WO2008147763A1 - Inhibiteurs des métalloprotéases matricielles (mmp) et leurs méthodes d'utilisation - Google Patents

Inhibiteurs des métalloprotéases matricielles (mmp) et leurs méthodes d'utilisation Download PDF

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WO2008147763A1
WO2008147763A1 PCT/US2008/064209 US2008064209W WO2008147763A1 WO 2008147763 A1 WO2008147763 A1 WO 2008147763A1 US 2008064209 W US2008064209 W US 2008064209W WO 2008147763 A1 WO2008147763 A1 WO 2008147763A1
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compound
alkyl
formula
compounds
mmp
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PCT/US2008/064209
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WO2008147763A8 (fr
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Andrew M. Fryer
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Array Biopharma Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to alkylsulfamide-substituted triazole compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly it relates to certain alkylsulfamide-substituted triazole compounds useful in the treatment and prevention of diseases alleviated by the inhibition of matrix metalloproteases. DESCRIPTION OF THE STATE OF THE ART
  • MMPs Matrix metalloproteases
  • MMPs are a family of endopeptidases that are part of a larger group of proteases called metzincins. MMPs are involved in the degradation and remodeling of connective tissues, and are present in various cell types that reside in or are associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells, and invasive or metastatic tumor cells.
  • MMP family shares a number of properties, including zinc and calcium dependence. MMPs also share a common domain structure. The minimum common domains are the pro-peptide and the catalytic zinc domain, and commonly there is an additional hemopexin-like C-terminal domain, which is linked to the catalytic domain by a flexible hinge region.
  • the MMPs can be classified into several families based on their domain structure: matrilysin (minimal domain, MMP-7 and MMP-27), collagenase (hemopexin domain, MMP-I, MMP-8, MMP- 13 and MMP- 18), gelatinase (fibronectin domain, MMP-2, MMP-9), stromelysin (hemopexin domain, MMP-3, MMP-10, MMP-I l), metalloelastase (MMP- 12).
  • matrilysin minimal domain, MMP-7 and MMP-27
  • collagenase hemopexin domain, MMP-I, MMP-8, MMP- 13 and MMP- 18
  • gelatinase fibronectin domain, MMP-2, MMP-9
  • stromelysin hemopexin domain, MMP-3, MMP-10, MMP-I l
  • MMP- 12 transmembrane domain family
  • MT-MMPs transmembr
  • the catalytic zinc domain in MMPs is typically the focal point for inhibitor design. Modification of substrates by introducing a zinc binding group (ZBG) has generated MMP inhibitors.
  • Zinc binding groups in known MMP inhibitors include carboxylate, hydroxamate, pyrimidine-trione, hydantoin, thiol and phosphinyl groups.
  • Inhibition of matrix metalloproteases may be useful in the treatment of inflammatory diseases such as, arthritis (rheumatoid arthritis and osteoarthritis), bone resorptive diseases, such as osteoporosis, diseases characterized by abnormal blood vessel growth and remodeling, such as macular degeneration, diabetic retinopathy and restenosis, hyperproliferative diseases such as cancer, periodontitis, multiple sclerosis, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, ulceration of skin, and aneurysmal disease. Inhibition of the activity of one or more MMPs may be of benefit in these diseases or conditions.
  • MMP inhibitors are known, see for example, International Publication WO 2011/001100600A1
  • WO 2011/001100A1 International Publication WO 2011/001100A1
  • the present invention relates to novel compounds that are inhibitors of MMPs.
  • the compounds are inhibitors of MMP-2, MMP-9, MMP- 12 and/or MMP-13.
  • the compounds of Formula I include pharmaceutically acceptable salts thereof.
  • the compounds of Formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating enantiomers of compounds of Formula I.
  • the present invention provides a pharmaceutical composition, which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, as defined hereinabove.
  • the pharmaceutical composition includes the compound of Formula I together with a pharmaceutically acceptable diluent or carrier.
  • the compounds of the present invention can be used as prophylactics or therapeutic agents for treating diseases or disorders including, but not limited to, diseases and disorders mediated by MMP-2, MMP-9, MMP- 12 or MMP-13.
  • the compounds and compositions containing them are therefore useful in the treatment of diseases associated with the MMP-2, MMP-9, MMP- 12 or MMP- 13 -induced excessive degradation of matrix and connective tissue within the mammal, such as arthritis (rheumatoid arthritis and osteoarthritis), bone resorptive diseases (such as osteoporosis), diseases characterized by abnormal blood vessel growth and remodeling such as macular degeneration, diabetic retinopathy and restenosis, hyperproliferative diseases such as cancer, periodontitis, multiple sclerosis, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, ulceration of skin, and aneurysmal disease.
  • Another aspect of the invention provides methods of treating or preventing diseases or conditions described herein by administering to a mammal, such as a human, a therapeutically effective amount of a compound of Formula I.
  • An additional aspect of the invention is the use of a compound of Formula I in the preparation of a medicament for treating MMP2, MMP-9, MMP- 12 or MMP- 13 -mediated diseases and conditions.
  • the present invention provides a compound of
  • the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament to treat an immunologic disorder.
  • alkyl includes linear or branched-chain radicals of carbon atoms.
  • alkyl moieties have been abbreviated, for example, methyl (“Me”), ethyl
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • phrases "therapeutically effective amount” or “effective amount” mean an amount of a compound of the present invention that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • the amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • a “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • squamous cell cancer e.g., epithelial squamous cell cancer
  • lung cancer including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
  • NSCLC non-small cell lung cancer
  • adenocarcinoma of the lung and squamous carcinoma of the lung cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer,
  • phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention.
  • the compounds of this invention also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of this invention and/or for separating enantiomers of compounds of this invention.
  • mammal means a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
  • a as used herein means one or more.
  • R and R are independently H, C 1 -C 6 alkyl, aryl, or 5 or 6 membered heteroaryl, wherein the alkyl, aryl and heteroaryl may be optionally substituted;
  • Y is a five or six membered aryl or heteroaryl ring, optionally substituted with one or more Z 1 groups;
  • Z 1 is selected from the group consisting of H 5 F 5 Cl 5 Br 5 I 5 CN 5 CF 3 , C 1 -C 6 alkyl, 0-(C 1 -C 6 alkyl), or (C 1 -C 6 alkyl)-OH.
  • R 1 is H.
  • R 1 is C 1 -C 6 alkyl. hi certain embodiments, R 1 is methyl.
  • R 2 is H.
  • R 2 is C 1 -C 6 alkyl. In certain embodiments, R 2 is methyl.
  • R 1 and R 2 may be aryl. In a further embodiment, R 1 and R 2 may be C 5 -C 6 aryl.
  • R 1 and R 2 may be aryl. In a further embodiment, R 1 and R 2 may be C 6 aryl. In a further embodiment, R 1 and R 2 may be phenyl.
  • Y is independently selected from the structures:
  • Z 1 is H, F, Cl, Br, I, CN 5 CF 3 , Cj-C 6 alkyl, 0-(C 1 -C 6 alkyl), or (C 1 -C 6 alkyl)-OH.
  • Y is a six membered aryl ring. In a further embodiment, Y is a six membered aryl ring having the structure:
  • Y is a six membered heteroaryl ring. In a further embodiment, Y is a six membered heteroaryl ring having the structure:
  • Y is a five or six membered heteroaryl ring optionally substituted with one or more Z 1 groups. In certain embodiments, Y is a five or six membered heteroaryl ring containing one or two nitrogen heteroatoms and optionally substituted with one or more Z 1 groups. In certain embodiments, Y is a five or six membered heteroaryl ring containing one nitrogen heteroatom and optionally substituted with one or more Z 1 groups. In certain embodiments, Y is a six membered heteroaryl ring containing one nitrogen heteroatom and optionally substituted with one or more Z 1 groups. In certain embodiments, Y is pyridinyl optionally substituted with one or more Z 1 groups. In certain embodiments, Y is pyridin-2-yl optionally substituted with one or more Z 1 groups.
  • Z 1 is a halogen selected from the group consisting of
  • Z 1 is Cl
  • Z 1 is Ci-C 6 alkyl. In certain embodiments, Z 1 is methyl.
  • Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Sigma- Aldrich (St. Louis, MO), Alfa Aesar (Ward Hill, MA), or TCI (Portland, OR), or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database).
  • Schemes 1-4 show a general method for preparing the compounds of the present invention as well as key intermediates.
  • Examples section below For a more detailed description of the individual reaction steps, see the Examples section below.
  • Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds.
  • specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
  • many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethyleneoxycarbonyl (Fmoc).
  • BOC t-butoxycarbonyl
  • CBz benzyloxycarbonyl
  • Fmoc 9- fluorenylmethyleneoxycarbonyl
  • Scheme 1 shows a method of preparing compound (6) of Formula I, wherein
  • Y, R 1 and R 2 are as defined herein.
  • amines (1) can be treated with chlorosulfonic acid in the presence of a base such as triethylamine to give sulfamic acids (2).
  • sulfamic acids can be chlorinated with chlorinating agents such as PCl 5 to give sulfamoyl chlorides (3).
  • Treatment of (3) with appropriately substituted propargylamines (4) yields propargyl sulfamides (5).
  • Alkynes (5) can be converted to the triazole sulfamides (6) by heating in the presence of copper (I) iodide, and azidotrimethylsilane.
  • Scheme 2 shows a method of preparing compound (6) of Formula I, wherein
  • Y, R 1 and R 2 are as defined herein.
  • appropriately substituted propargylamines (4) are converted into sulfamoyl oxazoladinones (7) by reacting with chlorosulfonyl isocycanate and 2-chloroethanol in the presence of a base such as N- methylmorpholine.
  • Coupling of sulfamoyl oxazolidinones (7) with amines (1) with heating gives propargyl sulfamides (5).
  • Alkynes (5) can be converted to the triazole sulfamides (6) by heating in the presence of copper (I) iodide, and azidotrimethylsilane.
  • Scheme 3 shows a method of preparing compound (6) of Formula I, wherein
  • Y, R 1 and R 2 are as defined herein.
  • appropriately substituted propargylamines (4) are converted into their Boc-protected derivatives (8) with Boc anhydride.
  • the protected aminomethyl triazoles (9) are then prepared by a cycloaddition reaction with heating in the presence of copper (I) iodide, and azidotrimethylsilane.
  • an acid e.g., TFA
  • the liberated aminomethyl triazoles (10) are reacted with chlorosulfonyl isocycanate and 2-chloroethanol in the presence of a base such as N-methylmorpholine to give the triazole sulfamoyl oxazolidinones (11).
  • Displacement of the oxazolidinone by heating with amines (1) gives the triazole sulfamides (6).
  • Scheme 4 shows a method of preparing compound (6) of Formula I, wherein
  • Y, R 1 and R 2 are as defined herein.
  • sulfamoyl chlorides (3) can be treated with appropriately substituted aminotriazoles (10) with heating in the presence of a base to give the triazole sulfamides (6).
  • Another aspect of the present invention provides a process for preparing compounds of Formula I, comprising: a) reacting a compound of Formula 1 :
  • Y is a five or six membered aryl or heteroaryl ring, optionally substituted with one or more Z 1 groups;
  • Z 1 is selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , C 1 -C 6 alkyl, 0-(C 1 -C 6 alkyl), or (C 1 -C 6 alkyl)-OH; and
  • X is a halogen or suitable leaving group, with a compound of Formula 2:
  • R 1 and R 2 are independently H, C 1 -C 6 alkyl, aryl, or 5 or 6 membered heteroaryl, wherein the alkyl, aryl and heteroaryl may be optionally substituted; or a salt thereof, to form a compound of Formula I; or b) heating a compound of Formula 3 :
  • R 1 and R 2 are independently H, C 1 -C 6 alkyl, aryl, or 5 or 6 membered heteroaryl, wherein the alkyl, aryl and heteroaryl may be optionally substituted;
  • Y is a five or six membered aryl or heteroaryl ring, optionally substituted with one or more Z 1 groups; and
  • Z 1 is selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , C 1 -C 6 alkyl, 0-(C 1 -C 6 alkyl), or (C 1 -C 6 alkyl)-OH; with copper (I) iodide and azidotrimethylsilane to form a compound of Formula I; or c) reacting a compound of Formula 4:
  • R 1 and R 2 are independently H, C 1 -C 6 alkyl, aryl, or 5 or 6 membered heteroaryl, wherein the alkyl, aryl and heteroaryl may be optionally substituted; with a compound of Formula 5:
  • Y is a five or six membered aryl or heteroaryl ring, optionally substituted with one or more Z 1 groups; and Z 1 is selected from the group consisting of H, F, Cl, Br, I, CN, CF 3 , C 1 - C 6 alkyl, 0-(C 1 -C 6 alkyl), or (C 1 -C 6 alkyl)-OH; to form a compound of Formula I.
  • the process is preferably performed in a suitable solvent, such as acetonitrile, 1,4-dioxane, tetrahydrofuran, dimethylformamide (“DMF”), or dimethylacetamide, preferably acetonitrile.
  • the reaction is preferably performed in the presence of a base, such as triethylamine, diisopropylethylamine ( ⁇ unig's base), or iV-methylmorpholme, preferably triethylamine.
  • a base such as triethylamine, diisopropylethylamine ( ⁇ unig's base), or iV-methylmorpholme, preferably triethylamine.
  • the reaction may be performed at a temperature ranging from about 60°C to about 100°C, and preferably at a temperature of about 8O 0 C.
  • X may be a halogen or other suitable leaving group.
  • X is a halogen, and most preferably X is chlorine.
  • the compound of Formula 2 may be in salt form.
  • the preferred salt of Formula 2 is the hydrochloride salt.
  • step b) of the above process the process is preferably performed in a suitable solvent such as DMF, methanol ("MeOH"), or a mixture thereof.
  • a suitable solvent such as DMF, methanol (“MeOH"), or a mixture thereof.
  • Other alcohol solvents can also be used in combination with DMF such as ethanol, isopropanol, n-butanol and t-butanol.
  • the preferred solvent is a 1:1 mixture of DMF and MeOH.
  • the reaction may be performed at an external temperature ranging from about 80 0 C to about 12O 0 C, preferably at an external temperature ranging from about 90 0 C to about HO 0 C, and most preferably at an external temperature of about 100 0 C.
  • the reaction is preferably performed in a sealed vessel.
  • step c) of the above process the process is preferably performed in a suitable solvent, such as acetonitrile, 1,4-dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, preferably acetonitrile.
  • a suitable solvent such as acetonitrile, 1,4-dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, preferably acetonitrile.
  • the reaction is preferably performed in the presence of a base, such as triethylamine, diisopropylethylamine (Hunig's base), or N- methylmorpholine, preferably triethylamine.
  • the reaction may be performed at a temperature ranging from about 60 0 C to about 100 0 C, preferably at a temperature ranging from about 7O 0 C to about 90 0 C, and most preferably at a temperature of about 80 0 C.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • Enantiomers can also be separated by use of a chiral HPLC column.
  • a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr., 113(3):283-302).
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: “Drug Stereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, ⁇ -methyl- ⁇ -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • a diastereomeric pair E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p. 322
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, ⁇ -methoxy- ⁇ - (trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem., (1982) 47:4165), of the racemic mixture, and analyzing the 1 H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers.
  • Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111).
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. ofChromatogr., (1990) 513:375- 378).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • the ability of the compounds of Formula I to inhibit matrix metalloprotease activity may be demonstrated by a variety of in vitro assays known to those of ordinary skill in the art, such as the MMP Enzymatic Assay described in FEBS, 296, 263, (1992) or modifications thereof as described in more detail in Example A. ADMINISTRATION AND PHARMACEUTICAL FORMULATIONS [0071]
  • the compounds of the invention may be administered by any convenient route appropriate to the condition to be treated.
  • Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.
  • the compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (8 th Ed. 2004); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20 th Ed. 2000); and Raymond C. Rowe, Handbook of Pharmaceutical Excipients, (5 Ed. 2005).
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • One embodiment of the present invention includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • METHODS OF TREATMENT WITH COMPOUNDS OF THE INVENTION [0075]
  • the compounds of the present invention can be used as prophylactics or therapeutic agents for treating diseases or disorders including, but not limited to, diseases and disorders mediated by MMP-2, MMP-9, MMP- 12 or MMP-13.
  • the compounds and compositions containing them are therefore useful in the treatment of diseases associated with the MMP-2, MMP-9, MMP- 12 or MMP- 13 -induced excessive degradation of matrix and connective tissue within the mammal, such as arthritis (rheumatoid arthritis and osteoarthritis), bone resorptive diseases (such as osteoporosis), destruction of articular cartilage, periodontitis, multiple sclerosis, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, ulceration of skin, aneurysmal disease, and in complications of diabetes.
  • diseases associated with the MMP-2, MMP-9, MMP- 12 or MMP- 13 -induced excessive degradation of matrix and connective tissue within the mammal such as arthritis (rheumatoid arthritis and osteoarthritis), bone resorptive diseases (such as osteoporosis), destruction of articular cartilage, period
  • a method of treating or preventing diseases or conditions described herein by administering to a mammal, such as a human, a therapeutically effective amount of a compound of Formula I is provided.
  • a mammal such as a human
  • a therapeutically effective amount of a compound of Formula I is provided.
  • Formula I in the preparation of a medicament for treating MMP2, MMP-9, MMP- 12 or MMP-13 -mediated diseases and conditions is provided.
  • Another embodiment of the present invention provides a compound of
  • a further embodiment of the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament to treat an immunologic disorder.
  • the compounds of this invention and stereoisomers and pharmaceutically acceptable salts thereof may be employed alone or in combination with other therapeutic agents for treatment.
  • the compounds of the present invention can be used in combination with one or more additional drugs, for example, an anti-inflammatory compound that works by a different mechanism of action.
  • the second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of this invention such that they do not adversely affect each other.
  • Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
  • the compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
  • Murphy (1992) FEBS Letters 296 (3), 263-266) is based on intramolecular fluorescence resonance energy transfer for detection of the activity of Matrix Metalloproteinase 13 (MMP- 13) using a quenched-fluorogenic substrate.
  • MMP- 13 Matrix Metalloproteinase 13
  • the cleavage reaction is detected continuously by the elevation of the fluorescence due to release from quenching.
  • the fluorescence of the product increases in proportion to progress of the cleavage reaction.
  • MMP- 13 (baculovirus expressed full-length protein) and inhibitor in assay buffer (50 niM HEPES, pH 7.4, 100 mM NaCl, 5 mM CaCl 2 , 0.005% Brij-35, final DMSO concentration 1% (v/v)) are pre-incubated for 10 minutes at ambient temperature.
  • compounds of Examples 1-5 had an IC 50 of ⁇ 10 ⁇ M.
  • Inhibitors are also tested in the same buffer with 0.5% HSA (Human Serum Albumin, Sigma) to assess shift in activity in the presence of serum albumin.
  • Step A 4-(5-(Trifluoromethyl)pyridin-2-yl)piperazine-l-sulfonyl chloride: 1-
  • Step B Preparation of tert-butyl prop-2-ynylcarbamate: A solution of propargylamine (5.00 g, 90.8 mmol) and BoC 2 O (18.8 g, 86.2 mmol) in DCM (200 mL) was stirred for 12 hours.
  • Step C Preparation of tert-butyl (lH-l,2,3-triazol-5-yl)methylcarbarnate: A solution of tert-butyl prop-2-ynylcarbamate (2.00 g, 12.9 mmol), azidotrimethylsilane (2.60 mL, 19.3 mmol), and CuI (123 mg, 0.65 mmol) in 9:1 DMFVMeOH (25 mL) was heated at a temperature of 95°C in a sealed vessel for 12 hours. The mixture was concentrated in vacuo, the resulting oil was diluted with DCM, and the undissolved solids were filtered off. The filtrate was concentrated in vacuo to give 1.80 g of the title compound.
  • Step D Preparation of (lH-l 5 2 5 3-triazol-5-yl)methanamine hydrochloride: A solution of tert-butyl (lH-l 5 2,3-triazol-5-yl)methylcarbamate (1.80 g, 9.1 mmol) in 4.0 M HCl in dioxane (40 mL) was stirred for 2 hours resulting in the formation of a precipitate. The mixture was concentrated in vacuo to 1/4 volume, diluted with acetonitrile, and filtered to give 1.3 g (100%) of the title compound as a solid.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 8.60 (br s, 4H), 7.94 (s, IH), 4.04 (m, 2H).
  • Step E N-((lH-l,2,3-triazol-5-yl)methyl)-4-(5-(trifluoromethyl)pyridin-2- yl)piperazine- 1 -sulfonamide : 4-(5 -(trifluoromethyl)pyridin-2-yl) piperazine- 1 -sulfonyl chloride (123 mg, 0.372 mmol) and ( IH-1 ,2,3 -triazol-4-yl)methanamine hydrochloride (50.0 mg, 0.372 mmol) were dissolved in acetonitrile (0.2 M).
  • Step A Preparation of N-(2-methylbut-3-yn-2-yl)-2-oxooxazolidine-3- sulfonamide: A 0.2 M solution of chlorosulfonyl isocyanate (4.19 mL, 48.1 mmol) in acetonitrile was cooled in an ice bath, and 2-chloroethanol (3.23 mL, 48.1 mmol) was added. After stirring at a temperature of O 0 C for 30 minutes, the reaction mixture was warmed to room temperature for 1 hour.
  • Step B Preparation of 4-(4-chlorophenyl)-N-(2-methylbut-3-yn-2- yl)piperazine-l -sulfonamide: Triethylamine (0.126 mL, 0.904 mmol) and l-(4- chlorophenyl)piperazine (59.3 mg, 0.301 mmol) were added to a solution of iV-(2-methylbut- 3-yn-2-yl)-2-oxooxazolidine-3-sulfonamide (70.0 mg, 0.301 mmol) in acetonitrile (2.0 mL).
  • Step C Preparation of N-(2-( IH-1, 2,3 -triazol-4-yl)propan-2-yl)-4-(4- chlorophenyl)piperazine-l -sulfonamide: CuI (2.57 mg, 0.0135 mmol) and azidotrimethylsilane (0.0715 mL, 0.539 mmol) were added to a solution of 4-(4- chlorophenyl)-N-(2-methylbut-3-yn-2-yl)piperazine-l -sulfonamide (92.1 mg, 0.269 mmol) in 2 mL of 1:1 DMF/MeOH.
  • Step A Tert-butyl 2-methylbut-3-yn-2-ylcarbamate: A solution of dimethylpropargylamine (3.0 g, 36 mmol) and Boc anhydride (7.5 g, 34 mmol) in DCM (73 mL) was stirred at room temperature for 15 hours. The reaction mixture was washed with dilute aqueous HCl 5 and the organic layer was dried with MgSO 4 . The organic layer was concentrated in vacuo to afford tert-butyl 2-methylbut-3-yn-2-ylcarbamate (6.0 g, 91%) as a white solid.
  • 1 H NMR 400 MHz. CDCl 3 ) ⁇ 2.30 (s, IH), 1.55 (s, 3H), 1.53 (s, 3H), 1.46 (s, 9H).
  • Step B Tert-butyl 2-(3H-l,2,3-triazol-4-yl)propan-2-ylcarbamate:
  • tert-butyl 2-methylbut-3-yn-2-ylcarbarnate 6.00 g, 32.7 mmol
  • 9:1 DMF/methanol 65 mL
  • CuI 0.12 g, 1.64 mmol
  • TMSN 3 azidotrimethylsilane
  • Step C 2-( IH-1, 2,3 -triazol-4-yl)propan-2-amine: Tert-butyl 2-(3H-l,2,3- triazol-4-yl)propan-2-ylcarbamate (0.500 g, 2.21 mmol) was dissolved in 1:1 DCM/trifluoroacetic acid (10 mL). After 90 minutes, the reaction mixture was concentrated in vacuo. The residue was dissolved in methanol (“MeOH”) (10 mL) and free-based using a polystyrene supported diisopropylethylamine base (“PS-DIEA”) overnight (3 equivalents).
  • MeOH methanol
  • PS-DIEA polystyrene supported diisopropylethylamine base
  • Step E N-(2-(lH-l,2,3-triazol-4-yl)propan-2-yl)-2-oxooxazolidine-3- sulfonamide: 2-Chloroethanol (0.148 mL, 2.21 mmol) was added to a 0.2 M solution of chlorosulfonyl isocyanate (0.192 mL, 2.21 mmol) in acetonitrile cooled in an ice bath.
  • Step F N-(2-(3H-l,2,3-triazol-4-yl)propan-2-yl)-4-(5-cyanopyridin-2- yl)piperazine-l-sulfonamide: 6-(Piperazin-l-yl)nicotinonitrile (59.6 mg, 0.316 mmol) and N- (2-(lH-l,2,3-triazol-4-yl)propan-2-yl)-2-oxooxazolidine-3-sulfonamide (87.1 mg, 0.316 mmol) were dissolved in acetonitrile (2 mL).
  • Triethylamine (0.882 mL, 0.632 mmol) was added to the solution, and the reaction mixture was heated to a temperature of 80 0 C for 15 hours. After purification by reverse phase HPLC, N-(2-(3H-l,2,3-triazol-4-yl)propan-2-yl)- 4-(5-cyanopyridin-2-yl)piperazine-l-sulfonamide (25 mg, 21%) was isolated as a solid. MS APCI (-) m/z 375.0 detected. 1 H NMR (400 MHz.

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Abstract

L'invention concerne des inhibiteurs des métalloprotéases matricielles (MMP) représentés par la formule générale (I) dans laquelle R1, R2 et Y désignent des éléments définis dans la description, ces inhibiteurs étant utiles dans le traitement et/ou la prévention de maladies et de troubles induits par les métalloprotéases matricielles.
PCT/US2008/064209 2007-05-23 2008-05-20 Inhibiteurs des métalloprotéases matricielles (mmp) et leurs méthodes d'utilisation WO2008147763A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075108A1 (fr) * 1999-06-04 2000-12-14 Astrazeneca Uk Limited Inhibiteurs de metalloproteases
WO2004032846A2 (fr) * 2002-10-07 2004-04-22 Bristol-Myers Squibb Company Derives de la triazolone et de la triazolethione, inhibiteurs des metalloproteinases de matrices et/ou de l'enzyme de conversion du tnf$g(a)
WO2005058808A1 (fr) * 2003-12-15 2005-06-30 Japan Tobacco Inc. Composes de n-sulfonylaminocyclopropane n-substitue et leur utilisation pharmaceutique
WO2005058884A2 (fr) * 2003-12-15 2005-06-30 Japan Tobacco Inc. Composes de cyclopropane et utilisation pharmaceutique de ceux-ci
WO2005061477A1 (fr) * 2003-12-04 2005-07-07 Wyeth Sulfonamides biaryliques inhibiteurs de mmp
WO2008024784A1 (fr) * 2006-08-22 2008-02-28 Array Biopharma, Inc. Triazoles à substituant alkylsulfonamide en tant qu'inhibiteurs de la métalloprotéase matricielle

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075108A1 (fr) * 1999-06-04 2000-12-14 Astrazeneca Uk Limited Inhibiteurs de metalloproteases
WO2004032846A2 (fr) * 2002-10-07 2004-04-22 Bristol-Myers Squibb Company Derives de la triazolone et de la triazolethione, inhibiteurs des metalloproteinases de matrices et/ou de l'enzyme de conversion du tnf$g(a)
WO2005061477A1 (fr) * 2003-12-04 2005-07-07 Wyeth Sulfonamides biaryliques inhibiteurs de mmp
WO2005058808A1 (fr) * 2003-12-15 2005-06-30 Japan Tobacco Inc. Composes de n-sulfonylaminocyclopropane n-substitue et leur utilisation pharmaceutique
WO2005058884A2 (fr) * 2003-12-15 2005-06-30 Japan Tobacco Inc. Composes de cyclopropane et utilisation pharmaceutique de ceux-ci
WO2008024784A1 (fr) * 2006-08-22 2008-02-28 Array Biopharma, Inc. Triazoles à substituant alkylsulfonamide en tant qu'inhibiteurs de la métalloprotéase matricielle

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