EP2079715A1 - Triazines and their use as inhibitors of metalloproteinases - Google Patents

Abstract

The present invention relates to compounds or pharmaceutically acceptable salts thereof, to processes for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in therapeutical use. In particular, the compounds are inhibitors of metalloproteinases involved in tissue degradation and various physiological and pathophysiological processes.

Description

Triazines and their use as inhibitors of metalloproteinases

Description TECHNICAL FIELD

The present invention relates to compounds or pharmaceutically acceptable salts thereof, to processes for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in therapeutical use. In particular, the compounds are inhibitors of metalloproteinases involved in tissue degradation and various physiological and pathophysiological processes.

BACKGROUND OF THE INVENTION

Metalloproteinases are a superfamily of enzymes, the numbers of which have increased dramatically in recent years. Based on structural and functional considerations they have been classified into families and subfamilies'¹'²¹ . Examples of metalloproteinases include the matrix metalloproteinases (MMPs) which are zinc-dependent endopeptidases involved in the degradation and remodeling of connective tissues. Members of these MMPs are present in various cell types that reside in or are associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells, and invasive or metastatic tumor cells. MMP expression is stimulated by growth factors and cytokines in the local tissue environment, where these enzymes act to specifically degrade protein components of the extracellular matrix, such as collagen, proteoglycans, fibronectin and laminin. These ubiquitous extracellular matrix components are present in the linings of joints, interstitial connective tissues, basement membranes, cartilage and others'³¹. Excessive degradation of extracellular matrix by MMPs is implicated in the pathogenesis of many diseases, including rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, myelin degradation such as multiple sclerosis, angiogenesis dependent diseases, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontitis, gingivitis, corneal epidermal or gastric ulceration, tumor metastasis invasion and growth, and in complications of diabetes. Therefore the inhibition of the involved MMPs is recognized as a good target for therapeutic intervention'⁴'⁵¹. The MMPs share a number of properties including zinc and calcium dependence, secretion as zymogens, and 40-50% amino acid sequence homology. At present, there are eighteen known human MMPs which are characterized by structural and functional properties and include gelatinases, stromelysins, collagenases,

CONRRMATION COPY matrilysin, metalloelastase and membrane-type MMPs₁ as discussed in greater detail below.

The gelatinases include two distinct, but highly related enzymes: a 72-kD enzyme (HFG, MMP-2, or gelatinase A) secreted by fibroblasts and a wide variety of other cell types, and a 92-kD enzyme (HNG, MMP-9, or gelatinase B) released by mononuclear phagocytes, neutrophils, corneal epithelial cells, tumor cells, cytotrophoblasts and keratinocytes. These gelatinases have been shown to degrade gelatins (denatured collagens), collagen types IV (basement membrane) and V, fibronectin and insoluble elastin. Stromelysins 1 and 2 have been shown to cleave a broad range of matrix substrates, including laminin, fibronectin, proteoglycans and collagen types IV and IX in their non-helical domains.

Interstitial collagenases catalyze the initial and rate-limiting cleavage of native collagen types I, Il and III. Collagen, the major structural protein of mammals, is an essential matrix component of many tissues like cartilage, bone, tendon and skin, for example. Interstitial collagenases are very specific matrix metalloproteinases which cleave these collagens resulting in two fragments which spontaneously denature at physiological temperatures and therefore become susceptible to cleavage by less specific enzymes. Cleavage by the collagenases results in the loss of structural integrity of the target tissue, which is essentially an irreversible process. There are currently three known human collagenases. The first is human fibroblast collagenase (HFC, MMP-1 , or collagenase-1 ) and is produced by a wide variety of cells including fibroblasts and macrophages. The second is human neutrophil collagenase (HNC, MMP-8, or collagenase-2) that has so far only been demonstrated to be produced by neutrophils and keratinocytes. The most recently discovered member of this group of MMPs is human collagenase-3 (MMP-13) which was originally found in breast carcinomas, but has been shown to be also produced by chondrocytes. Matrilysin (MMP-7, PUMP-1 ) has been shown to degrade a wide range of matrix substrates including proteoglycans, gelatin, fibronectin, elastin, and laminin. Its expression has been documented in mononuclear phagocytes, rat uterine explants and in tumors.

Other less characterized MMPs include human macrophage elastase (MMP-12, HME), membrane type-1 MMP (MMP-14, MT-1 MMP) and stromelysin-3 (MMP- 11 ). A recent review of matrix metalloproteinases provides an excellent source for detailed information and references on these enzymes¹⁶¹.

Further examples of metalloproteinases include the reprolysin or adamalysin (ADAM) family which includes the secretases and sheddases such as TNF-α converting enzyme (ADAM-17), the astacin family which includes enzymes such as procollagen processing proteinase (PCP), and other metalloproteinases such as aggrecanase, the endothelin converting enzyme family and the angiotensin converting enzyme family. ADAM-17, also known as tumor necrosis factor-alpha converting enzyme (TACE), is the most well known ADAM. ADAM-17 is resposible for cleavage of cell bound tumor necrosis factor-alpha (TNF-α). TNF-α is recognized to be involved in many infectious and autoimmune diseases. Furthermore, TNF-α is the prime mediator of the inflammatory response seen in sepsis and septic shock^m. There are two forms of TNF-α, a type Il membrane protein of relative molecular mass 26 kD and a soluble 17 kD form generated from the cell bound protein by specific proteolytic cleavage. The soluble 17 kD form of TNF-α is released by the cell and is associated with the deleterious effects of TNF-α. This form of TNF-α is also capable of acting at sites distant from the site of synthesis. Thus, inhibitors of TACE prevent the formation of soluble TNF-α and prevent the deleterious effects of the soluble factor. Other ADAMs that have shown expression in pathological situations include ADAM TS-1 , and ADAM-10, - 12 and -15, respectively¹⁸-⁹¹. As knowledge of the expression, physiological substrates and disease application of the ADAMs increases, the full significance of the role of inhibition of this class of proenzymes will be appreciated. Inhibitors of metalloproteinases may provide useful treatments for diseases associated with the excessive degradation of extracellular matrix, such as arthritic diseases (rheumatoid arthritis and osteoarthritis), bone resorptive diseases (such as osteoporosis), the enhanced collagen destruction associated with diabetes, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, corneal or gastric ulceration, ulceration of the skin, tumor invasion and metastasis. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumor growth as well as psoriasis, proliferative retinopathies, neovascularglaucoma, oculartumors, angiofibromas and hemoangiomas. However, it is recognized that different combinations of MMPs and ADAMs are expressed in different pathological situations. According to this, inhibitors with specific selectivities for individual ADAMs and/or MMPs may be preferred for individual diseases. For example, rheumatoid arthritis is an inflammatory joint disease characterized by excessive TNF-G levels and the loss of joint matrix constituents. In this case, a compound that inhibits TACE as well as MMPs such as MMP-13 may be preferred for therapeutical use. In contrast, in less inflammatory joint disease such as osteoarthritis, compounds that inhibit matrix degrading MMPs such as MMP-13 but not TACE may be preferred. Many known MMP inhibitors are peptide derivatives, based on naturally occurring amino acids, and are analogues of the cleavage site in the collagen molecule¹¹⁰'¹¹'. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually have a functional group capable of binding to the zinc(ll)site in the MMP which is known to be the catalytic center, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, sulphydryl, 5-thioxo-1 ,3,4- thiadiazole, and oxygenated phosphorus group. Known compounds show potent in vitro activities, but are generally poorly absorbed following oral administration. It is known that a number of factors can influence oral absorption (such as aqueous solubility, pKa, log p and molecular weight), and the design of pseudo- or non- peptide enzyme inhibitors with high oral absorption is far from straightforward¹¹²'¹³¹.

The design and use of metalloproteinase inhibitors are the subject of numerous patents and patent applications'¹⁴¹. The value of triazines as inhibitors of metalloproteinases has not hitherto been recognized however. They provide potency for high selectivity against individual MMPs. Moreover, the compounds claimed in this invention are apparently novel and have not been previously described in the literature.

SUMMARY OF THE INVENTION

In a first aspect of the invention we provide triazine compounds represented by formula (I)

wherin Ri is H, CN₁ CrC₆ alky!, C₁-C₆ alkyloxy, COOR with R = H, CrC₆ alkyl, or halogen; R₂ is independently selected from the group of hydrogen, halogen, -NO₂, -CN, -CF₃, - OH, -NH₂, Ci-C₆ alkyl, -S-Ci-C₆ alkyl, -SO-CrC₆ alkyl, -SO₂-Ci-C₆ alkyl, -SO₂NH₂, Ci-C₆ alkoxy, C4-C₁₀ aryloxy and COOR wherein R is hydrogen or Co-C₆ alkyl; L is Ci-Cβ alkylen or absent;

Y may be present or absent and is selected from -SO₂-, -NH-, -S-, -SO-, -Si;

R₃ is selected from H₁ CrC₆ alkyl, Ci-C₆ alkyloxy, CR₄,or COR₄;

R₄ is H, C1-C₆ alkyl, NHR₅ or a 5, 6 or 7 membered alkyl, aryl, heteroalkyl or heteroaryl ring comprising one, two or three heteroatoms selected from O, S and N which may optionally substituted with one, twothree or four substituents being independently selected from halogen, Ci-Cβ alkyl or oxo group;

Rs is H, Ci-Ce alkyl, C3-C7 cycloalkyl, C₄-CiO aryl, C₄-CiO heteroaryl, C5-C12 aralkyl,

C₅-C₁₂ heteroarylalkyl, all optionally substituted by one, two or three groups independently selected from NO₂, OH, CF₃, NH₂, CO-NH₂, COOH, halogen, Ci-C₄ alkyl, Ci-C₄ alkyloxy, carboxy (CrC₄) alkyl or C3-C6 cycloalkyl, or a heterocyclic 5, 6 or 7 membered ring comprising one, two or three of O, S and N which may be substituted being independently selected from halogen, CrCe alkyl or oxo group; ring A is a 5, 6 or 7 membered aliphatic ring and may optionally be mono - or disubstituted by optionally substituted Ci-Cβ alkyl or Ci-Cβ alkoxy, each substituent being independently selected from halogen, Ci-Ce alkyl or an oxo group, or may be absent; ring B is a monocyclic alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ring comprising up three to twelve ring atoms and containing no, one, two or three heteroatoms independently chosen from N, O, and S or a pharmaceutically acceptable salt thereof, or solvates or hydrates.thereof.

In a second aspect of the invention we provide triazine compounds represented by formula (II)

wherin R₁, R₂, R₃, R₄, R5, X and Y are defined as above and ring C is a monocyclic or bicyclic alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ring having three to twelve ring automs and comtaining no, one, two or three heteroatoms independendtly chosen from N, O, and S₁ or an pharmaceutically acceptable salt thereof, or solvates or hydrates thereof.

Any alkyl groups outlined above may be straight chain or branched. It will be appreciated that the particular substitutients and number of substituents on rings A B and C are selected so as to avoid sterically undesirable combinations. Depending on substituents, the compounds of formula (I) or (II) may exist in geometric, optical and other isomeric forms and this invention embraces any of these isomers or enantiomers.

A third aspect of this invention relates to methods for preparing compounds of formula (I) and (II).

A fourth aspect of this invention relates to pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof admixed with at least one pharmaceutically acceptable excipient.

A fifth aspect of this invention relates to methods for treating mammals having a disease state alleviated by the inhibition of matrix metalloproteinases or by the inhibition of ADAMs, by administering an effective amount of a compound of formula (I) or (II) or its pharmaceutically acceptable salts, or solvates or hydrates thereof, or a pharmaceutical composition thereof, to the mammal. Such disease states include arthritic diseases (rheumatoid arthritis and osteoarthritis), bone resorptive diseases (such as osteoporosis), the enhanced collagen destruction associated with diabetes, the enhanced collagen destruction associated with ultraviotet-B irradiation, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, corneal or gastric ulceration, ulceration of the skin, tumor invasion and metastasis.

Illustrative examples of compounds according to preferred embodiments of the present invention include, but are not limited to:

Λ/-[4-(6-cyano-3,5-dioxo-4,5-dihydro-1 ,2,4-triazin-2(3H)-yl)phenyl]acetamide; 2-(4-aminophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1 ,2,4-triazine-6-carboxylic acid;

4-(1 ,r-biρhenyl-4-ylsulfony))-1 ,2,4-triazine-3,5(2H,4H)-dione;

Λ/-(5-[(1 , 1 '-biphenyl-4-ylsulfonyl)methyl]-6-methyl-1 ,2,4-triazin-3-yl)-/V-phenylurea;

5-{[(4-methoxyphenyl)sulfonyl]methyl}-6-methyl-1,2_I4-triazin-3-amine;

Λ/-(4-chlorophenyl)-/V-{6-methyl-5-[(phenylsulfonyl)methyl]-1 ,2,4-triazin-3-yl}urea; Λ/-(4-ch!orophenyl)-/V-{6-methyl-5-[(1 ,1 ^'-biphenyl-4-ylsulfonyl)methyl]-1 ,2,4-triazin-3- yljurea;

5-[(1 , 1 '-biphenyl-4-ylsulfonyl)methyl]-6-methyl-1 ,2,4-triazin-3-amine;

4-[(4-methylphenyl)sulfonyl]-1 ,2,4-triazine-3,5(2H,4H)-dione; Λ/-(4-methylphenyl)-/V-{6-methyl-5-[(1 ,1 ^'-biphenyl-4-ylsulfonyl)methy!]-1 ,2,4-triazin-3- yl}urea;

Λ/-(6-methyl-5-{[(4-methylphenyl)sulfonyl]methyl}-1 ,2,4-triazin-3-yl)-/V-phenylurea;

Λ/-{6-methyl-5-[(phenylsulfonyl)methyl]-1 _I2,4-triazin-3-yl}-Λ/'-phenylurea; Λ/-{5-[(benzylsulfonyl)methyl]-6-methyl-1 , 2,44^^-3^1}-^ -phenylurea;

5-[(benzylsulfonyl)methyl]-6-methyl-1,2,4-triazin-3-amine;

/V-(5-{[(4-methoxyphenyl)sulfonyl]methyl}-6-methyl-1 ,2,4-triazin-3-yl)-/V-phenylurea;

6-methyl-5-{[(4-methylphenyl)sulfonyl]methyl}-1 ,2,4-triaziπ-3-amine;

Λ/-(4-methylphenyl)-Λ/'-{6-methyl-5-[(phenylsulfonyl)methyl]-1 ,2,4-triazin-3-yl}urea; 2-(4-phenoxyphenyl)-1 ,2,4-triazine-3,5(2H,4H)-dione;

2-[4-(hexylsulfonyl)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1 ,2_I4-triazine-6-carbonitrile;

S.S-dioxo^-^-CpentylsulfonyOphenylj^.SΛ.δ-tetrahydro-i ^^-triazine-δ-carbonitrile;

2-[4-(butylsulfonyl)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

S.S-dioxo^-K^propylsulfonyOphenyO^.S^.S-tetrahydro-i^^-triazine-β-carbonitrile; 2-[4-(ethylsulfonyl)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitriIe;

2-[4-(methylsulfonyl)phenyl]-3_l5-dioxo-2,3,4_l5-tetrahydro-1 ,2,4-triazine-6-carbonitrile;

4-(6-cyano-3,5-dioxo-4,5-dihydro-1 ,2,4-triazin-2(3/-/)-yl)-Λ/-(2,6-dimethoxypyrimidin-4- yl)benzenesulfonamide;

2-[4-(morpholin-4-ylsulfonyl)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1 ,2,4-triazine-6- carbonitrile;

4-methyl-/V-[(1 ,2,4-triazin-3-ylamino)carbonyl]benzene-sulfonamide;

Λ/-{[(5_l6-dimethyl-1 _l2,4-triazin-3-yl)amino]carbonyl}-4-methylbenzenesulfonamide;

Methyl-2-[({[4-(6-cyano-3,5-dioxo-4,5-dihydro-1 ,2,4-triazin-2(3H)-yl)phenyl]su!fonyl} acetyl)amino]propanoate; 2-{4-[(carboxymethyl)sulfonyl]phenyl}-3,5-dioxo-2,3,4,5-tetrahydro-1 ,2,4-triazine-6- carboxylic acid;

{[4-(6-cyano-3,5-dioxo-4,5-dihydro-1 ,2,4-triazin-2(3/-/)-yl)phenyl]sulfonyl}acetic ac!d;

DETAILED DESCRIPTION OF THE INVENTION

As previously outlined, the compounds of the invention are inhibitors of metalloproteinases. Recent efforts by a number of laboratories have provided several classes of MMP inhibitors which have been extensively reviewed¹¹⁵I In general, each class contains a zinc ligand attached to a small molecule, like small peptide fragment which is capable of binding to specificity pockets of the MMP enzymes, usually on the primed side. In general, the use of hydroxamates as the zinc ligand provides for the most effective MMP inhibitors. However, hydroxamates are often found to be biologically labile which has prompted additional efforts toward the discovery of new chelating groups suitable for use in MMP inhibitor templates. To explore this issue further, we undertook a broad screening effort using the catalytic domain of MMP-8 as the screening enzyme. From this, a number of triazines were identified which were weak (>40 μM) inhibitors of cdMMP-8. After elaboration of this compound series, improvement of enzyme potency, determination of structure-activity-relationships (SAR) and determination of MMP- specificity, we have found, that triazines of formula (I) and (II) potentially are novel, nonpeptidic alternatives to peptide-mimetic hydroxamate MMP inhibitors. Under the assumption that either the exocyclic nitrogen (formula (I)) or the N-4 of the heterocycle (formula (II)) chelates to the catalytic zinc, with the triazine-heterocycle and its position-5 (formula (I)) or the N-2 (formula (II)) residue generally located toward the unprimed side, several analogues were synthesized to improve primed side binding affinity. Selected compounds of this invention were further assayed in vitro for the inhibition of the catalytic domain of ADAM-9 and show remarkable selectivity. These results suggest that triazines can provide selective inhibitors of MMPs or ADAMs with a novel binding mode and increased oral bioavailablity because of their non-peptidic nature.

Dispite of this, the compounds of the present invention are also useful scientific research tools for studying functions and mechanisms of action of matrix metalloproteinases or ADAMs in both in vivo and in vitro systems. For example the present compounds can be used to modulate MMP action, thereby allowing the researcher to observe the effects of reduced MMP activity in the experimental biological system under study.

The following triazines are particularly preferred compounds according to the present invention, the Kj values of the compounds with respect to various MMPs determined according to the methods as described below are given:

5-[(benzylsulfonyl)methyl]-6-methyl-1,2,4-triazin-3-amine

K₁ [nM] cdMMP-2 19600; MMP-7 800; cdMMP-8 12800; cdMMP-9 9700; cdMMP-12 >50000; cdMMP-13 221 ; cdMMP-14 65

/V-(4-chlorophenyl)-/V-{6-methyl-5-[(phenylsulfonyl)methyl]-1 ,2,4-triazin-3-yl}urea

Kj [nM] cdMMP-2 4800; MMP-7 12; cdMMP-8 8200; cdMMP-9 >50000; cdMMP-12

>50000; cdMMP-13 50; cdMMP-14 >50000

Λ/-(5-[( 1 , 1 '-biphenyl-4-ylsulfonyl)methyl]-6-methyl-1 ^^-triazin-S-yO-ZV-phenylurea Kj [nM] cdMMP-2 10800; MMP-7 708; cdMMP-8 1800; cdMMP-9 8900; cdMMP-12 >24800; cdMMP-13 18; cdMMP-14 124;

Λ/-(5-{[(4-methoxyphenyl)sulfonyl]methyl}-6-methyl-1 ,2,4-triazin-3-yl)-/V-phenylurea Ki [nM] cdMMP-2 35000; MMP-7 265; cdMMP-8 22600; cdMMP-9 >50000; cdMMP- 12 >50000; cdMMP-13 193; cdMMP-14 2200

methyl-2-[({[4-(6-cyano-3,5-dioxo-4,5-dihydro-1 ,2,4-triazin-2(3H)-y!)phenyl]sulfonyl} acetyl)amino]propanoate

Ki [nM] cdMMP-2 14600; MMP-7 711 ; cdMMP-8 10700; cdMMP-9 2300; cdMMP-12

33600; cdMMP-13 98; cdMMP-14 1900

2-[4-(butylsulfonyl)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1 ,2,4-triazine-6-carbonitrile Kj [nM] cdMMP-2 28000; MMP-7 51 ; cdMMP-8 4000; cdMMP-9 10800; cdMMP-12 14900; cdMMP-132500; cdMMP-14222

2-[4-(morpholin-4-yisulfonyl)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1 ,2,4-triazine-6- carbonitrile

Ki [nM] cdMMP-2 29800; MMP-7 225; cdMMP-8 11300; cdMMP-9 >50000; cdMMP- 12 >50000; cdMMP-13 6; cdMMP-14 10000

4-(6-cyano-3,5-dioxo-4,5-dihydro-1 ,2,4-triazin-2(3/-/)-yl)-/V-(2,6-dimethoxypyrimidin-4- yl)benzenesulfonamide

Ki [nM] cdMMP-2 17600; MMP-7 21 ; cdMMP-8 9000; cdMMP-9 9100; cdMMP-12

21000; cdMMP-13 82; cdMMP-14 4300

PHARMACEUTICAL COMPOSITIONS The pharmaceutical compositions of this invention may be prepared by combining the compounds of formula (I) and (II) of this invention with a solid or liquid pharmaceutically acceptable carrier, and optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques.

The compounds of formula I and Il may be present in its base form or may be used as pharmaceutically acceptable salts thereof, or solvates or hydrates thereof. The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal, and parenteral administration to mammals, including man, to inhibit matrix metalloproteinases, and for the treatment of disorders responsive thereto, comprising an effective amount of a pharmacologically active compound of formula (I) or (II), alone or in combination, with one or more pharmaceutically acceptable carriers. Preferred are tablets and gelatin capsules comprising the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, and cellulose, lubricants, e.g, silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also binders, e.g. magnesium aluminium silicate, starch paste, gelatin, tra- gacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone, if desired disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures, and/or absorbants, colorants, flavors and sweeteners. Suppositories are advantageously prepared from fatty emulsions or suspensions. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compounds according to formula (I) or (II) as a soluble salt dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a suitably buffered isotonic solution having a pH of about 3.5 to 6.0. Pharmaceutically acceptable salts are well known in the art. They are described in detail for example by S. M. Berge et al^[1?!. Pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts. Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulphonic acids, e.g. hydrochloric acid, methanesulphonic acid, maleic acid, are also possible provided a basic group, such as amino, morpholino or pyridyl, constitutes part of the structure. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promotors, salts for regulating the osmotic pressure and/or buffers. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N- methylglucamine, L(+)-lysine and L(+)-arginine, to name a few. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient. Suitable formulations for transdermal application include an effective amount of a compound of formula (I) or (II) with a carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged time, and means to secure the device to the skin. Solar UV radiation damages human skin, affecting skin tone and resiliency and leading to premature aging (photoaging), the symtoms of which include leathery texture, wrinkles, mottled pigmentation, laxity and sallowness. This photoaging results largely from UV induction of matrix metalloproteinases that degrade skin collagen. Pretreatment of human skin with all-trans retinoic acid (tRA) inhibits UV induction of matrix metalloproteinases, suggesting that tRA can protect against UV-induced collagen destruction and may therefore be able to lessen the effects of photoaging¹¹⁸I According to this, the UV-induced collagen destruction may be prevented at an more effective level by the topical application of a compound of formula (I) or (II) in conjunction with all-trans retinoic acid to the skin prior to its exposure to UV radiation. Suitable formulations for topical application, e.g. to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well- known in the art. The pharmaceutical formulations contain an effective matrix metalloproteinase inhibiting amount of a compound of formula (I) or (II) as defined above either alone, or in combination with another therapeutic agent, e.g. all-trans retinoic acid, an antiinflammatory agent with cyclooxygenase inhibiting activity such as diclofenac sodium, other antirheumatic agents such as methotrexate, or antitumor agents such as bleomycin each at an effective therapeutic dose as reported in the art. Other therapeutic agents are well-known in the art. In conjunction with another active ingredient, a compound of formula (I) or (II) may be administered either simultaneously, before or after the other active ingredient, either separately by the same, by a different route of administration or together in the same pharmaceutical formulation. The dosage of active compound administered is dependent on the species of warm-blooded mammal, the body weight, age and individual condition, and on the form of administration. A unit dosage for oral administration to a mammal of about 50 to 70 kg may contain between about 10 and 1000 mg, advantageously between about 25 and 250 mg of the active ingredient.

IN VITRO METALLOPROTEINASE INHIBITION

Abbreviations

Abbreviations which have been used in the description that follows are: APMA for p-aminophenylmercuric acetate, MCA for (7-methoxycoumarin-4-yl)acetyl-, MRB for Microfluorometric Reaction Buffer, HEPES for N-[2-hydroxyethyl]piperazine-N'- [2-ethanesulphonic acid], PEG 8000 for polyethyleneglycol av. mol. wt.: 8000, PMNL for polymorphonuclear neutrophil leucocyte, DMSO for dimethylsulfoxide, MMP for matrix metalloproteinase, M for molar, cd for catalytic domain and [S] for substrate concentration.

MMPs

The tested MMP enzymes were prepared in the laboratories of the applicants, with the exception of MMP-7. Recombinant human MMP-7 expressed in E.coli was purchased from Calbiochem-Novabiochem Corporation, San Diego. Preparation of the recombinant catalytic domain of human Gelatinase A (cdMMP- 2): The catalytic domain of Pro-Gelatinase A was prepared using an E. coli expression system according to the method described by Kroger et af^9]. The proenzyme was activated with 0.5 mM APMA at 37⁰C prior to use in the assay. Preparation of the recombinant catalytic domain of human neutrophile Collagenase (cdMMP-8^Met80): The enzyme was expressed in E. coli as an active variant by the method of Kleine et al^[20]. Preparation of PMNL-Gelatinase (MMP- 9): Latent PMNL-pro-Gelatinase was prepared from human plasma buffy coat as described by Tschesche et al^t21!. PMNL-pro-Gelatinase was activated prior to use by incubation with Trypsin at 37⁰C for 10 min. Inactivation of Trypsin was accomplished with Aprotinin. Preparation of the recombinant catalytic domain of human Macrophage Elastase (cdMMP-12): The catalytic domain of MMP-12 was expressed in E. coli. The overexpressed protein was isolated as inclusion bodies and the renatured protein was purified by affinity chromatography with a hydroxamate inhibitor coupled to a column as described[²²]. Preparation of the recombinant catalytic domain of human Collagenase-3 (cdMMP-13): Human pro- cdMMP-13 was prepared using an E. coli expression system according to the method described[²³1. The isolated pro-cdMMP-13 was activated prior to use by incubation with 5 mM HgCb for 2 h at 37⁰C. Preparation of the recombinant catalytic domain of Membrane-Type- 1 MMP (cdMMP-14): The catalytic domain of MMP-14 was expressed in E. coli and was activated by autocatalysis¹²⁴

Determination of MMP inhibition

The enzymatic activity was measured using a modified version of a resonance energy transfer fluorogenic assay as described¹²⁶¹. Progress curves were monitored by following the increase in fluorescence at 393 nm (λ_ex = 328 nm), induced by the cleavage of the (7-methoxycoumarin-4-yl)acetyl-Pro-l_eu-Gly-Leu- (3-[2,4-dinitro-phenyl]-L-2,3-diamino-propionyl)-Ala-Arg-NH2 (Mca-Pro-Leu-Gly- Leu-Dpa-Ala-Arg-NH₂) fluorogenic substrate by MMPs. The fluorescent MCA- group is quenched by resonance energy transfer to the 2,4-dinitrophenyl group. Matrix metalloproteinases cleave this substrate at the Gly-Leu bond. Cleavage results in the loss of energy transfer and a large increase in fluorescence of the MCA group. This substrate is commercially available from Bachem, Switzerland. Enzyme inhibition assays were carried out in MRB which consisted of 50 mM HEPES/NaOH, pH 7.0, 10 mM CaCI₂ and 0,02% (w/v) PEG 8000 at 25°C. A standard screening procedure was used to determining the inhibitory activity. Mesurements were carried out with a fluorescence spectrometer LS 50B (Perkin- Elmer, Germany) in 10 mm cuvettes containing 2 ml buffer including 0.5 - 1 % DMSO vehicle, a final substrate concentration of 4 - 10 μM MCA-peptide, approximately 0.3 to 5 nM MMP and variable inhibitor concentrations. From a 30 mM stock (100% DMSO) the inhibitors were serially diluted with MRB to 75, 30, 15, 10, 5, 3, 1 , 0.6, 0.3, 0.1 , 0.05, 0.015 and 0.005 μM final assay concentration. After preincubation for 30 min at 25⁰C the reaction was started by addition of substrate. Each measurement was done in triplicate to ensure statistically significant results. The experiment was further controlled for background fluorescence of the substrate, for fluorescence of fully cleaved substrate and for fluorescence quenching or augmentation from solutions containing the test compounds.

IC₅₀ and Kj determination in microfluorometry assay The response of inhibition was determinated for each inhibitor concentration by comparing the amount of hydrolysis (fluorescence units generated over 30 minutes of hydrolysis) of cuvettes containing compound with the "enzyme-only" cuvette. With the program GraFit (Erithacus Software Limited) a 4 parameter logistic fit to the dose-response data was used to calculate IC50 values for each compound.

For each MMP, initial rate measurements in the absence of inhibitor were made for eight different substrate concentrations. From these data, K_m values were determined by nonlinear fit using the program GraFit. The K_m values determined for cdMMP-2, MMP-7, cdMMP-8, MMP-9, cdMMP-12, cdMMP-13, cdMMP-14 and were 9.1 , 1.9, 5.9, 1.8, 27.3, 7.5 and 6.8 μM, respectively.

Assuming competitive inhibition Kj values were calculated automatically for each enzyme tested based upon the equation previously described by Cheng and Prusoff¹²⁷¹:

Ki = (K_m x lC₅₀)/(K_m + [S])

The results of the obtained tests are presented above with the preferred examples.

INHIBITION OF THE ADAMALYSIN FAMILY INCLUDING ADAM-9 AS A REPRESENTATIVE OF ITS CLASS

ADAMs

The tested recombinant catalytic domain of ADAM-9 was prepared in the laboratories of the applicants by the method of Schwettmann et al^t2B1. The enzyme was expressed in Pichia Pastoris and activated by yeast proteases during maturation.

Test procedure for measuring cdADAM-9 inhibition

Quartz cuvettes received a solution composed of 7 μL cdADAM-9 (final concentration 0.2 nM), 2 mL Tris buffer, pH 7.5 (20 mM Tris/HCI, 500 mM NaCI, 5 mM CaCb and 0.5 mM ZnCb) containing 14 uL of compound 31 solution in H2O (final concentration: 20 μM) and were incubated for 30 minutes at 37⁰C. The reaction was initiated by addition of a fluorogenic peptide substrate for TNF-a converting enzyme (Mca-Pro-Leu-Ala-Gln-Ala-Val-Dap(Dnp)-Arg-Ser-Ser-Ser-Arg- NH₂. final concentration: 2 μM) to each cuvette. This substrate is commercially available from Bachem, Switzerland.

Initial rates of cleavage were monitored by measuring the rate of increase in fluorescence at 393 nm (λ_ex = 328 nm) over 60 min with a LS50B fluorimeter (Perkin-Elmer, Germany). The increase in fluorescence over time was plotted as a linear line. The slope of the line was calculated and represents the reaction rate. The rate of reaction in the presence of test compound was compared to that in the absence of test compound.

PREPARATION OF COMPOUNDS OF FORMULA (\) Abbreviations

Abbreviations which have been used in the descriptions of the schemes and the examples that follows are: EtOH for ethanol, MeOH for methanol, TLC for Thin- Layer Chromatography, mp for melting point, TMS for tetramethylsilane, ESI for Electron Spray Ionization, DHB for 2,5-dihydroxybenzoic acid, dec for decomposition, and DEI for Direct Electron Impact.

Chemistry

The compounds of the invention may be prepared by the use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the inhibitors, with more detailed particular examples being presented below in the experimental section describing the working examples. The preferred process for synthesising compounds of formula (I) involves the sulfonylation of the electron-rich 5-methyl carbanion generated by abstraction of the acidic proton by a base and following conventional addition of an isocyanate on the amino group according to the following reaction scheme:

OCN R,

The products are generally worked-up by permitting the reaction mixture to cool or concentrating it in vacuo. The resultant residues are recrystallized from an appropriate solvent, e.g., a mixture of a lower alkanol with, e.g., acetone, acetonitrile or ethyl acetate, e.g., methanol/ acetonitrile or methanol/ethyl acetate, producing the preferred product.

The substituted sulphonylchlorides, 1 ,2,4-triazine and isocyanates which are employed as starting materials in the preparation of the compounds of formula (I) are either commercially available or, when unavailable, they are very readily prepared by standard chemical reactions which are well-known to those of ordinary skill in the art. For example, the substituted sulphonylchlorides may be prepared from substituted sulphonic acids according the procedure described^[30].

The following reaction scheme shows the chemical reactions and procedures for preparing compounds of formula (II). Via the formation of a sulfonamide and following reduction with SnCb the resulting amine was used for diazotation. The diazonium salt was coupled with N-cyanoacetylurethan to form the corresponding carbamate which is used for thermic cyclysation.

The products are generally worked-up by permitting the reaction mixture to cool or concentrating it in vacuo. The resultant residues are recrystallized from an appropriate solvent, e.g., a mixture of a lower alkanol with, e.g., acetone, acetonitrile or ethyl acetate, e.g., methanol/ acetonitrile or methanol/ethyl acetate, producing the preferred product.

The sulfonylchlorides and amines which are employed as starting materials in the preparation of the compounds of formula (II) are commercially available.

EXAMPLES

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

General Procedures

All reactions were performed in oven-dried glassware under a positive pressure of argon and were stirred magnetically. Sensitive liquids and solutions were transferred via syringe or cannula and were introduced into reaction vessels through rubber septa. Materials P.a. grade reagents and solvents were used without further purification. Many of the specialty organic starting materials and reagents were obtained from Sigma-AIdrich, Deisenhofen, and Lancaster-synthesis, Mϋhlheim. Solvents are generally obtained from Merck, Darmstadt and Baker, Groβ-Gerau.

Chromatography

Analytical TLC was performed on Alugram SiI G/UV254 pre-coated aluminium- backed silica gel plates (Macherey-Nagel, Dϋren). Visualization of spots was effected by one of the following techniques: (a) ultraviolet illumination and (b) immersion of the plate in a 3% solution of ninhydrin in ethanol followed by heating. Instrumentation

Melting points (mp) were determined with a Bϋchi 510 melting point apparatus and are uncorrected.

Proton (¹H) nuclear magnetic resonance (NMR) spectra were measured with a Bruker DRX-500 (500 MHz) spectrometer, and carbon thirteen (¹³C) NMR spectra were measured with a Bruker DRX-500 (125.8 MHz) spectrometer, both with TMS as an external standard. All of the compounds synthesized in the experiments below were analyzed by NMR, and the spectra were consistent with the proposed structures in each case. Mass spectral (MS) data were obtained on a Fisons Autospec VG spectrometer by the DCI/methane and DEI isobutane method. Most of the compounds synthesized in the experiments below were analyzed by mass spectrometry, and the spectra were consistent with the proposed structures in each case.

Elemental analysis were performed on a Leco CHNS-932 elemental analyser. All inhibitors synthesized in the experiments below were analyzed by elemental analysis and most of the compounds had values within the acceptable range of +/-

0.3% for CHN.

General procedure for the preparation of compounds of formula (I)

Sulfonylation: Method A

Into a solution of triazine (10 mmol) in chloroform (150 ml) containing triethylamine

(10 mmol), sulfonylchloride (10 mmol) in chloroform (20 ml) was added dropwise.The mixture was then heated with stirring under reflux for 20 hours. The resulting precipitate was collected on a filter. The filtrate was evaporated to dryness in vacuo to give a solid, which was washed with hexane and then with water. The solids were combined and recrystallized repeatedly from EtOH.

Sulfonylation: Method B

A solution of sulfonylchloride (10 mmol) in acetone (20 ml) was added dropwise to a suspension of triazine (10 mmol) and sodium bicarbonate (10 mmol) in acetone (50 ml). The mixture was refluxed for 20 hours, cooled on an ice bath and the resulting precipitate collected, washed repeatedly with water and recrystallized from EtOH.

Reaction with lsocyanates

The substrate (10 mmol) was dissolved in chloroform (150 ml) by gentle warming. To the resulting solution was added dropwise a solution of isocyanate (10 mmol) in chloroform (10 ml). The mixture was heated with stirring under reflux for 6 hours and then evaporated to dryness in vacuo. The residue was washed with cold hexane and recrystallized repeatedly from EtOH.

Example 1 5-[(benzylsulfonyl)methyl]-6-methyl-1 ,2,4-triazin-3-amine

yield: 1 ,1 g (40 %), green needles, mp: 229 ⁰C, ¹H-NMR (500 MHz, DMSO-d₆): δ 2.33 (S, 3H₁ CH₃), 2.40 (s, 2H, CH₂), 4.64 (s, 2H, CH₂), 6.98 (s, 2H, NH₂), 7.54 (dd, 5H, ³J=8.1 Hz, arom. H). ¹³C-NMR (125.8 MHz, DMSO-d₆): δ 17.8 (CH₃), 21.2 (CH₂), 60.4 (CH₂), 97.6, 128.1 , 129.9 (C_arom), 136.0, 145.0, 147.9, 149.9 (C_q). ESI MS: 278.9 [M+Hf. Anal, calcd. for C₁₂Hi₄N₄O₂S: C, 51.78 % H, 5.07 % N, 20.13 %. Found: C, 52.02 % H, 4.94 % N, 19.66 %.

Example 2 /V-(4-chlorophenyl)-/V-{6-methyl-5-[(phenylsulfonyl)methyl]-1 ,2,4-triazin-3-yl}urea

yield: 1 ,5 g (38 %), white powder, mp: 230 ⁰C, ¹H-NMR (500 MHz, DMSO-d₆): δ 2.48 (S₁ 3H, CH₃), 5.13 (s, 2H, CH₂), 7.36-7.92 (m, 9H, arom. H)₁ 10.40 (s, 1 H, NH)₁ 10, 71 (s, 1 H, NH). ¹³C-NMR (125.8 MHz, DMSO-d₆): δ 18.1 (CH₃), 59.3 (CH₂), 100.9, 121.5, 121.9, 126.1 , 126.9, 128.6, 128.9, 129.6, 134.5 (C_arom), 128.1 , 136.9, 137.2, 138.2, 150.8, 152.9, 156.8 (C_q, with one C=O). ESI MS: 418.0 [M+H]⁺. Anal, calcd. for Ci₈H₁₆CIN₅O₃S: C, 51.74 % H, 3.86 % N₁ 16.76 %. Found: C, 51.38 % H, 3.91 % N, 16.31 %. Example 3 /V-(5-[(1 ,1^l-biphenyl-4-ylsulfonyl)methyl]-6-methyl-1 ,2,4-triazin-3-yl)-/V-phenylurea

5 yield: 1 ,9 g (42 %), white needles, mp: 237 ⁰C, ¹H-NMR (500 MHz, DMSO-d₆): δ 2.59 (s, 3H, CH₃), 5.18 (s, 2H, CH₂), 7.05-8.01 (m, 14H, arom. H), 10.24 (s, 1 H, NH)₁ 10.71 (s, 1 H, NH). ¹³C-NMR (125.8 MHz, DMSOd₆): δ 18.6 (CH₃), 59.4 (CH₂), 119.7- 156.8 (C, with 14 C_arom and 8 C_q). ESI MS: 460.1 [M+H]⁺. Anal, calcd. for C₂₄H₂₁N₅O₃S: C, 62.73 % H, 4.61 % N, 15.24 %. Found: C, 62.40 % H, 4.70 % N,0 14.75 %.

Example 4 A/-(5-{[(4-methoxyphenyl)sulfonyl]methyl}-6-methyl-1 ,2,4-triazin-3-yl)-Λ/'-phenylurea 5 yield: 1,4 g (34 %), white powder, mp: 207 ⁰C, ¹H-NMR (500 MHz, DMSO-d₆): δ 2.52

- (S, 3H, CH₃), 3.67 (s, 3H₁ CH₃), 5.04 (s, 2H, CH₂), 7.01-7.86 (m, 9H, arom. H), 10.29

(S₁ 1 H₁ NH), 10.62 (s, 1 H₁ NH). ¹³C-NMR (125.8 MHz, DMSO-d₆): δ 18.2 (CH₃), 55.6

(CH₃), 59.8 (CH₂), 102.2, 119.0, 119.9, 120.4, 123.2, 128.4, 128.7, 130.5 (Carom),

129.6, 138.2, 149.8, 150.7, 152.8, 156.9, 163.7 (C_q with one C=O). ESI MS: 414.00 [M+H]⁺. Anal, calcd. for Ci₉Hi₉N₅O₄S: C, 55.19 % H, 4.63 % N₁ 16.94 %. Found: C, 55.03 % H, 4.80 % N, 16.70 %.

General procedure for the preparation of compounds of formula (II) 5

1) Preparation of sulfonamid

To a stirred slurry of sulfonylchlorid (18 mmol) in ether (150 ml) was added dropwise a solution of morpholine (17 mmol) in ether (50 ml). After the mixture was stirred for 3 hours at reflux, the solid was removed by filtration and washed with 6N HCI and recrystallised in EtOH.

2) Reduction

A solution of SnCI₂*2H₂O (290 mmol) in 13 ml of cone. HCI was added to a stirred slurry of sulfonamid (73 mmol) in acetone. After 2 hours at reflux, the mixture was poured into 100 ml of water with stirring. After 3 hours, the solid was separated by filtration and washed repeatedly with water. An aqueous suspension was made alkaline with 30% NaOH solution and then extracted with chloroforme. After drying over Na₂SO₄ removal of the solvent yielded a white solid.

3) Diazotation

A mixture of N-cyanoacetylurethane (26.9 mmol) and 30 g sodium acetat in 900 ml water was stirred gentle at 0⁰C while a solution of diazonium salt was added dropwise during 20 min. The diazonium salt was prepared by adding a solution of 1.4 g sodium nitrit in water to a cooled (O⁰C) solution (20 mmol) amin and 10 ml cone. HCI in 200 ml water. After stirring the mixture for 15 min 15 g sodium acetate in 40 ml water were added. The whole mixture was left standing overnight, the resulting hydrazone collected, washed repeatedly with water and recrystallized repeatedly from EtOH.

4) Cyclisation

A mixture of hydrazon (3.0 mmol) and Na₂CO₃ (330 mg) in 25 ml water was refluxed for 10 min. The solid was removed and the solution acidified with cone, acetic acid. After cooling and filtration, the solid was washed repeatedly with water and recrystallised from EtOH/water.

Example 5

Methyl-2-[({[4-(6-cyano-3,5-dioxo-4,5-dihydro-1 ,2,4-tπazin-2(3H)-yl)phenyl]sulfonyl} acetyl)amino]propanoate

yield: 923 mg (73 %), white powder, mp: 238 ⁰C, ¹H-NMR (500 MHz₁ DMSO-d₆): δ 1.20 (d, 3H, ³J=7.2 Hz, CH₃), 3.60 (s, 3H, CH₃), 4.20 (s, 2H, CH₂), 4.40 (q, 1 H, ³J = 2.8 Hz, CH), 7.88 (dd, 4H, ³J=8.6 Hz, arom. H), 8.69 (s, 1H, NH), 13.06 (s, 1H, NH) . ¹³C-NMR (125.8 MHz, DMSO-d₆): δ 16.9 (CH₃), 47.8 (CH), 52.0 (CH₃), 60.7 (CH₂), 125.9, 129.2 (C_arom), 112.3, 123.3, 139.0, 143.2, 146.9, 154.6, 160.7, 172.3 (C_q with four C=O). ESI MS: 278.9 [M+Na]⁺. Anal, calcd. for Ci₆H₁₅N₅O₇S: C, 45.60 % H, 3.59 % N, 16.62 %. Found: C, 45.35 % H, 3.63 % N, 16.87 %.

Example 6 2-[4-(butylsulfonyl)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1 ,2,4-triazine-6-carbonitrile

yield: 823 mg (82 %), orange needles, mp: 230 ⁰C, ¹H-NMR (500 MHz, DMSO-d₆): δ 0.82 (t, 3H, ³J=7.4 Hz, CH₃), 1.31-1.35 (m, 2H, CH₂), 1.50-1.53 (m, 2H, CH₂), 3.34- 3.37 (m, 2H₁ CH₂), 7.91 (dd, 4H, ³J=8.7 Hz, arom. H). ¹³C-NMR (125.8 MHz, DMSO- dβ): δ 13.4 (CH₃), 20.8 (CH₂), 24.3 (CH₂), 54.3 (CH₂), 112.3 (C_q), 123.2 (C_q), 126.3

(Car_om), 128.7 (Carom), 140.0 (Cq), 143.1 (C=O), 147.0 (Cq), 154.6 (C=O). ESI MS:

333.1 [M-H]-. Anal, calcd. for C₁₄H₁₄N₄O₄S: C, 50.29 % H, 4.22 % N, 16.76 %. Found: C, 50.40 % H, 4.22 % N, 16.67 %.

Example 7

2-[4-(morpholin-4-ylsulfonyl)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1 ,2,4-triazine-6- carbonitrile

yield: 338 mg (31 %), yellow powder, mp: >300 ⁰C, ¹H-NMR (500 MHz, DMSO-d₆): δ 2.49 (t, 4H₁ CH₂), 3.63 (t, 4H, CH₂), 7.84 (dd, 4H, ³J=8.7 Hz₁ arom. H). ¹³C-NMR (125.8 MHz, DMSO-de): δ 45.9 (CH₂), 65.3 (CH₂), 112.6 (C_q), 123.2 (Cq)₁ 126.3 (C_arom), 128.6 (Carom), 134.2 (Cq)₁ 143.1 (C=O)₁ 147.6 (C_q), 155.4 (C=O). ESI MS: 362.2 [M-H]-. Anal, calcd. for C₁₄H₁₃N₃O₄S: C₁ 46.28 % H₁ 3.39 % N₁ 19.27 %. Found: C, 44.87 % H, 3.66 % N₁ 19.14 %.

Example 8

4-(6-cyano-3,5-dioxo-4,5-dihydro-1 ,2,4-triazin-2(3/-/)-yl)-Λ/-(2,6-dimethoxypyπmidin-4- yl)benzenesulfonamide

yield: 725 mg (56 %), yellow powder, mp: 233 ⁰C, ¹H-NMR (500 MHz, DMSO-d₆): δ 3.73 (S₁ 3H₁ CH₃), 3.79 (s, 3H, CH₃), 5.96 (s, 1 H₁ CH), 7.91 (dd, 4H, ³J=8.7 Hz, arom. H). ¹³C-NMR (125.8 MHz, DMSO-d₆): d 53.9 (CH₃), 54.6 (CH₃), 84.8 (CH), 112.4 (Cq), 123.2 (Cq), 126.1 (C_arom), 128.1 (Carom), 140.0 (C_q), 142.6 (C=O), 147.1 (C_q), 154.8 (C=O), 159.7 (CH)₁ 159.9 (C=O), 171.7 (C_q). ESI MS: 432.2 [M+H]⁺. Anal, calcd. for C₁₆Hi₃N₇O₆S: C₁ 44.55% H, 3.04 % N₁ 22.73 %. Found: C₁ 44.53 % H, 2.94 % N, 22.98 %.

PHARMACEUTICAL COMPOSITION EXAMPLES

The compounds of the invention are useful to prepare compositions for the treatment of ailments and the like. The following composition examples do not limit the invention, but provide guidance to the skilled artisan to prepare and use the compounds and compositions of the invention. Example A

A tablet composition for oral administration, according to the present invention, is made comprising:

The above ingredients with the exception of the magnesium stearate are combined and granulated using water as a granulating liquid. The formulation is then dried, mixed with the magnesium stearate and formed into tablets with an appropriate tablet machine. Example B

A suppository form for rectal administration, according to the present invention, is made comprising:

The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.

Example C

A composition for parental administration is made comprising:

The compound is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient quantity of 0.9% saline solution is then added with stirring to provide 100 ml of the i.V. solution which is filtered through a 0.2 N membrane filter and packaged under sterile conditions.

Example D

A inhalation aerosol composition, according to the present invention, is made comprising:

The compound is dispersed in ethanol and the propellants and mixed with the other ingredients. The resulting mixture is then poured into an aerosol container fitted with a metering valve.

Example E

A topical sunscreen preparation, according to the present invention, is made comprising:

Component Amount (%w/w)

Example 8 3.0 all-trans retinoic acid 2.0

Ethanol 84.2

Citric acid 2.0

Myristyl lactat 5.8

Silicone oil 2.0

Hydroxypropyϊ cellulose 1.0 acetate

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Claims

Claims

1. A compound having a structure according to formula

wherin

Ri is H₁ CN, Ci-C₆ alkyl, Ci-C₆ alkyloxy, COOR with R = H, Ci-C₆ alkyl, or halogen; R₂ is independently selected from the group of hydrogen, halogen, -NO₂, -CN,

-CF₃, -OH, -NH₂, Ci-C₆ alkyl, -S-Ci-C₆ alkyl, -SO-Ci-C₆ alkyl, -SO₂-Ci-C₆ alkyl, -SO2NH₂, CrC₆ alkoxy, C4-C10 aryloxy and COOR wherein R is hydrogen or Ci-C₆ alkyl; L is Ci-C₆ alkylen or absent; Y may be present or absent and is selected from -SO₂-, -NH-, -S-, -SO-, -Si;

R₃ is selected from H, Ci-C₆ alkyl, CrC₆ alkyloxy, CR₄, or COR₄; R₄ is H, CrC₆ alkyl, NHR₅, or a 5, 6 or 7 membered alkyl, aryl, heteroalkyl or heteroaryl ring comprising one, two or three heteroatoms selected from O, S and N which may optionally substituted with one, twothree or four substituents being independently selected from halogen, CrC₆ alkyl or oxo group;

R5 is H, CrC₆ alkyl, C₃-C₇ cycloalkyl, C4-C10 aryl, C4-C10 heteroaryl, C5-C12 aralkyl, C₅-C1₂ heteroarylalkyl, all optionally substituted by one, two or three groups independently selected from NO₂, OH, CF₃, NH₂, CO-NH₂, COOH, halogen, C1-C4 alkyl, C1-C4 alkyloxy, carboxy (C1-C4) alkyl or C₃-C₆ cycloalkyl, or a heterocyclic 5, 6 or 7 membered ring comprising one, two or three of O, S and N which may be substituted being independently selected from halogen, CrC₆ alkyl or oxo group;

Ring A is a 5, 6 or 7 membered aliphatic ring and may optionally be mono - or disubstituted by optionally substituted CrC₆ alkyl or CrC₆ alkoxy, each substituent being independently selected from halogen, CrC₆ alkyl or an oxo group, or may be absent; Ring B is a monocyclic alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ring comprising up three to twelve ring atoms and containing no, one, two or three heteroatoms independently chosen from N, O, and S or a pharmaceutically acceptable salt thereof, or solvates or hydrates.thereof.

2. A compound having a structure according formula Il

wherin Ri, R2, R3, R4, R₅, X and Y are defined as above and ring C is a monocyclic or bicyclic alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ring having three to twelve ring automs and comtaining no, one, two or three heteroatoms independendtly chosen from N, O, and S, or an pharmaceutically acceptable salt thereof, or solvates or hydrates thereof.

3. A compound according to claim 1 or 2 wherin X is SO₂.

4. A compound according to any one of the preceding claims wherin R₁ is CH₃ or CN.

5. A compound according to any one of the claims 1 , 3 or 4 wherin ring B is an optionally substituted phenyl and R₃ is COR₄ with R₄ = NH-R₅.

6. A compound according to any one of claim 2 to 4 wherin Ri is CN, ring C is phenyl, and X is SO₂.

7. The use of a compound of any one of the preceding claims as an inhibitor of matrix metalloproteinases.

8. The use of a compound according to claim 1 to 7 as an inhibitor of a mammalian reprolysin.

9. The use of a compound according to any one of claims 1 to 6 as a therapeutically active substance.

10. A pharmaceutical composition comprising a compound according to any one of claims 1-6 and, optionally, a pharmaceutically acceptable exipient or carrier.

11. The use of a compound according to any one of claims 1 -6 for the preparation of a pharmaceutical composition for the treatment of a condition selected from the group consisting of arthritis inflammatory bowel disease, wound healing, spinal cord therapy, slipped disc, ulcus, Crohn^'s disease, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders, autoimmune disorders, Huntington^'s disease, Parkinson^'s disease, migraine, depression, emphysema, chronic obstructive pulmonary disease, Alzheimer^'s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, psoriasis, sclerititis, AIDS, sepsis and septic shock in a mammal.

12. A use of a compoud according to any one of claims 1-6 for the preparation of a pharmaceutical composition for the treatment of a condition which can be treated by the inhibition of matrix metalloproteinases in a mammal.

13. The use according to claim 12 wherin the matrix metalloproteinase is a mammalian reprolysin.

14. The use of a compound according to any one of claims 1-6 for the preperation of a pharmaceutical composition for the treatment of a disease-state which is alleviated by treatment with a matrix metalloproteinase inhibitor.

15. The use according to claim 14 wherin the disease-state results from ultraviolet- B (UVB) irradiation such as skin reddening, sun-burns, skin-cancer, leathery textures, wrinkles, or mottled pigmentations.

16. A method for treating a condition selected from the group consisting of arthritis inflammatory bowel disease, Crohn^'s disease, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporisis, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders, autoimmune disorders, Huntington's disease, Parkinson^'s disease, migraine, depression, emphysema, chronic obstructive pulmonary disease, Alzheimer^'s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, psoriasis, scleritis, AIDS, sepsis and septic shock in a mammal, comprising administering to said mammal a therapeutically effective anmount of a compound according any one of claims 1 -9, effective in treating such a condition.

17. A method for inhibiting of matrix metalloproteinases in a mammal, comprising administering to said mammal an effective amount of a compoud of any one of claims 1-6.

18. The method according to claim 17 for the inhibition of a mammalian reprolysin in a mammal.

19. The use of a compound according to any one of claims 1 -6 for the preparation of an UV radiation protection composition in conjunction with all-trans retinoic acid.

20. UV radiation protection composition comprising a compound according to any one of claims 1-6 and all-trans retinoic acid.