WO2008135537A1 - Tetrahydropyrrolopyrimidinediones and their use as human neutrophil elastase inhibitors - Google Patents

Abstract

Compounds of formula (I) and multimers therof are inhibitors of human neutrophil elastase activity, and of utility in the treatment of, e.g., COPD:(I) wherein A is aryl or heteroaryl; D is oxygen or sulphur; R1, R2 and R3 are independently each hydrogen, halogen, nitro, cyano, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, hydroxy or Cr1-C6-alkoxy or C2-C6-alkenyloxy, wherein C1-C6-alkyl and C1-C6-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and Cr1C4-alkoxy; R and R4 each independently represent a radical of formula -[X]m-[Alk1]p-[Q]n-[Alk2]q-[X1]k-Z wherein k, m, n, p and q are independently 0 or 1; AIk1 and AIk2 each independently represent an optionally substituted C1-C6 alkylene, or C2-C6 alkenylene radical which may optionally contain an ether (-O-), thioether (-S-) or amino (-NRA-) link wherein RA is hydrogen or C1-C3 alkyl; Q represents (i) -O-, -S-, -S(O)-, -S(O)2-, -S+(RA)-, -N(RA)-, -N+(RA)(RB)-, -C(O)-, -C(O)O-, -OC(O)-, -C(=O)NRA -, -NRAC(=O)-, -S(O2)NRA-, -NRAS(O2)-, -NRAC(=O)NRB-, -NRAC(=NRA)NRB-, -C(=NRD)NRE-, -NREC(=NRD)-, wherein RA, RB, RD and RE are independently hydrogen, d-C6 alkyl, or C3-C6 cycloalkyl, or RA and RB or RD and RE taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which my contain a further heteroatom selected from N, O and S, or (ii) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 3-6 ring members; X represents -(C=O)-, -S(O2)-, -C(O)O-, -(C=O)NRA-, or -S(O2)NRA-, wherein RA is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; X1 represents -O-, -S-, or -NH; and Z is hydrogen or an optionally substituted mono- or bicyclic carbocyclic or heterocyclic radical having 3-6 ring members.

Description

TETRAHYDROPYRROLOPYRIMIDINEDIONES AND THEIR USE AS HUMAN

NEUTROPHIL ELASTASE INHIBITORS Field of the Invention

This invention relates to heterocyclic compounds which are substituted 3,4,6,7-tetrahydro-1 H-pyrrolo[3,4-d]pyrimidine-2,5-diones, and their use in therapy. Background to the invention

Human neutrophil elastase (HNE) is a 32 kDa serine proteinase found in the azurophilic granules of neutrophils. It has a role in the degradation of a wide range of extracellular matrix proteins, including fibronectin, laminin, proteoglycans, Type III and Type IV collagens as well as elastin (Bieth, G. In Regulation of Matrix accumulation, Mecham, R. P. (Eds), Academic Press, NY, USA 1986, 217-306). HNE has long been considered to play an important role in homeostasis through repair and disposal of damaged tissues via degradation of the tissue structural proteins. It is also relevant in the defence against bacterial invasion by means of degradation of the bacterial body. In addition to its effects on matrix tissues, HNE has been implicated in the upregulation of IL-8 gene expression and also induces IL-8 release from the epithelial cells of the lung. In animal models of Chronic Obstructive Pulmonary Disease induced by tobacco smoke exposure both small molecule inhibitors and protein inhibitors of HNE inhibit the inflammatory response and the development of emphysema (Wright, J. L. et al. Am. J. Respir. Crit. Care Med. 2002, 166, 954-960; Churg, A. et al. Am. J. Respir. Crit. Care Med. 2003, 168, 199-207). Thus, HNE may play a role both in matrix destruction and in amplifying inflammatory responses in chronic respiratory diseases where neutrophil influx is a characteristic feature. Indeed, HNE is believed to play a role in several pulmonary diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), acute respiratory distress syndrome (ARDS), pulmonary emphysema, pneumonia and lung fibrosis. It is also implicated in several cardiovascular diseases in which tissue remodelling is involved, for example, in heart failure and the generation of ischaemic tissue injury following acute myocardial infarction. COPD is an umbrella term encompassing three different pathological conditions, all of which contribute to limitation of airflow: chronic bronchitis, emphysema and small-airway disease. Generally all three will exist to varying extents in patients presenting with COPD, and all three may be due to neutrophil-mediated inflammation, as supported by the increased number of neutrophils observed in bronchoalveolar leakage (BAL) fluids of COPD patients (Thompson, A. B.; Daughton, D.; et al. Am. Rev. Respir. Dis. 1989, 140, 1527-1537). The major pathogenic determinant in COPD has long been considered to be the protease-anti-protease balance (also known as the 'elastase:anti-elastase hypothesis'), in which an imbalance of HNE and endogenous antiproteases such as α1 -antitrypsin (α_rAT), Secretory leukocyte protease inhibitor (SLPI) and pre-elafin leads to the various inflammatory disorders of COPD. Individuals that have a genetic deficiency of the protease inhibitor u 1 -antitrypsin develop emphysema that increases in severity over time (Laurrell, C. B.; Erikkson, S Scand. J. Clin. Invest. 1963 15, 132-140). An excess of HNE is therefore destructive, leading to the breakdown of pulmonary morphology with loss of elasticity and destruction of alveolar attachments of airways in the lung (emphysema) whilst simultaneously increasing microvascular permeability and mucus hypersecretion (chronic bronchitis).

Multimeric ligands consist of multiple binding domains which are tethered together through a suitable scaffold. Hence individual binding domains are linked together into a single molecule, increasing the probability that the multimer will bind sequentially in a step-wise manner with multiple active sites resulting in high-affinity interactions (Handl, H. L. et al. Expert OpIn. Ther. Targets2004, 8, 565-586; Han, Y. F. et al., Bioorg. Med. Chem. Letts. 1999, 7, 2569-2575). Also, multiple binding interactions (either sequential or parallel) with relatively high off-rates can combine to yield an overall low off-rate for the multimeric ligand. Thus, a molecule consisting of a suitable linker and ligands may be expected to show advantage over the monomeric ligands alone in terms of potency and/or duration of action. Multimeric compounds are unlikely to be orally bioavailable (as predicted by Lipinski's "Rule of 5") which may be advantageous where an inhaled route of administration to the lungs is targeted, since even after inhaled administration, a large proportion of drug is likely to enter the Gl tract. Thus such compounds may be expected to show reduced systemic exposure after inhalation administration and hence an improved toxicity profile over orally administered therapies. Brief description of the invention

This invention provides novel compounds which are inhibitors of HNE, and are useful in the treatment of diseases or conditions in which HNE activity plays a part. The compounds of the invention may be used as monomers or, particularly in the case of topical pulmonary application by inhalation, in the form of multimers, such as dinners, covalently linked via a linker framework. Detailed Description of the Invention

In one embodiment, the invention provides a compound of formula (I),:

wherein

A is aryl or heteroaryl; D is oxygen or sulphur;

R¹ and R² are independently each hydrogen, halogen, nitro, cyano, C_rC₆-alkyl,

C₂-C₆-alkenyl, C₂-C₆-alkynyl, hydroxy or d-C₆-alkoxy or C₂-C₆-alkenyloxy, wherein CrC-₆-alkyl and C_rC₆-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and Ci-C₄- alkoxy;

R³ and R⁵ are independently each halogen, nitro, cyano, C_rC₆-alkyl, C₂-C₆- alkenyl, C₂-C₆-alkynyl, hydroxy or d-C₆-alkoxy or C₂-C₆-alkenyloxy, wherein Ci-C₆- alkyl and CrC₆-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and CrC₄- alkoxy;

R and R⁴ each independently represent a radical of formula -[X]_m-[Alk¹]_p-[Q]_n- [Alk²]_q-[X¹]_k-Z wherein k, m, n, p and q are independently 0 or 1 ;

AIk¹ and AIk² each independently represent an optionally substituted CrC₆ alkylene, or C₂-C₆ alkenylene radical which may optionally contain an ether (-O-), thioether (-S-) or amino (-NR^A-) link wherein R^A is hydrogen or d-C₃ alkyl;

Q represents (i) -O-, -S-, -S(=O)-, -S(=O)₂-, -S⁺(R^A)-, -N(R^A)-, -N⁺(R^A)(R^B)-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR^A -, -NR^AC(=O)-, -S(O₂)NR^A-, -NR^AS(O₂)-,

-NR^AC(=O)NR^B-, -NR^AC(=NR^A)NR^B-, -C(=NR^D)NR^E-, -NR^EC(=NR^D)-, wherein R^A, R^B,

R^D and R^E are independently hydrogen, CrC₆ alkyl, or C₃-C₆ cycloalkyl, or R^A and R^B> or R^D and R^E taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which my contain a further heteroatom selected from N, O and S, or (ii) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 3-6 ring members; X represents -(C=O)-, -S(O₂)-, -C(=0)0-, -(C=O)NR^A-, or -S(O₂)NR^A-, wherein

R^A is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

X¹ represents -O-, -S-, or -NH; and

Z is hydrogen or an optionally substituted mono- or bicyclic carbocyclic or heterocyclic radical having 3-6 ring members. The invention also includes a multimeric compound comprising two, three or four molecules of a compound of formula (I) above, covalently linked through a linker framework.

Compounds of formula (I) above and multimers thereof may be prepared in the form of salts, particularly pharmaceutically acceptable salts, N-oxides, hydrates and solvates thereof. Any claim to a compound herein, or reference to "compounds of the invention", compounds with which the invention is concerned", compounds of formula (I), and the like includes salts, N-oxides, hydrates and solvates of such compounds.

Compounds of the invention may be useful in the treatment or prevention of diseases in which HNE is implicated, for example chronic obstructive pulmonary disease (COPD), chronic bronchitis, lung fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), pulmonary emphysema, smoking-induced emphysema and cystic fibrosis.

Hence other aspects of the invention are (i) a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient; and (ii) the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which HNE is implicated. Terminology As used herein, the term "(C_a-C_b)alkyl" wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus when a is 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein the term "(C_a-C_b)alkenyl" wherein a and b are integers refers to a straight or branched chain alkenyl moiety having from a to b carbon atoms having at least one double bond of either E or Z stereochemistry where applicable. Thus when a is 2 and b is 6, for example, the term includes, for example, vinyl, allyl, 1- and 2- butenyl and 2-methyl-2-propenyl. As used herein the term "C_a-C_b alkynyl" wherein a and b are integers refers to straight chain or branched chain hydrocarbon groups having from a to b carbon atoms and having in addition one triple bond. Thus when a is 1 and b is 6, for example, the term includes for example, ethynyl (-C≡CH), 1 -propynyl, 1- and 2- butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

As used herein the term "divalent (C_a-C_b)alkylene radical" wherein a and b are integers refers to a saturated hydrocarbon chain having from a to b carbon atoms and two unsatisfied valences.

As used herein the term "divalent (C_a-C_b)alkenylene radical" wherein a and b are integers refers to a divalent hydrocarbon chain having from 2 to 6 carbon atoms, and at least one double bond.

As used herein the unqualified term "carbocyclic" refers to a mono-, bi- or tricyclic radical having up to 16 ring atoms, all of which are carbon, and includes aryl and cycloalkyl. As used herein the unqualified term "cycloalkyl" refers to a monocyclic saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein the unqualified term "aryl" refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical, and includes radicals having two monocyclic carbocyclic aromatic rings which are directly linked by a covalent bond. Illustrative of such radicals are phenyl, biphenyl and napthyl.

As used herein the unqualified term "heteroaryl" refers to a mono-, bi- or tricyclic aromatic radical containing one or more heteroatoms selected from S, N and O, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are directly linked by a covalent bond. Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.

As used herein the unqualified term "heterocyclyl" or "heterocyclic" or "heterocycloalkyl" includes "heteroaryl" as defined above, and in its non-aromatic meaning relates to a mono-, bi- or tri-cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical. Illustrative of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.

Unless otherwise specified in the context in which it occurs, the term "substituted" as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (CrC₆)alkyl, cycloalkyl, (C_rC₆)alkoxy, hydroxy, hydroxy(Ci-C₆)alkyl, mercapto, mercapto(Ci-C₆)alkyl, (d-C₆)alkylthio, phenyl, monocyclic heteroaryl having 5 or 6 ring atoms, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, -COOH, -COOR^A, -COR^A, -SO₂R^A, -CONH₂, -SO₂NH₂, -CONHR^A, -SO₂NHR^A, -CONR^AR^B, -SO₂NR^AR^B, -NH₂, -NHR^A, -NR^AR^B, -OCONH₂, -OCONHR^A , -OCONR^AR^B, -NHCOR^A, -NHCOOR^A, -NR^BCOOR^A, -NHSO₂OR^A, -NR⁸SO₂OH, -NR^BSO₂OR^A,-NHCONH₂, -NR^ONH₂₁ -NHCONHR⁶ -NR^ACONHR^B, -NHCONR^AR^B or -NR^ACONR^AR^B wherein R^A and R^B are independently a (CrC₆)alkyl, (C₃-C₆) cycloalkyl , phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, or R^A and R^B when attached to the same nitrogen atom form a cyclic amino ring, such as piperidinyl, morpholinyl or piperazinyl. An "optional substituent" may be one of the foregoing substituent groups.

As used herein the term "salt" includes base addition, acid addition and quaternary salts. Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D- glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like. Those compounds (I) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p- toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like. Those compounds (I) which have a basic nitrogen can also form quaternary ammonium salts with a pharmaceutically acceptable counter-ion such as chloride, bromide, acaetate, formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene-bis sulfonate, methanesulfonate, xinafoate, and the like. Compounds of the invention which contain one or more actual or potential chiral centres, because of the presence of asymmetric carbon atoms, can exist as a number of diastereoisomers with R or S stereochemistry at each chiral centre. The invention includes all such diastereoisomers and mixtures thereof.

In the monomeric compounds of the invention of formula (I), in any compatible combination:

The atom D may be O or S, but O is currently preferred. The ring A is aryl or heteroaryl and may be any of those rings listed above as examples of aryl or heteroaryl, especially phenyl and monocyclic heteroaryl having 5 or 6 ring atoms. Specific examples include pyridyl, such as 2- and 3-pyridyl, or pyrimidinyl such as pyrimidin-2-yl, but presently it is preferred that A be phenyl.

R¹ and R² may be selected from any of the substituent types for which they are defined in relation to formula (I), including hydrogen, halogen, nitro, cyano, Ci-C₃- alkyl, C₂-C₃-alkenyl, C₂-C₃-alkynyl, hydroxy or C_rC₃-alkoxy or C₂-C₃-alkenyloxy. Specific examples of such substitutuents include hydrogen, fluoro, chloro, bromo, cyano, methyl, methoxy and -C≡CH. For example, -AR¹R² may be 4-cyanophenyl or 4-ethynylphenyl.

R³ and R⁵ too may be selected from any of the substituent types for which they are defined in relation to formula (I), but in one currently preferred type of compound of the invention R⁵ and R³ are independently trifluoromethyl, fluoro, chloro or bromo. Preferred positions in the relevant phenyl ring for substitution by R⁵ and R³ are 3-, A-, and 5-.

Presently it is believed that the monomers of the invention can interact with HNE as inhibitors with the R or R⁴ substituent located remote from the binding interface, extending towards solvent. Hence those groups provide sites for modulation of solubility and other pharmacokinetic properties. Accordingly R and R⁴ may vary widely, and are defined in relation to formula (I) as a radical of formula -[X]_m- [Alk¹]_p-[Q]_n-[Alk²]_q-[X¹]_k-Z. According to that definition, k, m, n, p and q may all be 0, and Z may be hydrogen, so that R or R⁴ itself may be hydrogen. However, many other classes of R or R⁴ substituent are encompassed by selecting different combinations of values for the variables.

For example R or R⁴ may be selected from d-C₆-alkyl, formyl, aminocarbonyl, mono- or di-d-C-_f-alkylaminocarbonyl, C₃-C₈-cycloalkylcarbonyl, CrC₆-alkylcarbonyl, CrCβ-alkoxycarbonyl, N-(C_rC₄-alkylsulfonyl)-aminocarbonyl, N-(C_rC₄-alkylsulfonyl)- N-(CrC₄-alkyl)-aminocarbonyl, heteroaryl, heterocycloalkyl, heteroarylcarbonyl or heterocycloalkylcarbonyl; wherein CrC₆-alkyl, mono- and di-C_rC₄- alkylaminocarbonyl, Ci-C₆-alkylcarbonyl, d-Cβ-alkoxycarbonyl, heteroaryl and heterocycloalkyl can be substituted with one to three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxyl, C_rC₄-alkoxy, hydroxycarbonyl, CrCβ-alkoxycarbonyl, aminocarbonyl, mono and di-Ci-C₄- alkylaminocarbonyl, amino, mono- and di-Ci-C₄-alkylamino, C₁-C₄- alkylcarbonylamino, cyano, N-(mono- and di-Ci-C₄-alkylamino-Ci-C₄-alkyl)- aminocarbonyl, N-(Ci -C₄-alkoxy-Ci-C₄-alkyl)-aminocarbonyl and halogen.

In a particular subclass of compounds of the invention, R⁴ and/or R is radical of formula -[X]_m-[Alk¹]_p-[Q]_n-[Alk²]_q-[X¹]_k-Z wherein m is 0, and k, p, n and q are each 1 , Q is -N(R^A) or -N⁺(R^A)(R^B)-, and R^A, R^B AIk¹, AIk², X₁ and Z are as defined in relation to formula (I). In this subclass, X¹ may be, for example, -O-, and Z may be, for example optionally substituted phenyl or monocyclic hetroaryl, the latter having 5 or 6 ring atoms. In the compounds of the invention one of R and R⁴ may be hydrogen, while the other is a substitutent other than hydrogen

Other types of R and R⁴ groups have Formula (VINA), (VIIIB) or (VIIIC):

(VIIIA) (VIIIB) (VIIIC) wherein R ,₄A is hydrogen or CrC₆-alkyl, and s is 1 or 2. Further types of R and R⁴ groups have Formula (IX)

wherein

R^4B is hydrogen or C_rC₆-alkyl;

R^4C, R^4D, R^4E are each CrC₆-alkyl, and the nitrogen to which they are attached is quaternary and carries a positive charge; and additionally any two of R^4C, R^4D, R^4E may be joined to form a ring, optionally containing a second heteroatom selected from oxygen or nitrogen; or

One of R^4C, R^4D, R^4E is a lone pair and the other groups are as defined above, and the nitrogen to which they are attached is tertiary; and v1 and v2 are each independently 0-5. Other types of R and R⁴ groups are those selected from the following:

R^4B R^4G

^V1 D v2

wherein

R^4B is hydrogen or d-C₆-alkyl; R^4C, R^4D, R^4E are each CrC₆-alkyl, and the nitrogen to which they are attached is quaternary and carries a positive charge; and additionally any two of R^4C, R^4D, R^4E may be joined to form a ring, optionally containing a second heteroatom selected from oxygen or nitrogen; or one of R^4C, R^4D, R^4E is a lone pair and the other groups are as defined above, and the nitrogen to which they are attached is tertiary;

R^4Fand R⁴' are independently hydrogen or d-C₆-alkyl; R^4G and R^4H are independently hydrogen or CrC₆-alkyl, or R^4G and R^4H taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which my contain a further heteroatom selected from N, O and S; and v1 and v2 are each independently 0-5. In the multimeric compounds of the invention, two, three or four molecules of a monomeric compound of the invention are covalently linked through a linker framework. Since the linker framework need not play an active role in interacting with the HNE enzyme, its role is simply to allow binding contact between one or more of the monomeric elements and the enzyme. Hence a vast range of chemistries may be envisaged for the linker framework. Furthermore, the point of attachment of the monomeric elements to the linker framework may be selected according to the particular linker chemistry to be employed. Presently it is preferred that two, three or four of the monomeric molecules are linked to the linker framework via their respective nitrogen atoms shown in formula (I) as linked to R or R⁴. Furthermore, it is presently preferred that only two of the monomers are so linked. In the latter case, the linker framework may be, for example, the linker framework may be a divalent straight chain, saturated or unsaturated hydrocarbon radical having from 2 to 12 carbon atoms in the said chain, and wherein one or more carbons may be replaced by a divalent monocyclic or bicyclic carbocyclic or heterocyclic radical having from 3 to 7 ring atoms in the or each ring, or by -O-, -S-, -S(=O)-, -S(=O)₂-, -C(=O)-, -N(R^P)-, -N⁺(R^P)(R^Q)-, -C(=O)O-, -OC(=O)-, -C(=O)NR^A -, -NR^AC(=O)-, -S(O₂)NR^A-, -NR^AS(O₂)-, -NR^AC(=O)NR^B-, -NR^AC(=NR^A)NR^B-, -C(=NR^D)NR^E-, or -NR^EC(=NR^D)-, wherein R^A, R^B, R^D and R^E are independently hydrogen, C_rC₆ alkyl, or C₃-C₆ cycloalkyl, and R^p and R^Q are independently hydrogen, Ci-C₆ alkyl, or C₃-C₆ cycloalkyl, HO-(CrC₆ alkyl)-, R^AR^BN-(C_rC₆ alkyl)-, or HOC(=O)-(Ci-C₆ alkyl)-, or R^Aand R^B, or R^D and R^E, or R^p and R^Q taken together with the nitrogens to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which may contain a further heteroatom selected from N, O and S.

When one or more one or more -(CH₂)- groups of the linker framework is or are replaced by a divalent monocyclic or bicyclic carbocyclic or heterocyclic radical, the said radical may be selected from, for example, the following:

The linker framework may have, for example, one of the following structures (A), (B)₁(C), (D), (E), (G) and (E):

(CH₂)₂.₅-N(CH₃)-(CH₂)₂.₅- (A)

(CH₂)₂.₅-N⁺(CH₃)₂-(CH₂)₂._£ (B)

(CH₂)₂.₅ NH-(C=NH)-NH (CH₂)₂.₅ ^■ (C)

(D) (E) (CH₂)_1.2-CO-NH-(CH₂)_1.2-N(CH₃)-(CH₂)_1.2-NH-CO-(CH₂)₁.₂ (G)

(CH^^-CO-NH-tCH^^a-N^CH^CHaJ^-NH-CO-tCH_js),.^ (H)

Specific linker frameworks of the above type include those present in the dimer compounds of the examples herein.

Thus, one preferred subset of the multimers of the invention has the formula M-L-M¹ wherein L is a divalent linker radical, for example of the kinds discussed above as linker frameworks, and M and M¹ are each independently a radical of formula (IA) wherein D, A and R¹-R⁵ are as defined and discussed above:

Preferably also, M and M¹ are the same.

Another preferred subset of the multimers of the invention has the formula M- L-M¹ wherein L is a divalent linker radical for example of the kinds discussed above as linker frameworks, and M and M¹ are each independently a radical of formula (IB) wherein D, A and R, R¹, R², R³ and R⁵ are as defined and discussed above:

Here too, it is currently preferred that M and M¹ are the same. Specific examples of such dimeric compounds of formula (IA) and (IB) include those of the Examples herein.

The therapeutic utility of the present compounds is pertinent to any disease that is known to be at least partially mediated by the action of human neutrophil elastase. For example, the present compounds may be beneficial in the treatment of chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), acute respiratory distress syndrome (ARDS), pulmonary emphysema, pneumonia and lung fibrosis.

The present invention is also concerned with pharmaceutical formulations comprising, as an active ingredient, a compound of the invention. Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung. Thus the present invention is also concerned with pharmaceutical compositions for preventing and treating inflammatory diseases of the lung comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents. Suitable therapeutic agents for a combination therapy with compounds of the invention include: (1) a corticosteroid, for example fluticasone or budesonide; (2) a β2-adrenoreceptor agonist, for example salmeterol or formeterol; (3) a leukotriene modulator, for example montelukast or pranlukast; (4) anticholinergic agents, for example selective muscarinic-3 (M3) receptor antagonists such as tiotropium bromide; (5) phosphodiesterase-IV (PDE-IV) inhibitors, for example roflumilast or cilomilast; (6) an antitussive agent, such as codeine or dextramorphan; and (7) a non-steroidal anti-inflammatory agent (NSAID), for example ibuprofen or ketoprofen.

The weight ratio of the first and second active ingredients may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.

The magnitude of prophylactic or therapeutic dose of a compound of the invention will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration, and will generally be detrmined by clinical trial as required in the pharmaceutical art. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range will lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention. In therapeutic use, the active compound may be administered by any convenient, suitable or effective route. Suitable routes of administration are known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary. Delivery by inhalation is preferred.

Compositions suitable for administration by inhalation are known, and may include carriers and/or diluents that are known for use in such compositions. The composition may contain 0.01 -99% by weight of active compound. Preferably, a unit dose comprises the active compound in an amount of 1 μg to 10 mg.

The most suitable dosage level may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific amount for any particular patient will depend upon a variety of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment. For delivery by inhalation, the active compound is preferably in the form of microparticles. They may be prepared by a variety of techniques, including spray- drying, freeze-drying and micronisation. By way of example, a composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI). Propellants suitable for use in a PMDI are known to the skilled person, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCI2F2) and HFA-152 (CH4F2 and isobutane). In a preferred embodiment of the invention, a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI). Many types of DPI are known.

Microparticles for delivery by administration may be formulated with excipients that aid delivery and release. For example, in a dry powder formulation, microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung. Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 μm.

In the case of an aerosol-based formulation, a preferred composition is: Compound of the invention 24 mg / canister Lecithin, NF Liq. Cone. 1.2 mg / canister

Trichlorofluoromethane, NF 4.025 g / canister

Dichlorodifluoromethane, NF 12.15 g / canister.

Compounds of the invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which present compounds are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the invention. The agents of the invention may be administered in inhaled form. Aerosol generation can be carried out using, for example, pressure-driven jet atomizers or ultrasonic atomizers, preferably using propellant-driven metered aerosols or propellant-free administration of micronized active compounds from, for example, inhalation capsules or other "dry powder" delivery systems.

The active compounds may be dosed as described depending on the inhaler system used. In addition to the active compounds, the administration forms may additionally contain excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of systems are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is appropriate for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described EP-A-0505321). Methods of Synthesis

The compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilising the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

The compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above. The free acid or base form corresponding to isolated salts can be generated by neutralisation with a suitable base or acid such as sodium hydroxide, potassium carbonate, acetic acid and hydrochloric acid and extraction of the liberated free acid or base into an organic solvent followed by evaporation. The free form isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent followed by addition of the appropriate acid or base and subsequent evaporation, precipitation, or crystallisation.

It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to avoid their unwanted participation in a reaction leading to the formation of the compounds. Conventional protecting groups, for example those described by T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry" John Wiley and Sons, 1999, may be used.

Compounds of the invention may be prepared according to the routes illustrated in Schemes 1 , 2 and 3. The linker group, R and R' may be modified after dimerisation.

RNH₂

RNH₂ base base

H₂N-hnker-NH₂ H₂N-lιnker-NH₂ base base

Scheme 1

X = leaving group e g Br

Y = spacer eg (CH₂)_n

G = reactive group e g CO₂H

X-Y-lιnker-Y-X

X-Y-G NaH, DMF NaH, DMF

Bifunctional linker molecule

bromination bromination

RNH₂ RNH₂ base base

Bifunctional

linker molecule

Scheme 2

bromination

bromination R¹NH₂ base

Scheme 3

General Experimental Details

All solvents and commercial reagents were used as received. Where products were purified using an Isolute® SPE Si Il cartridge, 'Isolute SPE Si cartridge' refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles with average size of 50 μm and nominal 6θA porosity. 'CombiFlash® companion' refers to an automated flash silica chromatography system which uses pre-packed polypropylene (RediSep®) columns containing silica with average particle size 35-70 μm (230-400 mesh). HPLC conditions: HPLC system 1 :

C18-reverse-phase end-capped column (250 x 21.2 mm Gemini column with 5 μm particle size), eluting with a gradient of A: water; B: acetonitrile with a flow rate typically 17 ml/min and gradient of 1 %/min increasing in B. UV detection at 254 nm. LC-MS method 1 :

Waters Platform LC quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with a C18 reverse-phase column (30 x 4.6 mm Phenomenex Luna with 3μm particle size), elution with A: water + 0.1 % formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:

Gradient - Time flow ml/min %A %B

0.00 2.0 95 5

0.50 2.0 95 5

4.50 2.0 5 95

5.50 2.0 5 95

6.00 2.0 95 5

LC-MS method 2:

Waters Micromass ZQ2000 linked to a Hewlett Packard HP1100 LC system with a C18-reverse-phase column (100 x 3.0 mm Higgins Clipeus with 5 μm particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:

Gradient - Time flow ml/mm %A %B

0.00 1.0 95 5

1.00 1.0 95 5

15.00 1.0 5 95

20.00 1.0 5 95

22.00 1.0 95 5

25.00 1.0 95 5

Detection - MS, ELS, UV (100 μl split to MS with in-line UV detector) MS ionisation method - Electrospray (positive ion)

NMR Spectrometers

NMRs were run on either a Varian Unity Inova 400 MHz spectrometer or a

Bruker Avance DRX 400 MHz spectrometer. Abbreviations used in the experimental section:

DCM = dichloromethane

DIPEA = N,N-Diisopropylethyamine

HPLC = high performance liquid chromatography

RT = room temperature Rt = retention time

TFA = trifluoroacetic acid

THF = tetrahydrofuran

Intermediate 1

A mixture of (4-fluoro-3-trifluoromethylphenyl)urea (WO2008/003412) (2.5 g,

1 1.26 mmol), 4-cyanobenzaldehyde (1.77 g, 13.51 mmol), methyl acetoacetate (1.57 g, 13.51 mmol) and polyphosphoric acid (6.5 g) in THF (45 ml) was heated at reflux under argon for 2Oh. The bulk of the solvent was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was washed with water, aqueous potassium carbonate, water, and brine, dried (Na₂SO₄) and evaporated. The crude material was purified using a CombiFlash® companion (33Og cartridge) to yield the desired product as a pale yellow solid. Yield: 3.03 g, 62% LC-MS (Method 1 ): Rt = 3.64 min, m/z = 434 [M+H]⁺ Intermediate 2

A solution of bromine (0.23 ml, 4.5 mmol) in chloroform (2 ml) was added dropwise to a solution of Intermediate 1 (1.86 g, 4.29 mmol) in chloroform (35 ml) at RT with stirring. After 1.5h, the volatiles were removed under reduced pressure and the residue triturated with diethyl ether to give the product as a white solid. Yield: 1.91 g, 87% LC-MS (Method 1): Rt = 3.76 min, m/z = 512/514 [M+H]⁺

Intermediate 3

Intermediate 3 was prepared from (3-fluoro-5-trifluoromethylphenyl)urea (WO2008/003412), methyl acetoacetate and 4-cyanobenzaldehyde using a method similar to that used for Intermediate 1. Yield: 1.5O g, 51%

LC-MS (Method 1): Rt = 3.68 min, m/z = 434 [M+H]⁺ Intermediate 4

Intermediate 4 was prepared from Intermediate 3 in an analogous manner as Intermediate 2.

Yield: 0.73 g, 77%

LC-MS (Method 1): Rt = 3.78 min, m/z = 512/514 [M+H]⁺

Intermediate 5

t-Butyl bromoacetate (1.42 g, 7.30 mmol) was added to a solution of Example 3 (0.46 g, 0.487 mmol) in acetonitrile (15 ml) followed by DIPEA (0.94 g, 7.30 mmol) at RT. The reaction mixture was stirred at 5O⁰C for 17h. The volatiles were removed under reduced pressure and the residue triturated with diethyl ether (30 ml). The solid was collected by filtration under suction and then partitioned between water and DCM. The organic layer was separated, dried (Na₂SO₄) and evaporated. The crude product was purified on an Isolute® SPE Si Il cartridge (10 g) eluting with DCM, 10% MeOH in DCM and then 15% MeOH in DCM. Product containing fractions were combined and the solvent removed under reduced pressure to give the desired product as a cream coloured solid. Yield: 0.35 g, 63%

LC-MS (Method 1): Rt = 2.89 min, m/z = 1058 [M]⁺ Example 1

A solution of Intermediate 2 (0.45 g, 0.88 mmol) in anhydrous THF (10 ml) was added dropwise to a solution of N-(3-aminopropyl)-1 ,3-propanediamine (0.115 g, 0.88 mmol) and triethylamine (0.356 g, 3.52 mmol) in anhydrous THF (5 ml) at room temperature with stirring. After 2h, the volatiles were removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried (Na₂SO₄) and evaporated. The crude product was purified on an Isolute® SPE Si Il cartridge (5 g) eluting with DCM, 10% MeOH in DCM and then 18% MeOH in DCM. Pure fractions were combined and the solvent removed under reduced pressure. The residue was dissolved in 1 :1 MeCN/H₂O (10 ml) and then freeze-dried to give the desired product as a white solid. Yield: 0.122 g, 30%.

LC-MS (Method 2): Rt = 8.09 min, m/z = 930 [M+H]⁺ Example 2

Example 2 was prepared from Intermediate 4 using a similar procedure to that used in the synthesis of Example 1. Yield: 0.151 g, 28%

LC-MS (Method 2): Rt = 8.15 min, m/z = 930 [M+H]⁺ Example 3

Example 3 was prepared from Intermediate 2 (1.50 g, 2.93 mmol) and 3,3'- diamino-N-methyldipropylamine (0.319 g, 2.20 mmol), using a similar procedure to that employed in the synthesis of Example 1. Yield: 1.25 g, 90% LC-MS (Method 2): Rt = 8.15 min, m/z = 944 [M+H]⁺ Example 4

TFA (5 ml) was added to a solution of Intermediate 5 (0.34 g, 0.30 mmol) in DCM (8 ml) at RT with stirring. After 2Oh the volatiles were evaporated. The residue was partitioned between sat. aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer washed with brine, dried (Na₂SO₄) and evaporated. The crude material was purified by HPLC (System 1 ) and after freeze-dry, the desired product was obtained as a white solid. Yield: 155 mg, 55%

LC-MS (Method 2): Rt = 9.14 min, m/z = 1002 [M+H]⁺ Example 5

A solution of 2-phenylethylamine (52 mg, 0.43 mmol) and triethylamine (87 mg, 0.86 mmol) in anhydrous THF (3 ml) was added to a solution of Intermediate 2 (200 mg, 0.39 mmol) in anhydrous THF (5 ml) at room temperature with stirring. After 20 h, the volatiles were removed under reduced pressure and the residue partitioned between 1 N aqueous HCI and ethyl acetate. The organic layer was separated, washed with water, brine, dried (Na₂SO₄) and evaporated. The crude product was purified on an Isolute® SPE Si Il cartridge (5 g) eluting with DCM, 20% EtOAc in DCM and 5% MeOH in DCM. Pure fractions were combined and the solvent removed under reduced pressure to give the desired product as a white solid. Yield: 197 mg, 97%.

LC-MS (Method 2): Rt = 11.02 min, m/z = 521 [M+H]⁺

Example 6

By analogy to the procedure of Example 8 of WO2007/129060, and using Intermediate 20 therein as precursor, the above compound was prepared; yield 59%; LC-MS 7.36 (Method 3 in that WO publication); mass 844.51 . Example 7

By analogy to the procedure of Example 32 of WO2007/129060, and using the compound of Example 6 as precursor, the above compound was prepared; yield 69%; LC-MS 7.30 (Method 3 in that WO publication); mass 858.37. Biological Assays

Compounds of the invention were tested for their HNE inhibitory activity. Fluorescent peptide substrate Assays were performed in 96-well plates at a total assay volume of 10Oμl. The final concentration of the enzyme (human leukocyte elastase, Sigma E8140) was 0.00036 units/well. A peptide substrate (MeO-Suc-Ala-Ala-Pro-ValAMC, Calbiochem #324745) was used, at the final concentration of 100μM. The final concentration of DMSO was 1 % in the assay buffer (0.05M Tris.HCI, pH 7.5, 0.1 M NaCI; 0.1 M CaCI2; 0.0005% brij-35). The enzymatic reaction was started by adding the enzyme. The enzymatic reaction was performed at RT and after 30mins stopped by adding 50μl soybean trypsin inhibitor (Sigma T-9003) at a final concentration of 50μg/well. Fluorescence was read on the FLEXstation (Molecular Devices) using 380 nm excitation and 460 nm emission filters. The potency of the compounds was determined from a concentration series of 10 concentrations in range from 1000 nM to 0.051 nM. The results are means of two independent experiments, each performed in duplicate. Using Fluorescently labelled elastin

Assays were performed in 96-well plate at a total assay volume of 10Oμl. The final concentration of the enzyme (human leukocyte elastase, Sigma E8140) was 0.002 units/well. Fluorescently labelled, solubilised elastin from bovine neck ligament (Molecular Probes, E-12056) was used at the final concentration of 15 μg/ml. The final concentration of DMSO was 2.5% in the assay buffer (0.1 M Tris-HCL,pH8.0, containing 0.2mM sodium azide). The enzymatic reaction was started by adding the enzyme. The enzymatic reaction was performed at RT and read after 120 minutes. Fluorescence was read on the FLEXstation (Molecular Devices) using 485 nm excitation and 530 nm emission filters. The potency of the compounds was determined from a concentration series of 10 concentrations in range from 2500OnM to 1 nM. The results are means of two independent experiments, each performed in duplicate.

The IC50s of the compounds of the Examples herein in the above assay were each less than 10OnM.

Claims

1. A compound of formula (I):

wherein

A is aryl or heteroaryl;

D is oxygen or sulphur;

R¹ and R² are independently each hydrogen, halogen, nitro, cyano, C_rC₆-alkyl,

C₂-C₆-alkenyl, C₂-C₆-alkynyl, hydroxy or Ci-C₆-alkoxy or C₂-C₆-alkenyloxy, wherein CrC₆-alkyl and C_rC₆-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and d-C₄- alkoxy;

R³ and R⁵ are independently each halogen, nitro, cyano, Cι-C₆-alkyl, C₂-C₆- alkenyl, C₂-C₆-alkynyl, hydroxy or CrC₆-alkoxy or C₂-C₆-alkenyloxy, wherein CrC₆- alkyl and Ci-C6-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and CrC₄- alkoxy;

R and R⁴ each independently represent a radical of formula -[X]_m-[Alk¹]_p-[Q]_n- [Alk²]_q-[X¹]_k-Z wherein k, m, n, p and q are independently 0 or 1 ;

AIk¹ and AIk² each independently represent an optionally substituted Ci-C₆ alkylene, or C₂-C₆ alkenylene radical which may optionally contain an ether (-O-), thioether (-S-) or amino (-NR^A-) link wherein R^A is hydrogen or CrC₃ alkyl;

Q represents (i) -O-, -S-, -S(=O)-, -S(=O)₂-, -S⁺(R^A)-, -N(R^A)-, -N⁺(R^A)(R^B)-, - C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR^A -, -NR^AC(=O)-, -S(O₂)NR^A-, -NR^AS(O₂)-, -NR^AC(=O)NR^B-, -NR^AC(=NR^A)NR^B-, -C(=NR^D)NR^E-, -NR^EC(=NR^D)-, wherein R^A, R^B, R^D and R^E are independently hydrogen, C_rC₆ alkyl, or C₃-C₆ cycloalkyl, or R^A and R^B' or R^D and R^E taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which my contain a further heteroatom selected from N, O and S, or (ii) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 3-6 ring members; X represents -(C=O)-, -S(O₂)-, -C(=O)O-, -(C=O)NR^A-, or -S(O₂)NR^A-, wherein

R^A is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

X¹ represents -O-, -S-, or -NH; and

Z is hydrogen or an optionally substituted mono- or bicyclic carbocyclic or heterocyclic radical having 3-6 ring members.

2. A compound as claimed in claim 1 wherein R¹ and R² are independently each hydrogen, halogen, nitro, cyano, C|-C₃-alkyl, C₂-C₃-alkenyl, C₂-C₃-alkynyl, hydroxy, Ci-C₃-alkoxy or C₂-C₃-alkenyloxy, and R³ and R⁵ are independently each halogen, nitro, cyano, C_rC₃-alkyl, C₂-C₃-alkenyl, C₂-C₃-alkynyl, hydroxyl, d-C₃-alkoxy or C₂-C₃-alkenyloxy

3. A compound as claimed in claim 1 wherein R¹ and R² are independently each hydrogen, fluoro, chloro, bromo, cyano, methyl, methoxy or -C≡CH, and R³ and R⁵ are each halogen, nitro, cyano, C_rC₃-alkyl, C₂-C₃-alkenyl, C₂-C₃-alkynyl, hydroxyl, d- C₃-alkoxy or C₂-C₃-alkenyloxy.

4. A compound as claimed in any of the preceding claims wherein A is phenyl, pyridyl, or pyrimidinyl.

5. A compound as claimed in any of the preceding claims wherein one of R¹ and R² is methyl, -C≡CH or cyano.

6. A compound as claimed in claim 1 wherein -AR¹R² is 4-cyanophenyl or 4- ethynylphenyl.

7. A compound as claimed in any of the preceding claims wherein D is O.

8. A compound as claimed in any of the preceding claims wherein R⁵ and R³ are each independently trifluoromethyl, fluoro, chloro or bromo.

9. A compound as claimed in any of the preceding claims wherein R⁴ and/or R is radical of formula -[X]m-[Alk¹]_p-[Q]_n-[Alk²]_q-[X¹]_k-Z wherein m is O, k, p, n and q are each 1 , Q is -N(R^A) or -N⁺(R^A)(R^B)-, and R^A, R^B AIk¹, AIk², X¹ and Z are as defined in claim 1.

10. A compound as claimed in claim 9 wherein X¹ is -O-.

11. A compound as claimed in claim 9 or claim 10 wherein Z is optionally substituted phenyl or monocyclic heteroaryl, the latter having 5 or 6 ring atoms.

12. A compound as claimed in any of claims 9 to 11 wherein one of R and R⁴ is hydrogen.

13. A compound as claimed in any of claims 1 to 8 wherein R or R⁴ is selected from d-C-₆-alkyl, formyl, aminocarbonyl, mono- or di-Ci-d-alkylaminocarbonyl,

C₃-C₈-cycloalkylcarbonyl, Ci-C_θ-alkylcarbonyl, d-Cβ-alkoxycarbonyl, N-(CrC₄- aikylsulfonyl)-aminocarbonyl, N-(Ci-C₄-alkylsulfonyl)-N-(CrC₄-alkyl)-aminocarbonyl, heteroaryl, heterocycloalkyl, heteroarylcarbonyl or heterocycloalkylcarbonyl; wherein d-C-6-alkyl, mono- and di-d-d-alkylaminocarbonyl, d-C₆-alkylcarbonyl, d-C₆- alkoxycarbonyl, heteroaryl and heterocycloalkyl can be substituted with one to three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxyl, d-C₄-alkoxy, hydroxycarbonyl, d-C₆-alkoxycarbonyl, aminocarbonyl, mono and di-Ci-C₄-alkylaminocarbonyl, amino, mono- and di-Ci-C₄-alkylamino, Ci-C₄- alkylcarbonylamino, cyano, N-(mono- and di-Ci-C₄-alkylamino-CrC₄-alkyl)- aminocarbonyl, N-(Ci-C₄-alkoxy-CrC₄-alkyl)-aminocarbonyl and halogen.

14. A compound as claimed in any of claims 1 to 8 wherein R and/or R⁴ represents a group of Formula (VIIIA), (VIIIB) or (VIIIC):

(VlIlA) (VIIIB) (ViIIC)

wherein R^4A is hydrogen or d-C₆-alkyl, and s is 1 or 2;

15. A compound as claimed in any of claims 1 to 8 wherein R and/or R⁴ represents a group of Formula (IX)

wherein

R^4B is hydrogen or d-C₆-alkyl; R^4C, R^4D, R^4E are each CrC₆-alkyl, and the nitrogen to which they are attached is quaternary and carries a positive charge; and additionally any two of R^4C, R^4D, R^4E may be joined to form a ring, optionally containing a second heteroatom selected from oxygen or nitrogen; or one of R^4C, R^4D, R^4E is a lone pair and the other groups are as defined above, and the nitrogen to which they are attached is tertiary; and v1 and v2 are each independently 0-5.

16. A compound as claimed in any of claims 1 to 8 wherein R and/or R⁴ represents a group selected from the following:

_R4B _R4G

^V1 O v2

wherein

R^4B is hydrogen or CrC₆-alkyl; R^4C, R^4D, R^4E are each Ci-C₆-alkyl, and the nitrogen to which they are attached is quaternary and carries a positive charge; and additionally any two of R^4C, R^4D, R^4E may be joined to form a ring, optionally containing a second heteroatom selected from oxygen or nitrogen; or one of R^4C, R^4D, R^4E is a lone pair and the other groups are as defined above, and the nitrogen to which they are attached is tertiary; R^4Fand R⁴' are independently hydrogen or Ci-C₆-alkyl;

R⁴⁰ and R^4H are independently hydrogen or Ci-C₆-alkyl, or R^4G and R^4H taken together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which my contain a further heteroatom selected from N, O and S; and v1 and v2 are each independently 0-5.

17. A compound as claimed in any of claims 13 to 16 wherein R or R⁴, but not both, is hydrogen.

18. A compound as claimed in any of claims 13 to 16 wherein R or R⁴, but not both, is selected from C_rC₆-alkyl, formyl, aminocarbonyl, mono- or di-C_rC₄- alkylaminocarbonyl, C₃-C₈-cycloalkylcarbonyl, CrCβ-alkylcarbonyl, C₁-C₆- alkoxycarbonyl, N-(Ci-C₄-alkylsulfonyl)-aminocarbonyl, N-(Ci-C₄-alkylsulfonyl)-N-(Ci- C₄-alkyl)-aminocarbonyl, heteroaryl, heterocycloalkyl, heteroarylcarbonyl or heterocycloalkylcarbonyl; wherein CrC₆-alkyl, mono- and di-C_rC₄- alkylaminocarbonyl, d-Ce-alkylcarbonyl, CrC₆-alkoxycarbonyl, heteroaryl and heterocycloalkyl can be substituted with one to three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxyl, C_rC₄-alkoxy, hydroxycarbonyl, CrC₆-alkoxycarbonyl, aminocarbonyl, mono and di-Ci-C₄- alkylaminocarbonyl, amino, mono- and di-CrC₄-alkylamino, C₁-C₄- alkylcarbonylamino, cyano, N-(mono- and di-Ci-C₄-alkylamino-C_rC₄-alkyl)- aminocarbonyl, N-(CrC₄-alkoxy-C_rC₄-alkyl)-aminocarbonyi and halogen.

19 A multimeric compound comprising two, three or four molecules of a compound as claimed in any of claims 1 to 16, covalently linked through a linker framework.

20. A multimeric compound as claimed in claim 19 wherein two, three or four molecules of a compound as claimed in claim any of claims 1 to 16 are linked to the linker framework via their respective nitrogen atoms shown in formula (I) as linked to R.

21. A multimeric compound having the formula M-L-M¹ wherein L is a divalent linker radical and M and M¹ are each independently a radical of formula (IA) wherein D, A and R¹-R⁵ are as defined in any of claims 1 to 18:

22. A multimeric compound as claimed in claim 19 wherein two, three or four molecules as claimed in claim 7 are linked to the linker framework via their respective nitrogen atoms shown in formula (I) as linked to R⁴.

23. A multimeric compound having the formula M-L-M¹ wherein L is a divalent linker radical and M and M¹ are each independently a radical of formula (IB) wherein D, A and R, R¹, R², R³ and R⁵ are as defined in any of claims 1 to 18:

24. A compound as claimed in 21 or claim 23 wherein M and M¹ are the same.

25. A compound as claimed in claims 21 , claim 23 or claim 24 wherein the linker framework or linker radical L is a divalent straight chain, saturated or unsaturated hydrocarbon radical having from 2 to 12 carbon atoms in the said chain, and wherein one or more carbons may be replaced by a divalent monocyclic or bicyclic carbocyclic or heterocyclic radical having from 3 to 7 ring atoms in the or each ring, or by -O-, -S-, -S(=O)-, -S(=O)₂-, -C(=O)-, -N(R^P)-, -N⁺(R^P)(R^Q)-, -C(=O)O-, -OC(=O)-, -C(=O)NR^A -, -NR^AC(=O)-, -S(O₂)NR^A-, -NR^AS(O₂)-, -NR^AC(=O)NR^B-, -NR^AC(=NR^A)NR^B-, -C(=NR^D)NR^E-, or -NR^EC(=NR^D)-, wherein R^A, R^B, R^D and R^E are independently hydrogen, d-C₆ alkyl, or C₃-C₆ cycloalkyl, and R^p and R^Q are independently hydrogen, C_rC₆ alkyl, or C₃-C₆ cycloalkyl, HO-(C₁-C₆ alkyl)-, R^AR^BN-(C_rC₆ alkyl)-, or HOC(=O)-(Ci-C₆ alkyl)-, or R^Aand R^B, or R^D and R^E, or R^p and R^Q taken together with the nitrogens to which they are attached form a monocyclic heterocyclic ring of 5 to 7 ring atoms which may contain a further heteroatom selected from N, O and S.

26. A compound as claimed in claim 25 wherein when one or more one or more -(CH₂)- groups of the linker framework or linker radical L is or are replaced by a divalent monocyclic or bicyclic carbocyclic or heterocyclic radical, the said radical is selected from the following:

27. A compound as claimed in claim 25 wherein the linker framework or linker radical L has one of the following structures (A), (B)₁(C), (D) and (E):

(CH₂)₂.₅-N(CH₃)-(CH₂)_2.5- (A)

(CH₂)_2.5-N⁺(CH₃)₂-(CH₂)_2.5 (B)

(CH₂)₂.₅ NH-(C=NH)-NH (CH₂)₂.₅ ^■ (C)

(D) (E)

28. A compound as claimed in claim 25 wherein the linker framework or linker radical L has one of the following structures (G) and (E):

(CH₂)₁.₂-CO-NH-(CH₂)₁.₂-N(CH₃)-(CH₂)₁.₂-NH-CO-(CH₂)₁.₂ (G) (CH₂),.₂-CO-NH-(CH₂),.₂-H-(CH₃)₂-(CH₂),.₂-m-CO-(CH₂),.₂— (H) 29. A compound as claimed in claim 1 having any of the following structures

30. A compound as claimed in claim 1 having any of the following structures

31. A compound as claimed in any preceding claim, in pharmaceutically acceptable form.

32. A compound as claimed in any preceding claim, for use in therapy.

33. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 31 and a pharmaceutically acceptable carrier or excipient.

34. Use of a compound as claimed in any of claims 1 to 31 , for the manufacture of a medicament for use in the treatment of prevention of a disease or condition in which HNE is implicated.

35. A method of treatment of a disease or condition in which HNE is implicated, comprising administering to a subject suffering such disease an effective amount of a compound as claimed in any of claims 1 to 31.

36. Use according to claim 34, or a method of treatment according to claim 35, wherein the disease or condition is chronic obstructive pulmonary disease (COPD), chronic bronchitis, lung fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), pulmonary emphysema, smoking-induced emphysema or cystic fibrosis.

37. Use according to claim 34, or a method of treatment according to claim 35, wherein the disease or condition is asthma, rhinitis, psoriasis, dermatitis, (atopic and non-atopic), Crohn's disease, ulcerative colitis, or irritable bowel disease.