The present invention relates to novel hydroxamic acid derivatives as inhibitors of meprin β and/or a, pharmaceutical compositions comprising such compounds, methods for treatment or prophylaxis of diseases or conditions, especially such that are related to meprin β and/or a, and compounds and pharmaceutical compositions for use in such methods .

BACKGROUND ART

Meprin a and β both represent zinc-dependent metalloproteases of the astacin family and the metzincin superfamily. They show a similar domain structure and the human enzymes are of 45% sequence homology to each other. Meprin β is a type 1 transmembrane protein with extracellular protease activity whereas meprin a is shed during the secretory pathway and secreted into extracellular space. Both enzymes are expressed as zymogens with high expression rates in epithelial cells of the kidney and intestine, and they have been demonstrated in intestinal leukocytes, skin and certain cancer cells.

The meprins show distinct substrate specificity with a preference of acidic amino acids in the PI '-position (Becker-Pauly, C;

Barre, 0 .; Schilling, 0 .; in the basement, U .; Ohler, A .; Broder, C. et al. (2011), Mol Proteomics, doi:

10.1074/mcp . Mil 1.009233 ) . A number of in vitro substrates have been identified including extracellular matrix proteins, peptide hormones and cytokines. Known in vitro substrates of meprin β comprise orcokinin, gastrin 17, Peptide YY, kinetensin,

osteopontin, interleukin 1β, APP, MUC 2 mucin, and cystic fibrosis transmembrane conductance regulator E-cadherin, whereas known in vitro substrates of meprin a comprise bombesin, neurotensin, Substance P, angiotensin I, luteinizing hormone releasing hormone, valosin, vasoactive intestinal peptide, bradykinin, ot-melanocyte stimulating hormone, MCP-1, and occludin. Known in vitro

substrates of both meprin β and a are, e.g., the Gastrin-releasing peptide, and Cholecystokinin .

Although the function of meprins in vivo still remains to be elucidated, there is increasing evidence for their role in collagen assembly, inflammation, intestinal immune response and neurodegeneration .

Meprin β has been shown to act as β-secretase of amyloid precursor protein to form amyloid β (Αβ) peptides in vitro (Bien, Jessica; Jefferson, Tamara; Causevic, Mirsada; Jumpertz, Thorsten; Munter,

Lisa; Multhaup, Gerd et al . (2012), The Journal of biological chemistry 287 (40), pp. 33304-33313) . The Αβ peptide, which is abundantly found in the brains of patients suffering from

Alzheimer's disease, is central in the pathogenesis of this

disease. Said study showed that, in contrast to BACE I, meprin β is capable of formation of N- terminally truncated Αβ and

therefore might be involved in the generation of potentially more toxic species of Αβ. Accordingly, meprin β appears to be involved in the pathogenesis and/or disease progression of, e.g.,

Alzheimer's disease.

The lack of meprin β and a in mouse or the use of Actinonin (a meprin inhibitor) have been shown to protect against renal injury and bladder inflammation (Bylander, John; Li, Qing; Ramesh,

Ganesan; Zhang, Binzhi; Reeves, W. Brian; Bond, Judith S. (2008), /American journal of physiology. Renal physiology 294 (3), pp.

F480-90; Yura, Renee E.; Bradley, S. Gaylen; Ramesh, Ganesan;

Reeves, W. Brian; Bond, Judith S. (2009), /American journal of physiology. Renal physiology 296 (1), pp. F135-44) . Accordingly, meprin β and a appear to be involved in the pathogenesis and/or disease progression of, e.g., nephritis, renal injury, renal ischemic injury, ischemic acute tubular necrosis, acute renal failure, and bladder inflammation.

Both enzymes have been demonstrated to be C- and N-procollagen proteinases and to induce collagen maturation and assembly

(Biasin, Valentina; Marsh, Leigh M. ; Egemnazarov, Bakytbek;

Wilhelm, Jochen; Ghanim, Bahil; Klepetko, Walter et al . (2014), The Journal of pathology 233 (1), pp. 7-17; Prox, Johannes;

Arnold, Philipp; Becker-Pauly, Christoph (2015) , Matrix biology 44-46, pp. 7-13) . Under fibrotic conditions (keloids, pulmonary hypertension) , overexpression of the enzymes has been found in these studies. Accordingly, meprin β and a appear be involved in the pathogenesis and/or disease progression of, e.g., fibrosis and fibrotic conditions (keloids, pulmonary hypertension) and

interstitial lung disease (ILD) .

Meprin a has been shown to be a susceptibility gene for IBD

(Crohn's disease, ulcerative colitis) and that its absence increases chronic inflammation, while meprin β has proinflammatory activity and its lack results in some protection from injury (Banerjee, Sanjita; Jin, Ge; Bradley, S. Gaylen; Matters, Gail L.; Gailey, Ryan D. ; Crisman, Jacqueline M.; Bond, Judith S.

(2011), Am. J. Physiol. Gastrointest . Liver Physiol. 300 (2), pp. G273-82) . Accordingly, meprin β and a appear to be involved in the pathogenesis and/or disease progression of, e.g., chronic

inflammation, Crohn's disease, ulcerative colitis, and

inflammatory bowel disease (IBD) .

Pro-angiogenetic activity and non-polarized secretion have been described for meprin a, thereby increasing invasiveness of

colorectal cancer (Lottaz, Daniel; Maurer, Christoph A.; Noel, Agnes; Blacher, Silvia; Huguenin, Maya; Nievergelt, Alexandra et al. (2011), PloS one 6 (11), p. e26450) . Accordingly, meprin a pathogenesis and/or disease progression of cancer, especially colorectal cancer.

Several broad-spectrum metalloprotease and MMP inhibitors have been elucidated concerning their inhibitory activity towards meprin a and β (Broder, Claudia; Becker-Pauly, Christoph (2013) , The Biochemical Journal 450, 253-264) . Although some compounds showed inhibition of meprin a, for all the compounds, the

inhibition of Meprin β was much lower, (exhibiting inhibition constants in the micromolar range) or were lacking acceptable drug-like properties (Madoux F, Tredup C, Spicer TP, Scampavia L, Chase PS, Hodder PS, Fields GB, Becker-Pauly C, Minond D (2014), Biopolymers 102 (5), pp. 396-406) . Broder C, Characterization of the metalloproteases meprin a and meprin β within the protease web (August 2013; Doctoral dissertation; Universitatsbibliothek Kiel; Accession No. urn : nbn : de : gbv : 8-diss-l 46034 ; pp. 29, 53) discloses a phosphinic meprin β inhibitor (PMI) .

PROBLEMS TO BE SOLVED BY THE INVENTION

In view of the above prior art, the present invention aims, as a main object, to provide potent inhibitors of meprin β and/or a. A first object of the present invention is to provide selective inhibitors of meprin β. A second object of the present invention is to provide selective inhibitors of meprin a . A third object of the present invention is to provide dual inhibitors of meprin β and a . A fourth object of the present invention is to provide meprin inhibitors according to any of the aforementioned objects, wherein the inhibitors have acceptable drug-like properties .

A fifth object of the present invention is to provide a

pharmaceutical composition comprising a meprin inhibitor according to any of the aforementioned objects that is suitable for

administration to a subject in need thereof.

A sixth object of the present is to provide a method for producing the meprin inhibitors according to any of the aforementioned obj ects .

A seventh object of the present is to provide a method for treatment or prophylaxis of the human or animal body, and a compound or a pharmaceutical composition for use in such a method.

An eight object of the present is to provide a method for

treatment or prophylaxis of a subject suffering from or having risk of developing a disease or condition related to meprin β and/or a.

A ninth object of the present is to provide a method for treatment or prophylaxis of a subject suffering from or having risk of developing a disease or condition such as Alzheimer's disease, nephritis, renal injury, renal ischemic injury, ischemic acute tubular necrosis, acute renal failure, bladder inflammation, inflammatory bowel disease (IBD) , Crohn's disease, ulcerative colitis, chronic inflammation, colitis, fibrosis, fibrotic conditions, keloids, pulmonary hypertension, or interstitial lung disease (ILD) , or cancer, especially colorectal cancer, and/or a compound for use in such a method.

SUMMARY OF THE INVENTION

As a solution to the above-formulated problems, the present invention provides a compound represented by the following Formula I, its individual enantiomers, its individual diastereoisomers , its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof,

Formula I

wherein :

n = 1-3, preferably 1 or 2;

R1 , RJ and are independently selected from H and the group consisting of alkyl, alkenyl, alkynyl, carbocyclyl, aryl, arylalkyl, heterocyclyl , heteroaryl and heteroarylalkyl , each of which can be optionally substituted;

R^ is selected the group consisting of alkyl, alkenyl, alkynyl, carbocyclyl, aryl, arylalkyl, heterocyclyl,

heteroaryl and heteroarylalkyl, each of which is substituted;

wherein any two of R^ , R^ , R3 and R^ may be joined together to form a ring;

is preferably H;

X is -CH2-.

The present invention also provides a pharmaceutical composition comprising a compound according to above Formula I, its individual enantiomers, its individual diastereoisomers , its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

The present invention also provides a method for producing the above compounds .

The present invention also provides a method for treatment or prophylaxis of the human or animal body by surgery or therapy comprising administering a therapeutically effective amount of the above compound or pharmaceutical composition to a subject in need thereof, and/or a compound or pharmaceutical composition for use in such a method.

The present invention also provides a method for treatment or prophylaxis of Alzheimer's disease, nephritis, renal injury, renal ischemic injury, ischemic acute tubular necrosis, acute renal failure, bladder inflammation, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, chronic inflammation, colitis, fibrosis, fibrotic conditions, keloids, pulmonary hypertension, interstitial lung disease (ILD), or cancer,

especially colorectal cancer, comprising administering a

therapeutically effective amount of the above compound or

pharmaceutical composition to a subject in need thereof, and/or a compound or pharmaceutical composition for use in such a method.

DETAILED DESCRIPTION OF THE INVENTION

The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, prophylaxis, observation or experiment.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

The term "alkyl" as used herein, unless specifically limited, denotes a C]__]_2 alkyl group, suitably a C]__g alkyl group, e.g. C]__ g alkyl group, e.g. C]__ alkyl group. Alkyl groups may be straight chain or branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl) , butyl (e.g. n-butyl, iso-butyl, sec-butyl and tert-butyl) , pentyl (e.g. n-pentyl), hexyl (e.g. n-hexyl) , heptyl (e.g. n-heptyl) and octyl (e.g. n-octyl ) .

The term "alkyl" as used herein also comprises cycloalkyl groups. The expression "cycloalkyl", unless specifically limited, denotes a ^-iQ cycloalkyl group (i.e. 3 to 10 ring carbon atoms) , more suitably a C3_8 cycloalkyl group, e.g. a C3_g cycloalkyl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl . A most suitable number of ring carbon atoms is three to six.

The expression "alk", for example in the expressions "alkoxy", "haloalkyl" and "thioalkyl" should be interpreted in accordance with the definition of "alkyl". Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g. n-propoxy) , butoxy (e.g. n-butoxy) , pentoxy (e.g. n-pentoxy) , hexoxy (e.g. n-hexoxy) , heptoxy (e.g. n-heptoxy) and octoxy (e.g. n-octoxy) . Exemplary thioalkyl groups include methylthio. Exemplary haloalkyl groups include fluoroalkyl e.g. CF3; exemplary haloalkoxy groups include fluoroalkyl e.g. OCF3. The expressions "fluoro (C__g alkyl)" and "fluoro (C__g alkoxy) " denote a C__g alkyl and C__g alkoxy group, respectively, each of which is substituted by one or more fluoro atoms.

The expression "alkenyl", unless specifically limited, denotes a C2-12 alkenyl group, suitably a C2-g alkenyl group, e.g. a C2-4

alkenyl group, which contains at least one double bond at any desired location and which does not contain any triple bonds.

Alkenyl groups may be straight chain or branched. Exemplary alkenyl groups including one double bond include propenyl and butenyl . Exemplary alkenyl groups including two double bonds include pentadienyl, e.g. (1 E, 3E) -pentadienyl .

The expression "alkenyl" as used herein also comprises

cycloalkenyl groups. The expression " cycloalkenyl " , unless specifically limited, denotes a C5_io cycloalkenyl group (i.e. 5 to 10 ring carbon atoms) , more suitably a C3_g cycloalkenyl group e.g. a C _g cycloalkenyl group. Exemplary cycloalkenyl groups include cyclopropenyl , cyclohexenyl , cycloheptenyl and

cyclooctenyl . A most suitable number of ring carbon atoms is five to six.

The expression "alkynyl", unless specifically limited, denotes a C2-12 alkynyl group, suitably a C2-6 alkynyl group, e.g. a C2-4 alkynyl group, which contains at least one triple bond at any desired location and may or may not also contain one or more double bonds. Alkynyl groups may be straight chain or branched. Exemplary alkynyl groups include propynyl and butynyl .

The expression "alkylene" denotes a chain of formula ~(CH2)n-wherein n is an integer e.g. 2-5, unless specifically limited.

The expression "carbocyclyl" , unless specifically limited, denotes any ring system in which all the ring atoms are carbon and which contains between three and twelve ring carbon atoms, suitably between three and ten carbon atoms and more suitably between three and eight carbon atoms. Carbocyclyl groups may be saturated or partially unsaturated, but do not include aromatic rings. Examples of carbocyclyl groups include monocyclic, bicyclic, and tricyclic ring systems, in particular monocyclic and bicyclic ring systems. Other carbocylcyl groups include bridged ring systems (e.g.

bicyclo [ 2.2.1 ]heptenyl) . A specific example of a carbocyclyl group is a cycloalkyl group. A further example of a carbocyclyl group is a cycloalkenyl group.

The expression "aryl", unless specifically limited, denotes a Cg_ 12 aryl group, suitably a Cg_]_Q aryl group, more suitably a Cg_g aryl group. Aryl groups will contain at least one aromatic ring (e.g. one, two or three rings) . An example of a typical aryl group with one aromatic ring is phenyl. An example of a typical aryl group with two aromatic rings is naphthyl .

The expression "arylalkyl", unless specifically limited, denotes an aryl residue which is connected via an alkylene moiety, e.g., a C__4 alkylene moiety.

The expression "heterocyclyl", unless specifically limited, refers to a carbocyclyl group wherein one or more (e.g. 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and 0. A specific example of a heterocyclyl group is a cycloalkyl group (e.g. cyclopentyl or more particularly cyclohexyl) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S or 0.

Exemplary heterocyclyl groups containing one hetero atom include pyrrolidine, tetrahydrofuran and piperidine, and exemplary heterocyclyl groups containing two hetero atoms include morpholine and piperazine. A further specific example of a heterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S and 0. An example of such a group is dihydropyranyl (e.g. 3 , 4-dihydro-2H-pyran-2-yl- ) .

The expression "heteroaryl", unless specifically limited, denotes an aryl residue, wherein one or more (e.g. 1 , 2, 3, or 4, suitably 1 , 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and 0, or else a 5-membered aromatic ring containing one or more (e.g. 1 , 2, 3, or 4, suitably 1 , 2 or 3) ring atoms selected from N, S and 0. Exemplary monocyclic

heteroaryl groups having one heteroatom include: five membered rings (e.g. pyrrole, furan, thiophene) ; and six membered rings (e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl and pyridin-4- yl) . Exemplary monocyclic heteroaryl groups having two heteroatoms include: five membered rings (e.g. pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, such as imidazol-l-yl , imidazol-2-yl imidazol-4-yl) ; six membered rings (e.g. pyridazine,

pyrimidine, pyrazine) . Exemplary monocyclic heteroaryl groups having three heteroatoms include: 1 , 2 , 3-triazole and 1 ,2,4-triazole. Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole. Exemplary bicyclic heteroaryl groups include: indole (e.g. indol-6-yl), benzofuran,

benzthiophene , quinoline, isoquinoline, indazole, benzimidazole, benzthiazole, quinazoline and purine.

The expression "heteroarylalkyl " , unless specifically limited, denotes a heteroaryl residue which is connected via an alkylene moiety e.g. a C__4alkylene moiety.

The term "halogen" or "halo" comprises fluorine (F) , chlorine (CI) and bromine (Br) .

The term "amino" refers to the group -NH2.

The terms "optionally substituted" and "substituted" refer to (optional) substitution by one or several groups independently selected from a halogen atom, a cyano group, a hydroxyl group and a carboxyl group. These terms also refer to (optional)

substitution by one or several groups independently selected from -C (0) -0- (C]__g alkyl) group, a

-C(0)-NH2 group, a C]__g alkylsulfono group, C]__g alkoxy and a C]__g aliphatic, aromatic or heterocyclic group, each of which may be further substituted by one or several halogen atoms, carboxyl, cyano, and/or hydroxyl groups. Preferably, an alkyl group which is substituted does not have a keto group on the C atom that is directly bound to the N atom in Formula I .

The expressions "alkoxyaryl" , "carboxyaryl" , "cyanoaryl",

"haloaryl", "hydroxyaryl" and "heteroarylaryl" , unless

specifically limited, denote an aryl residue which is substituted by at least one alkoxy, carboxy, cyano, halo, hydroxy and heteroaryl group, respectively.

The expressions "alkoxyheteroaryl", "carboxyheteroaryl",

"cyanoheteroaryl" , "haloheteroaryl" and "hydroxyheteroaryl", unless specifically limited, denote a heteroaryl residue which is substituted by at least one alkoxy, carboxy, cyano, halo, and hydroxy group, respectively.

The expression "arylmethyl", unless specifically limited, denotes an aryl residue which is connected via a methylene moiety.

The expressions " (alkoxyaryl) methyl", " (hydroxyaryl ) methyl" ,

" ( carboxyaryl ) methyl" , " (heteroarylaryl ) methyl"

" (alkoxyheteroaryl) methyl", " (hydroxyheteroaryl ) methyl" and

" (carboxyheteroaryl) methyl", unless specifically limited, denote an alkoxyaryl, hydroxyaryl, carboxyaryl, heteroarylaryl,

alkoxyheteroaryl, hydroxyheteroaryl and carboxyheteroaryl residue respectively, which is connected via a methylene moiety.

Stereoisomers :

All possible stereoisomers of the claimed compounds are included in the present invention.

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers . It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

Preparation and isolation of stereoisomers:

Where the processes for the preparation of the compounds accordin to the invention give rise to a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in

racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-) -di-p-toluoyl-d-tartaric acid and/or (+) -di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base, or by salt formation with an optically active base, such as quinine, quinidine, quinotoxine, cinkotoxine, ( 5) -phenylethylamine, (If?, 25) -ephedrine, (R) -phenylglycinol , (5) -2-aminobutanol , followed by fractional crystallization and regeneration of the free acid. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

Polymorph crystal forms:

Furthermore, some of the crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

As used herein, the term "tautomer" refers to the migration of protons between adjacent single and double bonds. The

tautomerization process is reversible. Compounds described herein can undergo any possible tautomerization that is within the physical characteristics of the compound.

As used herein, the term "pharmaceutically acceptable" embraces both human and veterinary use. For example, the term

"pharmaceutically acceptable" embraces a veterinarily acceptable compound or a compound acceptable in human medicine and health care .

Pharmaceutically acceptable salts:

In view of the close relationship between the free compounds and the compounds in the form of their salts, hydrates or solvates, whenever a compound is referred to in this context, a

corresponding salt, solvate or polymorph is also intended, provided such is possible or appropriate under the circumstances.

Salts, hydrates and solvates of the compounds of Formula I and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the counter-ion or

associated solvent is pharmaceutically acceptable. However, salts, hydrates and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically

acceptable salts, hydrates and solvates.

Suitable salts according to the invention include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed from

hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic,

triphenylacetic, sulfamic, sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxaloacetic,

methanesulfonic, ethanesulfonic, arylsulfonic (for example p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic or

naphthalenedisulfonic) , salicylic, glutaric, gluconic,

tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy or halo substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid) , ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic) , naphthaleneacrylic (for example naphthalenes-acrylic) , benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (for example 1 , 4-benzenediacrylic) , isethionic acids, perchloric, propionic, glycolic,

hydroxyethanesulfonic, pamoic, cyclohexanesulfamic, salicylic, saccharinic and trifluoroacetic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and AJ-methyl-D-glucamine .

All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be embraced by the scope of this invention.

Prodrugs :

The present invention further includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Thus, in these cases, the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with prodrug versions of one or more of the claimed compounds, but which converts to the above specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

As used herein, the term "composition" is intended to encompass a product comprising the claimed compounds in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the claimed compounds.

Excipients (Carriers and additives for galenic formulations) :

Thus, for liquid oral preparations, such as for example,

suspensions, elixirs and solutions, suitable carriers and

additives may advantageously include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents,

lubricants, binders, disintegrating agents and the like.

Carriers, which can be added to the mixture, include necessary and inert pharmaceutical excipients, including, but not limited to, suitable binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, coatings, disintegrating agents, dyes and coloring agents .

Soluble polymers as targetable drug carriers can include

polyvinylpyrrolidone, pyran copolymer,

polyhydroxypropylmethacrylamidephenol ,

po1yhydroxyethylaspartamide-phenol , or polyethyleneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone , polyhydroxy butyeric acid, polyorthoesters , polyacetals, polydihydropyrans , polycyanoacrylates and cross-linked or amphipathic block

copolymers of hydrogels.

Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Protective Groups :

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional

protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W.

Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, Joh Wiley & Sons, 1991 , fully incorporated herein by reference. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

A protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. Protecting groups are e.g. alcohol protecting groups, amine protecting groups, carbonyl protecting groups, carboxylic acid protecting groups and phosphate protecting groups .

Examples for alcohol protecting groups are acetyl (Ac) , benzoyl (Bz) , benzyl (Bn, Bnl) β-methoxyethoxymethyl ether (MEM) ,

mimethoxytrityl [bis- (4-methoxyphenyl) phenylmethyl, DMT], methoxymethyl ether (MOM), methoxytrityl [ (4-methoxyphenyl ) diphenylmethyl , MMT) , p-methoxybenzyl ether (PMB) , methylthiomethyl ether, pivaloyl (Piv) , tetrahydropyranyl (THP) , trityl (triphenylmethyl , Tr) , silyl ethers (such as

trimethylsilyl ether (TMS) , tert-butyldimethylsilyl ether (TBDMS) tert-butyldimethylsilyloxymethyl ether (TOM) , and

triisopropylsilyl ether (TIPS)) ; methyl ethers and ethoxyethyl ethers (EE) .

Suitable amine protecting groups are selected from carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ) , ie f-butyloxycarbonyl (BOC) , 9-fluorenylmethyloxycarbonyl (FMOC) , acetyl (Ac) , benzoyl (Bz), benzyl (Bn) , p-methoxybenzyl (PMB) , 3, 4-dimethoxybenzyl (DMPM) , p-methoxyphenyl (PMP) , tosyl (Ts) , an other sulfonamides (Nosyl & Nps) .

Suitable carbonyl protecting groups are selected from acetals and ketals, acylals and dithianes.

Suitable carboxylic acid protecting groups are selected from methyl esters, benzyl esters, tert-butyl esters, silyl esters, orthoesters, and oxazoline.

Examples for phosphate protecting groups are 2-cyanoethyl and methyl (Me)

Compounds of Formula I

According to aspect 1, the present invention provides a compound represented by the following Formula I, its individual

enantiomers, its individual diastereoisomers , its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof,

Formula I

wherein :

n = 1-3, preferably 1 or 2 ;

R , and are independently selected from H and the group consisting of alkyl, aryl, arylalkyl, heteroaryl and

heteroarylalkyl , each of which can be optionally substituted;

R^ is selected the group consisting of alkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which can be optionally, and preferably is substituted;

wherein any two of , R^ , R3 and R^ may be joined together to form a ring;

R^ is preferably H;

X is -CH2-

According to an alternative embodiment of this aspect, and are preferably the same, and are more preferably joined together to form a carbocyclic or heterocyclic ring. is preferably H or is preferably selected from the group consisting of C]__g alkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl , each of which can be optionally substituted; and more preferably selected from the group consisting of methyl, ethyl, 1-propyl, 2-propyl, benzyl, phenyl carboxymethyl and 2-carboxyethyl . In one preferred

embodiment of this aspect, n = 2. In another preferred embodiment of this aspect, n = 3. Most preferably, n = 1.

According to aspect 2, the present invention provides the compound according to aspect 1, wherein is H.

According to aspect 3, the present invention provides the compound according to any of aspects 1-2, wherein and R^ are H.

According to aspect 4, the present invention provides the compound according to any of aspects 1-3, wherein is selected from the group consisting of arylmethyl, (alkoxyaryl) methyl,

(hydroxyaryl ) methyl, (carboxyaryl ) methyl,

(alkoxyheteroaryl ) methyl , (heteroarylaryl ) methyl ,

(hydroxyheteroaryl ) methyl and ( carboxyheteroaryl ) methyl , each of which can be optionally substituted.

According to aspect 5, the present invention provides the compound according to any of aspects 1-4, wherein R^- is represented by the following formula,

wherein :

(i) at least one of Rp and Rm, preferably Rm, is a

functional group having an acidic hydrogen and is optionally selected

from -COOH, -SO3H, -P (0) (0H)2, -C (0) -NH-OH, -OH and tetrazol-5-yl ; or

(ii) Rp and Rm are alkoxy groups that are joined together as a part of a 5- to 8-membered heterocycle ; or

(iii) at least one of Rp and Rm is selected from the group consisting of C]__g alkyl, C]__g alkoxy, fluoro (C]__g alkyl) , fluoro (C__g alkoxy),

-C(0)-NH2, -C(0)-0CH3? -C (0) -OCH2CH3? fluoro, chloro, bromo, iodo and cyano;

whereby R1 can be optionally further substituted.

According to aspect 6, the present invention provides the compound according to any of aspects 1-5, wherein

R is selected from the group consisting of ( 1 , 3-benzodioxol-5-yl) methyl, (3-carboxyphenyl) methyl, ( 4-carboxyphenyl ) methyl , (2,4-difluoro-3-hydroxy-phenyl) -methyl, (3, 5-difluoro-4-hydroxy-phenyl ) methyl , (2 , 6-difluoro-3-hydroxy-phenyl ) methyl , (4-fluoro-3-hydroxy-phenyl ) methyl , (2-fluoro-3-hydroxy-phenyl) methyl, (4-chloro-2-fluoro-3-hydroxy-phenyl ) -methyl , (4-chloro-2-fluoro-3-methoxy-phenyl ) -methyl , (2 , 4-difluoro-3-methoxy-phenyl ) methyl , ( 3-ethoxycarbonylphenyl ) methyl, (4-chloro-2-fluoro-phenyl ) methyl,

(3,4, 5-trimethoxyphenyl ) methyl , 2 , 3-dihydro-l , 4-benzodioxin-6-yl-methyl, (7-methoxy-l, 3-benzodioxol-5-yl) methyl and [3- (difluoromethoxy) phenyl ] methyl ; ; preferably selected from (3-carboxyphenyl ) methyl , 2 , 4-difluoro-3-hydroxy-phenyl ) -methyl , ( 4-chloro-2-fluoro-3-hydroxy-phenyl) -methyl and 1 , 3-benzodioxol-5-ylmethyl .

According to aspect 7, the present invention provides the compound according to any of aspects 1-6, wherein R^ is selected from the group consisting of aryl, alkoxyaryl, carboxyaryl, cyanoaryl, haloaryl, hydroxyaryl, alkoxyheteroaryl , cyanoheteroaryl ,

haloheteroaryl , heteroarylaryl , hydroxyheteroaryl and

carboxyheteroaryl , each of which can be optionally substituted.

According to aspect 8, the present invention provides the compound according to any of aspects 1-7, wherein is represented by the following formula,

wherein :

(i) at least one of Rp and Rm, preferably Rm, is a

functional group having an acidic hydrogen and is optionally selected

from -COOH, -SO3H, -P (0) (0H)2, -C (0) -NH-OH, -OH and tetrazol-5-yl ; or

(ii) Rp and Rm are alkoxy groups that are joined together as a part of a 5- to 8-membered heterocycle ; or

(iii) at least one of Rp and Rm is selected from the group consisting of C]__g alkyl, C]__g alkoxy, -C (0) - NH2( -C(0)-0CH3? -C (0) -OCH2CH3? fluoro (Cx-g alkyl), fluoro (C__g alkoxy), fluoro, chloro, bromo, iodo and cyano;

whereby R^ can be optionally further substituted.

According to aspect 9, the present invention provides the compound according to any of aspects 1-8, wherein R^ is selected from the group consisting of 1 , 3-benzodioxol-5-yl , 3-carboxyphenyl , 1,3-benzodioxol-5-yl , 3-carboxyphenyl, 4-carboxyphenyl , 3-carboxy-4-methoxyphenyl , 3, 5-dichloro-4-hydroxyphenyl, 4-chlorophenyl , 4-cyanophenyl, 4-fluorophenyl, 2 , 6-difluoro-4-methoxyphenyl , 3-fluoro-4-methoxyphenyl, 3-methoxyphenyl , 4-methoxyphenyl , 4-chlorophenyl , 4-methylphenyl, 2 , 4-difluoro-3-hydroxy-phenyl , 3,5-difluoro-4-hydroxy-phenyl, 2, 6-difluoro-3-hydroxy-phenyl, 4-fluoro-3-hydroxy-phenyl , 2-fluoro-3-hydroxy-phenyl, 4-chloro-2-fluoro-3-hydroxy-phenyl , 4-chloro-2-fluoro-3-methoxy-phenyl , 2, 4-difluoro-3-methoxy-phenyl, 3-ethoxycarbonylphenyl , 4-chloro-2-fluoro-phenyl , 3,4, 5-trimethoxyphenyl 2 , 3-dihydro-l , 4-benzodioxin-6-yl, 7-methoxy-l , 3-benzodioxol-5-yl , 2 , 4-difluoro-3-hydroxy-phenyl and 1 , 3-benzodioxol-5-yl ; preferably preferably selected from 3-carboxyphenyl , 2 , 4-difluoro-3-hydroxy-phenyl , 4-chloro-2-fluoro-3-hydroxy-phenyl and 1 , 3-benzodioxol-5-yl .

According to aspect 10, the present invention provides the compound according to any of aspects 1-9, wherein:

(i) R1 is ( 3-carboxyphenyl ) methyl and is H;

(ii) is 3-carboxyphenyl and R^ is H;

(iii) R1 is ( 3-carboxyphenyl ) methyl and R^ and R^ are H; or

(iv) R^ is 3-carboxyphenyl and R^ and R^ are H; or

(v) R1 is ( 2 , 4-difluoro-3-hydroxy-phenyl ) methyl and R^

2 , 4-difluoro-3-hydroxy-phenyl .

Compounds of Formula V (Series 4)

According to aspect 11, the present invention provides a compound of Formula V:

Formula V,

wherein R , R , R^ and R^ are defined as with respect to the above Formula I, with the proviso that is not H. In an alternative embodiment of this aspect, R^ can be H.

According to aspect 12, the present invention provides the compound according to aspect 11, wherein R^ is H.

According to aspect 13, the present invention provides the compound according to aspects 11-12, wherein R^ and R^ are H.

According to aspect 14, the present invention provides the compound according to any of aspects 11-13, wherein R^ is selected from the group consisting of arylmethyl, (alkoxyaryl ) methyl ,

(hydroxyaryl ) methyl, (carboxyaryl ) methyl,

(alkoxyheteroaryl ) methyl , (heteroarylaryl ) methyl ,

(hydroxyheteroaryl ) methyl and ( carboxyheteroaryl ) methyl , each of which can be optionally substituted.

According to aspect 15, the present invention provides the compound according to any of aspects 11-14, wherein is

represented by the following formula,

wherein: R

(i) at least one of Rp and Rm, preferably Rm, is a

functional group having an acidic hydrogen and is optionally selected

from -COOH, -SO3H, -P (0) (0H)2, -C (0) -NH-OH, -OH and tetrazol-5-yl ; or

(ii) Rp and Rm are alkoxy groups that are joined together as a part of a 5- to 8-membered heterocycle,

whereby R^- can be optionally further substituted.

According to aspect 16, the present invention provides the compound according to any of aspects 11-15, wherein R^- is selected from the group consisting of ( 1 , 3-benzodioxol-5-yl ) methyl , (3-carboxyphenyl ) methyl , and (4-carboxyphenyl) methyl; preferably (3-carboxyphenyl ) methyl .

According to aspect 17, the present invention provides the compound according to any of aspects 11-16, wherein R^ is selected from the group consisting of aryl, alkoxyaryl, carboxyaryl, cyanoaryl, haloaryl, hydroxyaryl, alkoxyheteroaryl ,

cyanoheteroaryl , haloheteroaryl , heteroarylaryl , hydroxyheteroaryl and carboxyheteroaryl, each of which can be optionally

substituted .

According to aspect 45, the present invention provides the compound according to any of aspects 38-44, wherein R^ is

represented by the following formula,

wherein

(i) at least one of Rp and Rm, preferably Rm, is a

functional group having an acidic hydrogen and is optionally selected

from -COOH, -SO3H, -P (0) (0H)2, -C (0) -NH-OH, -OH and tetrazol-5-yl ; or

Rp and Rm are alkoxy groups that are joined together as a part of a 5- to 8-membered heterocycle ; or

(iii) at least one of Rp and Rm is selected from the group consisting of C__g alkyl, C__g alkoxy, fluoro (C__g alkyl) , fluoro (C__g alkoxy), fluoro, chloro, bromo, iodo and cyano;

whereby R^ can be optionally further substituted.

According to aspect 18, the present invention provides the compound according to any of aspects 11-17, wherein R^ is selected from the group consisting of 1 , 3-benzodioxol-5-yl , 3-carboxyphenyl , 1 , 3-benzodioxol-5-yl , 3-carboxyphenyl , 4-carboxyphenyl , 3-carboxy-4-methoxyphenyl, 3 , 5-dichloro-4-hydroxyphenyl , 4-chlorophenyl , 4-cyanophenyl , 4-fluorophenyl, 2,6-difluoro-4-methoxyphenyl , 3-fluoro-4-methoxyphenyl, 3-methoxyphenyl , 4-methoxyphenyl , 4-chlorophenyl, and 4-methylphenyl .

According to aspect 19, the present invention provides the compound according to any of aspects 11-18, wherein:

(i) R1 is ( 3-carboxyphenyl ) methyl and R^ is H;

(ii) R^ is 3-carboxyphenyl and R^ is H

(iii) R1 is ( 3-carboxyphenyl ) methyl , and R^ and R^ are H;

or

(iv) R^ is 3-carboxyphenyl, and R^ and R4 are H.

Individual compounds

According to aspect 20, the compound according to the present invention is most preferably selected from the group consisting of:

 Pharmaceutical Compositions

Aspect 21 of the present invention provides a pharmaceutical composition comprising the compound according to any of the preceding aspects, its individual enantiomers, its individual diastereoisomers , its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient as defined above .

CLAIMS

A compound represented by the following Formula I, its individual enantiomers, its individual diastereoisomers , i hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof,

Formula I

wherein :

n = 1-3, preferably 1 or 2;

R1 , RJ and are independently selected from H and the group consisting of alkyl, aryl, arylalkyl, heteroaryl and

heteroarylalkyl , each of which can be optionally substituted;

R^ is selected the group consisting of alkyl, aryl,

arylalkyl, heteroaryl and heteroarylalkyl, each of which is substituted;

wherein any two of R^ , R^ , R3 and R^ may be joined together to form a ring;

R^ is preferably H; and

X is -CH2-

2. The compound according to claim 1 which is represented by the following Formula V:

Formula V

wherein :

R1 , R , R^ and are defined as in claim 1, with the proviso that R1 is not H.

3. The compound according to any of claims 1-2, wherein R^ is H.

4. The compound according to claims 1 or 3, wherein R1 and R^ are H .

5. The compound according to any of claims 1-3, wherein R1 is selected from the group consisting of arylmethyl,

(alkoxyaryl ) methyl , (hydroxyaryl ) methyl , (carboxyaryl) methyl, (alkoxyheteroaryl ) methyl , (heteroarylaryl ) methyl ,

(hydroxyheteroaryl ) methyl and ( carboxyheteroaryl ) methyl , each of which can be optionally substituted.

6. The compound according to any of claims 1-3 and 5, wherein R1 is represented by the following formula,

wherein: R

(i) at least one of Rp and Rm, preferably Rm, is a

functional group having an acidic hydrogen and is optionally selected

from -COOH, -SO3H, -P (0) (0H)2, -C (0) -NH-OH, -OH and tetrazol-5-yl ; or

(ii) Rp and Rm are alkoxy groups that are joined together as a part of a 5- to 8-membered heterocycle,

whereby R^- can be optionally further substituted.

The compound according to any of claims 1-3, 5 and 6, wherein R is selected from the group consisting of ( 1 , 3-benzodioxol-5-yl) methyl, (3-carboxyphenyl) methyl, and (4-carboxyphenyl ) methyl ; preferably (3-carboxyphenyl ) methyl .

The compound according to any of claims 1-7, wherein R^ is selected from the group consisting of aryl, alkoxyaryl, carboxyaryl, cyanoaryl, haloaryl, hydroxyaryl,

alkoxyheteroaryl , cyanoheteroaryl , haloheteroaryl ,

heteroarylaryl , hydroxyheteroaryl and carboxyheteroaryl , each of which can be optionally substituted.

The compound according to any of claims 1-8, wherein R^ is represented by the followin formula,

wherein:

(i) at least one of Rp and Rm, preferably Rm, is a

functional group having an acidic hydrogen and is optionally selected

from -COOH, -SO3H, -P(0) (0H)2, -C (0) -NH-OH, -OH and tetrazol-5-yl ; or

(ii) Rp and Rm are alkoxy groups that are joined together as a part of a 5- to 8-membered heterocycle; or

(iii) at least one of Rp and Rm is selected from the group consisting of C]__g alkyl, C]__g alkoxy, fluoro (C]__g alkyl) , fluoro (C]__g alkoxy),

fluoro, chloro, bromo, iodo and cyano;

whereby R' can be optionally further substituted.

10. The compound according to any of claims 1-9, wherein R 2 is selected from the group consisting of 1 , 3-benzodioxol-5- yl, 3-carboxyphenyl , 1 , 3-benzodioxol-5-yl , 3-carboxyphenyl , 4-carboxyphenyl , 3-carboxy-4-methoxyphenyl , 3, 5-dichloro-4- hydroxyphenyl , 4-chlorophenyl, 4-cyanophenyl , 4-fluorophenyl , 2, 6-difluoro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl , 3- methoxyphenyl , 4-methoxyphenyl , 4-chlorophenyl, and 4- methylphenyl .

11. The compound according to any of claims 1-3 and 5-10,

wherein :

(i) R1 is (3-carboxyphenyl) methyl and R^ is H ; or

(ii) R^ is 3-carboxyphenyl and R^ is H.

12. The compound according to claim 1 which is:

(i) selected from the group consisting of:

A pharmaceutical composition comprising:

the compound according to any of claims 1-12, its individual enantiomers, its individual diastereoisomers , its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof; and a

pharmaceutically acceptable excipient.

A compound according to any of claims 1-12 or a

pharmaceutical composition according to claim 13 use in method for treatment or prophylaxis of the human animal body by surgery or therapy.

A compound according to any of claims 1-12 or a

pharmaceutical composition according to claim 13 for use in method for treatment or prophylaxis of Alzheimer' s disease, nephritis, renal injury, renal ischemic injury, ischemic acute tubular necrosis, acute renal failure, bladder

inflammation, inflammatory bowel disease (IBD) , Crohn's disease, ulcerative colitis, chronic inflammation, colitis, fibrosis, fibrotic conditions, keloids, pulmonary

hypertension, interstitial lung disease (ILD), or cancer, especially colorectal cancer.

16. A method for treatment or prophylaxis of the human or animal body by surgery or therapy comprising administering a therapeutically effective amount of a compound according to any of claims 1-12 or a pharmaceutical composition according to claim 13 to a subject in need thereof.

17. A method for treatment or prophylaxis a disease or condition selected from Alzheimer's disease, nephritis, renal injury, renal ischemic injury, ischemic acute tubular necrosis, acute renal failure, bladder inflammation, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, chronic inflammation, colitis, fibrosis, fibrotic conditions, keloids, pulmonary hypertension, interstitial lung disease (ILD) and cancer, especially colorectal cancer, the method comprising administering a therapeutically effective amount of a compound according to any of claims 1-12 or a

pharmaceutical composition according to claim 13 to a subject in need thereof.