WO2013010573A1

WO2013010573A1 - Compounds with matrix-metalloproteinase inhibitory activity

Info

Publication number: WO2013010573A1
Application number: PCT/EP2011/062211
Authority: WO
Inventors: Guenter Haufe; Klaus Kopka; Stefan Wagner; Verena Hugenberg; Sven Hermann; Michael Schaefers; Hartmuth Kolb
Original assignee: Universitaet Muenster; Siemens Medical Solutions Usa, Inc.
Priority date: 2011-07-18
Filing date: 2011-07-18
Publication date: 2013-01-24

Abstract

The present invention relates to the field of therapeutic and diagnostic agents and more specifically to compounds of formula (I) that are inhibitors of matrix-metalloproteinases (MMPs) and are useful in the treatment of diseases related thereto such as cardiovascular diseases, inflammatory diseases and malignant diseases. One embodiment of the invention is a compound of formula (I) labeled with a 18-fluorine atom having matrix metalloproteinase inhibitory activity suitable for diagnostic imaging. Also disclosed in the present invention is a pharmaceutical composition comprising the inhibitors of matrix-metalloproteinases (MMPs) of the invention or the corresponding labeled compounds useful as diagnostic imaging agents of the invention in a form suitable for mammalian administration. The invention furthermore discloses intermediates in the synthesis of the inhibitors of matrix-metalloproteinases (MMPs) of the invention and of the diagnostic imaging agents of the invention.

Description

Compounds with matrix-metalloproteinase inhibitory activity

Technical Field of the Invention

The present invention relates to the field of pharmaceutical and diagnostic agents and more specifically to compounds that are inhibitors of matrix metalloproteinases (MMPs) and are useful in the treatment of diseases related thereto such as cardiovascular diseases, inflammatory diseases and malignant diseases. The compounds are useful for the field of in vivo diagnostic imaging and in particular in Positiron Emission Tomography (PET) imaging, as well.

Description of Related Art

The matrix metalloproteinases (MMPs) are a family of at least 20 zinc-dependent endo- peptidases which mediate degradation or remodeling of the extracellular matrix (ECM) [Massova et al., FASEB J 12 1075-95 (1998)]. Together, the members of the MMP family can degrade all of the components of the blood vessel wall and therefore play a major role in both physiological and pathological events that involve the degradation of components of the ECM. Since the MMPs can interfere with the cell-matrix interactions, that control cell behavior, their activity affects processes as diverse as cellular differentiation, migration, proliferation and apoptosis [Nagase and Woessner, J Biol Chem 274 21491-4 (1999)]. The negative regulatory controls that finely regulate MMP-activity in physiological situations do not always function as they should. Inappropriate expression of MMP-activity is thought to constitute part of the pathological mechanism in several disease states. MMPs are therefore targets for therapeutic inhibitors in many inflammatory, malignant and degenerative diseases [Whittaker et al., Chem Rev 99 2735-76 (1999)].

Consequently, it is believed that synthetic inhibitors of MMPs may be useful in the treatment of many inflammatory, malignant and degenerative diseases. Furthermore, it has been suggested that inhibitors of MMPs may be useful in the diagnosis of these diseases. WO 01/60416 discloses compounds which are proposed to be useful in the diagnosis of cardiovascular pathologies associated-with-extracellular matrix degradation such as atherosclerosis, heart failure and restenosis. The compounds disclosed therein comprise MMP inhibitors linked, via an optional linker, to a chelator capable of conjugating to a diagnostic metal. Preferred MMP inhibitors, chelators and linkers are described therein. A report by Zheng et al. [Nucl Med Biol 29 761-770 (2002)] documented the synthesis of MMP inhibitors labeled with the positron emission tomography (PET) tracers ¹¹C and ¹⁸F. These compounds described therein are postulated to be useful in the non-invasive imaging of breast cancer.

Summary of the Invention

Novel compounds of the invention having very potent MMP inhibitory activity, in particular against MMP-2, -8-, -9 and -13 are disclosed which possess high potency and fine-tuned hydrophilicity (fine-tuned) lipophilicity properties. Lipophilicity is an important parameter for any pharmaceutical and for any in vivo diagnostic agent as well, as a high lipophilicity can increase a generic non-specific binding of the drug to macromolecules resulting in a poor binding to the target tissue and at the same time in a poor system elimination. Indeed, this aspect is of even more relevance in case of diagnostic imaging that aims at a selective and at the same time specific accumulation of the diagnostic compound within the target tissue in combination with a fast elimination from non-target tissues which results in a very sensitive detection of the diagnostic compound and in a high signal to noise ratio (S/N). The compounds of the present invention achieve a good balance between the MMP inhibition potency and lipophilicity which render them particularly useful in the prevention, treatment and diagnostic imaging of diseases associated with a dysregulated MMP-activity.

The mentioned properties achieved by the compounds of the invention are in particular notable with respect to the lead compound FEtO CGS 25966 and CGS 27023A. Without being bound to any theory, it has been hypothesized that the introduction of a triazole group in the molecules of the present invention improves the inhibition potency and increases the hydrophilicity resulting in a fine-tuned balance between both parameters. The present properties are achieved by substituting the phenyl moiety of lead compound CGS 25966 or the pyridine moiety of lead compound CGS 27023A with a triazole ring. Additionally, it has been surprisingly observed that the above disclosed effects are maintained even if the triazole moiety is relatively "distant" from the "core" of the lead structure FEtO CGS 25966 .

Another aspect of the present invention relates to pharmaceutical compositions, useful in the prevention, treatment and diagnostic imaging of diseases associated with a dysregulated MMP-activity. The compounds of the present invention are useful for the prevention, the treatment and the in vivo diagnostic imaging of a range of disease states (inflammatory, malignant and degenerative diseases) where specific matrix metalloproteinases are known to be involved. These include:

(a) atherosclerosis, where various MMPs are overexpressed. Elevated levels of MMP-1 , -3, - 7, -9, -1 1 , -12, -13 and MT1-MMP have been detected in human atherosclerotic plaques [George, Exp Opin Invest Drugs 9 993-1007 (2000) and references therein]. Expression of MMP-2 [Li et al., Am J Pathol 148 121-128 (1996)] and MMP-8 [Herman et al., Circulation 104 1899-1904 (2001)] in human atheroma has also been reported;

(b) CHF (Peterson et al., Drug Dev Res, 55 29-44 (2002) reports that MMP-1 , -2, -3, -8, -9, - 13 and -14 are up-regulated in heart failure);

(c) cancer [Vihinen et al., Int J Cancer 99 57-186 (2002) review MMP involvement in cancers and particularly highlights MMP-2, -3, -7, and -9];

(d) arthritis [Jacson et al., Inflamm Res 50 183-186 (2001), MMP-2 is particularly discussed];

(e) amyotrophic lateral sclerosis [Lim et al., J Neurochem 67 251-259 (1996); where MMP-2 and MMP-9 are involved];

(f) brain metastases, where MMP-2, -9 and -13 have been reported to be implicated [Spinale, Circ Res, 90 520-530 (2002)];

(g) cerebrovascular diseases, where MMP-2 and -9 have been reported to be involved [Lukes et al., Mol Neurobiol 19 267-284 (1999)];

(h) Alzheimer's disease, where MMP-2 and -9 have been identified in diseased tissue [Backstrom et al., J Neurochem 58 983-992 (1992)];

(i) neuroinflammatory disease, where MMP-2, -3 and -9 are involved [Mun-Bryce et al., Brain Res 933 42-49 (2002)];

(j) COPD (i. e. chronic obstructive pulmonary disease) where MMP-1 , -2, -8 and -9 have been reported to be upregulated [Segura-Valdez et al., Chest 117 684-694 (2000)];

(k) eye pathology [Kurpakus-Wheater et al., Prog Histo Cytochem 36 179-259 (2001)];

(I) skin diseases [Herouy, Int J Mol Med 7 3-12 (2001)]. Figures

Figure 1 shows the synthesis of a precursor HUG 19 of the compounds of the invention.

Figure 2 shows the synthesis of the compound of the invention HUG 38 starting from the precursor HUG 19.

Figure 3 shows the synthesis of the compound of the invention HUG 30 starting from the precursor HUG 19.

Figure 4 shows the synthesis of the compounds of the invention HUG 30 and HUG 38 using the common precursors HUG 1 , HUG 12, HUG 15, HUG 17 and HUG 19.

Figure 5 shows the synthesis of HUG 41 starting from commercially available te/f-butylester of D-valine hydrochloride 1.

Figure 6 shows the IC₅₀ values of the compounds of the present invention tested for their activity on MMP-2, -8, -9 and -13.

Detailed Description of the Invention

The first aspect of the present invention provides a compound of formula (I)

wherein:

A-R is an optionally substituted 1 /-/-1 ,2,3-triazol-4-yl of structure A'

or an optionally substituted 1 ,2,3-triazol-1-yl-methyl of structure A

A'

or a phenyl substituted in para-position of structure

wherein

when A-R is an optionally substituted 1 H-1 ,2,3-triazol-4-yl of structure A'

R is H, Ci-C₆ alkyl, preferably ethyl or propyl, C C₆ haloalkyi, preferably C C₆ fluoroalkyi, more preferably CH₂-CH₂-F, and CH₂-CH₂-CH₂-F, -(CH₂-CH₂-0)_m-(pyrid-3-yl) wherein the pyridyl moiety bears one substituent R₅ preferably in position 2 (i.e. preferably -(CH₂-CH₂- 0)_m-(2-R₅-pyrid-3-yl)), -(CH₂-CH₂-0)_m-CH₂-CH₂-R₅, glucopyranosyl, preferably 2-deoxy-2- fluoro-β-D-glucopyranosyl, or R is

4-(R₅-(CH₂-CH₂-0)_m-CH₂)-1 ,2,3-triazol-1-yl-CH₂-CH₂-(0-CH₂-CH₂-)_p- of structure:

1-(R₅-(CH₂-CH₂-0)_m-CH₂-CH₂)-1 ,2,3-triazol-4-yl-CH₂-(0-CH₂-CH₂-)_p- of structure:

1-(glucopyranosyl)-1 ,2,3-triazol-4-yl-CH2-(0-CH2-CH₂-)p- of structure:

when A-R is an optionally substituted 1 ,2,3-triazol-1-yl-methyl of structure A"

R is H, Ci-C₆ alkyl, C C₆ haloalkyi, preferably C C₆ fluoroalkyi, more preferably CH₂-CH₂-F and CH2-CH2-CH2-F, -(CH2-CH₂-0)_m-(pyrid-3-yl) wherein the pyridyl moiety bears one substituent R⁵ preferably in position 2 i.e. preferably -(CH2-CH2-0)_m-(2-R₅-pyrid-3-yl)-(CH2- CH2-0)_m-CH2-CH₂-R5, glucopyranosyl, preferably 2-deoxy-2-fluoro^-D-glucopyranosyl, -CH₂- (0-CH₂-CH₂-)_m-R5, or R is

4-R₅-benzenesulfonamidomethyl- of structure:

wherein R₁₀ is H or C C₆ alkyl, preferably H or methyl,

or R is 1-(R5-(CH2-CH2-0)_m-CH2-CH₂)-1 ,2,3-triazol-4-yl-CH2-(0-CH2-CH2-)p-OCH2- of structure: .fib

1-(glucopyranosyl)-1 ,2,3-triazol-4-yl-CH2-(0-CH2-CH2-)p-OCH₂- of structure:

when A-R is a para-substituted phenyl of structure A'"

R is

4-(R5-(CH₂-CH₂-0)_m-CH₂)-1 ,2,3-triazol-1-yl-CH₂-CH₂-(0-CH₂-CH₂)p-0- of structure:

1-(R5-(CH₂-CH₂-0)_m-CH₂-CH₂)-1 ,2,3-triazol-4-yl-CH₂-(0-CH₂-CH₂)_p-0-of structure

or

R is a 1-(glucopyranosyl)-1 ,2,3-triazol-4-yl-CH₂-(0-CH₂-CH₂-)p-0- of structure

and is an optionally substituted C C₆ alkyl, preferably methyl or ethyl wherein the substituent is selected from halogen, preferably F, or is -(CH2-CH2-0)n-CH2-CH₂-R4, preferably R^ is

R₂ is Ci-C₆ alkyl, preferably isopropyl, C C₆ haloalkyl, preferably fluoroalkyl, preferably CH₂- CH₂-F

R₃ is OH or C C₆ alkoxy, preferably OH, f-butyloxy or tetrahydropyranyloxy

R₄ is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0₃SCH2CH2(CF₂)tCF₃, perfluorophenyl sulfonate or halogen, preferably F

R⁵ is H, N0₂, N⁺(R₉)₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf (triflate), 0₃SCH₂CH2(CF₂)7CF₃, perfluorophenyl sulfonate or halogen, preferably F

Rg is CrC₆alkyl, preferably methyl m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably m is 0, 1 , 2, 3, n is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 p is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably m is 0, 1 , 2, 3, t is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably t is 7 and enantiomers, esters and pharmaceutically acceptable salts thereof. In a further embodiment preferably m is 0, 1 , 2, 3 or 4; n is 0, 1 , 2, 3 or 4, p is 0, 1 , 2, 3 or 4; in a further embodiment preferably m is 0, 1 , 2, 3 or 4; n is 0, 1 , 2, 3 or 4, p is 0, 1 , 2, 3 or 4 and t is 7.

In a further embodiment of formula (I), R₄ is H or halogen, preferably F. In a further embodiment, R₅ is H, or halogen, preferably F. In a further embodiment R₄ is H or halogen, preferably F and R₅ is H, or halogen, preferably F. In a further embodiment R₄ is H and R₅ is F.ln a further embodiment R^ is methyl. In another embodiment preferably R^ is methyl and In a further embodiment of formula (I), A-R is an optionally substituted 1 /-/-1 ,2,3-triazol-4-yl of structure A' or an optionally substituted 1 ,2,3-triazol-1-yl-methyl of structure A" and R is C C₆ fluoroalkyl, more preferably CH₂-CH₂-F or R is glucopyranosyl, preferably 2-deoxy-2- fluoro^-D-glucopyranosyl and

Ri is methyl, CH₂-CH₂-F or R^ is -(CH₂-CH₂-0)_n-CH₂-CH₂-R₄

R₂ is isopropyl

R₃ is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH

R₄ is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0₃SCH₂CH₂(CF₂)₇CF₃, perfluorophenyl sulfonate or halogen, preferably F

R₅ is H, -C≡CH, N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf (triflate), 0₃SCH₂CH₂(CF₂)₇CF₃, perfluorophenyl sulfonate or halogen, preferably F; m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 n is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 preferably m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4 or enantiomers, esters or pharmaceutically acceptable salts thereof; more preferably R₄ is H or halogen, preferably F; R₅ is H, or halogen, preferably F; more preferably R₄ is H or halogen, preferably F and R₅ is H, or halogen, preferably F; more preferably R₄ is H and R₅ is F; more preferably R^ is methyl and R₅ is F.

In another embodiment the present invention is directed to a compound of formula (la)

wherein

Ri is methyl, CH₂-CH₂-F or Ri is -(CH₂-CH₂-0)_n-CH₂-CH₂-R₄

R₂ is isopropyl, R₃ is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH

R₄ is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0₃SCH₂CH₂(CF₂)7CF₃, perfluorophenyl sulfonate or halogen, preferably F

R₅ is H, C≡CH, N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,

0₃SCH₂CH2(CF₂)7CF₃, perfluorophenyl sulfonate or halogen, preferably F m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 or preferably m is 1 , 2 or 4 n is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 preferably m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4 or enantiomers, esters or pharmaceutically acceptable salts thereof.

In a further embodiment of formula (la) R₄ is H or halogen, preferably F; in a further embodiment R₅ is H , or halogen, preferably F; in a further preferredembodiment R₄ is H or halogen, preferably F and R₅ is H, or halogen, preferably F; more preferably R₄ is H and R₅ is F; more preferably is methyl and R₅ is F.

In another embodiment the present invention is directed to a compound of formula (lb)

wherein

Ri is methyl, CH₂-CH₂-F or is -(CH₂-CH₂-0)_n-CH₂-CH₂-R₄ R₂ is isopropyl,

R₃ is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH

R₅ is H, C≡CH, N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,

0₃SCH₂CH₂(CF₂)₇CF₃, perfluorophenyl sulfonate or halogen, preferably F m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably m is 1 , 2, 3 or 4 n is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 preferably m is 1 , 2, 3 or 4; or enantiomers, esters or pharmaceutically acceptable salts thereof.

In a further embodiment in formula (lb) R₄ is H or halogen, preferably F; in a further embodiment R₅ is H , or halogen, preferably F; in a further preferred embodiment in formula (lb) R₄ is H or halogen, preferably F and R₅ is H, or halogen, preferably F; more preferably R₄ is H and R₅ is F; more preferably is methyl and R₅ is F.

In another embodiment the resent invention is directed to a compound of formula (Ic)

wherein

Ri is methyl, CH₂-CH₂-F or Ri is -(CH₂-CH2-0)n-CH2-CH₂-R₄ R₂ is isopropyl,

R₃ is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH

R₄ is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, OsSCHzCHz CFz^CFs, perfluorophenyl sulfonate or halogen, preferably F

R₅ is H, C≡CH , N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,

03SCH₂CH2(CF₂)7CF3, perfluorophenyl sulfonate or halogen, preferably F m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably m is 1 , 2, 3 or 4; n is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 preferably m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4 and p is 1 , 2, 3 or 4 or enantiomers, esters or pharmaceutically acceptable salts thereof.

In a further embodiment in formula (lc) R₄ is H or halogen, preferably F; in a further embodiment R₅ is H , or halogen, preferably F; in a further preferred embodiment in formula (lc) R₄ is H or halogen, preferably F and R₅ is H , or halogen, preferably F; more preferably R₄ is H and R₅ is F; more preferably R^ is methyl and R₅ is F.

In another embodiment the resent invention is directed to a compound of formula (Id)

wherein

Ri is methyl, CH₂-CH₂-F or is -(CH₂-CH2-0)n-CH2-CH₂-R₄

R₂ is isopropyl,

R₃ is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH

R₅ is H, C≡CH, N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,

0₃SCH₂CH2(CF₂)7CF₃, perfluorophenyl sulfonate or halogen, preferably F m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 n is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 preferably m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4 and p is 1 , 2, 3 or 4 or enantiomers, esters or pharmaceutically acceptable salts thereof.

In a further embodiment in formula (Id) R₄ is H or halogen, preferably F; in a further embodiment R₅ is H , or halogen, preferably F; in a further preferred embodiment in formula (Id) R₄ is H or halogen, preferably F and R₅ is H , or halogen, preferably F; more preferably R₄ is H and R₅ is F; more preferably R^ is methyl and R₅ is F.

In another embodiment, the present invention is directed to a compound of formula (le)

wherein

Ri is methyl, CH₂-CH₂-F or R, is -(CH₂-CH2-0)n-CH2-CH₂-R₄ R₂ is isopropyl,

R₃ is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH

R₅ is H, C≡CH, N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,

In a further embodiment in formula (le) R₄ is H or halogen, preferably F; in a further embodiment R₅ is H, or halogen, preferably F; in a further preferred embodiment in formula (le) R₄ is H or halogen, preferably F and R₅ is H , or halogen, preferably F; more preferably R₄ is H and R₅ is F; more preferably R^ is methyl and R₅ is F.

In another embodiment the present invention is directed to a compound of formula (If)

wherein

F is methyl, CH₂-CH₂-F or is -(CH₂-CH2-0)n-CH2-CH₂-R4 R₂ is isopropyl,

R₃ is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH

R₄ is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, OsSCHzCHzCCFz^CFs, perfluorophenyl sulfonate or halogen, preferably F

R₅ is H, C≡CH , N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,

03SCH₂CH2(CF₂)7CF3, perfluorophenyl sulfonate or halogen, preferably F p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 preferably p is 1 , 2, 3 or 4 or enantiomers, esters or pharmaceutically acceptable salts thereof.

In a further embodiment in formula (If) R₄ is H or halogen, preferably F; in a further embodiment R₅ is H, or halogen, preferably F; in a further preferred embodiment in formula (If) R₄ is H or halogen, preferably F and R₅ is H, or halogen, preferably F; more preferably R₄ is H and R₅ is F; more preferably is methyl and R₅ is F.

In another embodiment the present invention is directed to a compound of formula (Ig)

wherein

Ri is methyl, CH₂-CH₂-F or Ri is -(CH₂-CH2-0)n-CH2-CH₂-R4 R₂ is isopropyl,

R₃ is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH

R₄ is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0₃SCH2CH2(CF₂)7CF₃, perfluorophenyl sulfonate or halogen, preferably F

R₅ is H, C≡CH, N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,

0₃SCH₂CH2(CF₂)7CF₃, perfluorophenyl sulfonate or halogen, preferably F p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 preferably p is 1 , 2, 3 or 4 or enantiomers, esters or pharmaceutically acceptable salts thereof, preferably F.

In a further embodiment in formula (Ig) R₄ is H or halogen, preferably F; in a further embodiment R₅ is H , or halogen, preferably F; in a further preferred embodiment in formula (Ig) R₄ is H or halogen, preferably F and R₅ is H, or halogen, preferably F; more preferably R₄ is H and R₅ is F; more preferably is methyl and R₅ is F.

In another embodiment the present invention is directed to a compound of formula (Ih)

wherein

R₃ is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH

R₅ is H, C≡CH, N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,

0₃SCH₂CH2(CF₂)7CF₃, perfluorophenyl sulfonate or halogen, preferably F m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10; n is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10; p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10; preferably m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4 and p is 1 , 2, 3 or 4; preferably when m=0 R₅ is -CH₂-CH₂-F or enantiomers, esters or pharmaceutically acceptable salts thereof

In a further embodiment in formula (Ih) R₄ is H or halogen, preferably F; in a further embodiment R₅ is H , or halogen, preferably F; in a further preferred embodiment in formula (Ih) R₄ is H or halogen, preferably F and R₅ is H, or halogen, preferably F; more preferably R₄ is H and R₅ is F; more preferably is methyl and R₅ is F.

In another embodiment, the present invention is directed to a compound of formula (li)

F is methyl, CH₂-CH₂-F or R, is -(CH₂-CH2-0)n-CH2-CH₂-R4 R₂ is isopropyl,

R₃ is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH

R₄ is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0₃SCH₂CH₂(CF₂)7CF3, perfluorophenyl sulfonate or halogen, preferably F

R₅ is H, C≡CH , N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,

03SCH₂CH2(CF₂)7CF3, perfluorophenyl sulfonate or halogen, preferably F m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 n is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 preferably m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4 and p is 1 , 2, 3 or 4 or enantiomers, esters or pharmaceutically acceptable salts thereof.

In a further embodiment in formula (li) R₄ is H or halogen, preferably F; in a further embodiment R₅ is H, or halogen, preferably F; in a further preferred embodiment in formula (li) R₄ is H or halogen, preferably F and R₅ is H, or halogen, preferably F; more preferably R₄ is H and R₅ is F; more preferably is methyl and R₅ is F.

In another embodiment, the present invention is directed to a compound of formula (II)

wherein

R₃ is OH, f-butyloxy, tetrahydropyranyloxy, preferably OH

R₅ is H, C≡CH , N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf,

03SCH₂CH2(CF₂)7CF3, perfluorophenyl sulfonate or halogen, preferably F n is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 preferably n is 1 , 2, 3 or 4 and p is 1 , 2, 3 or 4 or enantiomers, esters or pharmaceutically acceptable salts thereof.

In a further embodiment in formula (II) R₄ is H or halogen, preferably F; in a further embodiment R₅ is H, or halogen, preferably F; in a further preferred embodiment in formula (II) R₄ is H or halogen, preferably F and R₅ is H, or halogen, preferably F; more preferably R₄ is H and R₅ is F; more preferably is methyl and R₅ is F.

The compounds of the above mentioned formulae and embodiments have a carbon atom bearing radical R₂ having a "S" configuration or a "R" configuration.

Particularly preferred are the compounds:

racemates, esters and pharmaceutically acceptable salts thereof.

In another embodiment of the invention, the compounds of formulae I, la, lb, Ic, Id, le, If, Ig, Ih, li, II, the preferred and more preferred embodiment of formulae I, la, lb, Ic, Id, le, If, Ig, Ih, li, II, and the above individualized compounds have a carbon atom that bears a ¹⁸F as a substituent in addition or in place to a substituent already present on said carbon atom. In particular, in an aspect R₅ is ¹⁸F. Alternatively R₄ is ¹⁸F or alternatively is ¹⁸F-C C₆ alkyl; preferably F^ is ¹⁸F-CH₂-CH₂. More preferably, R₅ is ¹⁸F. More preferably, there is one ¹⁸F atom in a molecule. When in formula (I) A-R is A' or A", R may be ¹⁸F-C C₆ alkyl, preferably¹⁸F-CH₂-CH₂.

Preferred compounds are the following compounds:

racemate, esters and pharmaceutically acceptable salts thereof.

The compounds of the invention are for use as a medicament. In a further aspect, the present invention related to compounds for use in the prevention and/or treatment of pathological conditions associated with unpaired expression of matrix-metalloproteases in human and animal, in particular mammals.

In another aspect, the present invention relates to compounds of formula (I) which are labeled with a ¹⁸F atom for use as a diagnostic or imaging agent, in particular as an in vivo diagnostic or imaging agent and more in particular as diagnostic or imaging agent for Positron Emission Tomography (PET).

Said diagnostic or molecular imaging agents are for the visualization, assessment and quantitation of MMP-activity in cells and tissues. Preferably, said molecular imaging agents are for the visualization and quantitation of MMP-activity in mammalian cells and tissues, including human cells and tissues. Said quantitation may comprise the analysis of cellular or tissue radioactivity content, or the rate of uptake, displacement, dissociation or partitioning.

The compounds of the invention are for use in the prevention or treatment of pathological conditions associated with a dysregulated expression of matrix metalloproteinase in human and animal.

The radiolabeled compounds of the invention are for use in the diagnosis of pathological conditions associated with a dysregulated expression of matrix metalloproteinase in human and animal.

Preferably the pathological condition is selected from the group consisting of cardiovascular diseases, inflammatory diseases, autoimmune diseases and malignant diseases. In particular the cardiovascular diseases are selected from atherosclerosis and congestive heart failure. Inflammatory disease is chronic obstructive pulmonary disease. Autoimmune diseases are diabetes mellitus type 1 , rheumatoid arthritis, multiple sclerosis, and malignant diseases are cancers.

For example, the use of the diagnostic imaging compound of the invention permits the identification of active plaque burden, which allows risk stratification of patients with known or suspected coronary artery disease, i. e. patients with pain or a history of pain, or identified as high risk but asymptomatic. In addition, the diagnostic imaging agents of the invention permit identification of vulnerable plaques in symptomatic patients, which allows identification of high risk of acute myocardial infarction or stroke irrespective of stenosis and permits immediate risk stratification when the patient suffers from chest pain Furthermore, angioplasty of vulnerable plaques is high risk, and may lead to embolism of the artery tree post surgery. Thus imaging of this subtype of plaques may help reduce post-surgical complication.

In a further aspect the present invention relates to pharmaceutical composition comprising a compound of formula (I).

The present invention also provides a pharmaceutical or diagnostic composition comprising the compounds of the invention for the visualization, assessment and quantitation of MMP- activity.

The present invention provides pharmaceutical compositions comprising the compounds of the invention for in vivo imaging of MMP-activity in mammalian cells or tissue. In a further aspect the present invention relates to pharmaceutical composition comprising a compound of formula (I). Suitable preparations include for example tablets, capsules, suppositories, solutions, - particularly solutions for injection (s.c, i.v., i.m.) and infusion - syrups, elixirs, solution for inhalation.

The invention relates to pharmaceutical compositions comprising an effective amount, especially an amount effective in the treatment of one of the above-mentioned disorders, of the active ingredient together with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or intravenous or parenteral administration and that may be inorganic or organic, solid or liquid. They are used for oral administration especially tablets or gelatin capsules that comprise the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. Tablets may also comprise binders, for example magnesium aluminum silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate and/or effervescent mixtures or adsorbents, dyes, flavorings and sweeteners.

It is also possible to use the pharmacologically active compounds of the present invention in the form of intravenously and parentally administrable compositions or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions which, for example in the case of lyophilized compositions that comprise the active ingredient alone or together with a carrier, for example mannitol, can be made up prior to use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizes, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical compositions are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilizing processes, and comprise approximately from 1 % to 95%, especially from approximately 1 % to approximately 20%, active ingredient (s).

In a further aspect the present invention therefore provides a method for the molecular imaging of MM P-activity which comprises the steps of: a) contacting said cells or tissues with a radiolabeled compound of the present invention or composition of the present invention and b) detecting said MM P-activity. Preferably, the step of detecting said MMP-activity comprises the steps of positioning the subject within the detection field of a detection device and detecting said compounds in the subject with said detection device.

This method may be carried out also in vitro by contacting the cells or tissues with a compound or composition of the present invention by exposing, incubating, touching, associating or making the compound accessible to the cells or tissue. When the compound or composition of the present invention is radiolabeled, said MMP-activity can be detected in vitro, ex vivo and in vivo using any appropriate radiation detection device.

The compounds or compositions may be administered to a subject by any suitable administration method (oral, injection (intravenous (IV), intramuscular (IM), and subcutaneous, parenteral), via inhalation, etc.). Preferably, the compounds are administered intravenously.

When the compound or composition of the present invention is radiolabeled, said MMP- activity may be detected using a radiation detection device. Said radiation detection device may include a Positron Emission Tomography (PET) scanner or a Single Photon Emission Computed Tomography (SPECT) scanner. Preferably, said radiation detection device is a Positron Emission Tomography (PET) scanner combined with Computer Tomography (PET/CT) or Magnetic Resonance Tomography (PET/MR). Said PET scanner can detect pairs of gamma rays, emitted indirectly by positron-emitting radioisotopes such as ¹⁸F to produce a reconstructed 3D image of the radioactivity distribution within tissues. PET can therefore be used to produce a 3D image of the distribution of the radiolabeled compounds and compositions of the present invention within mammalian or human tissues.

In a further aspect the present invention is a direct method for in vivo imaging. The method may involve: a) administering to the subject a compound of the present invention or a composition of present invention; b) positioning the subject within the detection field of a detection device; and c) detecting said compounds in the subject with said detection device.

Said compound or composition may be administered to the subject by injection.

The imaging moiety can either be detected externally in a non-invasive manner or internally by the use of detectors designed for use in vivo, such as intravascular radiation detectors or radiation detectors designed for intra-operative use. Preferably, the imaging moiety is detected in a non-invasive manner.

The compounds are labeled and are detected by measuring the radiation emitted from the labeled compounds with a detection device for detecting radiation.

A further aspect of the present invention provides the use of the compounds of the present invention or the pharmaceutical compositions of the present invention for assessing the therapeutic effect of a test substance on MMP-activity in mammalian cells or tissues.

This method may involve: a) contacting mammalian cells or tissues with a compound of the present invention or a composition according to the present invention; b) positioning said mammalian cells or tissues within the detection field of a detection device; c) detecting the compounds with said detection device; d) repeating steps a), b) and c).

As a further aspect the present invention is directed to intermediate compounds useful in the preparation of the compounds of the invention i.e. the compounds of formula (I), (la), (lb), (lc), (Id), (le), (If), (Ig), (Ih), (li), (II)

The intermediate is a compound of any of formulae (Ilia) to (lllh)

wherein R₂ and p are as defined in formulae I, la, lb, Ic, Id, le, If, Ig, Ih and preferred and more preferred embodiment thereof

R₇ is NH-OH, NH-ORs, OH, C C₆-alkoxy and

R₈ is CrC₆alkyl or tetrahydropyranyl.

Preferably the intermediates are compounds:

The intermediates of the invention are used in a process for preparing the compounds of the invention, comprising compounds of formulae (Ilia), (1Mb), (lllc), (I I Id), (llle), (lllf), (I I lg) or (lllh) wherein R₇ is NH-OH or one of the above individualized intermediate compounds to a 1 ,3 dipolar cycloaddition.

The process comprises reacting a compound of formulae (Ilia), (lllc), (llle), or (lllg) wherein R₇ is NH-OH or the above individualized intermediate compounds, with a compound of formulae N₃-CH₂-CH₂-F, N₃-CH₂-CH₂-¹⁸F, N₃-(CH₂-CH₂-0)_rCH₂-CH₂-F or N₃-(CH₂-CH₂-0)_r- CH₂-CH₂-¹⁸F wherein r is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 3.

The process may further comprise preparing a compound of formula N₃-CH₂-CH₂-¹⁸F or a compound of formula N₃-(CH₂-CH₂-0)_rCH₂-CH₂-¹⁸F by reaction of a compound of formula N₃-CH₂-CH₂-OTs or a compound of formula N₃-(CH₂-CH₂-0)_r-CH₂-CH₂-OTs with a ¹⁸F containing reagent for nucleophile substitution. In place of the leaving group "OTs" any other suitable leaving group may be used. Examples of suitable leaving groups are: ONos (3- nitrobenzenesulfonate), mesylate, OTf (triflate), 0₃SCH₂CH₂(CF₂)₇CF₃, perfluorophenyl sulfonate, CI, Br, I.

Examples of ¹⁸F containing reagents for nucleophile substitution are the reagents [¹⁸F](Kryptofix222)KF and [¹⁸F]TBAF (tetrabutylammonium fluoride).

The process for preparing the compounds of formula (I) comprises reacting a compound of formulae 1Mb, llld, lllf, or lllh wherein R₇ is NH-OH, with a compound of formulae HC≡C-CH₂- CH2-CH2-F, HC≡C-CH₂-CH₂-CH₂-¹⁸F, HC≡C-(CH₂-CH₂-0)_r-CH₂-CH₂-F or HC≡C-(CH₂-CH₂- 0)_r-CH₂-CH₂-¹⁸F, wherein r is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 3.

The process may further comprise preparing a compound of formula HC≡C-CH₂-CH₂-CH₂- ¹⁸F or a compound of formula HC≡C-(CH₂-CH₂-0)_rCH₂-CH₂-¹⁸F by reaction of a compound of formula HC≡C-CH₂-CH₂-CH₂-OTs or a compound of formula HC≡C-(CH₂-CH₂-0)_r-CH₂- CH₂-OTs with a ¹⁸F containing reagent for nucleophile substitution. In place of the leaving group "OTs" any other suitable leaving group may be used. Examples of suitable leaving groups are: ONos (3-nitrobenzenesulfonate), mesylate, OTf, 0₃SCH₂CH₂(CF₂)₇CF₃, perfluorophenyl sulfonate, CI, Br, I.

Examples of ¹⁸F containing reagents for nucleophile substitution are the reagents

[¹⁸F](Kryptofix222)KF and [¹⁸F]TBAF (tetrabutylammonium fluoride).

In a further aspect the present invention is directed to an intermediate of formula IV

wherein

a) A, R, A-R, RL R₂, R₃, R₉, R₁₀, m, n, and p are as defined in any of the above formulae I, la, lb, lc, Id, le, If, Ig, Ih, li and II

and R₅ is OTs, ONos (3-nitrobenzenesulfonate), mesylate or OTf or

wherein

b) A, R, A-R, RL R₂, R₃, R₉, R₁₀, m, n, and p are as defined are as defined in any of the above formulae I, la, lb, lc, Id, le, If, Ig, Ih, li and II

R₅ is OTs, ONos (3-nitrobenzenesulfonate), mesylate or OTf and R₄ is H or halogen.

Preferably in formula IV (a) is methyl.

The preparation of this new class of triazole containing hydroxamic acid derivatives, wherein A is A' is based on the availability of the propargylic hydroxamic acid HUG 19 (see Fig. 1). For example, the reaction of commercially available tert-butylester of D-valine hydrochloride 1 and 4-methoxybenzenesulfonyl chloride in the presence of pyridine yielded the sulfonamide HUG 1. /V-alkylation with propargyl bromide under basic conditions and subsequent acidic hydrolysis of the ester HUG 12 with gaseous hydrochloric acid in dichloromethane provided the carboxylic acid HUG 15. Subsequently, HUG 15 is converted to the corresponding hydroxamic acid ester HUG 17 with O-terf-butylhydroxylamine hydrochloride, A/-((dimethylamino)-propyl)-/\/'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole hydrate (HOBT) and 4-methylmorpholine (NMM). Cleavage of the terf-butyl group is performed with hydrochloric acid gas in dichloroethane, yielding the hydroxamic acid HUG 19 as building block for the triazol syntheses.

1 ,3-Dipolar cycloaddition of the propargylic hydroxamic acid HUG 19 and an azide derivative provided the 1 /-/-1 ,2,3-triazol-4-yl substituted hydroxamic acid. Preferably this reaction is conducted using copper(ll) sulfate and sodium ascorbate in DMF. For example the 1 ,3- dipolar cycloaddition of HUG 19 and 2-fluoroethylazide (HUG 37) using copper(ll) sulfate and sodium ascorbate in DMF provided the /V-fluoroethyl-triazole substituted hydroxamic acid HUG 38 (Fig. 2).

Analogously, the fluoro-PEG-triazole substituted hydroxamic acid HUG 30 is prepared in 53% yield using HUG 19 and the PEG derivative HUG 27 that was synthesized following literature procedures (Fig. 3).

The new class of triazole containing hydroxamic acid derivatives, wherein A is para- substituted phenol derivative, is prepared by the reaction of commercially available tert- butylester of D-valine hydrochloride 1 and 4-methoxybenzenesulfonyl chloride in the presence of pyridine yielding the sulfonamide HUG 1. /V-alkylation with a bromide derivative (such as compound 4 in Fig. 4) under basic conditions and subsequent acidic hydrolysis of the obtained ester (such as compound 5 of Fig 4) with gaseous hydrochloric acid in dichloromethane provided the carboxylic acid 6. Subsequently, the carboxylic acid (e. g. compound 6 of Fig. 4) is converted to the corresponding hydroxamic acid ester e. g. compound 7 of Fig. 4) with O-terf-butylhydroxylamine hydrochloride, A/-((dimethylamino)- propyl)-/V'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole hydrate (HOBT) and 4-methylmorpholine (NMM). Cleavage of the terf-butyl group was performed with hydrochloric acid gas in dichloroethane, yielding the hydroxamic acid (e. g. compound 8 of Fig. 4) as building block of the syntheses of the compounds of the invention wherein A is a para-substituted phenyl subunit.

For example compound HUG 41 is prepared using compound 8 of Fig. 4 and 2- fluoroethylazide. Definitions

The term "CrC₆ alkyl", when used either alone or within other terms such as "haloalkyl" and "arylalkyl" or "heteroarylalkyl" embraces linear or branched radicals having C1-C6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, te/f-butyl, pentyl, isoamyl, hexyl. The term "alkylenyl" embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl.

The term "C₂-C₆ alkenyl", when used alone or in combination, embraces linear or branched radicals having at least one carbon-carbon double bond in a moiety having between two and six carbon atoms. Examples of alkenyl radicals include, without limitation, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term "alkenyl" encompasses radicals having "c/^'s" and "trans" orientations, or alternatively, "E" and "Z" orientations.

The term "CrC₆ alkoxy" or "alkoxyl", when used alone or in combination, embraces linear or branched oxygen-containing radicals each having alkyl portions of one or more carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and te/f-butoxy. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term "arylalkyl" is any C₇-C₂o group consisting of an alkyl and an aryl group as defined above.

The term "halo", when used alone or in combination, means halogens such as fluorine, chlorine, bromine or iodine atoms, preferably fluorine. The term "haloalkyl", when used alone or in combination, embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. For example, this term includes monohaloalkyi, dihaloalkyi and polyhaloalkyi radicals such as a perhaloalkyl. A monohaloalkyi radical, for example, may have either an iodo, bromo, chloro or fluoro atom within the radical, preferably a fluoro atom. Dihalo and polyhaloalkyi radicals may have two or more of the same halo atoms or a combination of different halo radicals.

The term "CrC₆ haloalkyl" embraces radicals having 1-6 carbon atoms and, for example, haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, fluoroethyl, difluoroethyl, fluoropropyl, difluoropropyl, dichloroethyl and dichloropropyl.

The term "C₂-C₆ haloalkenyl", when used alone or in combination, embraces radicals wherein any one or more of the alkyl carbon atoms are substituted with halo as defined above, preferably a fluorine atom. For example, this term includes monohaloalkenyl, dihaloalkenyl and polyhaloalkenyl radicals. A monohaloalkenyl radical, for example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkenyl radicals include fluorovinyl, fluoropropenyl, fluorobutenyl.

The term "aryl", when used alone or in combination, means a carbocyclic aromatic moiety containing one, two or even three rings wherein such rings may be attached together in a fused manner. Thus, the term "aryl" embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl, benzodioxazinyl. The "aryl" group may be substituted, such as with 1 to 5 substituents including lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and C C₆ alkylamino.

The term "heteroaryl", as used herein, either alone or in combination, means a fully unsaturated (aromatic) ring moiety formed from carbon atoms and having one or more heteroatoms selected from nitrogen, oxygen and sulfur. The ring moiety or ring system may contain one ("monocyclic"), two ("bicyclic") or even three ("tricyclic") rings wherein such rings are attached together in a fused manner. Every ring of a "heteroaryl" ring system need not be aromatic, and the ring(s) fused thereto (to the heteroaromatic ring) may be partially or fully saturated and optionally include one or more heteroatoms selected from nitrogen, oxygen and sulfur.

Examples of unsaturated heteroaryl radicals including unsaturated 5- to 6- membered heteromonocyclyl groups, containing 1 to 4 nitrogen atoms, including for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e. g., 4 - -1 ,2,4-triazolyl, ,2,3-triazolyl, 2 - -1 ,2,3-triazolyl] and tetrazole; unsaturated 7- to 10-membered heterobicyclic groups containing 1 to 4 nitrogen atoms, including for example, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl; unsaturated 5- to 6- membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2- furyl, 3-furyl, benzofuryl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated 5- to 6- membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e. g., 1 ,2,4-oxadiazolyl, 1 ,3,4- oxadiazolyl, 1 ,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl [e. g., 1 ,2,4-thiadiazolyl, 1 ,3,4-thiadiazolyl, 1 ,2,5-thiadiazolyl].

The term "aryl-alkyl" is any C₇-C₂o group consisting of an alkyl and an aryl group as defined above, preferably a benzyl group.

The term "hetero-aryl-alkyl" is any C₇-C₂o group consisting of an alkyl and a heteroaryl group as defined above, preferably a picolyl group, more preferably a 3-picolyl group.

The phrase "labeled with a ¹⁸F" used herein means that one of the atoms or substituents of formula (I) comprises a ¹⁸F either as an artificially enriched level of an atom intrinsic to the substructure, or as an additional essential feature that has been chemically attached via a functionality suitable for coupling said ¹⁸F.

By the term "biocompatible carrier" is meant a fluid, especially a liquid, in which the imaging agent can be suspended or dissolved, such that the composition is physiologically tolerable, i. e. it can be administered to the mammalian body without toxicity or undue discomfort. The biocompatible carrier is suitably an injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is either isotonic or not hypotonic); an aqueous solution of one or more tonicity-adjusting substances (e. g. salts of plasma cations with biocompatible counterions), sugars (e. g. glucose or sucrose), sugar alcohols (e. g. sorbitol or mannitol), glycols (e. g. glycerol), or other non-ionic polyol materials (e. g. polyethyleneglycols, propylene glycols and the like).

By the term "biocompatible cation" is meant a positively charged counterion which forms a salt with an ionised, negatively charged group, where said positively charged counterion is also non-toxic and hence suitable for administration to the mammalian body, especially the human body. Examples of suitable biocompatible cations include the alkali metals sodium or potassium; the alkaline earth metals calcium and magnesium; and the ammonium ion. Preferred biocompatible cations are sodium and potassium, most preferably sodium.

By the term "radioprotectant" is meant a compound which inhibits degradation reactions, such as redox processes, by trapping highly-reactive free radicals, such as oxygen- containing free radicals arising from the radiolysis of water. The radioprotectants of the present invention are suitably chosen from: ascorbic acid, para-aminobenzoic acid (i. e. 4- aminobenzoic acid), gentisic acid (i. e. 2, 5-dihydroxybenzoic acid) and salts thereof with a biocompatible cation as described above.

By the term "antimicrobial preservative" is meant an agent which inhibits the growth of potentially harmful micro-organisms such as bacteria, yeasts or moulds. The antimicrobial preservative may also exhibit some bactericidal properties, depending on the dose. The main role of the antimicrobial preservative(s) of the present invention is to inhibit the growth of any such microorganism in the pharmaceutical composition post-reconstitution, i. e. in the radioactive diagnostic product itself. The antimicrobial preservative may, however, also optionally be used to inhibit the growth of potentially harmful microorganisms in one or more components of the kit of the present invention prior to reconstitution. Suitable antimicrobial preservatives include: the parabens, i. e. methyl, ethyl, propyl or butyl paraben or mixtures thereof; benzyl alcohol; phenol; cresol; cetrimide and thiomersal. Preferred antimicrobial preservative (s) are the parabens.

The term "pH-adjusting agent" means a compound or mixture of compounds useful to ensure that the pH of the reconstituted kit is within acceptable limits (approximately pH 4.0 to 10.5) for human or mammalian administration. Suitable such pH-adjusting agents include pharmaceutically acceptable buffers, such as tricine, phosphate or TRIS [i. e. tris (hydroxymethyl) aminomethane], and pharmaceutical acceptable bases such as sodium carbonate, sodium bicarbonate or mixtures thereof. When the ligand conjugate is employed in acid salt form, the pH-adjusting agent may optionally be provided in a separate vial or container, so that the user of the kit can adjust the pH as part of a multi-step procedure.

By the term "filler" is meant a pharmaceutically acceptable bulking agent which may facilitate material handling during production and lyophilisation. Suitable fillers include inorganic salts such as sodium chloride, and water soluble sugars or sugar alcohols such as sucrose, maltose, mannitol or trehalose.

Examples

All chemicals, reagents and solvents for the synthesis of the compounds were analytical grade, purchased from commercial sources and used without further purification unless otherwise specified.

The melting points (mp) were determined in capillary tubes on a Stuart Scientific SMP3 capillary melting point apparatus. Column chromatography was performed on Merck silica gel 60 (0.040-0.063 mm). Thin layer chromatography (TLC) was carried out on silica gel-coated polyester backed TLC plates (Polygram, SIL G/UV254, Macherey-Nagel) using solvent mixtures of cyclohexane (CH), ethyl acetate (EA) and methanol (MeOH). Compounds were visualized by UV light (254 nm). (Radio-)HPLC was performed on the following system: Knauer K-1800 pumps, S-2500 UV detector (Herbert Knauer GmbH, Berlin, Germany), GabiStar γ-detector (raytest Isotopenmessgerate GmbH, Straubenhardt, Germany). The recorded data were processed by the ChromGate HPLC software (Knauer). NMR spectra were recorded on a Bruker ARX300 and a Bruker DPX300 (¹ H NMR, 300 MHz, ¹³CNMR, 75MHz, ¹⁹F NMR, 282 MHz), Bruker AMX 400 (¹ H NMR, 400 MHz, ¹³C NMR, 100 MHz) spectrometers. TMS (¹ H), and CDCI₃ (¹³C) were used as internal standards and all chemical shift values were recorded in ppm (<5). Mass spectra were recorded on Thermo-Finningan MAT8200 (El, 70 eV), Waters-Micromass GCT (GCToF, El), and Waters-Micromass Quatromicro GC (GC/CI and El, 70 eV) instruments. All air and moisture-sensitive reactions were performed under argon atmosphere. Solvents were purified and dried by literature methods where necessary. The chemical purities of each new non-radioactive compound were ≥ 90% assessed by analytical gradient reversed phase HPLC with a Nucleosil Eurosphere 100-5 C-18 column (250 mm x 4.6 mm) using solvent A (water/TFA 1000: 1 (v/v)) and solvent B (acetonitrile/TFA 1000: 1 (v/v)). The HPLC system started with 90% A and 10% B with a linear gradient to 10% A and 90% B over 18 min, holding for 20 min and back to 90% A and 10% B in 2 min, with a flow rate of 1.5 ml/min.

In general the strategy towards the preparation of the new class of triazole (of structure A') containing hydroxamic acid derivatives was based on the availability of the propargylic hydroxamic acid HUG 19 (see Fig. 1). The reaction of commercially available te/f-butylester of D-valine hydrochloride 1 and 4-methoxybenzenesulfonyl chloride in the presence of pyridine yielded the sulfonamide HUG 1. /V-Alkylation with propargyl bromide under basic conditions and subsequent acidic hydrolysis of the ester HUG 12 with gaseous hydrochloric acid in dichloromethane provided the carboxylic acid HUG 15. Subsequently, HUG 15 is converted to the corresponding hydroxamic acid ester HUG 17 with O-tert- butylhydroxylamine hydrochloride, A/-((dimethylamino)-propyl)-A/'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole hydrate (HOBT) and 4-methylmorpholine (NMM). Cleavage of the te/f-butyl group is performed with hydrochloric acid gas in dichloroethane, yielding the hydroxamic acid HUG 19 as building block for the triazol syntheses.

A/-[(Methoxyphenyl)sulfonyl]-D-valine te/f-butyl ester (HUG 1), 2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)ethylfluoride (HUG 27) and fluoroethylazide (HUG 37) were synthesised following literature procedures. Example 1 : Preparation of ( ?)- V-hydroxy-2-(4-methoxyphenylsulfonamido- V-(prop-2- yn-1-yl))-3-methylbutanoate (HUG 19)

1. 1 (R)-tert-butyl 2-(4-methoxyphenylsulfonamido)-3-methylbutanoate (HUG 1 )

The compound was obtained as a white solid.

Yield: 75%, mp 120.3 °C.

1.2 (R)-tert-Butyl 2-(4-methoxyphenylsulfonamido-N-(prop-2-yn- 1-yl))-3-methylbutanoate (HUG 12;

To a solution of (R)-tert-buty\ 2-(4-methoxyphenylsulfonamido)-3-methylbutanoate (HUG 1) (20.0 g, 58.2 mmol) in DMF (ca. 65 μηιοΙ/ΓΤΐΙ_, 900 ml_) propargyl bromide (80% in toluene, 58.2 mmol, 6.5 ml_) and potassium carbonate (582 mmol, 80 g) were added. The resulting suspension was stirred at room temperature for 2 days. The mixture was diluted with water (500 ml_) and extracted with EA (3 ^χ 200 ml_). The combined organic phases were washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel; CH/EA 6: 1). The product was obtained as colorless crystals (22.2 g, 58.1 mmol, 100%), mp 79°C.¹ H NMR (300 MHz, CDCIs) δ 7.84 (d, PhCH, ³ _H,H = 9.1 Hz, 2H), 6.94 (d, PhCH, ³ _H,H = 9.0 Hz, 2H), 4.38 (AB, dd, NCH₂, ² _H,H = 18.7 Hz, ⁴ _H,H = 2.5 Hz, 1 H), 4.16 (AB, dd, NCH₂, ² _H,H = 18.7 Hz, ⁴JH,H = 2.4 Hz, 1 H), 3.94 (d, NCH, ³J_H,H = 10.3 Hz, 1 H), 3.85 (s, OCH₃, 3H), 2.21 - 2.13 (m, CH(CH₃)₂, 1 H), 2.17 (t, C≡CH, ⁴J_H,H = 2.5 Hz, 1 H), 1.32 (s, C(CH₃)₃, 9H), 1.04 (d, CHCH₃, ³JH,H = 6.6 Hz, 3H), 0.96 (d, CHCH₃, ³J_H,H = 6.6 Hz, 3H). ¹³C NMR (75 MHz, CDCI₃) δ 169.7 (COOC(CH₃)₃), 162.9 (qPhCOCH₃), 131.9 (qPhCS0₂), 129.8 (PhCH), 113.8 (PhCH), 81.9 (C(CH₃)₃), 79.8 (C≡CH), 71.8 (C≡CH), 65.7 (NCH), 55.5 (OCH₃), 33.4 (NCH₂), 28.9 (CH(CH₃)₂), 27.7 (C(CH₃)₃), 19.8 (CH(CH₃)₂), 19.1 (CH(CH₃)₂). MS-ES-EM m/z = 404.1507 [(M+Na)⁺] calcd for Ci₉H₂₇N0₅SNa⁺: 404.1502.

1.3 2-(4-Methoxyphenylsulfonamido-N-(prop-2-yn-1-yl))-3-methylbutanoic acid (HUG 15) A stirred solution of the carboxylic acid ester HUG 12 (22.0 g, 57.67 mmol) in dichloromethane (100 ml_) was cooled to 0°C. Hydrochloric acid gas was bubbled through the solution. TLC was used to monitor the reaction progress (EA). After complete conversion the solvent was removed under reduced pressure to give HUG 15 as a colorless wax (18.6 g, 57.23 mmol, 99%). ¹ H NMR (400 MHz, CDCI₃) δ 9.02 (s, OH, 1 H), 7.83 (d, PhH, ³J_H,H = 9.0 Hz, 2H), 6.94 (d, PhH, ³ _H,H = 9.0 Hz, 2H), 4.27 (AB, dd, NCH₂, ²J_H,H = 18.9 Hz, ⁴J_H,H = 2.5 Hz, 1 H), 4.21 (AB, d, NCH₂, ²J_H,H = 18.9 Hz, ⁴J_H,H = 2.5 Hz, 1 H), 4.03 (d, NCH, ³J_H,H = 10.2 Hz, 1 H), 3.86 (s, OCH₃, 3H), 2.29 - 2.01 (m, CH(CH₃)₂, 1 H), 2.17 (t, C≡CH, ⁴J_H,H = 2.4 Hz), 0.98 (d, CHCH₃, ³J_H,H = 6.6 Hz, 3H), 0.96 (d, CHCH₃, ³J_H,H = 6.6 Hz, 3H). ¹³C NMR (101 MHz, CDCI₃) δ 176.0 (COOH), 163.1 (qPhCOCH₃), 131.0 (qPhCS0₂), 129.9 (PhCH), 1 13.9 (PhCH), 79.0 (C≡CH), 72.4 (C≡CH), 64.9 (NCH), 55.6 (OCH₃), 33.5 (NCH₂), 28.4 (CH(CH₃)₂), 19.8 (CH(CH₃)₂), 19.2 (CH(CH₃)₂). MS-ES-EM m/z = 348.0877 [(M+Na)⁺] calcd for Ci₅H₁₉N0₅SNa⁺: 348.0876.

1.4 (R)-N-(tert-Butoxy)-2-(4-methoxyphenylsulfonamido-N-(prop-2-yn-1-yl))-3- methylbutanamide (HUG Λ7)

To a solution of carboxylic acid H UG 15 (16.3 g, 49.94 mmol) in dichloromethane (0.06 mmol/mL, 830 mL) 1-hydroxybenzotriazole hydrate (HOBT, 6.7 g. 49.94 mmol), 4-methylmorpholine (NMM, 27.5 mL, 249.70 mmol), O-te/f-butylhydroxylamine hydrochloride (18.8 g, 149.82 mmol and A/-((dimethylamino)-propyl)-/\/'-ethylcarbodiimide hydrochloride (EDC, 12.4 g, 64.92 mmol) were added. After stirring overnight at room temperature the reaction mixture was diluted with water and extracted with dichloromethane (3 ^χ 200 mL). The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to give H UG 17 as a colorless wax (17.4 g, 43.80 mmol, 88%). [a]²⁰ _D +107.8 (c= 0.98 in CHCI₃); ¹ H NMR (300 MHz, CDCI₃) δ 8.38 (s, NH, 1 H), 7.87 (d, PhH, ³ _H,H = 8.9 Hz, 2H), 6.96 (d, PhH, ³ _H,H = 8.9 Hz, 2H), 4.36 (d, NCH₂, ⁴ _H,H = 2.5 Hz, 2H), 3.87 (s, OCH₃, 3H), 3.57 (d, NCH, ³J_H,H = 10.9 Hz, 1 H), 2.41 - 2.21 (m, CH(CH₃)₂, 1 H), 2.18 (t, C≡CH, ⁴J_H,H = 2.4 Hz, 1 H), 1.27 (s, C(CH₃)₃, 9H), 0.89 (d, CHCH₃, ³J_H,H = 6.5 Hz, 3H), 0.65 (d, CHCH₃, ³J_H,H = 6.6 HZ, 3H). ¹³C NMR (75 MHz, CDCI₃) δ 168.4 (CONH), 163.2 (qPhCOCH₃), 131.7 (qPhCS0₂), 129.7 (PhCH), 1 14.0 (PhCH), 82.4 (C(CH₃)₃), 79.1 (CCH), 72.4 (CCH), 63.7 (NCH), 55.6 (OCH₃), 32.8 (NCH₂), 27.1 (CH(CH₃)₂), 26.2 (C(CH₃)₃), 19.7 (CH(CH₃)₂), 19.4 (CH(CH₃)₂). MS-ES-EM m/z = 419.1614 [(M+Na)⁺] calcd for Ci₉H₂₈N₂0₅SNa⁺: 419.1611.

1.5 (R)-N-Hydroxy-2-(4-methoxyphenylsulfonamido-N-(prop-2-yn- 1-yl))-3- methylbutanamide (HUG 19;

The hydroxamic acid ester HUG 17 (17.3 g, 43.67 mmol) was dissolved in dichloroethane (0.06 mmol/mL, 400 mL) containing 1.0 eq. of ethanol (1.3 mL). The solution was cooled to 0°C and hydrochloric acid gas was bubbled through it. TLC was used to monitor the reaction progress (EA). After complete conversion the solvent was removed under reduced pressure. Column chromatography on silica gel (CH/EA 1 :1) yielded HUG 19 as a white solid (7.4 g, 21.75 mmol, 50%), mp 149°C. ¹ H NMR (300 MHz, DMSO) δ 10.75 (d, OH, ⁴ _H,H = 1.3 Hz, 1 H), 8.97 (d, HH, ⁴J_H,H = 1.5 Hz, 1 H), 7.78 (d, PhH, ³J_H,H = 9.0 Hz, 2H), 7.07 (d, PhH, ³J_H,H = 9.0 Hz, 2H), 4.67 (AB, dd, NCH₂, ²J_H,H = 18.8 Hz, ⁴J_H,H = 2.4 Hz, 1 H), 4.06 (AB, dd, NCH₂, ²JH_,H = 18.8 Hz, ⁴J_H,H = 2.4 Hz, 1 H), 3.84 (s, OCH₃, 3H), 3.66 (d, NCH, ³J_H,H = 10.7 Hz, 1 H), 3.13 (t, C≡CH, ⁴JH_,H = 2.4 Hz, 1 H), 2.32 - 1.91 (m, CH(CH₃)₂, 1 H), 0.87 (d, CHCH₃, ³J_H,H = 6.5 Hz, 3H), 0.81 (d, CHCH₃, ³ _H,H = 6.6 Hz, 3H). ¹³C NMR (75 MHz, DMSO) δ 165.9 (CONH), 162.5 (qPhCOCH₃), 131.4 (qPhCS0₂), 129.3 (PhCH), 1 14.2 (PhCH), 80.5 (C≡CH), 74.0 (C≡CH), 61.9 (NCH), 55.7 (OCH₃), 32.9 (NCH₂), 28.1 (CH(CH₃)₂), 19.9 (CH(CH₃)₂), 18.9 (CH(CH₃)₂). MS-ES-EM m/z = 363.0986 [(M+Na)⁺] calcd for Ci₅H₂oN₂0₅SNa⁺: 363.0985.

Example 2: Synthesis of (R)-2-(N-((1-(2-fluoroethyl)-1 H-1 ,2, 3-triazol-4-yl) methyl) -4-methoxy- phenylsulfonamido)-N-hydroxy-3-methylbutanamide (HUG 38)

HUG 38 was obtained from HUG 19 (340 mg, 1 .0 mmol) and fluoroethylazide (HUG 37, 1 .0 mmol), prepared from fluoroethyltosylate and sodium azide following literature procedure, after 5 h stirring at room temperature. Column chromatographic purification with EA gave a white solid (1 16 mg, 0.31 mmol, 31 %), mp 125°C (decomposition). ¹ H NMR (300 MHz, CDCI₃) δ 10.26 (s, OH, 1 H), 7.81 (s, CCHN, 1 H), 7.68 (d, PhH, ³J_H,H = 8.6 Hz, 2H), 6.83 (d, PhH, ³J_H,H = 8.6 Hz, 2H), 4.99 (d, NCH₂, ² _H,H = 16.6 Hz, 1 H), 4.87 - 4.65 (dm, CH₂F, ² _H,F = 46.6 Hz, 2H), 4.66 - 4.53 (dm, NCH₂CH₂F, ³ _H,H = 26.2 Hz, 2H), 4.55 (d, NCH₂, ²J_H,H = 16.5 Hz, 1 H), 3.90 (d, NCH, ³J_H,H = 10.8 HZ, 1 H), 3.78 (s, OCH₃, 3H), 2.46 - 2.21 (m, CH(CH₃)₂, 1 H), 0.83 (d, CHCH₃,

6.4 Hz, 3H), 0.57 (d, CHCH₃, 6.5 Hz, 3H).¹³C NMR (75 MHz, CDCI₃) δ 167.7 (CONH), 163.1 (qPhCOCH₃), 145.1 ( , 131.1 (qPhCS0₂), 129.4 (PhCH), 124.9 (CCHN), 1 14.2 (PhCH), 81.4 (d, CH₂F, ¹

72.9 Hz), 63.6 (NCH), 55.6 (OCH₃), 50.5 (d, CH₂CH₂F, 20.8 Hz), 39.6 (NCH₂), 27.4 (CH(CH₃)₂), 19.3 (CH(CH₃)₂), 19.1 (CH(CH₃)₂). ¹⁹F NMR (282 MHz, CDCI₃) δ - 222.04 (m, 1 F). MS-ES-EM m/z = 452.1375 [(M+Na)⁺] calcd for Ci₇H₂₄FN₅0₅Na⁺ 452.1374. HPLC t_R = 14.53 min (100%).

Example 3: Synthesis of (R)-2-(N-((1-(2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)-4-methoxyphenylsulfonamido)-N-hydroxy-3-methylbutanamide

(HUG 30j

HUG 30 was obtained from HUG 19 (340 mg, 1.0 mmol) and 2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)ethylfluoride (HUG 27, 221 mg, 1.0 mmol, prepared following literature procedure), after 2 h stirring at room temperature. Column chromatographic purification (silica gel, EA) gave a colorless, waxy oil (300 mg, 0.53 mmol, 53%). ¹ H NMR (300 MHz, CDCI₃) δ 9.86 (br s, OH 1 H), 7.82 (s, CCHN, 1 H), 7.67 (d, PhH, ³J_H,H = 8.9 Hz, 2H), 6.91 (d, PhH, ³J_H,H = 8.6 Hz, 2H), 4.90 (AB, d, NCH₂, ²J_H,H = 16.5 Hz, 1 H), 4.56 (dm, CH₂F, ²J_H,F = 47.8 Hz, 2H), 4.51 (AB, d, NCH₂, ²J_H,H = 16.5 Hz, 1 H), 4.55 - 4.46 (m, NCH₂CH₂0, 2H), 3.90 - 3.82 (m, NCH₂CH₂0, 2H), 3.84 (s, OCH₃, 3H), 3.82 - 3.58 (m, NCH, CH₂, 1 1 H), 2.42 - 2.24 (m, CH(CH₃)₂, 1 H), 0.85 (d, CH(CH₃)₂, ^ZJH,H = 6.5 Hz, 3H), 0.58 (d, CH(CH₃)₂, ^ZJH,H = 6.6 Hz, 3H). ¹³C NMR (75 MHz, CDCI₃) δ 167.04 (CONH), 163.0 (qPhCOCH₃), 144.5 (CCHN), 131.3 (qPhCS0₂), 129.4 (PhCH), 124.9 (CCHN), 1 14.1 (PhCH), 83.1 (d, CH₂F, ²J_C,F = 168.6 Hz), 70.7, 70.5, 70.4, (CH₂), 70.3 (d, CH₂CH₂F, ²JC,F = 19.6 Hz), 69.4 (NCH₂CH₂0), 63.6 (NCH), 55.6 (OCH₃), 50.1 (NCH₂CH₂0), 39.7 (NCH₂), 27.2 (CH(CH₃)₂), 19.4 (CH(CH₃)₂), 19.1 (CH(CH₃)₂). ¹⁹F NMR (282 MHz, CDCI₃) δ -222.72 (tt, ²J_H,F = 47.7 Hz, ³ _H,F = 30.0 Hz, 1 F). MS-ES-EM m/z = 584.2165 [(M+Na)⁺] calcd for C₂₃H₃₆FN₅0₈Na⁺ 584.2161. HPLC t_R = 15.18 min (92%).

Example 4: In vitro Assay for MMP-2, -8, -9 and -13 inhibitory activity

The synthetic fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl pro-Leu-Gly-Leu-(3- (2,4-dinitrophenyl)-L-2,3-diamino-propionyl)-Ala-Arg-NH₂ (R & D Systems, Minneapolis, MN) was used to assay activated MMP-2, MMP-8, MMP-9 and MMP-13 as described previously [Huang et al, J. Biol. Chem. 272, 22086-22091 (1997) ]. The inhibitions of human active MMPs by the compounds were assayed by preincubating MMP-2, MMP-8, MMP-9 and MMP-13 (each at 2 nM) and inhibitor compounds at varying concentrations (1 pM - 1 mM) in Tris HCI (50 mM), pH 7.5, containing NaCI (0.2 M), CaCI₂ (5 mM), ZnS0₄ (20 μΜ) and 0.05% Brij 35 at 37 °C for 30 min. An aliquot of substrate (10 μΙ of a 50 μΜ solution) was then added to the preincubated MMP/inhibitor mixture (90 μΙ_), and the fluorescence was determined at 37 °C by following product release with time. The fluorescence changes were monitored using a Fusion Universal Microplate Analyzer (Packard Bioscience, Massachusetts, USA) with excitation and emission wavelengths of 330 and 390 nm, respectively. Reaction rates were measured from the initial 10 min of the reaction profile where product release was linear with time and plotted as a function of inhibitor dose. From the resulting inhibition curves, the IC₅₀ values for each inhibitor were calculated by non-linear regression analysis, performed using the Grace 5.1.8 software (Linux).

Example 5: Determination of clog D

Log D values were calculated (= clog D) with ACD/Chemsketch Labs 6.00 software (log D = log P at physiological pH 7.4 with consideration of charged species).

The ICso with respect to MMP-2, MMP-8, MMP-9 and MMP-13 and the clog D value of tested compounds of the invention and the comparative compound FetO-GCS are reported in Fig. 6 and Table 1. As can be seen all the compounds have a clog D lower that the comparative compounds. The presence of the triazole moiety also allows keeping the IC₅₀ in the range of nM and reaching a good balance between lipophilicity and potency. Table 1

F!uorinated MMPIs with triazole-substituted hydroxamic acid structure

alog D values were calculated with ACD/Chemsketch Labs 6.00 (log D = log P at physiological pH 7.4 with consideration of charged species) ^bF18-version radiochemically available for preclinical application (rcy:27%, decay-corrected, 2 steps semi-automated)

Claims

1 . Compound of formula (I)

wherein:

A-R is an optionally substituted 1 /-/-1 , 2, 3-triazol-4-yl of structure A'

A'

optionally substituted 1 ,2,3-triazol-1 -yl-methyl of structure A"

or A-R is a phenyl substituted in para-position of structure

wherein

-when A-R is an optionally substituted 1 /-/-1 ,2,3-triazol-4-yl of structure A'

R is H , d-Ce alkyl, d-C₆ haloalkyi, preferably d-C₆ fluoroalkyi, more preferably CH₂-CH₂-F and CH2-CH2-CH2-F, -(CH2-CH₂-0)_m-(pyrid-3-yl) wherein the pyridyl moiety bears one substituent R₅ preferably in position 2 i.e. preferably -(CH2-CH2-0)_m-(2-R₅-pyrid-3-yl)-(CH2- CH2-0)_m-CH2-CH₂-R5, glucopyranosyl, preferably 2-deoxy-2-fluoro^-D-glucopyranosyl, or R is

4-(R5-(CH2-CH2-0)_m-CH₂)-1 ,2,3-triazol-1-yl-CH2-CH2-(0-CH2-CH2-)p-of structure:

1-(R₅-(CH2-CH2-0)_m-CH2-CH₂)-1 ,2,3-triazol-4-yl-CH2-(0-CH₂-CH₂-)p- of structure:

1-(glucopyranosyl)-1 ,2,3-triazol-4-yl-CH2-(0-CH2-CH₂-)p- of structure:

N

\\ .

-when A-R is an optionally substituted 1 ,2,3-triazol-1-yl-methyl of structure A"

R is H, Ci-C₆ alkyl, C C₆ haloalkyi, preferably C C₆ fluoroalkyi, more preferably

CH2-CH2-F and CH2-CH2-CH2-F, -(CH₂-CH₂-0)_m-(pyrid-3-yl) wherein the pyridyl moiety bears one substituent R₅ preferably in position 2, i.e. preferably -(CH₂-CH₂-0)_m-(2- R₅-pyrid-3-yl)- (CH2-CH2-0)_m-CH2-CH₂-R5 , glucopyranosyl, preferably 2-deoxy-2-fluoro^-d-glucopyranosyl, -CH2-(0-CH₂-CI-l2-)m-R5, or R is 4- R₅-benzenesulfonamidomethyl- of structure:

wherein R₁₀ is H or d-C₆ alkyl, preferably H or methyl, or

R is 1-(R5-(CH2-CH2-0)_m-CH2-CH₂)-1 ,2,3-triazol-4-yl-CH2-(0-CH2-CH2-)p-OCH2- of structure:

1-(glucopyranosyl)-1 ,2,3-triazol-4-yl-CH2-(0-CH2-CH2-)p-OCH₂- of structure:

or when A-R is a para-substituted phenyl of structure A'"

R is

4-(R5-(CH₂-CH2-0)_m-CH₂)-1 ,2,3-triazol-1-yl-CH₂-CH2-(0-CH2-CH₂)p-0- of structure:

or R is 1-(R5-(CH2-CH2-0)_m-CH2-CH2)-1 ,2,3-triazol-4-yl-CH2-(0-CH2-CH₂)p-0-of structure:

or R is a 1-(glucopyranosyl)-1 ,2,3-triazol-4-yl-CH2-(0-CH2-CH₂-)p-0- of structure:

and

is an optionally substituted C C₆ alkyl, preferably methyl or ethyl wherein the substituent is selected from halogen, preferably F, or is -(CH2-CH2-0)n-CH2-CH₂-R4, preferably is methyl or CH₂-CH₂-F;

R₂ is Ci-C₆ alkyl preferably isopropyl, C C₆ haloalkyi preferably fluoroalkyi preferably CH2-CH2-F, Ci-C_e haloalkenyl preferably CH=CH-F

R₃ is OH or C C₆ alkoxy, preferably OH, f-butyloxy or R3 is tetrahydropyranyloxy

R₅ is H, N0₂, N⁺(R₉)₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf (triflate group), 0₃SCH₂CH2(CF₂)7CF₃, perfluorophenyl sulfonate or halogen, preferably F

Rg is CrC₆alkyl, preferably methyl

m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10

n is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10

p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10

t is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10,

and enantiomers, esters and pharmaceutically acceptable salts thereof.

2. The compound of formula (I) according to claim 1 wherein:

A-R is an optionally substituted 1 /-/-1 ,2,3-triazol-4-yl of structure A' or an optionally substituted 1 ,2,3-triazol-1-yl-methyl of structure A" wherein R is C C₆ fluoroalkyl, more preferably CH₂-CH₂-F, glucopyranosyl, preferably 2-deoxy-2-fluoro^-D-glucopyranosyl, or

a compound according to claim 1 of formula la)

or a compound according to claim 1 of formula lb)

or a compound accordin to claim 1 of formula (lc)

or a compound according to claim 1 of formula (Id)

or a compound according to claim 1 of formula (le)

or a com ound according to claim 1of formula (If)

wherein in formulae (I), (la), (lb), (lc), (Id), (le), (If) and (Ig)

F is methyl, CH₂-CH₂-F or is -(CH₂-CH2-0)n-CH2-CH₂- R₄

R₂ is isopropyl

R₃ is OH, f-butyloxy, tetrahydropyranyloxy

R₄ is H, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf, OsSCHzCh^CFz CFs, perfluorophenyl sulfonate or halogen, preferably F, preferably H

R₅ is H, -C≡CH, N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf (triflate), 03SCH₂CH2(CF₂)7CF3, perfluorophenyl sulfonate or halogen, preferably F or H m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10

n is 0, 1,2, 3, 4, 5, 6, 7, 8, 9 or 10

pisO, 1,2,3, 4, 5, 6, 7, 8, 9 or 10

tisO, 1,2,3, 4, 5, 6, 7, 8, 9 or 10

enantiomers, esters or pharmaceutically acceptable salts thereof.

3. The compound according to claim 1

of formula Ih)

or of formula li)

or of formula (II)

wherein

Ri is methyl, CH₂-CH₂-F or R, is -(CH₂-CH2-0)n-CH2-CH₂-R4

R₂ is isopropyl,

R₃ is OH, f-butyloxy, tetrahydropyranyloxy

R₄ is H , OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf (triflate), 0₃SCH₂CH2(CF₂)7CF₃, perfluorophenyl sulfonate or halogen, preferably F

R₅ is H, -C≡CH, N₃, OTs, ONos (3-nitrobenzenesulfonate), mesylate, OTf (triflate), 0₃SCH₂CH₂(CF₂)₇CF₃, perfluorophenyl sulfonate or halogen, preferably F

m is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10;

n is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10;

p is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10;

enantiomers, esters or pharmaceutically acceptable salts thereof.

4. The compound according to claims 1 , 2 or 3 wherein the carbon atom bearing radical R₂ has a "S" configuration or a "R" configuration.

5. Compounds of formulae

racemates, esters and and pharmaceutically acceptable salts thereof.

6. A compound as defined in any of claims 1 , 2, 3, 4 and 5 wherein a carbon atom of said compound bears as a substituent a ¹⁸F in addition or in place to a substituent already present on said carbon atom.

7. The compound according to claims 1 to 4 and 6 wherein in formula (I) when A-R is A' or A", R is ¹⁸F-Ci-C₆ alkyl, preferably ¹⁸F-CH₂-CH₂.

8. The compound according to claims 1 to 4 and 6 wherein R₅ is ¹⁸F.

9. The compound according to claims 1 to 4 and 6 wherein R₄ is ¹⁸F.

10. The compound according to claims 1 to 4 and 6 wherein is ¹⁸F-C C₆ alkyl.

1 1. The compound according to claim 9 wherein is ¹⁸F-CH₂-CH₂.

12. Compounds of formulae

racemate, esters and pharmaceutically acceptable salts thereof.

13. A compound according to claims 1 to 5 for use as a medicament.

14. A compound according to claims 6 to 12 for use as a diagnostic agent.

15. A compound according to any of claims 1 to 5 for use in the prevention or treatment of pathological conditions associated with a dysregulated expression of matrix- metalloprotease in human and animal.

16. A compound according to any of claims 6 to 12 for use in the diagnosis of pathological conditions associated with an dysregulated expression of matrix- metalloprotease in human and animal.

17. The compound according to claim 15 or 16 wherein the pathological condition is selected from the group consisting of cardiovascular diseases, inflammatory diseases, malignant diseases and autoimmune disease.

18. The compound according to claim 17 wherein the cardiovascular diseases are selected from atherosclerosis and congestive heart failure and the inflammatory disease is chronic obstructive pulmonary disease.

19. A pharmaceutical composition comprising a compound as defined in any of claims 1 to 5 and a pharmaceutically acceptable carrier.

20. A diagnostic composition comprising a compound as defined in any of claims 6 to 12 and a pharmaceutically acceptable carrier.

21. An intermediate com ound of any of formulae (Ilia) to (lllh)

wherein R₂ and p are as defined in claims 1 -3

R₇ is NH-OH, NH-OR R₈, OH, C C₆-alkoxy and

R₈ is C C₆alkyl.

22. An intermediate com ound of formulae

23. Process for preparing a compound according to claims 1-12

comprising subjecting a compound of formulae Ilia, lllb, lllc, llld, llle, lllf, lllg, lllh wherein R₇ is NH-OH or a compound of claim 21 to a 1 ,3 dipolar cyclo-addition.

24. The process of claim 23 wherein the 1 ,3 dipolar cyclo-addition occurs by reacting a compound of any of formulae Ilia, lllc, llle, or lllg wherein R₇ is NH-OH or a compound of claim 21 ,

with a compound of formulae N₃-CH₂-CH₂-F, N₃-CH₂-CH₂-¹⁸F, N₃-(CH₂-CH₂-0)_rCH₂- CH₂-F or N₃-(CH₂-CH₂-0)_rCH₂-CH₂-¹⁸F

wherein r is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 3.

25. Process according to claim 24 wherein the compound of formula N₃-CH₂-CH₂-¹⁸F or a compound of formula N₃-(CH₂-CH₂-0)_rCH₂-CH₂-¹⁸F is prepared by reaction of a compound of formula N₃-CH₂-CH₂-OTs or of a compound of formula N₃-(CH₂-CH₂-0)_rCH₂-CH₂-OTs with a ¹⁸F containing reagent for nucleophile substitution of the group OTs.

26. The process of claim 23 wherein the 1 ,3 dipolar cyclo-addition occurs by reacting a compound of any of formulae 1Mb, llld, lllf, or lllh wherein R₇ is NH-OH,

with a compound of formulae HC≡C-CH₂-CH₂-F, HC≡C-CH₂-CH₂-¹⁸F, HC≡C-(CH₂-CH₂-0)_r- CH₂-CH₂-F or HC≡C-(CH₂-CH₂-0)_r-CH₂-CH₂-¹⁸F wherein r is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 3.

27. Process according to claim 26 wherein the compound of formula HC≡C-CH₂-CH₂-¹⁸F or a compound of formula HC≡C -(CH₂-CH₂-0)_rCH₂-CH₂-¹⁸F is prepared by reaction of a compound of formula HC≡C-CH₂-CH₂-OTs or of a compound of formula HC≡C-(CH₂-CH₂- 0)_rCH₂-CH₂-OTs with a ¹⁸F containing reagent for nucleophile substitution of the group OTs.

28. The process according to claims 25 or 27 wherein the ¹⁸F containing reagent is [¹⁸F](Kryptofix222)KF.

29. An intermediate of formula IV

wherein

a) A, R, A-R, R R₂, R₃, R₉, R₁₀, m, n, and p are as defined in any of claims 1 , 2 or 3 R₅ is OTs, ONos (3-nitrobenzenesulfonate), mesylate or OTf or

wherein

b) A, R, A-R, RL R₂, R₃, R₉, R₁₀, m, n, and p are as defined in any of claims 1 , 2 or 3, R₅ is OTs, ONos (3-nitrobenzenesulfonate), mesylate or OTf and R₄ is H or halogen.

0. A compound according to claim 29(a) wherein is methyl.