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WO2002003994A1 - Derives d'acides amines n sulfonyle inhibiteurs des metalloproteinases - Google Patents

Derives d'acides amines n sulfonyle inhibiteurs des metalloproteinases Download PDF

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Publication number
WO2002003994A1
WO2002003994A1 PCT/US2000/021024 US0021024W WO0203994A1 WO 2002003994 A1 WO2002003994 A1 WO 2002003994A1 US 0021024 W US0021024 W US 0021024W WO 0203994 A1 WO0203994 A1 WO 0203994A1
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group
alkyl
mmp
matrix metalloproteinase
compound
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PCT/US2000/021024
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English (en)
Inventor
William C. Stallings
Huey S. Shieh
Susan C. Howard
Gary A. De Crecenzo
Joseph J. Mc Donald
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G.D. Searle & Co.
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Priority claimed from PCT/US2000/016323 external-priority patent/WO2001005389A2/fr
Application filed by G.D. Searle & Co. filed Critical G.D. Searle & Co.
Priority to AU2000265100A priority Critical patent/AU2000265100A1/en
Publication of WO2002003994A1 publication Critical patent/WO2002003994A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to matrix metalloproteinase enzymes , inhibitors of matrix metalloproteinase enzymes , and to methods of changing the conformation of matrix metalloproteinase enzymes .
  • Connective tissue, extracellular matrix constituents, and basement membranes are required components of all mammals, including humans. These components are the biological materials that provide rigidity, differentiation, attachments, and, in come cases, elasticity to biological systems.
  • Connective tissue components include, for example, collagen, elastin, proteoglycans, fibronectin, and laminin. These biochemicals make up or are components of structures such as skin, bone, teeth, tendons, cartilage, basement membranes, blood vessels, cornea, and vitreous humor.
  • MMP matrix metalloproteinase
  • MMPs are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase, EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase, EC 3.4.24.34); collagenase III (MMP-13); stromelysin 1 (MMP-3 , EC 3.4.24.17); stromelysin 2 (MMP- 10, EC 3.4.24.22); proteoglycanase,- matrilysin (MMP-7,
  • gelatinase A MMP-2 , 72 kDa gelatinase, EC 3.4.24.24) gelatinase B (MMP-9, 92 kDa gelatinase,
  • MMP-12 human macrophage elastase, EC 3.4.24.65
  • MMP-14 MT1-MMP
  • MMP-15 MT3 -MMP
  • MMP-16 MT4-MMP
  • MMP-17 MT1-MMP
  • MMP-14 MT2-MMP
  • MMP-15 MT3 -MMP
  • MMP-16 MT4-MMP
  • MMP-17 MT4-MMP
  • the uncontrolled breakdown of connective tissue by MMPs is a feature of many pathological conditions . Examples include rheumatoid arthritis, osteoarthritis , septic arthritis, ulcerations (such as corneal, epidermal, or gastric ulcerations), periodontal disease, proteinuria; Alzheimer's Disease, coronary thrombosis, psoriasis, aneurysm, and bone disease. Defective injury repair processes also occur. This can produce improper wound healing leading to weak repairs, adhesions, and scarring.
  • MMP-8 also known as neutrophil collagenase
  • type II collagen and aggrecan a structural glycosaminoglycan found in the cartilage
  • MMP-8 has been found to be present in patients having osteoarthritis and rheumatoid arthritis and may participate significantly in the progression of these diseases.
  • Matrix Metalloproteinases .C. Parks and R.P. Mecham, ed. , Academic Press, San Diego (1998), pp. 32-33.
  • MMPs are also involved in the biosynthesis of tumor necrosis factor (TNF) .
  • TNF- ⁇ is a cytokine that is believed to be produced initially as a 28 kDa cell-associated molecule. It is released as an active, 17 kDa form that can mediate many deleterious effects in vi tro and in vivo .
  • TNF can cause or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects (such as post-ische ic reperfusion injury, congestive heart failure hemorrhage, coagulation, and hyperoxic alveolar injury) , radiation damage, and acute phase responses like those seen with infections and sepsis during shock such as septic shock and hemodynamic shock.
  • Chronic disease of active TNF can cause cachexia and anorexia.
  • Chronic release of TNF can be lethal.
  • TNF- ⁇ convertase is a metalloproteinase involved in the formation of active TNF- ⁇ . Inhibition of TNF- ⁇ convertase inhibits production of active TNF- a.
  • Some compounds that inhibit TNF- ⁇ convertase and MMPs involved in TNF- ⁇ biosynthesis are disclosed in PCT Patent Application No. WO 94/24140. Additional compounds that inhibit such enzymes are disclosed in PCT Patent Application No. WO 94/02466. Further inhibitors are disclosed in PCT Patent Application No. WO 97/20824.
  • Some compounds that inhibit certain MMPs have been shown to also inhibit the release of TNF (Gearing et al., Nature, 376, 555-557 (1994)). McGeehan et al . disclosed further compounds which inhibit MMPs and inhibit the release of TNF ⁇ Nature , 376, 558-561 (1994) ) .
  • MMPs are involved in other biochemical processes as well. Included are the control of ⁇ vulation, post- partum uterine involution, possibly implantation of fertilized ova, cleavage of APP ( ⁇ -Amyloid Precursor Protein) to the amyloid plaque and inactivation of ⁇ i- protease inhibitor ( ⁇ i-PI) . Inhibition of these metalloproteinases permits, for example, the control of fertility and the treatment or prevention of Alzheimer's Disease.
  • APP ⁇ -Amyloid Precursor Protein
  • ⁇ i-PI ⁇ i- protease inhibitor
  • an endogenous or administered serine protease inhibitor drug or biochemical such as ⁇ -PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases, and diseases of aging such as loss of skin or organ stretch and resiliency.
  • Inhibition of selected MMPs can also be desirable in other instances.
  • selective inhibition of MMP-3, MMP-2, MMP-9, or MMP-13 in the presence of MMP-1 may be useful for the treatment of cancer, prevention of metastasis of cancer cells, or the inhibition of angiogenesis .
  • a therapy which does not inhibit MMP-1 but does selectively inhibit one or more of the other MMPs can have a therapeutically useful profile.
  • Osteoarthritis another prevalent disease wherein it is believed that cartilage degradation in flamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by adminis ration of drugs which selectively inhibit MMP-13. See, for example, Mitchell et al . , J. Cl in . Invest . , 97, 761-768 (1996). See also Reboul et al., J. Clin. Invest., 97, 2011-2019 (1996).
  • MMPs Some inhibitors of MMPs are known. Examples include natural biochemicals such as tissue inhibitor of metalloproteinase (TIMP) , a 2 -macroglobulin, and their analogs or derivatives. These are high molecular weight protein molecules that form inactive complexes with metalloproteinases . Some smaller peptide-like compounds that inhibit MMPs have also been described. Thiol group-containing amide or peptidyl amide-based metalloproteinase (MMP) inhibitors are known as is shown in, for example, PCT Patent Application No. WO 95/12389. Further such inhibitors are described in PCT Patent Application No.
  • MMP Thiol group-containing amide or peptidyl amide-based metalloproteinase
  • Swartz et al disclose some peptidomimetic MMP inhibitors in Progr . Med . Chem . , 29_, 271-334 (1992). Further peptidomimetic MMP inhibitors are disclosed by Rasmussen et al . , in Pharmacol . Ther . , 75(1), 69-75 (1997). Denis et al . , disclose further peptidomimetic MMP inhibitors in Invest. New Drugs , 15(3), 175-185 (1997) .
  • MMP inhibitors are not very selective.
  • the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC 50 values of about 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3 , MMP-7 , and MMP-9.
  • Marimastat another peptidomimetic hydroxamate, was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum similar to batimastat, except that marimastat exhibits an IC 50 value against MMP-3 of about 230 nM.
  • the primary, secondary, and tertiary structures of the MMPs have a number of characteristic features.
  • Each MMP contains a catalytic domain which in turn comprises a zinc binding site and an adjacent site known as the Si' pocket.
  • the Si' pocket has been recognized as a major factor in substrate specificity of the MMPs. See for example B. Lovejoy et al . , Nat. Struct . Biol . , 6 (3), 217-221 (1999) at 218.
  • the Si' pocket is sometimes known as the specificity pocket.
  • Figure 1 shows a partial sequence alignment for MMP-1, MMP-3, and MMP-8.
  • the amino acid residues in the shaded boxes of Figure 1 comprise the residues included in the Si' pocket for each of these MMPs. Symbols in Figure 1 identifying the amino acid residues are commonly used by those of skill in the art.
  • the primary, secondary, and tertiary structures work together for each MMP to provide the catalytic activity, kinetics, and substrate specificity of the enzyme. These structures define the shape or conformation of the amino acid residue backbone of the enzyme.
  • the actual sequence of amino acid residues in the Si' pocket and the conformation of the residue backbone determine the specificity and kinetics of each MMP.
  • F. Grams et al . discloses X- ray structures of human neutrophil collagenase complexed with peptidomimetic hydroxamate and thiol inhibitors.
  • B. Lovejoy et al . disclose X-ray crystal structures of the catalytic domains of MMP-1 and MMP-13. Lovejoy et al .
  • MMP-1 SI' pocket undergoes a conformational change to accommodate certain diphenylether inhibitors but that the MMP-13 SI' pocket is larger and can accommodate the diphenylether inhibitors without undergoing a conformational change. They report that this difference determines the selectivity of these diphenylether compounds for preferentially inhibiting MMP-13 relative to MMP-1.
  • the X-ray crystal structure for MMP-2 was reported by E. Morgunova et al . ("Structure of Human Pro-Matrix Metalloproteinase-2 : Activation Mechanism Revealed," Science 284, 1667-1670 (1999)).
  • the present invention provides a matrix metalloproteinase inhibiting compound having the structure:
  • R 2 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkylaryl, arylalkyl, alkoxyalkyl , hydroxyalkyl , aminoalkyl , alkyla inoalkyl , heterocycloalkyl , and heterocycloalkylalkyl
  • R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, and heterocycloalkyl
  • R 20 is selected from the group consisting of -C(0)OH, -C(0)NHOH
  • the invention is further directed to a method of changing the conformation of a matrix metalloproteinase wherein the method comprises contacting the matrix metalloproteinase with a compound having the formula:
  • R 2 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkylaryl, arylalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, heterocycloalkyl, and heterocycloalkylalkyl
  • R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, and heterocycloalkyl
  • R 20 is selected from the group consisting of
  • the present invention is further provides a method of inhibiting a matrix metalloproteinase wherein the method comprises contacting the matrix metalloproteinase with a compound having the structure of Formula VIII or a salt, an enantiomer, a diastereomer, a racemate, or a tautomer thereof, thereby inhibiting the matrix metalloproteinase .
  • the present invention further provides a method of treating osteoarthritis in a mammal wherein the method comprises providing to the mammal an osteoarthritis- treating-effective amount of a compound having the structure of Formula VIII or an enantiomer, diastereomer, racemate, or tautomer thereof, thereby treating osteoarthritis.
  • Figure 1 shows a partial sequence alignment for MMP-1, MMP-3, and MMP-8.
  • Figure 2 shows the structures of inhibitor molecules of Formulae XII, IX, X, and XI superimposed upon one another.
  • Figure 3 shows MMP-8 SI' amino acid backbone residues which reside within 5 A of a complexed inhibitor molecule.
  • Figure 4 shows a comparison of the SI ' pockets of MMP-1 and of MMP-8.
  • Figures 5, 6, 7, and 8 show the effect of progressively lengthening the Pi' group of an MMP inhibitor on the conformation of the substituents on amino acid residues of the SI' pocket.
  • Figures 9, 10, 11, and 12 show the effect of progressively lengthening the Pi' group of an MMP inhibitor on the conformation of the backbone of the SI' pocket.
  • Figure 13 shows the temperature factor (B) distribution for MMP-8 complexes with inhibitor compounds .
  • Figure 14 shows the ( ⁇ , ⁇ ) distribution among the amino acid residues of MMP-8 from 222 to 231.
  • Figures 15 and 16 show electron density distributions of one aspect of the overall MMP-8 enzyme when different inhibitor compounds have been complexed.
  • Alkyl alkenyl
  • alkynyl unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to about 20 carbon atoms for alkyl or to about twenty carbon atoms for alkenyl and alkynyl.
  • the terms therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl, or hexyl; ethenyl, propenyl, butenyl, pentenyl, or hexenyl ; and ethynyl , propynyl, butynyl, pentynyl, or hexynyl respectively and isomers thereof.
  • Aryl means a fully unsaturated mono- or multi- ring carbocycle, including but not limited to substituted or unsubstituted phenyl, naphthyl, or anthracenyl.
  • Heterocycle means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or 0. This includes, for example, the following structures:
  • one or more of Z, Z a , Z°, or Z c is independently C, S, P, or N, with the proviso that one of Z, Z a , Z b , or Z c is other than carbon, but is not 0 or S when attached to another Z atom by a double bond or when attached to another O or S atom.
  • the optional substituents are understood to be attached Z, Z a , Z°, or Z c only when the atom to which the optional substituent is attached is C.
  • Heteroaryl means a fully unsaturated heterocycle. In either “heterocycle” or “heteroaryl” the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.
  • Cycloalkyl means a mono- or multi-ringed carbocycle wherein each ring contains three to about ten carbon atoms, and wherein any ring can contain one or more double or triple bonds .
  • halogen or halo means a fluoro, chloro, bromo or iodo group.
  • haloalkyl means alkyl substituted with one or more halogens .
  • diyl means a diradical moiety wherein the moiety has two points of attachment to a molecule of interest.
  • heterocycloalkylalkyl means an alkyl radical that is substituted with one or more heterocycle groups .
  • Preferable heterocycloalkylalkyl radicals are "lower heterocycloalkylalkyl” radicals having one or more heterocycle groups attached to an alkyl radical having one to ten carbon atoms .
  • the compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore included racemates and stereoisomers such as diastereomers and enantiomers, in both pure form and in admixture.
  • stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.
  • Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds of the present invention.
  • the compounds of the present invention also include their tautomers , salts, solvates, and prodrugs .
  • MMPs matrix metalloproteinases
  • substituted-aromatic ring sulfonamide hydroxamic acid substituted-aromatic ring sulfinamide hydroxamic acid, substituted-aromatic ring sulfenamide hydroxamic acid compounds, substituted-aromatic ring sulfonamide carboxylic acid, substituted-aromatic ring sulfinamide carboxylic acid or substituted-aromatic ring sulfenamide carboxylic acid compounds are effective for inhibition of collagenase Type III (MMP-13) and neutrophil collagenase (collagenase II, MMP-8), which are believed to be particularly destructive to tissue if present or generated in abnormal quantities or concentrations.
  • MMP-13 collagenase Type III
  • MMP-8 neutrophil collagenase
  • the present invention is directed to a matrix metalloproteinase inhibiting compound having the structure of Formula VII:
  • W is independently selected from the group consisting of -NR 5 COR 6 , -NR 5 S(0) z R 7 where z is zero, 1, or 2, -NR 5 COOR 8 , -NR 5 CONR 8 R 9 and -NR n R 12 •
  • R 1 is a hydrocarbyl diyl moiety or a substituted hydrocarbyl diyl moiety.
  • R 1 can be aromatic, for example 1 , 2-phenylene, 1, 3 -phenylene, 1, 4-phenylene, naphthalene-1, -diyl, or naphthalene-1, 5-diyl .
  • R 1 can be aliphatic, for example methylene, ethane-1, 2-diyl , propane-1 , 2-diyl, or propane-1 , 3-diyl .
  • R 1 can be a straight-chain hydrocarbyl diyl moiety, or it can be branched.
  • R 1 can be 2 -methylpropane-1, 3-diyl .
  • R 1 can contain one or more unsaturations.
  • R 1 can be prop-l-ene-1, 3-diyl or a cycloalkylene such as anti-1 , 4-cyclohexane diyl.
  • R 1 can also contain a heteroatom (e.g., 0, N, or S) .
  • R 1 can be a heteroarylene such as pyridine-2 , 5- diyl or R 1 can be an aliphatic heterocycle such as morpholine-1, 3-diyl .
  • R 1 contains a heteroatom, the point of attachment of R 1 to the molecule can be at a heteroatom of R 1 or it can be at a carbon atom of R 1 .
  • R 2 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkylaryl, arylalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, heterocycloalkyl, heterocycloalkylalkyl aralkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkyl, hydroxycarbonylalkyl, alkylcycloalkyl, heterocycloalkylalkyl, aroylalkyl, and heteroaroylalkyl group, -(CH ⁇ K -NR 1 ⁇ 1 , or - (CH 2 ) X -C (0) NR R 12 , wherein x is an integer from zero to 6.
  • R 3 and R 4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, and heterocycloalkyl, aryl, aralkyl, thioalkyl, heteroaralkyl, heteroaryl, alkoxyalkoxyalkyl , trifluoromethylalkyl , alkoxycarbonylalkyl , aralkoxycarbonylalkyl , hydroxycarbonylalkyl, alkoxyalkyl, heterocycloalkylalkyl, aryloxyalkyl , alkylthioalkyl, arylthioalkyl, heteroarylthioalkyl group, or a sulfoxide or sulfone of any of said thio-
  • R 4 is H or a Ci to about C 12 alkyl group. More preferably, R 4 is H or a C ⁇ _ to about C 4 alkyl group. Still more preferably R 4 is H. R 2 and R 3 together with the atom chain to which they are attached can optionally form a ring comprising about 3 to about 8 members .
  • R is selected from the group consisting of H and
  • Ci to about C 2 o alkyl group .
  • R s is selected from the group consisting of H, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, alkylaryl, heteroaralkyl , cycloalkylalkyl , heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkyl group, and a - (CH 2 ) X -NR 1:L R 12 group wherein x is an integer from zero to about 6.
  • the aryl or heteroaryl groups of R ⁇ are optionally substituted (unsubstituted or substituted) with one or more substituents independently selected from the group consisting of a halogen, Ci to about C 2 o alkyl, Ci to about Co alkenyl, Ci to about C 2 o alkynyl, Ci to about C 2 o alkoxy, nitro, cyano, hydroxy, carboxy, hydroxycarbonylalkyl, - (CH 2 ) x -NR 1:l R 12 , wherein x is an number from zero to about 6, trifluoromethyl , alkoxycarbonyl , aminocarbonyl , thio, alkylsulfonyl, carbonylamino, aminosulfonyl, alkylsulfonamino, alkoxyalkyl, cycolalkyloxy, alkylthioalkyl or alkylthio.
  • substituents independently selected from the group consisting of a
  • R 5 and R 5 together with the atom chain to which they are bonded can form an about 5- to about 7-membered a cyclic amide or imide that is substituted or unsubstituted.
  • R 5 and R 7 together with the atom chain to which they are bonded can form an about 5- to about 7-membered a cyclic sulfonamide that is substituted or unsubstituted.
  • R 7 is selected from the group consisting of R s and alkyl ;
  • R 8 and R 9 are independently selected from the group consisting of R s and alkyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form an about 5- to about 7-membered ring containing zero or one heteroatom that is oxygen, nitrogen or sulfur;
  • R 11 and R 12 are independently selected from the group consisting of H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, alkanoyl , aralkanoyl , and heteroaralkanoyl group, or R 11 and R 12 taken together form an about 5- to about 8-membered heterocyclo or heteroaryl ring; and
  • R 13 is selected from the group consisting of H or C 3 to about Cs alkyl group.
  • R 20 is selected from the group consisting of -C(0)0H, -C(0)NH0H, -SH, and -C(0)SH.
  • the compound of the present invention has a structure of Formula VIII:
  • R 2 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkylaryl, arylalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, heterocycloalkyl, and heterocycloalkylalkyl
  • R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, haloalkoxy, haloalkylthio, and heterocycloalkyl
  • R 20 is selected from the group consisting of
  • R 2 can be selected from the group consisting of any of the N-bonded substituent groups of the following bases: 4-acetyl cytidine; 5- ( carboxyhydroxyl ethyl ) uridine ; 2 ' -0- methylpseudouridine; beta, D-galactosylquiosine; 2 ' -0- methylguanosine; inosine; N6-isopentenyladenosine; 1- methyladenosine; 1-methylpseudouridine; 1- methylguanosine; 1-methylinosine; 2 , 2-dimethylguanosine; 2-methyladenosine; 2-methylguanosine; 3-methylcytidine; 5-methylcytidine; N6-methyladenosine; 7-methylguanosine; 5-methoxyaminomethyl-2-thiouridine; beta, D- mannosylqueosine; 5-methoxycarbonylmethyluridine; 5- methoxyuridine,-
  • R 2 can be selected from the group consisting of any of the side chains of the following amino acids: 2-aminoadipic acid; 3-aminoadipic acid; beta-alanine, beta-aminopropionic acid; 2-aminobutyric acid; 4-aminobutyric acid, piperidinic acid; 6- aminocaproic acid; 2-aminoheptanoic acid; 2- aminoisobutyric acid; 3-aminopimelic acid; 2,4- diaminobutyric acid; desmosine; 2 , 2 ' -diaminpimelic acid; 2 , 3-diaminopripionic acid; N-ethylglycine; N- ethylasparagine,- hydroxylysine ; allo-hydroxylysine; isodesmosine; allo-isoleucine,- N-methylglycine, sarcosine; N-methylisoleucine; N-methylvaline; norvaline; norleucine; and
  • R 20 of Formula VIII is selected from the group consisting of -C(0)0H and -C(0)NHOH.
  • R 21 and ; R 25 of Formula VIII are both H. More preferably, R 21 , R 22 , R 24 , and R 25 are H.
  • R 21 , R 22 , R 24 , and R 25 are H, preferably R 23 is C x to about C 2 o alkyl and more preferably R 23 is Ci to about C 2 o linear alkyl .
  • R 3 is preferably selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkoxy, haloalkylthio, and heterocycloalkyl; more preferably R 3 is heterocycloalkyl, and more preferably still R 3 is 2-(N- orpholino) ethyl.
  • R 3 is preferably selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkoxy, haloalkylthio, and heterocycloalkyl; more preferably R 3 is heterocycloalkyl, and more preferably still R 3 is 2-(N- morpholino) ethyl .
  • Table I shows preferred compounds of the present invention.
  • the represented compounds are meant to include their salts, enantiomers, diastereomers , racemates, and tautomers .
  • Table I shows preferred compounds of the present invention. The represented compounds are meant to include their salts, enantiomers, diastereomers , racemates, and tautomers .
  • some of the compounds of the present invention provide selective inhibition o.f certain MMPs, particularly MMP-8 or MMP-13, in part by causing a change in the conformation of the amino acid residue backbone of the inhibited MMP.
  • the present invention is further directed to a method of changing the conformation of a matrix metalloproteinase wherein the method comprises contacting the matrix metalloproteinase with a compound having the structure of Formula XIII:
  • R 2 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkylaryl, arylalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, heterocycloalkyl, and heterocycloalkylalkyl ;
  • R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, and heterocycloalkyl ;
  • R 20 is selected from the group consisting of
  • R 26 , R 27 , R 28 , R 29 , and R 30 are independently selected from the group consisting of about C 3 to about C 2 o alkyl, about C 3 to about C 2 o alkenyl, about C 3 to about C 2 o alkynyl, cycloalkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, nitroalkyl, heterocycloalkyl, and carboxyalkyl.
  • R 20 of Formula XIII is selected from the group consisting of -C(0)0H and -C(0)NH0H.
  • R 3 is preferably a Ci to about C ⁇ 2 alkyl, more preferably R 3 is a Ci to about C 4 alkyl, and more preferably still R 3 is isopropyl.
  • R 2 is preferably heterocycloalkylalkyl and more preferably R 2 is 2- (N-morpholino) ethyl .
  • R 26 and R 30 are H. More preferably, R 2 ⁇ , R 27 , R 29 , and R 30 are H.
  • R 28 can be an alkyl group of any convenient size.
  • R 28 is preferably about C 3 to about C 2 o alkyl and more preferably R 28 is about C 3 to about C 2 o linear alkyl. More preferably still R 28 is n-propyl, n-butyl, n-pentyl or n-hexyl .
  • Compounds IX, X, XI, and XII of Table I each is useful in the present invention.
  • the compounds of the Formula XIII are particularly useful in changing the conformation of MMP enzymes, especially MMP-8 and/or MMP-13.
  • Crystal structures of MMP-8 complexed with MMP inhibitor compounds of Formula XIII compared with crystal structures of MMP-8 complexed with the compound of Formula XIV or the compound of Formula XV establish a three-dimensional structure-activity relationship.
  • the inhibitors interact with the protein through chelation of the catalytic zinc ion, hydrogen bonding with the backbone -NH- of Leu 160, and hydrophobic interactions in the nonpolar SI' pocket.
  • the SI' pocket is formed from residues 193-197 that form a turn of a longer helix and residues 214-229 of a loop region.
  • the SI' pocket in MMP-8 is not as deep as in some other MMPs (e.g., stromelysin).
  • FIG. 2 shows the structures of inhibitor molecules of Formulae XII, IX, X, and XI superimposed upon one another, wherein the structures were determined by the X-ray crystallographic techniques described herein.
  • the Figure shows the co-extensive reach of the Pi' arms of the inhibitors, except that as the alkyl group of the 4-alkylbenzamide moiety increases in length, the steric requirements of each inhibitor also increases.
  • the PI' arm of each inhibitor fits into the MMP-8 SI' pocket. In order to accommodate an increase in the steric requirement of the Pi' arm, the amino acid residues of the SI' pocket must change their conformations .
  • Figure 3 shows MMP-8 SI' amino acid backbone residues which reside within 5 A of a complexed inhibitor molecule as determined by the X-ray crystallographic techniques described herein.
  • a blank in Figure 3 indicates that the residue lies within 5 A of the inhibitor whereas the word "no" indicates that the residue lies further than 5 A from the complexed inhibitor.
  • Figure 4 shows a comparison of the SI' pockets of MMP-1 and of MMP-8.
  • Figures 5, 6, 7, and 8 show the effect of progressively lengthening the PI' group of the MMP inhibitor on the conformation of the substituents on amino acid residues of the SI' pocket.
  • Figure 5 shows a comparison of the X-ray crystallographic conformation of amino acid residues in the SI' pocket of MMP-8 when either the compound of Formula XII (colored) or the compound of Formula XIV (grey) is complexed with MMP-8.
  • the figure shows that the Pi' group (including the 4-propylbenzamide moiety) of XII sterically interferes with the side chain of the Arg 222 (R222) residue of the SI' pocket while the Pi' group of XIV is much shorter and does not sterically interfere with the Arg 222 the side chain.
  • Complexed XII causes the Arg 222 the side chain to move out of the way of the large PI' group of XII.
  • Figure 6 shows a comparison of the X-ray crystallographic conformation of amino acid residues in the Si' pocket of MMP-8 when either the compound of Formula XII (colored) or the compound of Formula IX (grey) is complexed with MMP-8.
  • the Pi' group of IX (including the 4-pentylbenzamide moiety) is larger still than the PI' group of XII. Because of increased steric interference, the IX Pi' group causes the side chain of the Arg 222 (R222) residue of the SI' pocket to move even further away from the pocket than does the PI ' group of XII.
  • Figure 7 shows a comparison of the X-ray crystallographic conformation of amino acid residues in the SI' pocket of MMP-8 when either the compound of Formula XII (colored) or the compound of Formula X (grey) is complexed with MMP-8.
  • the Pi' group of X (including the 4-hexylbenzamide moiety) is larger still than the PI' group of XII. Because of increased steric interference, the PI' group of X causes the side chain of the Arg 222 (R222) residue of the SI' pocket to move as far or further away from the pocket than does the XII PI' group.
  • Figure 8 shows a comparison of the X-ray crystallographic conformation of amino acid residues in the SI' pocket of MMP-8 when either the compound of Formula XII (colored) or the compound of Formula XI (grey) is complexed with MMP-8. This Figure shows a result similar to that of Figure 7.
  • Figures 9, 10, 11, and 12 show the effect of progressively lengthening the PI' group of the MMP inhibitor on the conformation of the backbone of the SI' pocket.
  • Figure 9 shows a comparison of the X-ray crystallographic conformation of the amino acid backbone of the SI' pocket of MMP-8 when either the compound of Formula XII (green) or the compound of Formula XIV (red) is complexed with MMP-8.
  • Figure 9 demonstrates that XII affects the conformation of the side chain of the Arg 222 (R222) residue of the SI' pocket relative to XIV
  • Figure 9 also shows that each compound has essentially no effect on the conformation of the amino acid backbone (shown as a ribbon in Figure 9) .
  • Tyr 227 (Y227) shows little change when either XII or XIV is complexed in the SI' pocket.
  • Figure 10 shows a comparison of the X-ray crystallographic conformation of the amino acid backbone of the SI' pocket of MMP-8 when either the compound of Formula XII (red) or the compound of Formula X (yellow) is complexed with MMP-8.
  • the longer 4-pentylbenzamide moiety of X causes the backbone to deform significantly relative to the case in which XII is complexed.
  • X causes the Arg 222 and Tyr 227 side chains to move significantly relative to the case in which XII is complexed.
  • Figure 11 shows a comparison of the X-ray crystallographic conformation of the amino acid backbone of the SI' pocket of MMP-8 when either the compound of Formula XII (red) or the compound of Formula IX (yellow) is complexed with MMP-8.
  • the longer 4-pentylbenzamide moiety of IX causes the backbone to deform significantly relative to the case in which XII is complexed.
  • IX causes the Arg 222 and Tyr 227 side chains to move significantly relative to the case in which XII is complexed.
  • Figure 12 shows a comparison of the X-ray crystallographic conformation of the amino acid backbone of the SI' pocket of MMP-8 when either the compound of Formula XII (red) or the compound of Formula XI (blue) is complexed with MMP-8.
  • the longer 4-hexylbenzamide moiety of XI causes the backbone to deform significantly relative to the case in which XII is complexed.
  • XI causes the Arg 222 and Tyr 227 side chains to move significantly relative to the case in which XII is complexed.
  • Figure 13 shows the temperature factor (B) distribution for MMP-8 complexes with inhibitor compounds XII (red) , IX (orange) , X (yellow) , XI (blue) , and XIV (white) .
  • Complexes with XII and XIV show similar temperature factors indicating that the MMP-8 backbone has similar thermal motion in both cases.
  • XI, X, and IX complexes cause a progressive increase in the temperature factor in residues 221-230, indicating that they are causing greater thermal motion in that region of the SI' pocket of MMP-8 relative to compounds X or XIV.
  • Figure 14 shows the ( ⁇ , ⁇ ) distribution among the amino acid residues of MMP-8 from 222 to 231.
  • Figure 15 shows an electrostatic surface of one aspect of the overall MMP-8 enzyme in which the inhibitor compound of Formula XIV has been complexed.
  • Figure 16 shows an electrostatic surface of one aspect of the overall MMP-8 enzyme in which the inhibitor compound of Formula XI has been complexed.
  • Figure 16 (center) shows that the XI has caused a change in the conformation of MMP-8 relative to XIV as evidenced by the opening created by XI in the SI' pocket caused by the change in conformation of the amino acid residue backbone of MMP-8. This opening is absent from the XIV- MMP-8 complex shown in Figure 15.
  • the electrostatic surfaces were calculated and drawing using the GRASP program (A. Nicholls et al . , "Protein folding and association: Insights from the interfacial and thermodynamic properties of hydrocarbons," Protein Str . Funct . Gen . 11, 281-296 (1991)).
  • the present invention is also directed to a method of inhibiting a matrix metalloproteinase wherein the method comprises contacting the matrix metalloproteinase with a compound of Formula VIII (for which each of the substituents are as defined above) thereby inhibiting the matrix metalloproteinase.
  • R 20 of Formula XIII is selected from the group consisting of -C(0)0H and -C(0)NH0H.
  • R 3 is preferably a C x to about C ⁇ 2 alkyl, more preferably R 3 is a Ci to about C 4 alkyl, and more preferably still R 3 is isopropyl .
  • R 2 is preferably heterocycloalkylalkyl and more preferably R 2 is 2- (N-morpholino) ethyl .
  • R 21 and R 25 of Formula VIII are both H. More preferably, R 21 , R 22 , R 24 , and R 25 are H.
  • R 23 can be an alkyl group of any convenient size. When R 21 , R 22 , R 24 , and R 25 are H, preferably R 23 is C to about C 2 ⁇ alkyl and more preferably R 23 is Ci to about C 2 o linear alkyl.
  • Compounds IX, X, XI, and XII of Table I each is useful in the present invention.
  • the compounds of the present invention are particularly useful in inhibiting MMP-8 and/or MMP-13.
  • Another embodiment of the present invention is directed toward a method for the treatment of osteoarthritis in a mammal wherein the method comprises providing to the mammal an osteoarthritis-treating- effective amount of a compound of Formula VIII (for which each of the substituents are as defined above) .
  • the mammal can be, for example, a human.
  • the starting materials for use in the preparation of the compounds of the present invention are known or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art.
  • the compounds of the present invention can be prepared by methods described in detail in U.S. Patent Application No. 09/230,205, herein incorporated by reference.
  • Schemes I and III and Schemes 1, 2, 4, 5, 6, and 7 illustrate procedures with examples of chemical transformations that may be useful for the preparation of compounds of this invention.
  • These syntheses can be carried out under a dry inert atmosphere such a nitrogen or argon if desired.
  • Selected reactions known to those skilled in the art can be carried out under a dry atmosphere such as dry air whereas other synthetic steps, for example, aqueous acid or base ester or amide hydrolyses, can be carried out under laboratory air.
  • Scheme 1 shows the conversion of an N-substituted alpha-amino acid, protected or unprotected, into a compound of Formula I.
  • the amino acid may be protected with a group P such as an alkyl ester such as methyl, ethyl, tert-butyl, tetrahydropyranyl and the like or arylalkyl ester such as benzyl.
  • a group P such as an alkyl ester such as methyl, ethyl, tert-butyl, tetrahydropyranyl and the like or arylalkyl ester such as benzyl.
  • Treatment of this amine with a sulfonyl, sulfinyl or sulfenyl chloride would provide the corresponding amide.
  • a base would normally be used to inactivate the HCl released from the acid chloride and it would be such that it would not react with the sulfonyl chloride, i.e., ammonia, primary or secondary amines would not normally be used.
  • bases examples include, for example, metal hydroxides such as sodium, potassium, lithium or magnesium hydroxide, oxides such as those of sodium, potassium, lithium, calcium or magnesium, metal carbonates such as those of sodium, potassium, lithium, calcium or magnesium, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, primary, secondary or tertiary organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides.
  • metal hydroxides such as sodium, potassium, lithium or magnesium hydroxide
  • oxides such as those of sodium, potassium, lithium, calcium or magnesium
  • metal carbonates such as those of sodium, potassium, lithium, calcium or magnesium
  • metal bicarbonates such as sodium bicarbonate or potassium bicarbonate
  • primary, secondary or tertiary organic amines such as alkyl amines, arylalkyl amines, alky
  • such amines can include triethyl amine, tri ethyl a ine, diisopropyl amine, methyldiisopropyl amine, diazabicyclononane, tribenzyl amine, dimethylbenzyl amine, morpholine, N-methylmorpholine, N,N' -dimethylpiperazine, N-ethylpiperidine, 1,1,5,5- tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine and the like.
  • Non-limiting examples of ammonium hydroxides can include ammonium hydroxide, triethyl ammonium hydroxide, trimethyl ammonium hydroxide, methyldiiospropyl ammonium hydroxide, tribenzyl ammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholinium hydroxide, N- methylmorpholinium hydroxide, N, N' -dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like.
  • quaternary ammonium hydroxides can include tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide, dimethyldiiospropyl ammonium hydroxide, benzymethyldiisopropyl ammonium hydroxide, methyldiazabicyclononyl ammonium hydroxide, methyl ribenzyl ammonium hydroxide, N,N- dimethylmorpholinium hydroxide, N,N,N',N'- tetramethylpiperazenium hydroxide, and N-ethyl-N'- hexylpiperidinium hydroxide and the like.
  • Metal hydrides, amide or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like may also be suitable reagents.
  • Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl, phenyl or butyl lithium, Grignard reagents such as methylmagnesium bromide or methylmagnesium chloride, organocadmium reagents such as dimethylcad ium and the like may also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents.
  • the first reaction in Scheme 1 also illustrated the use of a mixed solvent THF/H2O.
  • the reaction media can consist of a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system.
  • the solvents can be protic, non-protic or dipolar aprotic .
  • protic solvents include water, methanol (MeOH) , denatured or pure 95% or absolute ethanol, isopropanol and the like.
  • Typical non-protic solvents include acetone, tetrahydrofuran (THF) , dioxane, diethylether (ether) , tert-butylmethyl ether (TBME) , aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC) , hexane, heptane, isooctane, cyclohexane and the like.
  • THF tetrahydrofuran
  • ether diethylether
  • TBME tert-butylmethyl ether
  • aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chlor
  • Dipolar aprotic solvents include compounds such as dimethylformamide (DMF) , dimethylacetamide (DMAc) , acetonitrile, nitromethane, tetramethylurea, N-methylpyrrolidone and the like.
  • Non-limiting examples of ammonium hydroxides can include ammonium hydroxide, triethyl ammonium hydroxide, trimethyl ammonium hydroxide, methyldiiospropyl ammonium hydroxide, tribenzyl ammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholinium hydroxide, N- methylmorpholinium hydroxide, N, N' dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like.
  • quaternary ammonium hydroxides can include tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide, dimethyldiiospropyl ammonium hydroxide, benzymethyldiisopropyl ammonium hydroxide, methyldiazabicyclononyl ammonium hydroxide, methyltribenzyl ammonium hydroxide, N,N- dimethylmorpholinium hydroxide, N,N,N',N'- tetramethylpiperazenium hydroxide, and N-ethyl-N'- hexylpiperidinium hydroxide and the like.
  • Metal hydrides, amide or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like may also be suitable • reagents .
  • Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl, phenyl or butyl lithium, Grignard reagents such as methylmagnesium bromide or methylmagnesium chloride, organocadmium reagents such as dimethylcadmium and ⁇ the like may also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents.
  • the first reaction in Scheme 1 also illustrated the use of a mixed solvent THF/H 2 0.
  • the reaction media can consist of a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system.
  • the solvents can be protic, non-protic or dipolar aprotic.
  • protic solvents include water, methanol (MeOH) , denatured or pure 95% or absolute ethanol, isopropanol and the like.
  • Typical non-protic solvents include acetone, tetrahydrofurane (THF) , dioxane, diethylether (ether) , tert-butylmethyl ether (TBME) , aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC) , hexane, heptane, isooctane, cyclohexane and the like.
  • THF tetrahydrofurane
  • ether diethylether
  • TBME tert-butylmethyl ether
  • aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, m
  • Dipolar aprotic solvents include compounds such as dimethylformamide (DMF) , dimethylacetamide (DMAc) , acetonitrile, nitromethane, tetramethylurea, N-methylpyrrolidone and the like.
  • Non-limiting examples of reagents that can be used as solvents or as part of a mixed solvent system include organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols, ammonia or amines for making esters or amides and the like.
  • organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols, ammonia or amines
  • Acids are used in many reactions during various synthesis.
  • Scheme 1 illustrates acid use for the removal of the THP protecting group to produce the hydroxamic acid of Formula I.
  • the acid might be mono-, di- or tri-protic organic or inorganic acids.
  • acids include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorus acid, p-toluene sulfonic acid, trifluoromethane sulfonic acid, trifluoroacetic acid, difluoroacetic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid, 2 , 6-dimethylbenzene sulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid, and the like.
  • a preferred solvent in this type reaction is dioxane eith an alcohol or water however almost any solvent system with one component being a protic solvent can be useful.
  • Scheme I illustrates conversion of a carboxylic acid protected as an ester or amide into an hydroxamic acid derivative such as a O-arylalkylether or 0- cycloalkoxyalkylether group.
  • an hydroxamic acid derivative such as a O-arylalkylether or 0- cycloalkoxyalkylether group.
  • the protecting group on the hydroxylamine is the
  • THP group In the case where hydroxylamine is used, treatment of an ester or amide with one or more equivalents of hydroxylamine hydrochloride at room temperature or above in a solvent or solvents, usually protic or partially protic, such as those listed above can provide a hydroxamic acid directly. This exchange process may be further catalyzed by the addition of additional acid.
  • a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol, can be used to form hydroxylamine from hydroxylamine hydrochloride in situ which can exchange with an ester or amide.
  • exchange can be carried out with a protected hydroxyl amine such as tetrahydropyranyl-hydroxyamine (THPONH2), benzylhydroxylamine (BnONH2), and the like in which case compounds such as shown in Scheme 1 that are tetrahydropyranyl (THP) or benzyl (Bn) hydroxamic acid derivatives are the products.
  • a protected hydroxyl amine such as tetrahydropyranyl-hydroxyamine (THPONH2), benzylhydroxylamine (BnONH2), and the like in which case compounds such as shown in Scheme 1 that are tetrahydropyranyl (THP) or benzyl (Bn) hydroxamic acid derivatives are the products.
  • Removal of the protecting groups when desired, for example, following further transformations in another part of the molecule or following storage is accomplished by standard methods well known in the art such as acid hydrolysis of the THP group as discussed above or reductive removal of the benzyl group with hydrogen and
  • This compound is a secondary sulfonamide and, as such, is acidic and can be alkylated with an R 2 group.
  • Alkylation a process well known in the art, can be carried by treatment of the sulfonamide with base to form the corresponding anion, adding an electrophilic reagent and allowing the S 2 reaction to proceed.
  • Electrophiles include halogen derivatives, sulfonate esters, epoxides and the like.
  • the bases and solvents discussed with regard to Scheme I are applicable in this Scheme. Preferred bases are those that are hindered such that competition with the electrophile is minimized. Additional preferred bases are metal hydrides, amide anions or organometallic bases such as a butyl lithium.
  • the solvents, solvent mixtures or solvent/reagent mixtures discussed are satisfactory but non-protic or dipolar aprotic solvents such as acetone, acetonitrile, DMF and the like are examples of preferred classes.
  • Scheme III illustrates the potential for use of a sulfonyl chloride reagent, specifically nitrobenzenesulfonyl chloride, to prepare compounds of this invention. It should be noted that this reagent is for illustration and is not to be considered limiting or required.
  • the nitrosulfonamide can be reduced to provide a useful amino compound.
  • the amino sulfonamide can also be reacted with a carbonic acid ester chloride as shown in Scheme IV, a sulfonyl chloride as shown in Scheme V or in
  • Schemes II through VI also illustrate the possible reduction of a nitrobenzenesulfonamide to produce an amino sulfonamide.
  • the reduction of nitro groups to amines is will know in the art with a preferred method being hydrogenation.
  • a metal catalyst such as Rh, Pd, Pt, Ni or the like with or without an additional support such as carbon, barium carbonate and the like.
  • Solvents can be protic or non-protic pure solvents or mixed solvents as required.
  • the reductions can be carried out at atmospheric pressure to a pressure of multiple atmospheres with atmospheric pressure to about 40 pounds per square inch (psi) preferred.
  • Other sulfonyl chloride reagents can also be used in the preparation of compounds of this invention as outline in the Schemes.
  • Examples are fluoroaryl or fluoroheteroaryl sulfonyl chlorides, azidoaryl or azidoheteroaryl or amide, carbonate, carbamate or urea substituted aryl or heteroaryl sulfonyl chloride reagents.
  • Azides for example, can be reduced to an amino group using hydrogen with a metal catalyst or metal chelate catalyst or activated hydride transfer reagent.
  • the fluoro substituted sulfonic acid or sulfonamide can be treated with a nucleophile such as ammonia or a primary amine, under pressure if desired, to provide an amino or substituted (R5) amino group that can then be reacted a reagent as outline in Scheme III and in Schemes 4-7 inclusive.
  • a nucleophile such as ammonia or a primary amine
  • optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes well known in the art, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base.
  • appropriate acids are tartaric, diacetyltartaric , dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers .
  • Still another available method involves synthesis of covalent diastereoisomeric molecules, e.g., esters, amides, acetals, ketals, and the like, by reacting compounds of Formula I with an optically active acid in an activated form, a optically active diol or an optically active isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomericaly pure compound. In some cases hydrolysis to the parent optically active drug is not necessary prior to dosing the patient since the compound can behave as a prodrug.
  • the optically active compounds of Formula I can likewise be obtained by utilizing optically active starting materials.
  • Contemplated equivalents of the general formulas set forth above for the MMP inhibitor compounds and derivatives as well as the intermediates are compounds otherwise corresponding thereto and having the same general properties such as tautomers thereof and compounds wherein one or more of the various R groups are simple variations of the substituents as defined therein, e.g., wherein R is a higher alkyl group than that indicated.
  • a substituent is designated as, or can be, a hydrogen
  • the exact chemical nature of a substituent which is other than hydrogen at that position e.g., a hydrocarbyl radical or a halogen, hydroxy, amino and the like functional group, is not critical so long as it does not adversely affect the overall activity and/or synthesis procedure.
  • two hydroxyl groups, two amino groups, two thiol groups or a mixture of two hydrogen-heteroatom groups on the same carbon are know not to be stable without protection or as a derivative.
  • a process for treating a host mammal having a condition associated with pathological matrix metalloproteinase activity comprises administering a metalloproteinase inhibitor described hereinbefore in an MMP enzyme- inhibiting effective amount to a mammalian host having such a condition.
  • the use of administration repeated a plurality of times is particularly contemplated.
  • a contemplated inhibitor compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloproteinase activity.
  • a contemplated metalloproteinase inhibitor compound in the treatment of a disease state that can be affected by the activity of metalloproteinases such as TNF- ⁇ convertase.
  • metalloproteinases such as TNF- ⁇ convertase.
  • Exemplary of such disease states are the acute phase responses of shock and sepsis, coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia.
  • a contemplated MMP inhibitor compound in treating a disease condition associated with pathological matrix metalloproteinase activity, can be used, where appropriate, in the form of an amine salt derived from an inorganic or organic acid.
  • exemplary acid salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate; benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide , hydroiodide, 2- hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate,
  • a basic nitrogen-containing group can be quaternized with such agents as lower alkyl (C ⁇ _-Cg) halides, such as methyl, ethyl, propyl , and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain (Cg-C2 ⁇ ) halides such as decyl, lauryl, myristyl and dodecyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others to provide enhanced water-solubility. Water or oil- soluble or dispersible products are thereby obtained as desired.
  • the salts are formed by combining the basic compounds with the desired acid.
  • salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.
  • the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.
  • Total daily dose administered to a host mammal in single or divided doses of an MMP enzyme-inhibiting effective amount can be in amounts, for example, of about 0.001 to about 30 mg/kg body weight daily and more usually about 0.01 to about 10 mg .
  • Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • a suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose, should such dosing be desired by the person prescribing the drug.
  • the dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination.
  • the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above.
  • a compound useful in the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania; 1975 and Liberman, H.A. and Lachman, L., Eds.,
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3 -butanediol .
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides .
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono-, di-, or triglycerides , fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
  • formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
  • Certain of the sulfonamide, sulfinamide or sulfenamide, compounds of this invention that are administered in accordance with an above-discussed process can serve as prodrugs to other compounds of this invention.
  • Prodrugs are drugs that can be chemically converted in vivo or in vi tro by biological
  • process methods of the present invention can be performed as follows .
  • Part B A solution of the sulfonamide of part A (37.15 g, 123 mmol) and a catalytic amount of H 2 S0 4 in dichloromethane/dioxane (IL) was subjected to isobutylene for 18 hours. The solution was cooled to zero degrees Celsius and quenched with saturated NaHC0 3 . The aqueous layer was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over MgS0 4 . Chromatography (on silica, ethyl acetate/hexane) provided the t-butyl ester as a solid (16.7 g, 38 %) .
  • Part C To a solution of the t-butyl ester of part B (16.5 g, 46 mmol) in DMF (60 mL) was added 4- (2- chloroethyl) morpholine hydrochloride (17.2 g, 92 mmol) and K 2 C0 3 (25.5 g, 184 mmol) and the solution was heated to sixty degrees Celsius for 7 hours. The solution was partitioned between ethyl acetate and H 2 0 and the organic layer was washed with saturated NaCl and dried over Na 2 S0 4 . Chromatography (on silica, ethyl acetate/hexane) provided the morpholine compound as a solid (21.5 g, 99 %) .
  • Part D To a solution of the morpholine compound of part C (21.5 g, 45.6 mmol) in THF (200 mL) in a flask purged with H 2 was added 4% Pd/C (3.04 g) and the solution was hydrogenated until uptake ceased. The solution was filtered through Celite® to remove the excess catalyst and the filtrate was concentrated in vacuo to provide the aniline as an oil (19.2 g, 95 %) .
  • Part E To a solution of the aniline of part D (2.60 g, 5.88 mmol) in THF (20 mL) was added triethylamine (3.2 mL, 22.8 mmol) and the solution was cooled to four degrees Celsius. To this solution was added 4-pentylbenzoyl chloride (2.1 g, 10.0 mmol) and the solution was stirred for 18 hours at ambient temperature. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated NaHC0 3 . The organic layer was washed with saturated NaHC0 3 and saturated NaCl and dried over Na 2 S0 4 . Chromatography (ethyl acetate/hexane) provided the benzamide as a solid (2.09 g, 58 %) . Part F: A solution of the benzamide of part E
  • Part A To a solution of the acid of Example 1, part F (1.52 g, 2.56 mmol) in DMF (5 mL) was added N-hydroxybenzotriazole (414 mg, 3.07 mmol) and the solution was cooled to four degrees Celsius. To this solution was added 4-methylmorpholine (1.69 mL, 15.6 mmol ) , 1- (3 -dimethyla inopropyl ) -3 -ethylcarbodiimide hydrochloride (687 mg, 3.58 mmol) and tetrahydropyranyl hydroxylamine (449 mg, 3.84 mmol) and was stirred for 1 hour at ambient temperature.
  • Part B To a solution of the ester of part A (1.54 g, 2.34 mmol) in methanol (1 mL) was added 4N HCl (10 mL) and the solution was stirred for 18 hours at ambient temperature. The solution was concentrated in vacuo .
  • Part A To a solution of the aniline of Example 1, part D (2.5 g, 5.7 mmol) was added triethylamine (3.2 mL, 22.8 mmol) and the solution was cooled to four degrees Celsius. To this solution was added 4- hexylbenzoyl chloride (2.18 g, 9.69 mmol) and the solution was stirred overnight at ambient temperature. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated NaHC0 3 . The organic layer was washed with saturated NaHC0 3 and saturated NaCl and dried over Na 2 S0 4 .
  • Part B A solution of the benzamide of part A (2.7 g, 4.3 mmol) in 4N HCl in dioxane (20 mL) was stirred for 72 hours. The solution was concentrated in vacuo and the residue was dissolved into ethyl acetate (5 mL) . This solution was dropped into ethyl ether. The resulting precipitate was collected by vacuum filtration to provide the acid as a solid (2.5 g, 95 %) .
  • Part C To a solution of the acid of part B (2.03 g, 3.33 mmol) in DMF (5 mL) was added N-hydroxybenzotriazole (540 mg, 4.00 mmol) and the solution was cooled to four degrees Celsius . To this solution was added 4-methylmorpholine (2.19 mL, 20.0 mmol) , 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (894 mg, 4.66 mmol) and tetrahydropyranyl hydroxylamine (615 mg, 5.00 mmol) and the solution was stirred for 1 hour at ambient temperature.
  • Part D To a solution of the ester of part C (2.01 g, 3.24 mmol) in methanol (1 mL) was added 4N HCl (10 mL) and the solution was stirred for 18 hours at ambient temperature. Reverse phase chromatography (on silica, acetonitrile/H 2 O(0.05% HCl)) provided the title compound, (R) -4-hexyl-N- [4- [ [ [1- (hydroxyamino) carbonyl] - 2-methylpropyl] [2- (4-morpholinyl) ethyl] amino] sulfonyl] - phenylbenzamide, monohydrochloride, as a white solid (1.23 g, 61 %). MS(CI) MH + calculated for C 3 oH 44 N 4 0 6 S: 589, found: 589.
  • Example 4 Cloning, expression and purification of the catalytic domain of MMP-8.
  • the MMP-8 catalytic domain was cloned by PCR amplification from a cDNA contruct of full-length MMP-8.
  • the amplified DNA was cloned into Ndel/Hindlll restriction sites in an in-house pRec expression vector.
  • Protein was expressed in a bacterial expression system by induction with nalidixic acid. Recombinant protein was expressed primarily as inclusion bodies. Purified protein was recovered in high yield following ion exchange chromatography of denatured protein. Refolding from denaturant and subsequent purification using a second ion exchange step resulted in active protein that was used for crystallography.
  • Crystallization of inhibitor complexes Crystals were grown by vapor equilibration in sitting drops following a procedure similar to that described by Bode et al .
  • Bode et al The X-ray crystal structure of the catalytic domain of human neutrophil collagenase inhibited by a substrate analogue reveals the essentials for catalysis and specificity," FEBS Letters 338, 227- 233 (1994).
  • a solution of the enzyme inhibitor complex is mixed with a precipitating reagent to form the sitting drop which is equilibrated against a high-salt solution. Slow dehydration of the drop leads to formation of single crystals of the inhibitor complex. Details are below.
  • Protein 12 mg/ml MMP-8 in 10 mM MES pH 6.0, 100 mM NaCl, 5 mM CaCl2 pre-incubated with 1 mM inhibitor for 10 minutes at ambient temperature.
  • Sitting Drop 4 ul of the protein-inhibitor complex mixed with 6.8 ul 10% PEG6000 and 0.2 M MES pH 6.0
  • Reservoir 0.8 to 2.5 M sodium/potassium phosphate pH 6.0 (not mixed with protein/inhibitor/PEG drop) .
  • X-ray Data Collection Intensities from crystals of the enzyme inhibitor complexes were measured on a MAR image plate at -140 °C , X-rays were generated from a rotating anode generator using a Cu target. The CuK ⁇ X-rays were focused onto the samples using long Pt and Ni mirrors. The data were integrated and scaled using the program DENZO (Otwinowski, Z. and Minor W. in Proceedings of CCP4 Study Weekend: Data Collection and Processing (eds. Sawyer, L., Issacs, N. , and Bailey, S. pp. 56-62 (SERC Daresbury Laboratories, Warrington, UK 1993) ) .
  • a Inhibitor code b lattice constants (unit cell dimensions). c data resolution; d Rsym (internal consistency) for overall and highest resolution shell; e I/sigma (signal/noise ratio) for overall and highest resolution shell;

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Abstract

La présente invention concerne un composé inhibiteur des métalloprotéinases matricielles représenté par la structure (I), ou un sel, un énantiomère, un diastéréomère, un racémate, ou un tautomère de celui-ci. Dans d'autres modes de réalisation, la présente invention concerne une méthode visant à modifier la conformation d'une métalloprotéinase matricielle, une méthode d'inhibition des métalloprotéinases matricielles, et une méthode de traitement de l'ostéoarthrite.
PCT/US2000/021024 2000-07-12 2000-08-01 Derives d'acides amines n sulfonyle inhibiteurs des metalloproteinases WO2002003994A1 (fr)

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PCT/US2000/016323 WO2001005389A2 (fr) 1999-07-16 2000-07-12 Methode de changement de la conformation d'une metalloproteinase matricielle
USPCT/US00/16323 2000-07-12

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US7956752B2 (en) 2005-01-14 2011-06-07 Matthew Henderson Transponder bolt seal and a housing for a transponder
US20170023571A1 (en) * 2014-02-27 2017-01-26 Oy Medix Biochemica Ab Mmp-8 activation product, its determination and use

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EP0757037A2 (fr) * 1995-07-28 1997-02-05 Ono Pharmaceutical Co., Ltd. Dérivés d'acide sulfonylamino comme inhibiteurs de métalloprotéinase
EP0757984A1 (fr) * 1995-08-08 1997-02-12 Ono Pharmaceutical Co., Ltd. Dérivés d'acide hydroxamique utiles pour l'inhibition gélatinase
EP0950656A1 (fr) * 1996-01-23 1999-10-20 Shionogi & Co., Ltd. Derives d'acides amines sulfones et inhibiteurs de metalloproteinases contenant ces derives
WO1998003166A1 (fr) * 1996-07-22 1998-01-29 Monsanto Company Inhibiteurs de metalloproteases a base de sulfonamide de thiol
WO1998039329A1 (fr) * 1997-03-04 1998-09-11 Monsanto Company Composes d'acide hydroxamique sulfonamide a cycle amidoaromatique
WO1999042433A1 (fr) * 1998-02-18 1999-08-26 Inha University Foundation Nitration de composes aromatiques par un procede de nitration de type non acide
JPH11236369A (ja) * 1998-02-23 1999-08-31 Kotobuki Seiyaku Kk スルホンアミド誘導体及びその製造法並びにこれを含有する医薬組成物
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7956752B2 (en) 2005-01-14 2011-06-07 Matthew Henderson Transponder bolt seal and a housing for a transponder
US20170023571A1 (en) * 2014-02-27 2017-01-26 Oy Medix Biochemica Ab Mmp-8 activation product, its determination and use
US10488415B2 (en) * 2014-02-27 2019-11-26 Oy Medix Biochemica Ab MMP-8 activation product, its determination and use
US11378579B2 (en) 2014-02-27 2022-07-05 Oy Medix Biochemica Ab MMP-8 activation product, its determination and use

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