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  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates generally to bis-amide containing metalloprotease inhibiting compounds, and more particularly to substituted bis-amide MMP- 13 inhibiting compounds.
• MMPs and aggrecanases are, therefore, targets for therapeutic inhibitors in several inflammatory, malignant and degenerative diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation (which leads to restenosis and ischemic heart failure) and tumor metastasis.
• the ADAMTSs are a group of proteases that are encoded in 19 ADAMTS genes in humans.
• the ADAMTSs are extracellular, multidomain enzymes whose functions include collagen processing, cleavage of the matrix proteoglycans, inhibition of angiogenesis and blood coagulation homoeostasis (Biochem. J. 2005, 386, 15-27; Arthritis Res. Ther. 2005, 7, 160-169; Curr. Med. Chem. Anti-Inflammatory Anti-Allergy Agents 2005, 4, 251-264).
• the mammalian MMP family has been reported to include at least 20 enzymes, ⁇ Chem. Rev. 1999, 99, 2735-2776).
• Collagenase-3 (MMP- 13) is among three collagenases that have been identified. Based on identification of domain structures for individual members of the MMP family, it has been determined that the catalytic domain of the MMPs contains two zinc atoms; one of these zinc atoms performs a catalytic function and is coordinated with three histidines contained within the conserved amino acid sequence of the catalytic domain.
• MMP- 13 is over-expressed in rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, breast carcinoma, squamous cell carcinomas of the head and neck, and vulvar squamous cell carcinoma.
• the principal substrates of MMP- 13 are fibrillar collagens (types I, II, III) and gelatins, proteoglycans, cytokines and other components of ECM (extracellular matrix).
• the activation of the MMPs involves the removal of a propeptide, which features an unpaired cysteine residue complexes the catalytic zinc (II) ion.
• X-ray crystal structures of the complex between MMP-3 catalytic domain and TMP-I and MMP- 14 catalytic domain and TEMP-2 also reveal ligation of the catalytic zinc (II) ion by the thiol of a cysteine residue.
• the difficulty in developing effective MMP inhibiting compounds comprises several factors, including choice of selective versus broad-spectrum MMP inhibitors and rendering such compounds bioavailable via an oral route of administration.
• MMP-3 stromelysin-1; transin-1 is another member of the MMP family (Woesner; FASEB J. 1991; 5:2145-2154). Human MMP-3 was initially isolated from cultured human synoviocytes. It is also expressed by chondrocytes and has been localized in OA cartilage and synovial tissues (Case; Am. J. Pathol. 1989 Dec; 135(6): 1055-64).
• MMP-3 is produced by basal keratinocytes in a variety of chronic ulcers. MMP-3 mRNA and Protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. MMP-3 may this prevent the epidermis from healing (Saarialho-Kere, J. Clin. Invest. 1994 JuI; 94(l):79-88)).
• MMP-3 serum protein levels are significantly elevated in patients with early and long- term rheumatoid arthritis (Yamanaka; Arthritis Rheum. 2000 Apr;43(4):852-8) and in osteoarthritis patients (Bramono; Clin Orthop Relat Res. 2004 Nov;(428):272-85) as well as in other inflammatory diseases like systemic lupus erythematosis and ankylosing spondylitis (Chen, Rheumatology 2006 Apr;45(4):414-20.).
• MMP-3 acts on components of the ECM as aggrecan, fibronectin, gelatine, laminin, elastin, fibrillin and others and on collagens of type III, IV, V, VII, KX, X (Bramono; Clin Orthop Relat Res. 2004 Nov;(428):272-85). On collagens of type II and IX, MMP-3 exhibits telopeptidase activity (Sandell, Arthritis Res. 2001 ;3(2):107-13; Eyre, Clin Orthop Relat Res. 2004 Oct;(427 Suppl):Sl 18-22.). MMP-3 can activate other MMP family members as MMP- 1; MMP-7; MMP-8; MMP-9 and MMP-13 (Close, Ann Rheum Dis 2001 Nov;60 Suppl 3:iii62-7).
• MMP-3 is involved in the regulation of cytokines and chemokines by releasing TGF ⁇ l from the ECM, activating TNF ⁇ , inactivation of IL-I ⁇ and release of IGF (Parks, Nat Rev Immunol. 2004 Aug;4(8):617-29).
• a potential role for MMP-3 in the regulation of macrophate infiltration is based on the ability of the enzyme to converse active MCP species into antagonistic peptides (McQuibban, Blood. 2002 Aug 15; 100(4): 1160-7.)-
• a series of MMP-13 inhibiting compounds containing a bis-amide functional group in combination with a pyrimidine ring is disclosed in WO 02/064571, WO 04/041788 and WO 04/060883.
• This invention discloses metalloprotease inhibitors with surprising and unexpected improvements in the properties metalloprotease inhibitors bearing an R 2 substituent in the compounds of Claim 1. Furthermore, the specific substitution (R 2 vs. R 3 ) is critical as compounds bearing an R 3 substituent have poorer activity.
• the unexpected advantages observed for selective R 2 -substituted compounds of this invention include improvements in microsomal stability and cell viability, as is evident by comparing the results observed for the uns ⁇ bstituted pyrimidine-4,6-dicarboxylic acid 4-(3- methoxybenzylamide) 6-[4-(lH-tetrazol-5-yl)-benzylamide] (Example 104Od) with the improvements seen with Example 1005. It is believed that these new findings and the specific structural modifications which this invention discloses will lead to inhibitors of metalloproteases, in particular MMP-13 with improved pharmaceutical value.
• the present invention relates to a new class of substituted bis-amide containing pharmaceutical agents.
• the present invention provides a new class of metalloprotease inhibiting compounds containing a pyrimidinyl bis-amide group in combination with a substituted moiety that exhibit potent MMP-13 inhibiting activity and are highly selective toward MMP- 13 compared to currently known MMP inhibitors.
• the present invention provides a new class of substituted bis-amide metalloprotease inhibiting compounds that are represented by the general Formula (I):
• R 1 , R 2 , R 3 , R 4 , R 22 , and R 23 are as described hereinbelow.
• the substituted bis-amide metalloprotease inhibiting compounds of the present invention may be used in the treatment of metalloprotease mediated diseases.
• the substituted bis-amide metalloprotease inhibiting compounds of the present invention may be used in the treatment of MMP- 13 mediated osteoarthritis and may be used for other MMP- 13 mediated symptoms, inflammatory, malignant and degenerative diseases characterized by excessive extracellular matrix degradation and/or remodelling, such as cancer, and chronic inflammatory diseases such as arthritis, rheumatoid arthritis, osteoarthritis atherosclerosis, abdominal aortic aneurysm, inflammation, multiple sclerosis, and chronic obstructive pulmonary disease, and pain, such as inflammatory pain, bone pain and joint pain.
• MMP- 13 mediated osteoarthritis characterized by excessive extracellular matrix degradation and/or remodelling
• chronic inflammatory diseases such as arthritis, rheumatoid arthritis, osteoarthritis atherosclerosis, abdominal aortic aneurysm, inflammation, multiple sclerosis, and chronic obstructive pulmonary disease
• pain such as inflammatory pain, bone pain and joint pain.
• the present invention also provides substituted bis-amide metalloprotease inhibiting compounds that are useful as active ingredients in pharmaceutical compositions for treatment or prevention of metalloprotease - especially MMP- 13 - mediated diseases.
• the present invention also contemplates use of such compounds in pharmaceutical compositions for oral or parenteral administration, comprising one or more of the substituted bis-amide metalloprotease inhibiting compounds disclosed herein.
• the present invention further provides methods of inhibiting metalloproteases, by administering formulations, including, but not limited to, oral, rectal, topical, intravenous, parenteral (including, but not limited to, intramuscular, intravenous), ocular (ophthalmic), transdermal, inhalative (including, but not limited to, pulmonary, aerosol inhalation), nasal, sublingual, subcutaneous or intraarticular formulations, comprising the heterobicyclic metalloprotease inhibiting compounds by standard methods known in medical practice, for the treatment of diseases or symptoms arising from or associated with metalloprotease, especially MMP-13, including prophylactic and therapeutic treatment.
• formulations including, but not limited to, oral, rectal, topical, intravenous, parenteral (including, but not limited to, intramuscular, intravenous), ocular (ophthalmic), transdermal, inhalative (including, but not limited to, pulmonary, aerosol inhalation), nasal, sublingual, subcutaneous or intraarticular formulations, comprising the heterobicycl
• the substituted bis-amide metalloprotease inhibiting compounds of the present invention may be used in combination with a disease modifying antirheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2 selective inhibitor, a COX-I inhibitor, an immunosuppressive, a steroid, a biological response modifier or other anti-inflammatory agents or therapeutics useful for the treatment of chemokine mediated diseases.
• alkyl or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups.
• exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like.
• substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (— COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH 2 -CO--), substituted carbamoyl ((R IO )(R U )N ⁇ CO--- wherein R 10 or R 11 are as defined below, except that at least one of R 10 or R 11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (-SH).
• groups halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group),
• lower alk or “lower alkyl” as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.
• alkoxy denotes an alkyl group as described above bonded through an oxygen linkage (—0--).
• alkenyl denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain.
• exemplary unsubstituted such groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like.
• substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (--COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH 2 -CO-), substituted carbamoyl ((R 10 )(R ⁇ )N ⁇ CO- wherein R 10 or R n are as defined below, except that at least one of R 10 or R 1 ' is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (--SH).
• alkynyl denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain.
• exemplary unsubstituted such groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like.
• substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (--COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH 2 -CO-), substituted carbamoyl ((R 10 )(R M )N ⁇ CO ⁇ wherein R 10 or R 11 are as defined below, except that at least one of R 10 or R 11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (-SH).
• cycloalkyl denotes optionally substituted, saturated cyclic hydrocarbon ring systems, including bridged ring systems, desirably containing 1 to 3 rings and 3 to 9 carbons per ring.
• exemplary unsubstituted such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl.
• substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
• Exemplary unsubstituted such groups include, but are not limited to, adamantyl, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane and cubane.
• Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
• spiroalkyl denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom.
• exemplary unsubstituted such groups include, but are not limited to, spiro[3.5]nonane, spiro[4.5]decane or spiro[2.5]octane.
• substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
• spiroheteroalkyl denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom and at least one carbon atom is replaced by a heteroatom independently selected from N, O and S.
• the nitrogen and sulfur heteroatoms may optionally be oxidized.
• Exemplary unsubstituted such groups include, but are not limited to, l,3-diaza-spiro[4.5]decane-2,4-dione.
• substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
• aromatic or aryl, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons.
• exemplary unsubstituted such groups include, but are not limited to, phenyl, biphenyl, and naphthyl.
• exemplary substituents include, but are not limited to, one or more nitro groups, alkyl groups as described above or groups described above as alkyl substituents.
• heterocycle or “heterocyclic system” denotes a heterocyclyl, heterocyclenyl, or heteroaryl group as described herein, which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused to one or more heterocycle, aryl or cycloalkyl groups.
• the nitrogen and sulfur heteroatoms may optionally be oxidized.
• the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
• the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom.
• heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H,6H-1 ,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H- quinolizinyl, 6H-l,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolinyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinn
• heterocycles include, but not are not limited to,
• heterocycloalkyl groups such as 7-oxa-bicyclo[2.2.1]heptane, 7-aza- bicyclo[2.2.1]heptane, and l-aza-bicyclo[2.2.2]octane.
• ⁇ eterocyclenyl denotes a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 atoms, desirably about 4 to about 8 atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond.
• Ring sizes of rings of the ring system may include 5 to 6 ring atoms.
• the designation of the aza, oxa or thia as a prefix before heterocyctenyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
• heterocyclenyl may be optionally substituted by one or more substituents as defined herein.
• the nitrogen or sulphur atom of the heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• Heterocyclenyl as used herein includes by way of example and not limitation those described in Paquette, Leo A. ; "Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and "J.
• Exemplary monocyclic azaheterocyclenyl groups include, but are not limited to, 1,2,3,4- tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1 ,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3- pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like.
• Exemplary oxaheterocyclenyl groups include, but are not limited to, 3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl.
• An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2. l]heptenyl.
• ⁇ eterocyclyl or “heterocycloalkyl,” denotes a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, desirably 4 to 8 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur.
• Ring sizes of rings of the ring system may include 5 to 6 ring atoms.
• the designation of the aza, oxa or thia as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
• the heterocyclyl may be optionally substituted by one or more substituents which may be the same or different, and are as defined herein.
• the nitrogen or sulphur atom of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• Heterocyclyl as used herein includes by way of example and not limitation those described in Paquette, Leo A. ; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1 , 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc. ", 82:5566 (1960).
• Exemplary monocyclic heterocyclyl rings include, but are not limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
• Heteroaryl denotes an aromatic monocyclic or multicyclic ring system of about 5 to about 10 atoms, in which one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system include 5 to 6 ring atoms.
• the “heteroaryl” may also be substituted by one or more subsituents which may be the same or different, and are as defined herein.
• the designation of the aza, oxa or thia as a prefix before heteroaryl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
• a nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide.
• Heteroaryl as used herein includes by way of example and not limitation those described in Paquette, Leo A. ; "Principles of Modem Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc. ", 82:5566 (1960).
• heteroaryl and substituted heteroaryl groups include, but are not limited to, pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1,2,3- triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzthiazolyl, dioxolyl, furanyl, imidazolyl,
• heterocycloalkyl fused aryl includes, but is not limited to, 2,3-dihydro- benzo[l,4]dioxine, 4H-benzo[l,4]oxazin-3-one, 3H-Benzooxazol-2-one and 3,4-dihydro-2H- benzo[/] [ 1 ,4]oxazepin-5-one.
• amino denotes the radical -NH 2 wherein one or both of the hydrogen atoms may be replaced by an optionally substituted hydrocarbon group.
• exemplary amino groups include, but are not limited to, n-butylamino, tert-butylamino, methylpropylamino and ethyldimethylamino.
• cycloalkylalkyl denotes a cycloalkyl-alkyl group wherein a cycloalkyl as described above is bonded through an alkyl, as defined above. Cycloalkylalkyl groups may contain a lower alkyl moiety. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl, cyclopentylpropyl, and cyclohexylpropyl.
• arylalkyl denotes an aryl group as described above bonded through an alkyl, as defined above.
• heteroarylalkyl denotes a heteroaryl group as described above bonded through an alkyl, as defined above.
• heterocyclylalkyl or “heterocycloalkylalkyl,” denotes a heterocyclyl group as described above bonded through an alkyl, as defined above.
• halogen as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine.
• haloalkyl denotes a halo group as described above bonded though an alkyl, as defined above ⁇ Fluoroalkyl is an exemplary group.
• aminoalkyl denotes an amino group as defined above bonded through an alkyl, as defined above.
• pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Examples therefore may be, but are not limited to, sodium, potassium, choline, lysine, arginine or N-methyl-glucamine salts, and the like.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
• inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
• organic acids such as, but not limited to
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
• Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
• phrases "pharmaceutically acceptable” denotes those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable carrier denotes media generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans. Such carriers are generally formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-r containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms.
• Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art.
• a pharmaceutically acceptable carrier are hyaluronic acid and salts thereof, and microspheres (including, but not limited to poly(D,L)-lactide-co-glycolic acid copolymer (PLGA), poly(L-lactic acid) (PLA), poly(caprolactone (PCL) and bovine serum albumin (BSA)).
• Pharmaceutically acceptable carriers particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
• inert diluents such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate
• Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example celluloses, lactose, calcium phosphate or kaolin
• non-aqueous or oil medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
• compositions of the invention may also be formulated as suspensions including a compound of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension.
• pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.
• Carriers suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g.
• suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia
• dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g.
• polyoxyethylene stearate polyoxyethylene stearate
• a condensation product of ethylene oxide with a long chain aliphatic alcohol e.g., heptadecaethyleneoxycethanol
• a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride e.g., polyoxyethylene sorbitan monooleate
• thickening agents such as carbomer, beeswax, hard paraffin or cetyl alcohol.
• the suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
• preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate
• coloring agents such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate
• flavoring agents such as sucrose or saccharin.
• sweetening agents such as sucrose or saccharin.
• Cyclodextrins may be added as aqueous solubility enhancers.
• Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -, ⁇ -, and ⁇ -cyclodextrin.
• the amount of solubility enhancer employed will depend on the amount of the compound of the present invention in the composition.
• formulation denotes a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
• the pharmaceutical formulations of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical carrier.
• N-oxide denotes compounds that can be obtained in a known manner by reacting a compound of the present invention including a nitrogen atom (such as in a pyridyl group) with hydrogen peroxide or a peracid, such as 3-chloroperoxy-benzoic acid, in an inert solvent, such as dichloromethane, at a temperature between about -10-80 0 C, desirably about O 0 C.
• polymorph denotes a form of a chemical compound in a particular crystalline arrangement. Certain polymorphs may exhibit enhanced thermodynamic stability and may be more suitable than other polymorphic forms for inclusion in pharmaceutical formulations.
• the compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
• stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
• the chemical structures depicted herein, and therefore the compounds of the invention encompass all of the . corresponding enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
• racemic mixture denotes a mixture that is about 50% of one enantiomer and about 50% of the corresponding enantiomer relative to all chiral centers in the molecule.
• the invention encompasses all enantiomerically-pure, enantiomerically-enriched, and racemic mixtures of compounds of Formulas (I) through (VI).
• Enantiomeric and stereoisomeric mixtures of compounds of the invention can be resolved into their component enantiomers or stereoisomers by well-known methods.
• Examples include, but are not limited to, the formation of chiral salts and the use of chiral or high performance liquid chromatography "HPLC" and the formation and crystallization of chiral salts. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley- Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.
• Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
• Substituted is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
• moieties of a compound of the present invention are defined as being unsubstituted, the moieties of the compound may be substituted.
• the moieties of the compounds of the present invention may be optionally substituted with one or more groups independently selected from:
• a ring substituent may be shown as being connected to the ring by a bond extending from the center of the ring.
• the number of such substituents present on a ring is indicated in subscript by a number.
• the substituent may be present on any available ring atom, the available ring atom being any ring atom which bears a hydrogen which the ring substituent may replace.
• R x were defined as being:
• R x substituents may be bonded to any available ring atom.
• R x substituents may be bonded to any available ring atom.
• configurations such as:
• substituted bis-amide metalloprotease inhibiting compounds are represented by the general Formula (I):
• R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused heteroaryl, cycloalkyl fused heteroaryl, cycloal
• R 1 is optionally substituted one or more times, or
• R 1 is optionally substituted by one R 16 group and optionally substituted by one or more R 9 groups;
• R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl, COOR 10 , CONR 10 R 11 , SO 2 R 10 and SO 2 NR 10 R 11 wherein alkyl, haloalkyl, fluoroalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl-alkyl, arylalkyl, and heteroarylalkyl are optionally substituted one or more times;
• R 3 is selected from the group consisting of hydrogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl, COOR 10 , CONR 10 R 11 , SO 2 R 10 and SO 2 NR 10 R 11 wherein alkyl, haloalkyl, fluoroalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl-alkyl, arylalkyl, and heteroarylalkyl are optionally substituted one or more times;
• R 4 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused heteroarylalkyl, and
• R 9 in each occurrence is independently selected from the group consisting of R 10 , hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF 2 , CF 3 , OR 10 , SR 10 , COOR 10 , CH(CH 3 )CO 2 H, (C 0 -C 6 )-alkyl-COR 10 , (Co-C 6 )-alkyl-OR 10 , (C 0 -C 6 )-alkyl-NR 10 R n , (C 0 -C 6 )-alkyl-NO 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y OR 10 , (C 0 -C 6 )-alkyl-P(O) 2 OH, (C 0 - C 6 )-alkyl-S(O)yNR 10 R n ,
• each R 9 group is optionally substituted, or
• each R 9 group is optionally substituted by one or more R 14 groups
• R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted, or R 10 and R 11 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S, or NR 50 and which is optional
• R 14 is independently selected from the group consisting of hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;
• R 16 is selected from the group consisting of cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (
• R 30 is selected from the group consisting of alkyl and (C 0 -C 6 )-alkyl-aryl, wherein alkyl and aryl are optionally substituted;
• R 50 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, C(O)R 10 , C(O)NR 10 R 11 , SO 2 R 10 and SO 2 NR 10 R 11 , wherein alkyl* aryl, and heteroaryl are optionally substituted;
• X is selected from the group consisting of a bond and (CR 10 R 11 ⁇ E(CR 10 R 1 ⁇ ;
• g and h are independently selected from 0-2;
• w is independently selected from 0-4;
• x is selected from O to 2;
• y is selected from 1 and 2;
• R 1 may be:
• R 18 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11 and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl are optionally substituted one or more times;
• R 25 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, CO 2 R 10 , C(O)NR 10 R 11 and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times ;
• Bi is selected from the group consisting of NR 10 , 0 and S(O) x ;
• D 2 , G 2 , L 2 , M 2 and T 2 are independently selected from the group consisting of CR 18 and N;
• Z is a 5- to 8-membered ring selected from the group consisting of cycloalkyl, heterocycloalkyl, or a 5- to 6-membered ring selected from the group consisting of aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted one or more times. More specifically, R 1 may be, but is not limited to, the following:
• R 1 may include a bicyclic ring system.
• R may be: 6 049521
• R 18 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11 and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times; T7US2006/049521
• R 25 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, CO 2 R 10 , C(O)NR 10 R 11 and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times;
• J and K are independently selected from the group consisting of CR 10 R 18 , NR 10 , 0 and
• a 1 is selected from the group consisting of NR 10 , 0 and S(O) x ;
• D 2 , G 2 , J 2 , L 2 , M 2 and T 2 are independently selected from the group consisting of CR 18 and N.
• R 1 may be, but is not limited to, the following:
• R 1 may be:
• R 18 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl
• R 25 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, CONR 10 R 11 and haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times;
• L 2 , M 2 , and T 2 are independently selected from the group consisting of CR 18 and N; .
• D 3 , G 3 , L 3 , M 3 , and T 3 are independently selected from N, CR 18 , (i), or (ii),
• one of L 3 , M 3 , T 3 , D 3 , and G 3 is (i) or (ii);
• Bi is selected from the group consisting of NR 10 , O and S(O) x ;
• Q 2 is a 5- to 8-membered ring selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which is optionally substituted one or more times with R 19 .
• R 1 may be, but is not limited to, the following:
• R.' may be, but is not limited to, the following:
• R 2 is selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl-alkyl, arylalkyl, heteroarylalkyl, COOR 10 , CONR 10 R 11 , SO 2 R 10 and SO 2 NR 10 R 11 wherein alkyl, haloalkyl, fluoroalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl-alkyl, arylalkyl, and heteroarylalkyl are optionally substituted one or more times; and
• R 3 is hydrogen
• R 2 is selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, COOR 10 , CONR 10 R 11 , wherein alkyl, haloalkyl, fluoroalkyl are optionally substituted one or more times; and
• R >3 i-s hydrogen.
• R 2 is alkyl, which is optionally substituted one or more times;
• R 3 is hydrogen
• R 4 may be:
• R 6 is independently selected from the group consisting of R 9 , alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, C(O)OR 10 , CH(CH 3 )CO 2 H, (C 0 -C 6 )-alkyl-COR 10 , (C 0 -C 6 )-alkyl-OR 10 , (C 0 - C 6 )-alkyl-OR 10 , (C 0 - C 6 )-alkyl-NR 10 R n , (Co-C 6 )-alkyl-N0 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y OR l0 s (C 0 -C 6 )- 00
• Bi is selected from NR 10 , 0 or S(O) x ;
• L, M, T, D and G are independently selected from C or N;
• Z is a 5- to 8-membered ring selected from the group consisting of cycloalkyl, heterocycloalkyl, or a 5- to 6-membered ring selected from the group consisting of aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted one or more times.
• R 4 may be, but is not limited to, the following:
• R 6 is selected from the group consisting of
• R 9 is selected from the group consisting of hydrogen, alkyl, halo, CF 3 , COR 10 , OR 10 ,
• R 51 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and haloalkyl, wherein alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and haloalkyl are optionally substituted;
• R 52 is selected from the group consisting of hydrogen, halo, hydroxy, alkoxy, fluoroalkoxy, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, haloalkyl, C(O)NR 10 R 11 and SO 2 NR 10 R 11 , wherein alkoxy, fluoroalkoxy, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and haloalkyl are optionally substituted.
• R 6 may be COOH or heteroaryl. More specifically, in some embodiments R 6 may be:COOH, dioxole, imidazole, furan, thiazole, isothiazole, isoxazole, morpholine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4- oxadiazole, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxirane, oxazole, 5-oxo-l,2,4-oxadiazole, 5-oxo-l,2,4-thiadiazole, piperzine, piperidine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrazine, tetrazole, thiazine, 1,2,3-thiadiazole, 1,2,
• R 4 may be, but is not limited to, the following:
• the compounds of Formula (I) may be selected from, but are not limited to, the following: ;
• the compounds of the present invention represented by the Formulas described above include all diastereomers and enantiomers, as well as racemic mixtures. Racemic mixtures may be separated by chiral salt resolution or by chiral column HPLC chromatography.
• the present invention also is directed to pharmaceutical compositions including any of the substituted bis-amide metalloprotease inhibiting compounds of the present invention described above.
• some embodiments of the present invention provide a pharmaceutical composition which may include an effective amount of a substituted bis-amide metalloprotease inhibiting compound of the present invention and a pharmaceutically acceptable carrier.
• the present invention also is directed to methods of inhibiting metalloproteases, in particular MMP- 13 and methods of treating diseases or symptoms mediated by an metalloprotease enzyme, in particular an MMP- 13 enzyme.
• Such methods include administering a substituted bis-amide metalloprotease inhibiting compound of the present invention, such as a compound of Formula (I), as defined above, or a pharmaceutically acceptable salt thereof.
• diseases or symptoms mediated by an metalloprotease mediated enzyme - in particular the MMP- 13 enzyme - include, but are not limited to, rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer (e.g.
• melanoma gastric carcinoma or non-small cell lung carcinoma
• inflammation atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease
• ocular diseases e.g. but not limited to ocular inflammation, retinopathy of prematurity, macular degeneration with the wet type preferred and corneal neovascularization
• neurologic diseases e.g. but not limited to ocular inflammation, retinopathy of prematurity, macular degeneration with the wet type preferred and corneal neovascularization
• psychiatric diseases thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimers disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis
• gram negative sepsis granulocytic ehrlichiosis
• hepatitis viruses herpes, herpes viruses, HIV, hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia, hypersensitivity, hypoxemia, inflammatory bowel disease, interstitial pneumonitis, ischemia reperfusion injury, kaposi's sarcoma associated virus, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, .
• osteoporosis periodontitis, peritonitis associated with continous ambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatory hypertension, renal reperfusion injury, respiratory viruses, restinosis, right ventricular hypertrophy, sarcoidosis, septic shock, small airway disease, sprains, strains, subarachnoid hemorrhage, surgical lung volume reduction, thrombosis, toxic shock syndrome, transplant reperfusion injury, traumatic brain injury, ulcerative colitis, vasculitis, ventilation-perfusion mismatching, and wheeze.
• CAPD continous ambulatory peritoneal dialysis
• the substituted bis-amide metalloprotease inhibiting compounds defined above are used in the manufacture of a medicament for the treatment of a disease mediated by a metalloprotease enzyme, in particular an MMP- 13 enzyme.
• the substituted bis-amide metalloprotease inhibiting compounds defined above may be used in combination with a drug, agent or therapeutic such as, but not limited to: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal antiinflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-I inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; or (h) other anti- inflammatory agents or therapeutics useful for the treatment of chemokine mediated diseases.
• a drug, agent or therapeutic such as, but not limited to: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal antiinflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-I inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; or (h) other anti- inflammatory agents or therapeutics useful for the treatment of chemokine
• disease modifying antirheumatic drugs include, but are not limited to, methotrexate, azathioptrineluflunomide, penicillamine, gold salts, mycophenolate, mofetil and cyclophosphamide.
• nonsteroidal antiinflammatory drugs include, but are not limited to, piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen.
• COX-2 selective inhibitors include, but are not limited to, rofecoxib, celecoxib, and valdecoxib.
• COX-I inhibitor includes, but is not limited to, piroxicam.
• immunosuppressives include, but are not limited to, methotrexate, cyclosporin, leflunimide, tacrolimus, rapamycin and sulfasalazine.
• steroids examples include, but are not limited to, p-methasone, prednisone, cortisone, prednisolone and dexamethasone.
• biological response modifiers include, but are not limited to, anti-TNF antibodies, TNF- ⁇ antagonists, IL-I antagonists, anti- CD40, anti-CD28, IL-IO and anti- adhesion molecules.
• anti-inflammatory agents or therapeutics include, but are not limited to, p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptor antagonists, thalidomide, leukotriene inhibitors and other small molecule inhibitors of pro-inflammatory cytokine production.
• a pharmaceutical composition may include an effective amount of a compound of the present invention, a pharmaceutically acceptable carrier and a drug, agent or therapeutic selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-
• the compounds of Formula (I) are synthesized by the general method shown in Scheme 1.
• This compound is further treated with a slight molar excess OfNH 2 CR 2 R 3 R 4 in a suitable solvent and heated to give the final desired adduct after purification.
• the final adduct can be obtained by one skilled in the art through comparable coupling reactions.
• the compounds of Formula I are synthesized by the general method shown in Scheme 2.
• a dimethyl pyrimidine-4,6-dicarboxylate derivative is treated with one equivalent sodium hydroxide to give the monomethyl pyrimidine-4,6-dicarboxylate derivative.
• an activated acid coupling e.g. HOBt/EDCI, HOAt/HATU, PyBroP or ethyl chloroformate
• This compound is further treated with one equivalent sodium hydroxide and then coupled via an activated acid (e.g. HOBt/EDCI, HOAt/HATO, PyBroP or ethyl chloroformate) with R 1 NH 2 to give the pyrimidine-4,6-bis-amide.
• the R group can be further manipulated (e.g. saponification of a COOMe group in R).
• the MMP- 13 inhibiting activity of the bis-amide metalloprotease inhibiting compounds of the present invention may be measured using any suitable assay known in the art.
• a standard in vitro assay for MMP-13 inhibiting activity is described in Example 999 and a description of the the microsomal stability assay is described in Example 999a.
• the bis-amide metalloprotease inhibiting compounds of the invention have an MMP-13 inhibition activity (IC 50 MMP-13) ranging from about 1 nM to about 20 ⁇ M, and typically, from about 8 nM to about 2 ⁇ M.
• Bis-amide metalloprotease inhibiting compounds of the invention desirably have an MMP inhibition activity ranging from about 1 nM to about 20 nM.
• Table 1 lists typical examples of bis-amide metalloprotease inhibiting compounds of the invention that have an MMP-13 activity lower than about 1 ⁇ M, particularly about 1 nM to 300 nM, and more specifically about 1 nM to 50 nM.
• Preparative examples 1-205 are directed to intermediate compounds useful in preparing the compounds of the present invention.
• amines NH 2 R 1 or NH 2 CR 2 R 3 R 4 are not commercially available, they can be synthesized in a similar way as described in the following section.
• step A above di-tert-butyl dicarbonate (1.02 g) and nickel(II) chloride hexahydrate (56 mg) were dissolved in dry methanol (25 mL) and cooled to 0 0 C. Then sodium borohydride (400 mg) was added in portions and the ice bath removed. The mixture was vigorously stirred for 14 h, then diethylenetriamine (300 ⁇ L) was added and the mixture was concentrated to dryness.
• step A above di-tert-butyl dicarbonate (1.3 g) and nickel(II) chloride hexahydrate (50 mg) were dissolved in dry methanol (30 mL) and cooled to O 0 C. Then sodium borohydride (500 mg) was added in portions and the ice bath removed. The mixture was vigorously stirred for 6 h, then diethylenetriamine (300 ⁇ L) was added and the mixture was concentrated to dryness.
• step A To the intermediate from step A above was added DBU (0.35 mL). The solution was stirred for 4 h. The mixture was loaded directly on a short silca gel column and rinsed with hexane to give the title compound (1.7 g).
• step B To the intermediate from step B above was added hydrogen chloride in diethyl ether (10 mL, 2N). The reaction was stirred for 1 h and the resulting precipitate was collected by filtration and rinsed with diethyl ether (5 mL) to give the title compound (0.88 g).
• step D zinc cyanide (706 mg), palladium tetrakis triphenylphosphine (330 mg) in anhydrous dimethylforamide (5 mL) was heated to 100 0 C overnight. The reaction mixture was concentrated to dryness and purified by silca gel chromatography to give the title compound.
• step E To the intermediate from step E above was added hydrogen chloride in diethyl ether (10 mL, 2N). The reaction was stirred for 1 h and the resulting precipitate was collected by filtration and rinsed with diethyl ether (5 mL) to give the title compound (0.85 g; 75%).
• step C To the intermediate from step C above was added anhydrous hydrochloric acid (5 mL, 4 ⁇ in dioxane) and the reaction was stirred for 1 h at room temperature. The colourless solid that was formed was collected and rinsed with diethyl ether to give the titlecompound (246 mg; quantitative for 2 steps).
• the typical assay for MMP-13 activity is carried out in assay buffer comprised of 5OmM Tris, pH 7.5, 15OmM NaCl, 5mM CaCl 2 and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 ⁇ L aliquots. 10 ⁇ L of 40 nM stock solution of MMP-13 enzyme is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 20 minutes at room temperature. Upon the completion of incubation, the assay is started by addition of 40 ⁇ L of 12.5 ⁇ M stock solution of MMP-13 fluorogenic substrate (Calbiochem Cat. No. 444235).
• Example 1007 Following the procedure described in Example 1007, except using the acid from Preparative Example 204 and the amine indicated in the table below, the title compound was prepared.
• Example 1012 Example 1012
• Example 1000 The title compound from Example 1000 and the amine according the table below were coupled with PyBop at room temperature in dry THF. Purification by silica gel chromatography to afforded the title compound indicated in the table below.
• step A The intermediate from step A above was dissolved in dimethylformamide (1 mL), and cooled to 0 0 C in an ice bath. Pyridine (9 ⁇ L) was added followed by the addition of isobutyl chloroformate (13.7 ⁇ L). The reaction was kept at same temperature for 30 min, and concentrated to dryness to give the intermediate as a brown oil.
• Example 1019 The title compound from Example 1019 (67.5 mg) was dissolved in tetrahydrofuran (2 mL), and cooled to 0 0 C in an ice bath. Pyridine (15 ⁇ L) was added followed by the addition of trifluoroacetic anhydride (24 ⁇ L). The reaction was kept for 2 h, and concentrated to dryness to give the intermediate, which was used without further purification.
• Example 1039a-1039b Following the procedure described in Example 1039, except using the alcohols indicated in the table below, the title compound was prepared.

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• 2006
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