benzonitrile,

(5S)-5-({ [4-(2,3-Dihydro-l-benzofuran-5-yl)-3,6-dihydropyridin-l(2H)- yl] sulfonyl } methyl)-5 -methylimidazolidine-2,4-dione, (5S)-5-Methyl-5-{[(4-methyl-3',6'-dihydro-2,4'-bipyridin-l'(2'H)- yl)sulfonyl]methyl}imidazolidine-2,4-dione,

(5S)-5-( { [4-(4-Chloro-3-methylphenyl)-3,6-dihydropyridin- 1 (2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione,

2-Methyl-4-[ 1 -( { [(4S)-4-methyl-2,5-dioxoimidazolidin-4- yl]methyl } sulfonyl)piperidin-4-yl]benzonitrile, and pharmaceutically acceptable salts and solvates thereof.

10. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as defined in claim 1 which comprises, (a) reacting a compound of formula

1 2 in which G and G are as defined in formula (I), with a compound of formula

wherein L represents a leaving group and R is as defined in formula (I); or

(b) reacting a compound of formula

1 1 2 wherein R , G and G are as defined in formula (I), with potassium cyanide and ammonium carbonate; and optionally after (a) or (b) forming a pharmaceutically acceptable salt or solvate.

11. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 9 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

12. A process for the preparation of a pharmaceutical composition as claimed in claim 11 which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as defined in any one of claims 1 to 9 with a pharmaceutically acceptable adjuvant, diluent or carrier.

13. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 9 for use in therapy.

14. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 9 in the manufacture of a medicament for use in the treatment of an obstructive airways disease.

15. Use according to claim 14, wherein the obstructive airways disease is asthma or chronic obstructive pulmonary disease.

16. A method of treating a disease or condition mediated by MMP 12 and/or MMP9 which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 9.

17. A method of treating an obstructive airways disease which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 9.