AP968A - (4-Arylsulfonylamino)-Tetrahydropyran-4-Carboxylic acid hydroxamides. - Google Patents

(4-Arylsulfonylamino)-Tetrahydropyran-4-Carboxylic acid hydroxamides. Download PDF

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AP968A
AP968A APAP/P/1999/001505A AP9901505A AP968A AP 968 A AP968 A AP 968A AP 9901505 A AP9901505 A AP 9901505A AP 968 A AP968 A AP 968A
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aryl
heteroaryl
disease
compound
alkoxy
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Lawrence Alan Reiter
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Pfizer Prod Inc
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Abstract

A compound of the formula or a pharmaceutical acceptable salt thereof. wherein Q is: (CrC6) alkyl, (C6-Ci0) aryl, (6-Ci0)aryloxy, (Cz'-Cg) heteroaryl or a combination of 2 or 3 of them together or with (C2-C9) heteroaryloxy..

Description

(4-ARYLSULFONYLAMINO)-TETRAHYDROPYRAN-4-CARBOXYLIC ACID
HYDROXAMIDES
Background of the Invention
The present invention relates to (4-arylsulfonylamino)-tetrahydropyran-4-carboxylic acid hydroxamide derivatives , and to pharmaceutical compositions and methods of treatment.
The compounds of the present invention are inhibitors of zinc metalioendopeptidases, especially those belonging to the matrix metalloproteinase (also called MMP or matrixin) and reprolysin (also known as adamylsin) subfamilies of the metzincins (Rawlings, et al., Methods in Enzymology, 248,183-228 (1995) and Stocker, etal., Protein Science, 4, 823-840 (1995)).
The MMP subfamily of enzymes, currently contains seventeen members (MMP-1,
MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16, MMP-17, MMP-18, MMP-19, MMP-20). The MMP’s are most well known for their role in regulating the turn-over of extracellular matrix proteins and as such play important roles in normal physiological processes such as reproduction, development and differentiation. In addition, the MMP's are expressed in many pathological situations in which abnormal connective tissue turnover is occurring. For example, MMP-13 an enzyme with potent activity at degrading type II collagen (the principal collagen in cartilage), has been demonstrated to be overexpressed in osteoarthritic cartilage (Mitchell, et al., J. Clin. Invest., 97, 761 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are also overexpressed in osteoarthritic cartilage and inhibition of some or all of these MMP’s is expected to slow or block the accelerated loss of cartilage typical of joint diseases such as osteoarthritis or rheumatoid arthritis.
The mammalian reprolysins are known as ADAMs (A Disintegrin And Metalloproteinase) (Wolfberg, et al., J. Cell Biol., 131, 275-278 (1995)) and contain a disintegrin domain in addition to a metalloproteinase-like domain. To date twenty three distinct ADAM’s have been identified.
ADAM-17, also known as tumor necrosis factor-alpha converting enzyme (TACE), is the most well known ADAM. ADAM-17 (TACE) is responsible for cleavage of cell bound tumor necrosis factor-alpha (TNF-α, also known as cachectin). TNF-α is recognized to be involved in many infectious and auto-immune diseases (W. Friers, FEBS Letters, 285, 199 (1991)). Furthermore, it has been shown that TNF-α is the prime mediator of the inflammatory response seen in sepsis and septic shock (Spooner, et al·, Clinical Immunology and Immunopathology, 62 S11 (1992)). There are two forms of TNF-α, a type II membrane protein of relative molecular mass 26,000 (26 kD) and a soluble 17 kD form generated from the cell bound protein by specific proteolytic cleavage. The soluble 17 kD form of TNF-α is released by the cell and is associated with the deleterious effects of TNF-α. This form of
9S/01505
a.
AP 00968
TNF-α is also capable of acting at sites distant from the site of synthesis. Thus, inhibitors of TACE prevent the formation of soluble TNF-α and prevent the deleterious effects of the soluole factor.
Select compounds of the invention are potent inhibitors of aggrecanase, an enzyme important in the degradation of cartilage aggrecan. Aggrecanase is also believed to be an
ADAM. The loss of aggrecan from the cartilage matrix is an important factor in the progression of joint diseases such as osteoarthritis and rheumatoid arthritis and inhibition of aggrecanase is expected to slow or block the loss of cartilage in these diseases.
Other ADAMs that have shown expression in pathological situations include ADAM TS-1 (Kuno, et ak, J. Biol. Chem., 272, 556-562 (1997)), and ADAM’S 10, 12 and 15 (Wu, et ak, Biochem. Biophys. Res. Comm., 235, 437-442, (1997)). As knowledge of the expression, physiological substrates and disease association of the ADAM'S increases the full significance of the role of inhibition of this class of enzymes will be appreciated.
Diseases in which inhibition of MMP’s and or ADAM'S will provide therapeutic benefit include: arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn’s disease, emphysema, acute respiratory distress syndrome, asthma chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, bums, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, sderitis, AIDS, sepsis, septic shock and other diseases characterized by metalloproteinase or ADAM expression.
This invention also relates to a method of using the compounds of the invention in the treatment of the above diseases in mammals, especially humans, and to the pharmaceutical compositions useful therefore.
It is recognized that different combinations of MMP’s and ADAM'S are expressed in different pathological situations. As such inhibitors with specific selectivities for individual ADAM’S and/or MMP’s may be preferred for individual diseases. For example, rheumatoid arthritis is an inflammatory joint disease characterized by excessive TNF levels and the loss in o
o
JO •JO [t
AP 00968
-35 of joint matrix constituents. In this case, a compound that inhibits TACE and aggrecanase as well as MMP’s such as MMP-13 may be the preferred therapy. In contrast, in a less inflammatory joint disease such as osteoarthritis, compounds that inhibit matrix degrading MMP's such as MMP-13 but not TACE may be preferred.
The present inventors have also discovered that it is possible to design inhibitors with 10 differential metalloprotease activity. Specifically, for example, the inventors have been able to design molecules which selectively inhibit matrix metalloprotease-13 (MMP-13) preferentially over MMP-1.
Matrix metalloproteinase and reprolysin inhibitors are well known in the literature. Specifically, PCT Publication WO 96/33172, published October 24, 1996, refers to cyclic arylsulfonylamino hydroxamic acids that are useful as MMP inhibitors. United States Patent 5,672,615, PCT Publication WO 97/20824, PCT Publication WO 98/08825, PCT publication WO 98/27069, and PCT Publication WO 98/34918, published August 13, 1998, entitled Arylsulfonyl Hydroxamic Acid Derivatives all refer to cyclic hydroxamic acids that are useful as MMP inhibitors. PCT Publications WO 96/27583 and WO 98/07697, published March 7,
1996 and February 26, 1998, respectively, refer to arylsulfonyl hydroxamic acids. PCT
Publication WO 98/03516, published January 29, 1998 refers to phosphinates with MMP activity. PCT Publication 98/34915, published August 13, 1998, entitled N-Hydroxy-bSulfonyl Propionamide Derivatives, refers to propionylhydroxamides as useful MMP inhibitors. PCT Publication WO 98/33768, published August 6, 1998, entitled
Arylsulfonylamino Hydroxamic Acid Derivatives, refers to N-unsubstituted arylsulfonylamino hydroxamic acids. PCT Publication WO 98/30566, published July 16, 1998, entitled Cyclic Sulfone Derivatives, refers to cyclic sulfone hydroxamic acids as MMP inhibitors. United States Provisional Patent Application 60/55208, filed August 8, 1997, refers to biaryl hydroxamic acids as MMP inhibitors. United States Provisional Patent Application Serial No.
60/55207, filed August 8, 1997, entitled Aryloxyarylsulfonylamino Hydroxamic Acid
Derivatives, refers to aryloxyarylsulfonyl hydroxamic acids as MMP inhibitors. United States Provisional Patent Application 60/62766, filed October 24, 1997, entitled 'The Use of MMP-13 Selective Inhibitors For The Treatment of Osteoarthritis and Other MMP Mediated Disorders, refers to the use of MMP-13 selective inhibitors to treat inflammation and other disorders.
United States Provisional Patent Application Serial No. 60/68261, filed December 19, 1997, refers to the use of MMP inhibitors to treat angiogenesis and other disorders. Each of the above referenced publications and applications is hereby incorporated by reference in its entirety.
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AP 00968
Summary of the Invention
The present invention relates to a compound of the formula O
o
SO^Q or the pharmaceutically acceptable salts thereof, wherein
Q is (C,-C6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C1D)aryloxy(C,-C6)alkyl, (C610 Clo)aryloxy(C6-Cw)aryl, (C6-C,0)aryloxy(C2-C9)heteroaryl, (Cg-C^JaryKCrCgJalkyl, (C6Cio)aryl(Cg-Cio)aryi, (Cg-C10)aryl(C2-C9)heteroaryl, (Cg-CiQ)aryl(Cg-C,9)aryl{Ci-Cg)alkyl, (CgC10)aryl(C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C.3)aryl(C2-C9)heteroaryl, (C2-C9)heteroaryl(Cr C6)alkyl, (C2-C9)heteroaryl(C6-C10)aryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (Cg-C^JaryKC,C6)aIkoxy(C,-C6)alkyl, (Cg-C5o)aryi(Ci-Cg)alkoxy(Cg-CiQ)aryl, (Cg-CiQ)aryl(C,-Cg)alkoxy(C215 C9)heteroaryl, (C2-C9)heteroaryloxy(C1-C6)alkyl, (CrC^heteroaryloxyiCg-C^aryl, (C2C9)heteroaryloxy(C2-C9)heteroary!, (CjA^heteroaryl^-CJalkoxy^-CgJalkyl, (C2C9)heteroaryl(C,-C6)alkoxy(C6-C10)aryl or (C2-C9)heteroaryl(C,-C6)alkoxy(C2-C9)heteroaryl;
wherein each (C6-C10)aryl or (C2-C9)heteroaryl moieties of said (C6-C10)aryl, (C2C9)heteroaryl, (C5-C10)aryloxy(C,-C6)alkyl, (C6-C10)aryloxy(C6-Ci0)aryl, (C6-C10)aryloxy(C220 C9)heteroaryl, (Cg-Cio)aryl(Ci-Cg)aikyl, (Cg-Cio)aryl(Cg-CiQ)aryl, (Cg-Ci9)aryl(C2-C9)heteroaryl, (C6-C10)aryl(C6-Cio)aryl(Ci-C6)alkyl, (Cg-Ci0)aryl(Cg-Cio)aryl(Cg-C1Q)arytl (Cg-Ci9)aryl(CgC10)aryl(C2-C9)heteroaryl, (C2-C9)heteroaryl(Ci-C6)alkyl, (C2-C9)heteroaryl{C6-C,0)aryl, (C2C9)heteroaryl(C2-C9)heteroaryl, (Cg-C^aryl^-Cg/alkoxyiCpCg^lkyl, (Cg-C^Jaryl/C,Cs)alkoxy(C6-C,0)aryl, (Cg-C10)aryl(C1-C6)alkoxy(C2-C9)heteroaryl, (C2-C9)heteroaryloxy(C,25 C6)alkyl, (C2-C9)heteroaryloxy(C6-C10)aryl, (C2-C9)heteroaryloxy(C2-C9)heteroaryl, (C2CgJheteroarylfCrCgJalkoxy/Ct-CgJalkyl, (C2-C9)heteroaryl(C1-Cg)alkoxy(Cg-C10)aryl or (C2CgJheteroaryKCrCgjalkoxy/Cj-CgJheteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or more substituents per ring independently selected from fluoro, chloro, bromo, (CrCg)alkyl, (C^-Cgjalkoxy, perfluoro(C,-C3)alkyl, perfluoro(C,-C3)alkoxy and (C6-C,0)aryloxy;
or a pharmaceutically acceptable salt thereof.
The term alkyl, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The tern alkoxy, as used herein, includes O-alkyl groups wherein alkyl is defined
AP/P/ 9 9 / 0 1 5 0 5 above.
AP 00968
-55 The term aryl, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, bromo, perfluoro(C,-Cs)alkyl (including trifluoromethyl), (C ,-C6)alkoxy, (C6-C10)aryloxy, perfluorofCpC^alkoxy (including trifluorcmethoxy and difluoromethoxy) and (C,-C6)alkyl.
The term heteroaryl, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyrroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl. thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C,-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C,C6)alkyl. Preferred heteroaryls include pyridyl, furyl, thienyl, isothiazolyl, pyrazinyl, pyrimidyl, pyrazolyl, isoxazolyl, thiazolyl or oxazolyl. Most preferred include pyridyl, furyl or thienyl.
Preferred compounds of formula I include those wherein Q is optionally substituted (C620 C,0)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C.c)aryloxy(C6-C10)aryl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C6-C10)aryl(C2-C9)heteroaryl, (C2C9)heteroaryl(C6-C10)aryl, (C2-C9)heteroaryloxy(C6-C10)aryl, (C6-C10)aryl(C,-C5)alkoxy(C6C10)aryl, or (C2-C9)heteroaryl(C,-C6)alkoxy(C6-C,0)aryl.
Other preferred compounds of formula I include those wherein Q is optionally substituted (C6-C,0)aryloxy(C6-C10)aryl.
Specific preferred compounds of formula I include the following:
4-[4-(4-F!uorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;
4-[4-(4-Chlorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;
4-[4-(Phenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxyiic acid hydroxyamide;
4-[4-(4-Pyridyloxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;
4-[4-(4-Fluorophenyl)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;
4-[4-(4-Fluorophenylmethoxy)bezenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;
4-[4-(Phenylmethoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide; and
AP/TZ 9 9 / 0 1 5 0 5
AP
09 68
4-[4-(4-Fluorophenylethoxy)benzenesulforylamino]tetrahydropyran-4-carboxylic acid hydroxyamide.
The present invention also relates to a pharmaceutical composition for the treatment of a condition selected from the group consisting of arti-.ritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn’s disease, emphysema, chronic obstructive pulmonary disease, Alzheimer’s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer breast cancer, lung cancer and prostrate cancer and hematopoietic malignancies including leukemias and lymphomas), tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial pint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington’s disease, Parkinson’s disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, bums, diabetes, tumor invasion, tumor growth, tumor metastasis, comeal scarring, scleritis, AIDS, sepsis, septic shock and other diseases characterized by metalloproteinase activity and other diseases characterized by mammalian reprolysin activity in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for the inhibition of (a) matrix metalloproteinases or other metalloproteirases involved in matrix degradation, or (b) a mammalian reprolysin (such as aggrecanase or ADAM’s TS-1, 10, 12, 15 and 17, most preferably ADAM-17) in a mammal, including a human, comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for treating a condition selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, Alzheimer’s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury.
neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease,
AP/P/ 9 9 / 0 1 5 0 5
AP
Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, bums, diabetes, tumor invasion, tumor growth, tumor metastasis, comeal scarring, scleritis, AIDS, sepsis, septic shock and other diseases characterized by metalloproteinase activity and other diseases characterized by mammalian reprolysin activity in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition.
The present invention also relates to a method for the inhibition of (a) matrix metalloproteinases or other metalloproteinases involved in matrix degradation, or (b) a mammalian reprolysin (such as aggrecanase or ADAM's TS-1, 10, 12, 15 and 17, preferably ADAM-17) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the formula I. This invention also encompasses methods of treating or preventing disorders that can be treated or prevented by the inhibition of matrix metalloproteinases or the inhibition of mammalian reprolysin comprising administering prodrugs of compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
One of ordinary skill in the art will appreciate that the compounds of the invention are useful in treating a diverse array of diseases. One of ordinary skill in the art will also appreciate that when using the compounds of the invention in the treatment of a specific disease that the compounds of the invention may be combined with various existing therapeutic agents used for that disease.
For the treatment of rheumatoid arthritis, the compounds of the invention may be combined with agents such as TNF-α inhibitors such as anti-TNF monoclonal antibodies and
TNF receptor immunoglobulin molecules (such as Enbrel®), low dose methotrexate, lefunimide, hydroxychloroquine, d-penicilamine, auranofin or parenteral or oral gold.
ΑΡ/Γ/ 9 9/01505
AP 00968
-8The compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAID’s) such as piroxicam, diclofenac, propionic acids such as naproxen, fiubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, 10 apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib and rofecoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc.
The compounds of the present invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, 15 daunomycin, cis-platinum, etoposide, taxoi, taxotere and alkaloids, such as vincristine, and antimetabolites such as methotrexate.
The compounds of the present invention may also be used in combination with cardiovascular agents such as calcium channel blockers, lipid lowering agents such as statins, fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptor antagonists and platelet aggregation inhibitors.
The compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as deprenyl, L-dopa, requip, miratex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,
Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase), and anti-Alzheimer’s drugs such as Aricept, tacrine, COX-2 inhibitors, propentofylline or metryfonate.
The compounds of the present invention may also be used in combination with osteoporosis agents such as droloxifene or fosomax and immunosuppressant agents such as
FK-506 and rapamycin.
Detailed Description of the Invention
The following reaction Scheme illustrates the preparation of the compounds of the present invention. Unless otherwise indicated, Q in the reaction Schemes and the discussion that follows is defined as above.
ΑΗ/ΓΖ 9 9 / 0 1 5 0 5
AP 00968
-9Scheme 1
AP/P/ 9 9 / 0 1 5 0 5
ΑΡ 00968
-10ΖΈ
Scheme 1 (continued)
Ο
Ο
ΑΡ/Ρ/ 9 9 / 0 1 5 0 5
AP 00968
-115 Scheme 1 refers to the preparation of compounds of the formula I.
Referring to Scheme 1, the compound of formula I is prepared from the carboxylic acid of formula II by treatment with 1-{3-dimethylaminopropyl)-3-ethylcarbodiimide and 1hydroxybenztriazole in a polar solvent, such as N.N-dimethylformamide, followed by the addition of hydroxylamine to the reaction mixture after a time period between about 15 minutes to about 1 hour, preferably about 30 minutes. The hydroxylamine is preferably generated in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as triethylamine.
Alternatively the compound of formula I can be prepared from a compound of formula II by reaction with a protected derivative of hydroxylamine or its salt form, where the hydroxyl group is protected as a tert-butyl, benzyl, allyl or 2-trimethylsilylethyl ether. Removal of the hydroxyl protecting group is carried out by hydrogenolysis for a benzyl protecting group (5% palladium on barium sulfate is the preferred catalyst) or treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyltinhydride and acetic acid in the presence of catalytic bis(triphenylphosphine) palladium(ll)chloride. The 2-trimethylsilylethyl ether may be removed by reaction with a strong acid such as trifluoroacetic acid or by reaction with a fluoride source such as boron trifluoride etherate.
The reaction of II with hydroxylamine, a salt of hydroxylamine, a protected derivative of hydroxylamine or a salt of a protected derivative of hydroxylamine may also be earned out in the presence of (benztriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate and a base such as triethylamine in an inert solvent, such as methylene chloride. The reaction mixture is stirred at a temperature between about 0°C to about 50°C, preferably room temperature, for a time period between about 1 hour to about 3 days, preferably about 1 day.
Another procedure for converting a compound of formula II to a compound of formula I is to react the compound of formula II with O-benzylhydroxylamine hydrochloride in the presence of (benztriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate and triethylamine using methylene chloride as solvent. Subsequent removal of the O-benzyl protecting group to afford a compound of formula I is then carried out by hydrogenolysis under 3 atmospheres hydrogen at room temperature using 5% palladium on barium sulfate as catalyst. The preferred solvent is methanol. The reaction time may vary from about 1 hour to about 2 days (8 hours is preferred).
The preferred procedure for converting a compound of formula II to a compound of formula I is to react the compound of formula II with oxalyl chloride in methylene chloride in the presence of a catalytic amount of DMF for 16 hours. The resulting acid chloride is reacted at
0°C with N, O- bis trimethylsilyl hydroxylamine formed by reacting hydroxyamine hydrochloride with chlorotrimethyl-silane in pyridine at 0°C to room temperature. The product of formula I is
AP/P/ 9 9/01505
AP 00968
-125 obtained after a few hours reactions at 0°C to room temperature followed by an acidic aqueous workup which removes all trimethyl silyl residues.
In certain instances it is preferred to obtain the compound of formula I by reaction of hydroxylamine, a salt of hydroxylamine, a protected derivative of hydroxylamine or a salt of a protected derivative of hydroxylamine with an activated ester of formula III. The reaction is earned out in an inert solvent, such as Ν,Ν-dimethyl-formamide at a temperature ranging from about room temperature to about 80°C, preferably about 60°C for a time period of about 1 hour to about 2 days. If a protected derivative of hydroxylamine or a salt of a protected derivative of hydroxylamine is used, removal of the protecting group is carried out as described above. The activated ester derivative of formula III is obtained by treatment of the compound of formula II with (benztriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate and a base such as triethylamine in an inert solvent, such as methylene chloride. The reaction mixture is stirred at a temperature between about 0°C to about 50°C, preferably room temperature, for a time period between about 1 hour to about 3 days, preferably about 1 day.
The intermediate compound of formula II is prepared by saponification of a compound of formula IV. The reaction is carried out at in a solvent, such as aqueous ethanol, with an excess of a metal hydroxides, such as sodium hydroxide or lithium hydroxide, at a temperature of about 20° C to about 100° C, (i.e. room temperature to the reflux temperature of the solvent), preferably about 80° C. The reaction mixture is normally agitated at room temperature for a time period between about 30 minutes to about 1 week, preferably about 16 hours.
The compound of formula IV is prepared by reacting a compound of formula V with a reactive functional derivative of a sulfonic acid (QSO2OH), such as the sulfonyl chloride (QSO2CI), in the presence of a base. Suitable bases include sodium hydroxide, triethylamine or diisopropylethylamine, preferably triethylamine. Suitable solvents include dimethylformamide (DMF), methylene chloride, tetrahydrofuran, dioxane, water or acetonitrile, preferably DMF. The reaction mixture is stirred at a temperature between about 0°C to about 50°C, preferably at about 20°C to about 25°C (i.e. room temperature), for a time period between about 10 minutes to about 2 days, preferably about 1 day.
The compound of formula V is prepared by hydrolysis of a compound of formula IV. Specifically, the compound of formula VI is treated with aqueous acid, preferably in the presence of an immiscible organic solvent such ethyl ether, diisopropyl ether or methylene chloride. Suitable acids include hydrochloric and sulfuric. The reaction mixture is stirred at a temperature between about 0°C to about 50°C, preferably at about 20°C to about 25°C (i.e. room temperature), for a time period between about 10 minutes to about 2 days', preferably about 1 day.
90910/66 Zd/dV
AP 00968
-135 The compound of formula VI is prepared by reaction of the amino acid derivative of the formula VII with a compound of the formula VIII in the presence of a base and a solvent, wherein X is Cl, Br, I, tosylate or mesylate. Suitable bases include ethlyene glycol, sodium hydride, lithium diisopropylamide, or sodium hexamethyl disilazide. Suitable solvents include dimethylether, dimethylformamide, tetrahydrofuran or dimethylsulfoxide. The reaction mixture is stirred at a temperature between about -20°C to about 25°C, preferably at about 0°C to about 20°C (i.e. room temperature), for a time period between about 10 minutes to about 2 days, preferably about 1 day.
The compounds of formulae VII and VIII can be prepared by methods well known to those of ordinary skill in the art. Examples of such compounds include methylglycine benzophenone imine and ethyl glycine benzophenone imine.
Pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methylammonium slats.
Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids e.g. hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.
The ability of the compounds of formula I or their pharmaceutically acceptable salts 25 (hereinafter also referred to as the compounds of the present invention) to inhibit metalloproteinases or mammalian reprolysin and, consequently, demonstrate their effectiveness for treating diseases characterized by metalloproteinase or the production of tumor necrosis factor is shown by the following in vitro assay tests.
Biological Assay
Inhibition of Human Collagenase (MMP-1)
Human recombinant collagenase is activated with trypsin. The amount of trypsin is optimized for each lot of collagenase-1 but a typical reaction uses the following ratio: 5 pg trypsin per 100 pg of collagenase. The trypsin and collagenase are incubated at room temperature for 10 minutes then a five fold excess (50 mg/10 mg trypsin) of soybean trypsin inhibitor is added.
Stock solutions (10 mM) of inhibitors are made up in dimethylsulfoxide and then diluted using the following scheme:
mM-> 120 pM-> 12 pM-> 1.2 pM-> 0.12 pM
Twenty-five microliters of each concentration is then added in triplicate to appropriate wells of a 96 well microfluor plate. Pie final concentration of inhibitor will be a 1:4 dilution after
AP/P/ 9 9 / 0 1 5 0 5
AP 00968 ·14· addition of enzyme and substrate. Positive controls (enzyme, no inhibitor) are set up in wells D7-D12 and negative controls (no enzyme, no inhibitors) are set in wells D1-D6.
Collagenase-1 is diluted to 240 ng/ml and 25 ml is then added to appropriate wells of the microfiuor plate. Final concentration of collagenase in the assay is 60 ng/ml.
Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is made as a 5 mM stock in dimethylsulfoxide and then diluted to 20 μΜ in assay buffer. The assay is initiated by the addition of 50 ml substrate per well of the microfiuor plate to give a final concentration of 10 mM.
Fluorescence readings (360 nM excitation, 460 nm emission) are taken at time 0 and then at 20 minute intervals. The assay is conducted at room temperature with a typical assay time of 3 hours
Fluorescence versus time is then plotted for both the blank and collagenase containing samples (data from triplicate determinations is averaged). A time point that provides a good signal (at least five fold over the blank) and that is on a linear part of the curve (usually around 120 minutes) is chosen to determine IC» values. The zero time is used as a blank for each compound at each concentration and these values are subtracted from the 120 minute data. Data is plotted as inhibitor concentration versus % control (inhibitor fluorescence divided by fluorescence of collagenase alone x 100). ICsq's are determined from the concentration of inhibitor that gives a signal that is 50% of the control.
If ICjo's are reported to be less than 0.03 mM then the inhibitors are assayed at concentrations of 0.3 mM, 0.03 mM, and 0.003 mM.
Inhibition of Gelatinase (MMP-2)
Human recombinant 72 kD gelatinase (MMP-2, gelatinase A) is activated for 16-18 hours with 1mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock in 0.2 N NaOH) at 4°C, rocking gently.
10 mM dimethylsulfoxide stock solutions of inhibitors are diluted serially in assay buffer (50 mM TRIS, pH 7.5, 200 mM NaCI, 5 mM CaCI2. 20 μΜ ZnCI2 and 0.02% BRIJ-35 (vol./vol.)) using the following scheme:
mM—> 120 μΜ-> 12 μΜ--> 1.2 μΜ-> 0.12 μΜ
Further dilutions are made as necessary following this same scheme. A minimum of four inhibitor concentrations for each compound are performed in each assay. 25 pL of each concentration is then added to triplicate wells of a black 96 well U-bottomed microfiuor plate. As the final assay volume is 100 pL, final concentrations of inhibitor are the result of a further
1:4 dilution (i.e. 30 μΜ-> 3 μΜ —> 0.3 μΜ —> 0.03 μΜ, etc.). A blank (no enzyme, no inhibitor) and a positive enzyme control (with enzyme, no inhibitor) are also prepared in triplicate.
AP/P/ 9 9 / 0 1 5 0 5
AP 00968
-15Activated enzyme is diluted to 100 ng/mL in assay buffer, 25 pL per well is added to appropriate wells of the microplate. Final enzyme concentration in the assay is 25 ng/mL (0.34 nM).
A five mM dimethylsulfoxide stock solution of substrate (Mca-Pro-Leu-Gly-Leu-DpaAla-Arg-NH2) is diluted in assay buffer to 20 μΜ. The assay is initiated by addition of 50 pL of diluted substrate yielding a final assay concentration of 10 pM substrate. At time zero, fluorescence reading (320 excitation; 390 emission) is immediately taken and subsequent readings are taken every fifteen minutes at room temperature with a PerSeptive Biosystems CytoFluor Multi-Well Plate Reader with the gain at 90 units.
The average value of fluorescence of the enzyme and blank are plotted versus time.
An early time point on the linear part of this curve is chosen for IC50 determinations. The zero time point for each compound at each dilution is subtracted from the latter time point and the data then expressed as percent of enzyme control (inhibitor fluorescence divided by fluorescence of positive enzyme control x 100). Data is plotted as inhibitor concentration versus percent of enzyme control. ICm's are defined as the concentration of inhibitor that gives a signal that is 50% of the positive enzyme control.
Inhibition of Stromelysin Activity (MMP-3)
Human recombinant stromelysin (MMP-3, stromelysin-1) is activated for 20-22 hours with 2 mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock in 0.2 N NaOH) at 37°C.
10 mM dimethylsulfoxide stock solutions of inhibitors are diluted serially in assay buffer (50 mM TRIS, pH 7.5, 150 mM NaCI, 10 mM CaCI2 and 0.05% BRIJ-35 (vol./vol.)) using the following scheme:
mM—> 120 pM—> 12 pM-> 1.2 pM—> 0.12 pM
Further dilutions are made as necessary following this same scheme. A minimum of four inhibitor concentrations for each compound are performed in each assay. 25 pL of each concentration is then added to triplicate wells of a black 96 well U-bottomed microfluor plate. As the final assay volume is 100 pL, final concentrations of.inhibitor are the result of a further 1:4 dilution (i.e. 30 pM —> 3 pM —> 0.3 pM —> 0.03 pM, etc.). A blank (no enzyme, no inhibitor) and a positive enzyme control (with enzyme, no inhibitor) are also prepared in triplicate.
Activated enzyme is diluted to 200 ng/mL in assay buffer, 25 pL per well is added to appropriate wells of the microplate. Final enzyme concentration in the assay is 50 ng/mL (0.875 nM).
A ten mM dimethylsulfoxide stock solution of substrate (Mca-Arg-Pro-Lys-Pro-Val40 Glu-Nva-Trp-Arg-Lys(Dnp)-NH2) is diluted in assay buffer to 6 pM. The assay is initiated by
AP/P/ 99/01505
AP 00968
-165 addition of 50 pL of diluted substrate yielding a final assay concentration of 3 μΜ substrate. At time zero, fluorescence reading (320 excitation; 390 emission) is immediately taken and subsequent readings are taken every fifteen minutes at room temperature with a PerSeptive Biosystems CytoFluor Multi-Well Plate Reader with the gain at 90 units.
The average value of fluorescence of the enzyme and blank are plotted versus time.
An early time point on the linear part of this curve is chosen for IC^, determinations. The zero time point for each compound at each dilution is subtracted from the latter time point and the data then expressed as percent of enzyme control (inhibitor fluorescence divided by fluorescence of positive enzyme control x 100). Data is plotted as inhibitor concentration versus percent of enzyme control. ICm's are defined as the concentration of inhibitor that gives a signal that is 50% of the positive enzyme control.
Inhibition of MMP-13
Human recombinant MMP-13 is activated with 2mM ΑΡΜΑ (p-aminophenyl mercuric acetate) for 2.0 hours, at 37°C and is diluted to 240 ng/ml in assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5mM calcium chloride, 20mM zinc chloride, 0.02% brij 35). Twenty20 five microliters of diluted enzyme is added per well of a 96 well microfluor plate. The enzyme is then diluted in a 1:4 ratio in the assay by the addition of inhibitor and substrate to give a final concentration in the assay of 60 ng/ml.
Stock solutions (10 mM) of inhibitors are made up in dimethylsutfoxide and then diluted in assay buffer as per the inhibitor dilution scheme for inhibition of human collagenase-1 (MMP25 1): Twenty-five microliters of each concentration is added in triplicate to the microfluor plate.
The final concentrations in the assay are 30 mM, 3mmM, 0.3m mM, and 0.03 mmM.
Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is prepared as for inhibition of human collagenase (MMP-1) and 50 μΙ is added to each well to give a final assay concentration of 10 μΜ. Fluorescence readings (360 nM excitation; 450 nM emission) are taken at time 0 and every 5 minutes for 1 hour.
Positive controls and negative controls are set up in triplicate as outlined in the MMP-1 assay.
ICm's are determined as per inhibition of human collagenase (MMP-1). If ICm's are reported to be less than 0.03 mM, inhibitors are then assayed at final concentrations of 0.3 mM,
0.03 mmM, 0.003 mmM and 0.0003 mM.
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AP 00968
-175 Inhibition of TNF Production
The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating diseases involving the production of TNF is shown by the following in vitro assay:
Human mononuclear cells were isolated from anti-coagulated human blood using a one10 step Ficoll-hypaque separation technique. (2) The mononuclear cells were washed three times in Hanks balanced salt solution (HBSS) with divalent cations and resuspended to a density of 2 x 106 /ml in HBSS containing 1% BSA. Differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that monocytes ranged from 17 to 24% of the total cells in these preparations.
180 μΙ of the cell suspension was aliquoted into fiat bottom 96 well plates (Costar).
Additions of compounds and LPS (100 ng/ml final concentration) gave a final volume of 200 μΙ. All conditions were performed in triplicate. After a four hour incubation at 37°C in an humidified CO2 incubator, plates were removed and centrifuged (10 minutes at approximately 250 x g) and the supernatants removed and assayed for TNFa using the R&D ELISA Kit.
Inhibition of Soluble TNF-α Production
The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit the cellular release of TNF-α and, consequently, demonstrate their effectiveness for treating diseases involving the disregulation of soluble TNF -a is shown by the following in vitro assay:
Method for the evaluation of recombinant TNF-α Converting Enzyme Activity
Expression of recombinant TACE
A DNA fragment coding for the signal sequence, preprodomain, prodomain and catalytic domain of TACE (amino acids 1-473), can be amplified by polymerase chain reaction using a human lung cDNA library as a template. The amplified fragment is then cloned into pFastBac vector. The DNA sequence of the insert is confirmed for both the strands. A bacmid prepared using pFastBac in E. coli DHIOBac is transfected into SF9 insect cells. The virus particles is then amplified to P1, P2, P3 stages. The P3 virus is infected into both Sf9 and High Five insect cells and grown at 27°C for 48 hours. The medium is collected and used for assays and further purification.
Preparation of fluorescent quenched substrate:
A model peptidic TNF-α substrate (LY-LeucineAlanineGlutamineAlanineValineArginineSerine-SerineLysine(CTMR)-Arginine (LY=Lucifer Yellow;
CTMR=Carboxytetramethyl-Rhodamine)) is prepared and the concentration estimated by absorbance at 560 nm (E56O. 60,000 M-1CM-1) according to the method of Geoghegan, KF,
Improved method for converting an unmodified peptide to an energy-transfer substrate for a
AP/P/ 9 9 / 0 1 5 0 5
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-135 proteinase. Bioconjugate Chem. 7, 385-391 (1995). This peptide encompasses the cleavage cite on pro-TNF which is cleaved in vivo by TACE.
Expression of recombinant TACE
A DNA fragment coding for the signal sequence, preprodomain, prodomain and catalytic domain of TACE (amino acids 1-473), is amplified by polymerase chain reaction using a human lung cDNA library as a template. The amplified fragment is cloned into pFastBac vector. The DNA sequence of the insert is confirmed for both the strands. A bacmid prepared using pFastBac in E. coli DHIOBac is transfected into SF9 insect cells. The virus particles were amplified to P1, P2, P3 stages. The P3 virus is infected into both Sf9 and High Five insect cells and grown at 27°C for 48 hours. The medium is collected and used for assays and further purification.
Enzyme reaction.
The reaction, carried out in a 96 well plate (Dynatech), is comprised of 70 μΙ of buffer solution (25 mM Hepes-HCI, pH7.5, plus 20 uM ZnCI2), 10 μΙ of 100 μΜ fluorescent quenched substrate, 10 μΙ of a DMSO (5%) solution of test compound, and an amount of r-TACE enzyme which will cause 50% cleavage in 60 minutes - in a total volume of 100 μΙ. The specificity of the enzyme cleavage at the amide bond between alanine and valine is verified by HPLC and mass spectrometry. Initial rates of cleavage are monitored by measuring the rate of increase in fluorescence at 530 nm (excitation at 409 nm) over 30 minutes. The experiment is controlled as follows: 1) for background fluorescence of substrate; 2) for fluorescence of fully cleaved substrate; 3) for fluorescence quenching or augmentation from solutions containing test compound.
Data is analyzed as follows. The rates from the non-test compound containing “control reactions were averaged to establish the 100% value. The rate of reaction in the presence of test compound was compared to that in the absence of compound, and tabulated as “percent of non-test compound containing control. The results are plotted as “% of control vs. the log of compound concentration and a half-maximal point or ICM value determined.
All of the compounds of the invention have IC^ of less than 1 μΜ, preferably less than 50nM. Most preferred compounds of the invention are at least 100 fold less potent against rMMP-1 than in the above TACE assay.
Human Monocyte Assay
Human mononuclear cells are isolated from anti-coagulated human blood using a onestep Ficoll-hypaque separation technique. (2) The mononuclear cells are washed three times in
Hanks balanced salt solution (HBSS) with divalent cations and resuspended to a density of 2 x
106 /ml in HBSS containing 1% BSA. Differential counts determined using the Abbott Cell Dyn
AP/P/ 9 9 / 0 1 5 0 5
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-195 3500 analyzer indicated that monocytes ranged from 17 to 24% of the total cells in these preparations.
180m of the cell suspension was aliquoted into flat bottom 96 well plates (Costar). Additions of compounds and LPS (100 ng/ml final concentration) gave a final volume of 200 μΙ. All conditions were performed in triplicate. After a four hour incubation at 37°C in an humidified
CO2 incubator, plates were removed and centrifuged (10 minutes at approximately 250 x g) and the supernatants removed and assayed for TNF-α using the R&D ELISA Kit.
Aggrecanase Assay
Primary porcine chondrocytes from articular joint cartilage are isolated by sequential trypsin and coilagenase digestion followed by coilagenase digestion overnight and are plated at 2 X 105 cells per well into 48 well plates with 5 pCi / ml 35g (1000 Ci/mmol) sulphur in type l collagen coated plates. Cells are allowed to incorporate label into their proteoglycan matrix (approximately 1 week) at 37°C, under an atmosphere of 5% CO2.
The night before initiating the assay, chondrocyte monolayers are washed two times in DMEM/1% PSF/G and then allowed to incubate in fresh DMEM /1% FBS overnight.
The following morning chondrocytes are washed once in DMEM/1%PSF/G. The final wash is allowed to sit on the plates in the incubator while making dilutions.
/99/01505
Media and dilutions can be made as described in the Table below.
Control Media DMEM alone (control media)
IL-1 Media DMEM + IL-1 (5 ng/ml)
Drug Dilutions Make all compounds stocks at 10 mM in DMSO. Make a 100 uM stock of each compound in DMEM in 96 well plate. Store in freezer overnight. The next day perform serial dilutions in DMEM with IL-1 to 5 uM, 500 nM. and 50 nM. Aspirate final wash from wells and add 50 ul of compound from above dilutions to 450 ul of IL-1 media in appropriate wells of the 48 well plates. Final compound concentrations equal 500 nM, 50 nM, and 5 nM. All samples completed in triplicate with Control and IL-1 alone samples on each plate.
PSL «X
Plates are labeled and only the interior 24 wells of the plate are usjed. On one of the plates, several columns are designated as IL-1 (no drug) and Control (no IL-1, no drug).
These control columns are periodically counted to monitor 35S-proteoglycan release. Control
AP 00968
-205 and IL-1 media are added to wells (450 ul) followed by compound (50 ul) so as to initiate the assay. Plates are incubated at 37°C, with a 5% CO2 atmosphere.
At 40-50 % release (when CPM from IL-1 media is 4-5 times control media) as assessed by liquid scintillation counting (LSC) of media samples, the assay is terminated (912 hours). Media is removed from all wells and placed in scintillation tubes. Scintillate is added and radioactive counts are acquired (LSC). To solubilize cell layers, 500 ul of papain digestion buffer (0.2 M Tris, pH 7.0, 5 mM EDTA, 5 mM DTT, and 1 mg/ml papain) is added to each well. Plates with digestion solution are incubated at 60°C overnight The cell layer is removed from the plates the next day and placed in scintillation tubes. Scintillate is then added, and samples counted (LSC).
The percent of released counts from the total present in each well is determined.
Averages of the triplicates are made with control background subtracted from each well. The percent of compound inhibition is based on IL-1 samples as 0% inhibition (100% of total counts).
For administration to mammals, including humans, for the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF), a variety of conventional routes may be used including orally, parenterally and topically. In general, the active compound will be administered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
The compounds of the present invention can be administered in a wide variety of different dosage forms, in general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably com, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or
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-215 flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. In the case of animals, they are advantageously contained in an animal feed or drinking water in a concentration of 5-5000 ppm, preferably 25 to 500 ppm.
For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes.
The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art In the case of animals, compounds can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to 3 divided doses.
For topical ocular administration, direct application to the affected eye may be employed in the form of a formulation as eyedrops, aerosol, gels or ointments, or can be incorporated into collagen (such as poly-2-hydroxyethylmethacrylate and co-polymers thereof), or a hydrophilic polymer shield. The materials can also be applied as a contact lens or via a local reservoir or as a subconjunctival formulation.
For intraorbital administration a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention in an aqueous solution or suspension (particle size less than 10 micron) may be employed. The aqueous solutions should be suitably adjusted and buffered, preferably at a pH between 5 and 8, if necessary and the liquid diluent first rendered isotonic. Small amounts of polymers can be added to increase viscosity or for sustained release (such as cellulosic polymers, Dextran, polyethylene glycol, or alginic acid). These solutions are suitable for intraorbital injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art In the case of animals, compounds can be administered intraorbitally at dosage levels of about 0.1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to 3 divided doses.
The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
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AP 00968
-225 For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
The present invention is illustrated by the following Preparations and Examples, but it is not limited to the details thereof.
Example 1
4-[4-(4-FHJOROPHENOXY)BENZENESULFONYLAMlNO]-TETRAHYDRO
PYRAN-4-CARBOXYLIC ACID HYDROXYAMIDE (A) 4-[N-(Diphenylmethylene)amino]tetrahydropyran-4-carboxylic acid ethyl ester
To a suspension of sodium hydride (6.56 grams. 0.164 mole) in ethylene glycol dimethyl ether (150 mL) at 0°C was added a solution of the N-(diphenylmethylene)glycine ethyl ester (20.60 grams, 0.07398 mole) in ethylene glycol dimethyl ether (50 mL) dropwise via addition funnel. A solution of 2-bromoethyl ether (23.21 grams, 0.090 mole) in ethylene glycol dimethyl ether (50 mL) was then added, in 10 mL portions over approximately 5 minutes, to the ethylene glycol dimethyl ether solution. The ice bath was removed and the reaction was stirred at room temperature for 16 hours. The mixture was diluted with diethyl ether and washed with water. The aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated to afford a cloudy yellow oil (28.692 grams). Chromatography on silica gel eluting first with 4 L of 5% ethyl acetate/hexane followed by 4 liters of 10% ethyl acetate/hexane gave 4-[N-(diphenylmethylene)amino]tetrahydropyran-4-carboxylic acid ethyl ester as a clear yellow oil (16.114 g, 64 %).
’HNMR (CDCl3) δ 7.58 (d, 2H), 7.36 (m, 4H), 7.28 (t, 2H), 7.08 (m, 2H), 3.99 (m, 2H),
3.70, (m, 2H), 3.66 (q, 2H), 2.10 (m, 2H), 1.99 (m, 2H), 1.08 (t, 3H). MS Atmospheric Pressure Chemical Ionization Mass Spectra: 338 (M++1).
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AP 00968
-235 (B) 4-Aminotetrahydropyran-4-carboxylic acid ethyl ester
To a solution of 4-[N-(diphenylmethylene)amino]tetrahydropyran-4-carboxylic acid ethyl ester (16.0 grams, 0.047 mole) in diethyl ether (120 mL) was added 1M aqueous hydrochloric acid solution (100 mL). The mixture was stirred vigorously at room temperature for 16 hours. The layers were separated and the aqueous layer washed with diethyl ether.
The aqueous layer was brought to pH 10 with dilute aqueous ammonium hydroxide solution and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated to give 4-aminotetrahydropyran-4-carboxylic acid ethyl ester (7.128 g, 71.7%) as an oil.
1HNMR (CDCI3) δ 4.15 (q, 2H), 3.82 (m, 2H), 3.62 (m, 2H), 2.07 (m, 2H), 1.60 (s, 2H),
1.44 (m, 2H), 1.24 (t, 3H). 13CNMR (CDCI3) d 176.48, 63.70, 61.09, 54.78, 35.05, 14.15. MS
Atmospheric Pressure Chemical Ionization Mass Spectra: 210 (M++1).
(C) 4-[4-(4-Fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4carboxylic acid ethyl ester
To a solution of 4-aminotetrahydropyran-4-carboxylic acid ethyl ester (7.00 grams,
0.0404 mole) in N,N-dimethylformamide (40 mL) was added triethylamine (5.94 mL, 0.043 mole). Solid 4-(4-fluorophenoxy)benzenesulfonyl chloride (12.165 grams, 0.0424 mole) was added in portions. The resulting mixture was stirred at room temperature for 16 hours and then most of the solvent was removed by evaporation under vacuum. The residue was partitioned between saturated sodium bicarbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent under vacuum provided crude 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxyiic acid ethyl ester as an amber oil (21.05 grams). Flash chromatography on silica gel eluting with 25% ethyl acetate / hexane followed by 50% ethyl acetate / hexane provided 4-(4-(430 fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid ethyl ester as an offwhite crystalline solid (12.15 grams, 71%, mp 116-117°C).
1HNMR (CDCI3) δ 7.79 (d, 2H), 7.09 (t, 2H) 7.02 (m, 2H), 6.97 (d, 2H), 5.10 (s, 1H), 4.01 (q, 2H), 3.60 (m, 4H), 2.08 (m, 2H), 1.84 (br d, 2H), 1.23 (t, 3H), M S Atmospheric Pressure Chemical Ionization Mass Spectra: 424 (M*+1).
(D) 4-[4-<4-Fluorophenoxy)-benzenesuIfonylamino]tetrahydropyran-4carboxylic acid
Method A
A solution of 4-[4-(4-fluorophenoxy)benzenesulfonylamin0]tetrahydropyran-4carboxylic acid ethyl ester (12.1 grams, 0.0286 mole) in tetrahydrofuran (190 mL) was treated with aqueous 3 M sodium hydroxide solution (95 mL, 0.286 mole) and stirred at room
SOStO/66/d/dV
AP 00968
-24temperature for 4 days. The solvent was evaporated under vacuum and the residue partitioned between water and diethyl ether. The aqueous layer was washed with diethyl ether, acidified to pH 1 with 3N aqueous hydrochloric acid solution and extracted with dichloromethane. After washing with water, the organic extract was dried over sodium sulfate, and concentrated to give 4-[4-(4-fluorophenoxy)-benzenesulfonylaminojtetrahydropyran-4carboxylic acid (11.241 grams, 99%) as a yellowish solid foam.
Method B
A solution of 4-[4-{4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4carboxylic acid ethyl ester (34.19 grams, 0.807 mole) in ethanol (330 mL) was treated with aqueous 3 M sodium hydroxide solution (330 mL, 0.990 mole) and heated to reflux overnight. The solvent was evaporated under vacuum and the residue partitioned between water and diethyl ether. The aqueous layer was washed with diethyl ether, acidified to pH 1 with 3N aqueous hydrochloric acid solution and extracted with ethyl acetate. After washing with water, the organic extract was dried over sodium soulfate, and concentrated to give 4-(4-(4fluorophenoxy)benzenesuifonylamino]tetrahydropyran-4-carboxylic acid (31.26 grams, 98%) as a white crystalline solid.
’HNMR (CDCI3) δ 7.73 (d. 2H), 7.03 (t, 2H) 6.96 (m, 2H), 6.91 (d. 2H), 3.56 (m, 2H). 3.43 (br m, 3H), 2.01 (m, 2H), 1.80 (br d, 2H). MS Atmospheric Pressure Chemical Ionization Mass Spectra: 394 (M*-1) (-ion).
(E) 4-[4-{4-Fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4carboxylic acid N-benzyloxyamide
Diisopropyl ethylamine (3.89 grams, 0.030 mole) and (benzotriazol-l-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (13.27 grams, 0.030 mole) were added sequentially to a solution of 4-[4-(4-fluorophenoxy)-benzenesulfonylamino] tetrahydropyran-4carboxylic acid (11.22 grams, 0.028 mole) in anhydrous Ν,Ν-dimethylformamide (140 mL). The resulting solution was stirred at room temperature for 16 hours. Additional diisopropyl ethylamine (4.0 mL, 0.051 mole) and O-benzyl hydroxylamine hydrochloride (5.46 grams, 0.034 mole) were then added and the resulting mixture was stirred at 60°C for 18 hours. After concentration under vacuum, the residue was treated with 0.5N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate solution, water, and brine. The solution was dried over magnesium sulfate, filtered and concentrated to one fourth original volume. Addition of an equal volume of hexane precipitated 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid N-benzyloxyamide (11.595 g, 81.6%) as a white crystalline solid (mp 175-176°C).
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AP 00968
-25’HNMR (CDCI3) δ 7.76 (d, 2H), 7.35 (m, 5H), 7.05 (t. 2H). 6.96 (m, 4H) 5.38 (br s, 1H), 4.86 (s, 2H), 3.57 (m, 2H), 3.44 (m, 2H), 2.01 (m, 2H), 1.77 (br d, 2H). 1.54 (br s, 1H). MS Atmospheric Pressure Chemical Ionization 501 (M*+1).
(F) 4-[4-(4-Fluorophenoxy)benzenesulfonylamino]-tetrahydropyran-4carboxylic acid hydroxyamide
Method A
A solution of 4-[4-(4-fiuorophenoxy)benzenesulfonylamino]tetrahydropyran-4carboxylic acid N-benzyloxyamide( 11.28 grams, 0.0225 mole) in ethyl acetate (600 mL) was treated with 5% palladium on barium sulfate (5.0 grams) and hydrogenated in a Parr™ shaker at 3 atmospheres pressure for 18 hours. After filtration through nylon (pore size 0.45 mm) to remove the catalyst, the filter pad was rinsed with methanol. Combined filtrate and rinse were evaporated and the residue taken up in hot methanol. Cooling afforded crude 4-(4-(4fluorophenoxy)benzenesulfonylamino]-tetrahydropyran-4-carboxylic acid hydroxyamide (5.941 grams, 64%, mp 176-177°C) as a white crystalline solid. The mother liquor was evaporated and the residue crystallized from 50% methanol/dichloromethane to give additional 4-(4-(420 fluorophenoxy)benzenesulfonylamino]-tetrahydropyran-4-carboxylic acid hydroxyamide (0.660 grams, mp 184-185°C) as white needles. The mother liquor was again evaporated and the residue crystallized from methanol/dichloromethane to give additional product (1.861 grams, mp 176-177°C). Recrystallization of the first lot from methanol/dichloromethane provided analytically pure 4-(4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide (3.091 grams, mp 184-185°C).
Method B
Oxalyl chloride (11.83 grams, 0.0932 mole, 1.1 eq.) and DMF (0.13 mL) were added to a stirred suspension of the carboxylic acid (33.25 grams, 0.0841 mole) in dry methylene chloride (300 mL) at room temperature. Some bubbling was observed. The suspension, which slowly became a yellowish solution was stirred overnight at room temperature. Meanwhile, a solution of hydroxylamine hydrochloride (7.65 grams, 0.110 mole, 1.3 eq.) in dry pyridine (51.4 mL, 0.635 mole, 7.5 eq.) at 0°C was treated with chlorotrimethylsilane causing a white precipitate to form. This suspension was stirred at room temperature overnight. Both flasks were then cooled to 0°C and the solution of acid chloride was added to the suspension of silylated hydroxylamine. The resulting mixture was stirred at 0°C for 1 hour and room temperature for 2 hours. Added 1000 mL aqueous 2N HCI and stirred at room temperature for 1 hour. The layers were separated, the aqueous layer was extracted, three times with ethylacetate (500 mL). Combined organic layers were washed with water and brine and dried over magnesium sulfate, filtered and the volume of the filtrate reduced to 300 mL at which point a large amount of white crystalline solid had precipitated. This was cooled overnight in a
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-265 refrigerator. The solid was collected by vacuum filtration, rinsed with cold 1:1 ethylacetate/hexane and dried under high vacuum to give 30.311 grams of the desired hydroxamic acid (87.8%) as a white crystalline solid (mp 189-190°C).
’HNMR (d6 DMSO) δ 10.35 (br s, 1H), 8.68 (br s, 1H), 7.78 (br s, 1H), 7.74 (d, 2H), 7.26 (t, 2H), 7.16 (m, 2H), 7.04 (d, 2H), 3.40 (m, 2H), 3.31 (m, 2H), 1.78 (m, 4H). 13CNMR (DMSO) δ 169.65, 160.66, 137.50, 129.39, 122.34, 122.25, 117.75, 117.44, 117.24, 62.94, 58.45, 33.34. MS Atmospheric Pressure Chemical Ionization Mass Spectra: 409 (M+-1) (ion).
Preparation A
4-<4-Fluorophenoxy)benzenesulfonyl chloride
Chlorosulfonic acid (26 mL, 0.392 mole) was added dropwise to ice-cooled 4fiuorophenoxybenzene (36.9 grams, 0.196 mole) with mechanical stirring. When addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The product, 4-(4-fluorophenoxy)benzene-sulfonylchloride (18.6 grams, 33%) was collected by filtration and dried in the air.
20 Preparation B
Sodium 4-(3-methylbutoxy)benzenesulfonate
A solution of 4-hydroxybenzenesulfonic acid (10.0 grams, 43.1 mmole) and sodium hydroxide (3.3 grams, 83 mmole) in water (40 mL) was mixed with a solution of 1-iodo-3methylbutane (11.3 mL, 86.4 mmole) in isopropanol (60 mL) and the resulting mixture was heated at reflux for 2 days. The isopropanol was removed by evaporation under vacuum. The title compound, 10.0 grams (87%), was collected by filtration and washed with isopropanol.
Preparation C
4-{3-Methylbutoxy)benzenesulfonyl chloride
A mixture of sodium 4-{3-methylbutoxy)benzenesulfonate (2.5 grams, 9.4 mmole), 30 thionyl chloride (10 mL), and 5 drops of Ν,Ν-dimethylformamide was heated at reflux for 5 hours. After cooling, the excess thionyl chloride was evaporated and the residue was taken up in ethyl acetate. The solution was cooled in an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated to afford the title compound as an oil, 2.34 grams (95%).
Preparation D
Sodium 4-(2-cyclopentylethoxy)benzenesulfonate
A solution of 4-hydroxybenzenesulfonic acid (6.5 grams, 28.2 mmole) and sodium hydroxide (2.2 grams, 55 mmole) in water (15 mL) was mixed with a solution of 2(bromoethyl)cyclopentane (15.0 grams, 84.7 mmole) in isopropanol (40 mL) and the resulting mixture was heated at reflux for 2 days. The isopropanol was removed by evaporation under
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0 9 6 8
-275 vacuum. The titled compound, 4.7 grams (57%), was collected by filtration and washed with isopropanoi.
Preparation E
4-(3-Methylbutoxy)benzenesulfonyl chloride
A mixture of sodium 4-(2-cycJopentylethoxy)-benzenesulfonate (2.5 grams, 8.6 mmole), thionyl chloride (15 mL), and a few drops of Ν,Ν-dimethylformamide was heated at reflux for 5 hours. After cooling, the excess thionyl chloride was evaporated and the residue was taken up in ethyl acetate. The solution was cooled in an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated to afford the title compound as an oil, 2.24 grams (90%).
Preparation F
4-Fiuorobiphenylsuifonyl chloride
Chiorosulfonic acid (8.7 mL, 0.13 mole) was added dropwise to 4-fiuorobiphenyl (10.2 grams, 59 mmol) while stirring in an ice bath. Stirring was continued with ice cooling for 0.5 hours and then the reaction mixture was poured onto ice. The resulting white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water and brine, dried over magnesium sulfate and concentrated to afford a white solid. The desired product, 4-fluorobiphenylsulfonyl chloride (4.3 grams, 27%), was separated from 4fluorobiphenylsulfonic acid (an unwanted side product) by crystallization of the latter from ethyl acetate and crystallization of the remaining material from hexane.
Preparation G
Sodium 4-{4-fluorobenzyloxy)benzenesuifonate
To a solution of 4-hydroxybenzenesulfonic acid (5.13 grams, 22.1 mmole) in 1N aqueous sodium hydroxide solution (23 mL) was added a solution of 4-fluorobenzylbromide (3.3 mL, 26.5 mmole) in ethanol (20 mL). The resulting mixture was heated at reflux for 2 days. Upon cooling and standing, a white solid precipitated. The precipitated product, sodium 4-(4fiuorobenzyloxy)benzenesulfonate, 4.95 grams (74%) was collected by filtration and washed with ethyl acetate and diethyl ether.
Preparation H
4-(4-Fluorobenzyloxy)benzenesutfonyl chloride
To a slurry of sodium 4-(4-fluorobenzyloxy)benzenesulfonate (0.5 grams, 1.64 mmole), in methylene chloride (5 mL) was added phosphorus pentachloride (275 mg, 1.31 mmole). The resulting mixture was heated at reflux for 7 hours. After cooling in an ice bath and quenching with water (15 mL), the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to afford 4-(440 fiuorobenzyloxy)benzenesutfonyl chloride a white solid (130 mg, 26%).
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-285 Preparation I
4-(4-Chlorophenoxy)benzenesulfonyl chloride
Chlorosulfonic acid (9.7 mL, 0.147 mole) was added dropwise to 4chlorophenoxybenzene (12.6 mL, 73.4 mmole) at room temperature with stirring. When addition was complete, the mixture was stirred at room temperature for 1 hour and then poured into ice water. The solid was collected by filtration, dried in the air, and recrystallized from petroleum ether and ethyl acetate to give 4-(4-chlorophenoxy)benzenesulfonylchloride (7.43 grams, 33%).
AP/P/ 9 9 / 0 1 5 0 5
0 9 6 8 Having now particularly described and
-29ascertained my/oursaid invention and m what manner the same is to be performed l/we declare that what I/we claim is —

Claims (11)

1. A compound of the formula O
O
HONH or the pharmaceutically acceptable salts thereof, wherein
Q is (CrC6)alkyl, (C6-C10)aiyl, (C2-C9)heteroaryl, (C6-C10)aryloxy(C,-C6)alkyl. (C6Cl0)aryloxy(C6-C10)aryl, (C6-C10)aryloxy(C2-C9)heteroaryl, (Cg-C^aryKC^-CgJalkyl, (C6θιο)3ΓΥΐ(θ6-£ιο)3ΙΎΐ· (C6-C10)aryl(C2-C9)heteroaryl, (Cg-C^Jary^Cg-Cn^aryl^-CJalkyl, (CgCio)3ryl(C6-C1o)aryl(C6-Cw)aryl, (Cg-C10)aryl(C5-Cio)aryl(C2-Cg)heteroaryl, (C^-CgJheteroarylfC,C6)alkyl, (C2-C9)heteroaryl(C6-C10)aryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C6-C10)aryl(Cr C6)alkoxy(C,-Cg)alkyl, (Cg-C10)aryl(C5-Cg)alkoxy(Cg-CiQ)aryl, (Cg-C,o)aryl(Ci-Cg)alkoxy(C2Cg)heteroaryl, (CrCgjheteroaryloxy^-CgJalkyl, (C2-C9)heteroaryloxy(C6-C,0)aryl, (C2C9)heteroaryloxy(C2-C9)heteroaryl, (CrCgJheteroaryKC^-CgJalkoxy^-CfJalkyl, (C2C9)heteroaryl(C1-C6)alkoxy(C6-C10)aryl or (C2-C9)heteroaryl(C,-C6)alkoxy(C2-C9)heteroaryl;
wherein each (C6-C10)aryl or (C2-C9)heteroaryl moieties of said (C6-C10)aryl, (C2C9)heteroaryl, (Cg-C^aryloxy^-Cgjalkyl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryloxy(C2Cg)heteroaryl, (Cg-Cio)aryl(Ci-Cg)alkyl, {Cg-Cio)aryl(Cg-Cio)aryl, (Cg-CiQ)aryl(C2-C9)heteroaryl, (Cg'CnjjaryliCg-C-UarylfCy-CgJalkyl, (Cg-C1Q)aryl(Cs-C10)aryl(Cg-C10)aryl, (C6-Cio)aryl(C6C10)aryl(C2-C9)heteroaryl, (C2-C9)heteroaryl(CrC6)alkyl, (C2-C9)heteroaryl(C6-C10)aryl, (C2C^heteroaryKCj-CgJheteroaryl, (Cg-C^aryKCpCsJalkoxyiCrCgJalkyl, (C6-C10)aryl(C,C6)alkoxy(Cg-C1o)aryl, (Cg-Cio)aryl(Ci-Cg)alkoxy(C2-C9)heteroaryl, (C2-C9)heteroaryloxy(Ci* C6)alkyl, (C2-C9)heteroaryloxy(C6-C10)aryl, (C2-C9)heteroaryloxy(C2-C9)heteroaryl, (C2C^heteroatyKCi-Cgjalkoxy^-CgJalkyl, (C2-C9)heteroaryl(C,-C6)alkoxy(C6-Cw)aryl or (C2Cg)heteroaryl(Ci-Cg)alkoxy(C2-C9)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or more substituents per ring independently selected from fluoro, chloro, bromo, (C^gjalkyl, ((X-CJalkoxy, perfiuoro(C1-C3)alkyl, perfluoro(C5-C3)alkoxy and (C6-C,0)aryloxy;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein Q is optionally substituted (C6θιο)30/Ι. (Cg-C10)aryl(Cg-C10)aryl, (Cg-Cio)arytoxy(Cg-CiQ)aryl, (Cg-CiQ)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (Cs-C,0)aryl(C2-C9)heteroaryl, (C2-C9)AP/P/ 9 9 / 0 1 5 0 5
AP 00968
-305 heteroaryl(C6-C10)aryl, (C2-C9)heteroaryloxy(C6-C10)aryl, (C6-C,0)aryl(CrC6)alkoxy(C6-C10)-aryl, or (C2-C9)heteroaryl(C1-C6)alkoxy(C6-C10)aryl.
3. A compound according to claim 1, wherein Q is optionally substituted (C6C10)aryloxy(C6-C,0)aryl.
4. A compound according to claim 3, wherein the (C6-C.0)aryloxy ring of said (C610 Ci0)aryloxy(C6-C10)aryl group is optionally mono-substituted in the 4-position of the ring.
5. A compound according to claim 1, wherein said compound is selected from the group consisting of:
4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;
15 4-[4-(4-chlorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;
4-[4-(phenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;
4-[4-(4-pyridyloxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid
20 hydroxyamide;
4-[4-(4-fluorophenyl)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;
4-[4-(4-fluorophenylmethoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;
25 (phenylmethoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide; and
4-[4-(4-Fluorophenylethoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;
6. A pharmaceutical composition for the treatment of a condition selected from the
30 group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn’s disease, emphysema, chronic obstructive pulmonary disease, Alzheimer’s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture),
35 aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson’s disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple
40 sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing,
AP/P/ 9 9 / 0 1 5 0 5
AP 00968
-31bums, diabetes, tumor invasion, tumor growth, tumor metastasis, comeal scarring, scleritis, AIDS, sepsis and septic shock in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier.
7. The use of a therapeutically effective amount of the compound of claim 1 for treating a condition in a mammal, including a human, selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn’s disease, emphysema, chronic obstructive pulmonary disease, Alzheimer’s disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infraction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington’s disease, Parkinson’s disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, comeal injury, macular degeneration, abnormal wound healing, bums, diabetes, tumor invasion, tumor growth, tumor metastasis, comeal scarring, scleritis, AIDS, sepsis and septic shock.
8. A pharmaceutical composition for the treatment of a condition which can be treated by the inhibition of matrix metalloproteinases in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition for the treatment of a condition which can be treated by the inhibition of a mammalian reprolysin in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier.
10. The use of a therapeutically effective amount of a compound of claim 1 for the inhibition of matrix metalloproteinases in a mammal, including a human.
11. The use of a therapeutically effective amount of a compound of claim 1 for the inhibition of a mammalian reprolysin in a mammal, including a human.
APAP/P/1999/001505A 1998-04-10 1999-04-08 (4-Arylsulfonylamino)-Tetrahydropyran-4-Carboxylic acid hydroxamides. AP968A (en)

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Families Citing this family (323)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG72752A1 (en) * 1996-10-31 2000-05-23 Hitachi Chemical Co Ltd Heat resistant resin composition and adhesive sheet using the same
US6495579B1 (en) 1996-12-02 2002-12-17 Angiotech Pharmaceuticals, Inc. Method for treating multiple sclerosis
US6303636B1 (en) * 1997-02-03 2001-10-16 Pfizer Inc Arylsulfonylamino hydroxamic acid derivatives
US20030225150A1 (en) * 1997-04-21 2003-12-04 Pharmacia Corporation Method of using a COX-2 inhibitor and a topoisomerase II inhibitor as a combination therapy in the treatment of neoplasia
US20040072889A1 (en) * 1997-04-21 2004-04-15 Pharmacia Corporation Method of using a COX-2 inhibitor and an alkylating-type antineoplastic agent as a combination therapy in the treatment of neoplasia
US20040122011A1 (en) * 1998-12-23 2004-06-24 Pharmacia Corporation Method of using a COX-2 inhibitor and a TACE inhibitors as a combination therapy
US20030203956A1 (en) * 1998-12-23 2003-10-30 Masterrer Jaime L. Method of using a cyclooxygenase-2 inhibitor and one or more ornithine decarboxylase inhibitors as a combination therapy in the treatment of neoplasia
US20020103141A1 (en) * 1998-12-23 2002-08-01 Mckearn John P. Antiangiogenic combination therapy for the treatment of cancer
US20030013739A1 (en) * 1998-12-23 2003-01-16 Pharmacia Corporation Methods of using a combination of cyclooxygenase-2 selective inhibitors and thalidomide for the treatment of neoplasia
US20040053900A1 (en) * 1998-12-23 2004-03-18 Pharmacia Corporation Method of using a COX-2 inhibitor and an aromatase inhibitor as a combination therapy
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US20030119895A1 (en) * 1998-12-23 2003-06-26 Pharmacia Corporation Methods using a combination of a 3-heteroaryl-2-indolinone and a cyclooxygenase-2 inhibitor for the treatment of neoplasia
US6858598B1 (en) 1998-12-23 2005-02-22 G. D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
MXPA01012265A (en) * 1999-05-28 2002-07-30 Pfizer Prod Inc 3-(arylsulfonylamino)-tetrahydropyran-3-carboxylic acid hydroxamides.
EP2266607A3 (en) 1999-10-01 2011-04-20 Immunogen, Inc. Immunoconjugates for treating cancer
IL138686A0 (en) 1999-10-01 2001-10-31 Pfizer Prod Inc α- SULFONYLAMINO HYDROXAMIC ACID INHIBITORS OF MATRIX METALLOPROTEINASES FOR THE TREATMENT OF PERIPHERAL OR CENTRAL NERVOUS SYSTEM DISORDERS
UA74803C2 (en) 1999-11-11 2006-02-15 Осі Фармасьютікалз, Інк. A stable polymorph of n-(3-ethynylphenyl)-6,7-bis(2-methoxyetoxy)-4-quinazolinamine hydrochloride, a method for producing thereof (variants) and pharmaceutical use
EP1261610A2 (en) * 2000-02-17 2002-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino carbocycles and heterocycles as inhibitors of a-beta protein production
HUP0300235A2 (en) * 2000-03-21 2003-08-28 The Procter & Gamble Co. Heterocyclic side chain containing, n-substituted metalloprotease inhibitors, pharmaceutical compositions containing them and their use
EP1265865A2 (en) 2000-03-21 2002-12-18 The Procter & Gamble Company Difluorobutyric acid derivatives and their use as metalloprotease inhibitors
EP1265863A1 (en) * 2000-03-21 2002-12-18 The Procter & Gamble Company Heterocyclic side chain containing metalloprotease inhibitors
EP1138680A1 (en) * 2000-03-29 2001-10-04 Pfizer Products Inc. Gem substituted sulfonyl hydroxamic acids as MMP inhibitors
US6436629B1 (en) * 2000-10-27 2002-08-20 The Regents Of The University Of California Modulating angiogenesis
MX337162B (en) 2001-01-05 2016-02-15 Pfizer Antibodies to insulin-like growth factor i receptor.
DE60215793T2 (en) * 2001-05-03 2007-09-06 F. Hoffmann-La Roche Ag COMBINATION OF A GELATINASE HEATHER AND ANTI-TUMOR AGENT, AND THEIR USE
AU2002345792A1 (en) 2001-06-21 2003-01-08 Pfizer Inc. Thienopyridine and thienopyrimidine anticancer agents
US6607550B1 (en) 2001-09-06 2003-08-19 Anodyne Therapeutics, L.L.C. Method of treating neuropathy using a photo energy device
AR039067A1 (en) 2001-11-09 2005-02-09 Pfizer Prod Inc ANTIBODIES FOR CD40
JP4313678B2 (en) * 2001-12-27 2009-08-12 大日本住友製薬株式会社 Hydroxamic acid derivative and MMP inhibitor containing the same
DE10206404A1 (en) * 2002-02-14 2003-08-28 Gruenenthal Gmbh Synthesis of substituted sulfonylamines
EP1483268A2 (en) 2002-03-01 2004-12-08 Pfizer Inc. Indolyl-urea derivatives of thienopyridines useful as anti-angiogenic agents
PL401638A1 (en) 2002-03-13 2013-05-27 Array Biopharma Inc. N3 alkylated benzimidazole derivatives as MEK inhibitors
UA76059C2 (en) 2002-05-29 2006-06-15 Merck & Co Inc Compounds used for treating anthrax or inhibiting lethal factor
UA77303C2 (en) 2002-06-14 2006-11-15 Pfizer Derivatives of thienopyridines substituted by benzocondensed heteroarylamide useful as therapeutic agents, pharmaceutical compositions and methods for their use
DK1585743T3 (en) 2002-12-19 2007-09-17 Pfizer 2- (H-indazol-6-ylamino) -benzamide compounds as protein kinase inhibitors, useful for treating ophthalmic diseases
ES2502490T3 (en) 2003-02-26 2014-10-03 Sugen, Inc. Aminoheteroaryl compounds as protein kinase inhibitors
US20040215335A1 (en) * 2003-04-25 2004-10-28 Brin David S. Methods and apparatus for treatment of aneurysmal tissue
WO2004106319A1 (en) * 2003-05-30 2004-12-09 Pfizer Products Inc. Crystal forms of 4-[4-(4-fluorophenoxy)benzenesulfonylamino]-tetrahydropyran-4-carboxylic acid hydroxyamide
HN2004000285A (en) 2003-08-04 2006-04-27 Pfizer Prod Inc ANTIBODIES DIRECTED TO c-MET
GB0319069D0 (en) * 2003-08-14 2003-09-17 Glaxo Group Ltd Therapeutically useful compounds
US20050107350A1 (en) * 2003-08-22 2005-05-19 Pharmacia Corporation Method for the treatment or prevention of bone disorders with a cyclooxygenase-2 inhibitor alone and in combination with a bone disorder treatment agent and compositions therewith
WO2005021554A1 (en) 2003-08-29 2005-03-10 Pfizer Inc. Thienopyridine-phenylacet amides and their derivatives useful as new anti-angiogenic agents
US7144907B2 (en) 2003-09-03 2006-12-05 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
AR045563A1 (en) 2003-09-10 2005-11-02 Warner Lambert Co ANTIBODIES DIRECTED TO M-CSF
ATE495155T1 (en) 2003-11-19 2011-01-15 Array Biopharma Inc HETEROCYCLIC INHIBITORS OF MEK
CA2547283C (en) * 2003-11-26 2010-11-09 Pfizer Products Inc. Aminopyrazole derivatives as gsk-3 inhibitors
EP1747212A4 (en) 2004-05-11 2009-03-25 Merck & Co Inc PROCESS FOR PRODUCING N-SULFINATED AMINO ACID DERIVATIVES
JP2008506681A (en) 2004-07-16 2008-03-06 ファイザー・プロダクツ・インク Combination therapy for non-blood malignant tumors using anti-IGF-1R antibody
EA013678B1 (en) 2004-08-26 2010-06-30 Пфайзер Инк. Enantiomeric pure amino-heteroaryl compounds as proteicinase inhibitors
MY146381A (en) 2004-12-22 2012-08-15 Amgen Inc Compositions and methods relating relating to anti-igf-1 receptor antibodies
US7429667B2 (en) 2005-01-20 2008-09-30 Ardea Biosciences, Inc. Phenylamino isothiazole carboxamidines as MEK inhibitors
TW201238952A (en) 2005-05-18 2012-10-01 Array Biopharma Inc Heterocyclic inhibitors of MEK and methods of use thereof
US8101799B2 (en) 2005-07-21 2012-01-24 Ardea Biosciences Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK
JP5055284B2 (en) 2005-09-20 2012-10-24 オーエスアイ・フアーマシユーテイカルズ・エル・エル・シー Biological markers for predicting anti-cancer responses to insulin-like growth factor-1 receptor kinase inhibitors
TWI405756B (en) 2005-12-21 2013-08-21 Array Biopharma Inc Novel hydrogen sulphate
AU2007218053B2 (en) * 2006-02-15 2010-05-27 Merck Sharp & Dohme Corp. Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
US7842836B2 (en) 2006-04-11 2010-11-30 Ardea Biosciences N-aryl-N'alkyl sulfamides as MEK inhibitors
AU2007237901B2 (en) 2006-04-18 2012-07-05 Ardea Biosciences, Inc. Pyridone sulfonamides and pyridone sulfamides as MEK inhibitors
JP5167250B2 (en) * 2006-05-16 2013-03-21 メルク・シャープ・エンド・ドーム・コーポレイション Aminotetrahydropyran as a dipeptidyl peptidase IV inhibitor for the treatment or prevention of diabetes
DK2038310T3 (en) * 2006-07-12 2010-09-27 Novartis Ag Actinically crosslinkable copolymers for making contact lenses
EP2121626A1 (en) 2006-12-15 2009-11-25 Pfizer Products Inc. Benzimidazole derivatives
MX2009007661A (en) 2007-01-19 2009-12-14 Ardea Biosciences Inc Inhibitors of mek.
JP4782239B2 (en) 2007-04-18 2011-09-28 ファイザー・プロダクツ・インク Sulfonylamide derivatives for the treatment of abnormal cell proliferation
US8530463B2 (en) 2007-05-07 2013-09-10 Hale Biopharma Ventures Llc Multimodal particulate formulations
EP2175885B1 (en) 2007-07-30 2016-10-12 Ardea Biosciences, Inc. Combinations of mek inhibitors and raf kinase inhibitors and uses thereof
EP2543368A1 (en) 2007-12-11 2013-01-09 Viamet Pharmaceuticals, Inc. Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties
BRPI0819529A2 (en) 2007-12-19 2015-05-26 Genentech Inc "compound of formula I, pharmaceutical composition, method for inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal and method for treating an inflammatory disease in a mammal"
JP5710269B2 (en) 2007-12-21 2015-04-30 ジェネンテック， インコーポレイテッド Azaindolizines and usage
WO2009088990A1 (en) 2008-01-04 2009-07-16 Intellikine, Inc. Certain chemical entities, compositions and methods
US8193182B2 (en) 2008-01-04 2012-06-05 Intellikine, Inc. Substituted isoquinolin-1(2H)-ones, and methods of use thereof
EP2252293B1 (en) 2008-03-14 2018-06-27 Intellikine, LLC Kinase inhibitors and methods of use
EP2271347B1 (en) 2008-03-28 2016-05-11 Hale Biopharma Ventures, Llc Administration of benzodiazepine compositions
BRPI0915231A2 (en) 2008-07-08 2018-06-12 Intellikine Inc kinase inhibitor compounds and methods of use
JP5836125B2 (en) 2008-10-16 2015-12-24 ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション Fully human antibodies against high molecular weight melanoma-related antigens and uses thereof
US8476282B2 (en) 2008-11-03 2013-07-02 Intellikine Llc Benzoxazole kinase inhibitors and methods of use
JO2870B1 (en) * 2008-11-13 2015-03-15 ميرك شارب اند دوهم كورب Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
NZ593473A (en) 2009-01-12 2013-02-22 Pfizer Ltd Sulfonamide derivatives
CN108727407B (en) 2009-02-05 2022-01-28 伊缪诺金公司 Novel benzodiazepine derivatives
WO2010090764A1 (en) 2009-02-09 2010-08-12 Supergen, Inc. Pyrrolopyrimidinyl axl kinase inhibitors
EP2400985A2 (en) 2009-02-25 2012-01-04 OSI Pharmaceuticals, LLC Combination of an either an anti-igf-1r antibody or an igf binding protein and a small molecule igf-1r kinase inhibitor
JP2012519170A (en) 2009-02-26 2012-08-23 オーエスアイ・ファーマシューティカルズ，エルエルシー INSITU method for monitoring EMT status of tumor cells in vivo
WO2010099364A2 (en) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
EP2401614A1 (en) 2009-02-27 2012-01-04 OSI Pharmaceuticals, LLC Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
WO2010098866A1 (en) 2009-02-27 2010-09-02 Supergen, Inc. Cyclopentathiophene/cyclohexathiophene dna methyltransferase inhibitors
WO2010099138A2 (en) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
ES2543608T3 (en) 2009-03-27 2015-08-20 Ardea Biosciences, Inc. Dihydropyridine sulfonamides and dihydropyridine sulfonamides as MEK inhibitors
EP2427195B1 (en) 2009-05-07 2019-05-01 Intellikine, LLC Heterocyclic compounds and uses thereof
WO2011014726A1 (en) 2009-07-31 2011-02-03 Osi Pharmaceuticals, Inc. Mtor inhibitor and angiogenesis inhibitor combination therapy
US9085560B2 (en) 2009-08-17 2015-07-21 Intellikine, Inc. Heterocyclic compounds and uses thereof
EP2473500A2 (en) 2009-09-01 2012-07-11 Pfizer Inc. Benzimidazole derivatives
JP5734981B2 (en) 2009-09-02 2015-06-17 メルク・シャープ・エンド・ドーム・コーポレイション Aminotetrahydropyran as a dipeptidyl peptidase IV inhibitor for the treatment or prevention of diabetes
WO2011037793A1 (en) 2009-09-25 2011-03-31 Merck Sharp & Dohme Corp. Substituted aminopiperidines as dipeptidyl peptidase-iv inhibitors for the treatment of diabetes
US9034861B2 (en) 2009-10-13 2015-05-19 Allomek Therapeutics Llc MEK inhibitors useful in the treatment of diseases
WO2011049625A1 (en) 2009-10-20 2011-04-28 Mansour Samadpour Method for aflatoxin screening of products
PT2496567T (en) 2009-11-05 2017-11-15 Rhizen Pharmaceuticals S A NEW KINASE BENZOPIRAN MODULATORS
AU2011215900A1 (en) 2010-02-10 2012-07-26 Immunogen, Inc. CD20 antibodies and uses thereof
SG10201406805RA (en) 2010-02-12 2014-11-27 Pfizer Salts and polymorphs of 8-fluoro-2-{4-[(methylamino}methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd]indol-6-one
WO2011109572A2 (en) 2010-03-03 2011-09-09 OSI Pharmaceuticals, LLC Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors
US20110217309A1 (en) 2010-03-03 2011-09-08 Buck Elizabeth A Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors
CA2798080C (en) 2010-05-17 2020-08-25 Incozen Therapeutics Pvt. Ltd. 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases
US8604032B2 (en) 2010-05-21 2013-12-10 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
JP2013538042A (en) 2010-06-16 2013-10-10 ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション Antibodies against endoplasmin and uses thereof
JP5872552B2 (en) 2010-07-09 2016-03-01 ファイザー・リミテッドＰｆｉｚｅｒ Ｌｉｍｉｔｅｄ Chemical compound
WO2012052948A1 (en) 2010-10-20 2012-04-26 Pfizer Inc. Pyridine- 2- derivatives as smoothened receptor modulators
EP2637669A4 (en) 2010-11-10 2014-04-02 Infinity Pharmaceuticals Inc Heterocyclic compounds and uses thereof
NZ612909A (en) 2011-01-10 2015-09-25 Infinity Pharmaceuticals Inc Processes for preparing isoquinolinones and solid forms of isoquinolinones
JP2014510265A (en) 2011-02-02 2014-04-24 アムジェン インコーポレイテッド Methods and compositions for inhibition of IGF-IR
WO2012112708A1 (en) 2011-02-15 2012-08-23 Immunogen, Inc. Cytotoxic benzodiazepine derivatives and methods of preparation
WO2012116040A1 (en) 2011-02-22 2012-08-30 OSI Pharmaceuticals, LLC Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors in hepatocellular carcinoma
JP5808826B2 (en) 2011-02-23 2015-11-10 インテリカイン， エルエルシー Heterocyclic compounds and uses thereof
WO2012142164A1 (en) 2011-04-12 2012-10-18 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Human monoclonal antibodies that bind insulin-like growth factor (igf) i and ii
CA2830972C (en) 2011-04-19 2018-11-20 Pfizer Inc. Combinations of anti-4-1bb antibodies and adcc-inducing antibodies for the treatment of cancer
JP2014519813A (en) 2011-04-25 2014-08-21 オーエスアイ・ファーマシューティカルズ，エルエルシー Use of EMT gene signatures in cancer drug discovery, diagnosis, and treatment
KR101992311B1 (en) 2011-05-04 2019-09-27 리젠 파마슈티컬스 소시에떼 아노님 Novel compounds as modulators of protein kinases
EP3415139B8 (en) 2011-06-14 2022-05-18 Neurelis, Inc. Administration of benzodiazepine
TWI565709B (en) 2011-07-19 2017-01-11 英菲尼提製藥股份有限公司 Heterocyclic compounds and uses thereof
EP2734520B1 (en) 2011-07-19 2016-09-14 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
JP6105578B2 (en) 2011-07-21 2017-03-29 トレロ ファーマシューティカルズ， インコーポレイテッド Heterocyclic protein kinase inhibitors
RU2014111823A (en) 2011-08-29 2015-10-10 Инфинити Фармасьютикалз, Инк. HETEROCYCLIC COMPOUNDS AND THEIR APPLICATIONS
KR20140059246A (en) 2011-09-22 2014-05-15 화이자 인코포레이티드 Pyrrolopyrimidine and purine derivatives
US9630979B2 (en) 2011-09-29 2017-04-25 Infinity Pharmaceuticals, Inc. Inhibitors of monoacylglycerol lipase and methods of their use
WO2013050725A1 (en) 2011-10-04 2013-04-11 King's College London Ige anti -hmw-maa antibody
BR112014011115A2 (en) 2011-11-08 2017-06-13 Pfizer Methods for treating inflammatory disorders using anti-csf antibodies
WO2013126617A1 (en) 2012-02-22 2013-08-29 The Regents Of The University Of Colorado, A Body Corporate Bouvardin derivatives and therapeutic uses thereof
US9452215B2 (en) 2012-02-22 2016-09-27 The Regents Of The University Of Colorado Bourvadin derivatives and therapeutic uses thereof
AP3908A (en) 2012-03-30 2016-11-24 Rhizen Pharmaceuticals Sa Novel 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo [4,5-B] pyridine compounds as modulators of C-met protein kinases
WO2013152252A1 (en) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Combination anti-cancer therapy
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
DK2859017T3 (en) 2012-06-08 2019-05-13 Sutro Biopharma Inc ANTIBODIES INCLUDING PLACE-SPECIFIC NON-NATURAL AMINO ACID, PROCEDURE FOR MANUFACTURING ITS AND METHODS OF USE THEREOF
ES2611788T3 (en) 2012-06-26 2017-05-10 Sutro Biopharma, Inc. Modified Fc proteins comprising site-specific non-natural amino acid residues, conjugates thereof, methods for their preparation and methods for use
EP2887965A1 (en) 2012-08-22 2015-07-01 ImmunoGen, Inc. Cytotoxic benzodiazepine derivatives
EP3584255B1 (en) 2012-08-31 2022-02-16 Sutro Biopharma, Inc. Modified amino acids comprising an azido group
DK2909181T3 (en) 2012-10-16 2017-11-20 Tolero Pharmaceuticals Inc PKM2 modulators and methods for their use
CA2890105C (en) 2012-11-01 2023-03-21 Infinity Pharmaceuticals, Inc. Treatment of cancers using pi3 kinase isoform modulators
JP6440625B2 (en) 2012-11-14 2018-12-19 ザ・ジョンズ・ホプキンス・ユニバーシティー Methods and compositions for treating schizophrenia
US9901647B2 (en) 2013-02-28 2018-02-27 Immunogen, Inc. Conjugates comprising cell-binding agents and cytotoxic agents
WO2014134483A2 (en) 2013-02-28 2014-09-04 Immunogen, Inc. Conjugates comprising cell-binding agents and cytotoxic agents
US10202356B2 (en) 2013-03-14 2019-02-12 Tolero Pharmaceuticals, Inc. JAK2 and ALK2 inhibitors and methods for their use
WO2014151386A1 (en) 2013-03-15 2014-09-25 Infinity Pharmaceuticals, Inc. Salts and solid forms of isoquinolinones and composition comprising and methods of using the same
US9745319B2 (en) 2013-03-15 2017-08-29 Araxes Pharma Llc Irreversible covalent inhibitors of the GTPase K-Ras G12C
WO2014151147A1 (en) 2013-03-15 2014-09-25 Intellikine, Llc Combination of kinase inhibitors and uses thereof
US9227978B2 (en) 2013-03-15 2016-01-05 Araxes Pharma Llc Covalent inhibitors of Kras G12C
JP6473133B2 (en) 2013-03-15 2019-02-20 アラクセス ファーマ エルエルシー Covalent inhibitor of KRASG12C
BR112015029969A2 (en) 2013-05-30 2017-07-25 Infinity Pharmaceuticals Inc cancer treatment using pi3 isoform kinase modulators
WO2014194030A2 (en) 2013-05-31 2014-12-04 Immunogen, Inc. Conjugates comprising cell-binding agents and cytotoxic agents
ES2865473T3 (en) 2013-07-10 2021-10-15 Sutro Biopharma Inc Antibodies Comprising Multiple Site-Specific Unnatural Amino Acid Residues, Methods for Their Preparation, and Methods of Use
EP3363800A1 (en) 2013-10-03 2018-08-22 Kura Oncology, Inc. Heterocyclic inhibitors of erk and methods of use
WO2015051241A1 (en) 2013-10-04 2015-04-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
SG10201902074UA (en) 2013-10-04 2019-04-29 Infinity Pharmaceuticals Inc Heterocyclic compounds and uses thereof
JO3805B1 (en) 2013-10-10 2021-01-31 Araxes Pharma Llc Inhibitors of kras g12c
EP3636639A1 (en) 2013-10-10 2020-04-15 Araxes Pharma LLC Inhibitors of kras g12c
WO2015054658A1 (en) 2013-10-11 2015-04-16 Sutro Biopharma, Inc. Modified amino acids comprising tetrazine functional groups, methods of preparation, and methods of their use
WO2015061204A1 (en) 2013-10-21 2015-04-30 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
UA115388C2 (en) 2013-11-21 2017-10-25 Пфайзер Інк. 2,6-substituted purine derivatives and their use in the treatment of proliferative disorders
WO2015155624A1 (en) 2014-04-10 2015-10-15 Pfizer Inc. Dihydropyrrolopyrimidine derivatives
WO2015168079A1 (en) 2014-04-29 2015-11-05 Infinity Pharmaceuticals, Inc. Pyrimidine or pyridine derivatives useful as pi3k inhibitors
EA033919B1 (en) 2014-04-30 2019-12-10 Пфайзер Инк. Cycloalkyl-linked diheterocycle derivatives
GEP20207111B (en) 2014-06-19 2020-05-25 Ariad Pharma Inc Heteroaryl compounds for kinase inhibition
EP2957283B1 (en) 2014-06-19 2022-12-21 Symrise AG Process for identification of medicaments for acceleration of wound healing
WO2016001789A1 (en) 2014-06-30 2016-01-07 Pfizer Inc. Pyrimidine derivatives as pi3k inhibitors for use in the treatment of cancer
JP6811706B2 (en) 2014-07-31 2021-01-13 ザ ホンコン ユニヴァーシティ オブ サイエンス アンド テクノロジー Human monoclonal antibodies against EPHA4 and their use
JO3556B1 (en) 2014-09-18 2020-07-05 Araxes Pharma Llc Combination therapies for treatment of cancer
WO2016049568A1 (en) 2014-09-25 2016-03-31 Araxes Pharma Llc Methods and compositions for inhibition of ras
EP3197870B1 (en) 2014-09-25 2020-08-19 Araxes Pharma LLC Inhibitors of kras g12c mutant proteins
ES2746839T3 (en) 2014-12-18 2020-03-09 Pfizer Pyrimidine and triazine derivatives and their use as AXL inhibitors
EP3280708B1 (en) 2015-04-10 2021-09-01 Araxes Pharma LLC Substituted quinazoline compounds and methods of use thereof
EP3283462B1 (en) 2015-04-15 2020-12-02 Araxes Pharma LLC Fused-tricyclic inhibitors of kras and methods of use thereof
MX2017013383A (en) 2015-04-20 2017-12-07 Tolero Pharmaceuticals Inc Predicting response to alvocidib by mitochondrial profiling.
MX382566B (en) 2015-05-01 2025-03-13 Univ Emory Nucleoside analogs for treatment of the flaviviridae family of viruses and cancer
PL3298021T3 (en) 2015-05-18 2019-11-29 Tolero Pharmaceuticals Inc Alvocidib prodrugs having increased bioavailability
AR104020A1 (en) 2015-06-04 2017-06-21 Kura Oncology Inc METHODS AND COMPOSITIONS TO INHIBIT THE INTERACTION OF MENINA WITH MILL PROTEINS
WO2017009751A1 (en) 2015-07-15 2017-01-19 Pfizer Inc. Pyrimidine derivatives
US10144724B2 (en) 2015-07-22 2018-12-04 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
MX2018001289A (en) 2015-08-03 2018-04-30 Tolero Pharmaceuticals Inc Combination therapies for treatment of cancer.
AU2016322552B2 (en) 2015-09-14 2021-03-25 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinone derivatives, process of making, compositions comprising, and methods of using the same
US10875842B2 (en) 2015-09-28 2020-12-29 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
EP3356354A1 (en) 2015-09-28 2018-08-08 Araxes Pharma LLC Inhibitors of kras g12c mutant proteins
EP3356359B1 (en) 2015-09-28 2021-10-20 Araxes Pharma LLC Inhibitors of kras g12c mutant proteins
WO2017058902A1 (en) 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2017058728A1 (en) 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
EP3356349A1 (en) 2015-09-28 2018-08-08 Araxes Pharma LLC Inhibitors of kras g12c mutant proteins
EP3356351A1 (en) 2015-09-28 2018-08-08 Araxes Pharma LLC Inhibitors of kras g12c mutant proteins
EP3364977A4 (en) 2015-10-19 2019-09-04 Araxes Pharma LLC Method for screening inhibitors of ras
EA038635B9 (en) 2015-11-16 2021-10-26 Араксис Фарма Ллк 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof
MX2018006781A (en) 2015-12-03 2018-11-09 Agios Pharmaceuticals Inc Mat2a inhibitors for treating mtap null cancer.
US9988357B2 (en) 2015-12-09 2018-06-05 Araxes Pharma Llc Methods for preparation of quinazoline derivatives
CN109069664B (en) 2016-01-27 2022-05-13 苏特罗生物制药公司 anti-CD 74 antibody conjugates, compositions comprising anti-CD 74 antibody conjugates, and methods of use of anti-CD 74 antibody conjugates
CN114539284A (en) 2016-03-16 2022-05-27 库拉肿瘤学公司 Substituted MENIN-MLL inhibitors and methods of use
BR112018068702A2 (en) 2016-03-16 2019-01-15 Kura Oncology Inc menin-mll bridged bicyclic inhibitors and methods of use
US10822312B2 (en) 2016-03-30 2020-11-03 Araxes Pharma Llc Substituted quinazoline compounds and methods of use
CA3024556A1 (en) 2016-05-12 2017-11-16 The Regents Of The University Of Michigan Ash1l inhibitors and methods of treatment therewith
US11118233B2 (en) 2016-05-18 2021-09-14 The University Of Chicago BTK mutation and ibrutinib resistance
WO2017214269A1 (en) 2016-06-08 2017-12-14 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10646488B2 (en) 2016-07-13 2020-05-12 Araxes Pharma Llc Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof
CA3035081A1 (en) 2016-09-02 2018-03-08 Dana-Farber Cancer Institute, Inc. Composition and methods of treating b cell disorders
WO2018064510A1 (en) 2016-09-29 2018-04-05 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2018068017A1 (en) 2016-10-07 2018-04-12 Araxes Pharma Llc Heterocyclic compounds as inhibitors of ras and methods of use thereof
WO2018094275A1 (en) 2016-11-18 2018-05-24 Tolero Pharmaceuticals, Inc. Alvocidib prodrugs and their use as protein kinase inhibitors
WO2018098352A2 (en) 2016-11-22 2018-05-31 Jun Oishi Targeting kras induced immune checkpoint expression
WO2018119000A1 (en) 2016-12-19 2018-06-28 Tolero Pharmaceuticals, Inc. Profiling peptides and methods for sensitivity profiling
PL3558955T3 (en) 2016-12-22 2021-12-27 Amgen Inc. DERIVATIVES OF BENZISOTHIAZOL, ISOTHIAZOLO [3,4-B] PYRIDINE, CHINAZOLINE, PHTHALASINE, PYRIDO [2,3-D] PYRIDASINE AND PYRIDO [2,3-D] PYRIMIDINE AS INHIBITORS OF GRASP G12C OR TREATMENT
CN110382483A (en) 2017-01-26 2019-10-25 亚瑞克西斯制药公司 Condensed N- heterocyclic compound and its application method
WO2018140514A1 (en) 2017-01-26 2018-08-02 Araxes Pharma Llc 1-(6-(3-hydroxynaphthalen-1-yl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one derivatives and similar compounds as kras g12c inhibitors for the treatment of cancer
US11279689B2 (en) 2017-01-26 2022-03-22 Araxes Pharma Llc 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer
EP3573964A1 (en) 2017-01-26 2019-12-04 Araxes Pharma LLC Benzothiophene and benzothiazole compounds and methods of use thereof
US11059819B2 (en) 2017-01-26 2021-07-13 Janssen Biotech, Inc. Fused hetero-hetero bicyclic compounds and methods of use thereof
US11274093B2 (en) 2017-01-26 2022-03-15 Araxes Pharma Llc Fused bicyclic benzoheteroaromatic compounds and methods of use thereof
US11267885B2 (en) 2017-01-26 2022-03-08 Zlip Holding Limited CD47 antigen binding unit and uses thereof
US11944627B2 (en) 2017-03-24 2024-04-02 Kura Oncology, Inc. Methods for treating hematological malignancies and Ewing's sarcoma
JOP20190272A1 (en) 2017-05-22 2019-11-21 Amgen Inc Kras g12c inhibitors and methods of using the same
JP2020521741A (en) 2017-05-25 2020-07-27 アラクセス ファーマ エルエルシー Compounds for the treatment of cancer and methods of their use
CN110831933A (en) 2017-05-25 2020-02-21 亚瑞克西斯制药公司 Quinazoline derivatives as modulators of mutated KRAS, HRAS or NRAS
EP3630745A2 (en) 2017-05-25 2020-04-08 Araxes Pharma LLC Covalent inhibitors of kras
US11542248B2 (en) 2017-06-08 2023-01-03 Kura Oncology, Inc. Methods and compositions for inhibiting the interaction of menin with MLL proteins
US20200207859A1 (en) 2017-07-26 2020-07-02 Sutro Biopharma, Inc. Methods of using anti-cd74 antibodies and antibody conjugates in treatment of t-cell lymphoma
ES2928576T3 (en) 2017-09-08 2022-11-21 Amgen Inc KRAS G12C inhibitors and methods of use thereof
WO2019055579A1 (en) 2017-09-12 2019-03-21 Tolero Pharmaceuticals, Inc. Treatment regimen for cancers that are insensitive to bcl-2 inhibitors using the mcl-1 inhibitor alvocidib
MA50265A (en) 2017-09-18 2020-07-29 Sutro Biopharma Inc ALPHA ANTI-FOLATE ANTIBODY-RECEPTOR CONJUGATES AND THEIR USES
WO2019060365A1 (en) 2017-09-20 2019-03-28 Kura Oncology, Inc. Substituted inhibitors of menin-mll and methods of use
WO2019075367A1 (en) 2017-10-13 2019-04-18 Tolero Pharmaceuticals, Inc. Pkm2 activators in combination with reactive oxygen species for treatment of cancer
US11110177B2 (en) 2017-11-10 2021-09-07 The Regents Of The University Of Michigan ASH1L degraders and methods of treatment therewith
AU2018378935B2 (en) 2017-12-07 2024-10-31 The Regents Of The University Of Michigan NSD family inhibitors and methods of treatment therewith
BR112020020246A8 (en) 2018-04-05 2022-10-18 Sumitomo Dainippon Pharma Oncology Inc AXL KINASE INHIBITORS AND THEIR USE
CA3099118A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
MX2020010836A (en) 2018-05-04 2021-01-08 Amgen Inc Kras g12c inhibitors and methods of using the same.
MA52564A (en) 2018-05-10 2021-03-17 Amgen Inc KRAS G12C INHIBITORS FOR CANCER TREATMENT
WO2019232419A1 (en) 2018-06-01 2019-12-05 Amgen Inc. Kras g12c inhibitors and methods of using the same
EP3813784B1 (en) 2018-06-07 2024-01-10 The Regents Of The University Of Michigan Prc1 inhibitors and prc1 inhibitors for use in methods of treatment therewith
EP4268898A3 (en) 2018-06-11 2024-01-17 Amgen Inc. Kras g12c inhibitors for treating cancer
MA51848A (en) 2018-06-12 2021-04-21 Amgen Inc KRAS G12C INHIBITORS AND THEIR PROCEDURES FOR USE
EP3826684A4 (en) 2018-07-26 2022-04-06 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal acvr1 expression and acvr1 inhibitors for use in the same
BR112021001709A2 (en) 2018-08-01 2021-05-04 Araxes Pharma Llc heterocyclic spiro compounds and methods of using them for the treatment of cancer
WO2020060944A1 (en) 2018-09-17 2020-03-26 Sutro Biopharma, Inc. Combination therapies with anti-folate receptor antibody conjugates
JP7628305B2 (en) 2018-10-24 2025-02-10 アラクセス ファーマ エルエルシー 2-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-6-(1H-indazol-4-yl)-benzonitrile derivatives and related compounds as inhibitors of G12C mutant KRAS protein for inhibiting tumor metastasis - Patents.com
JP7516029B2 (en) 2018-11-16 2024-07-16 アムジエン・インコーポレーテツド Improved synthesis of key intermediates for KRAS G12C inhibitor compounds
CA3117222A1 (en) 2018-11-19 2020-05-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
JP7377679B2 (en) 2018-11-19 2023-11-10 アムジエン・インコーポレーテツド Combination therapy comprising a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancer
EP3887373A1 (en) 2018-11-29 2021-10-06 Araxes Pharma LLC Compounds and methods of use thereof for treatment of cancer
AU2019391097B2 (en) 2018-12-04 2025-07-03 Sumitomo Pharma America, Inc. CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
IL283639B2 (en) 2018-12-20 2024-06-01 Amgen Inc KIF18A inhibitors
JP2022513967A (en) 2018-12-20 2022-02-09 アムジエン・インコーポレーテツド Heteroarylamide useful as a KIF18A inhibitor
CA3123042A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
US12441736B2 (en) 2018-12-20 2025-10-14 Amgen Inc. KIF18A inhibitors
JP7662528B2 (en) 2019-02-12 2025-04-15 スミトモ ファーマ アメリカ， インコーポレイテッド Formulations Containing Heterocyclic Protein Kinase Inhibitors
US20230148450A9 (en) 2019-03-01 2023-05-11 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
AU2020232616A1 (en) 2019-03-01 2021-09-09 Revolution Medicines, Inc. Bicyclic heterocyclyl compounds and uses thereof
WO2020191326A1 (en) 2019-03-20 2020-09-24 Sumitomo Dainippon Pharma Oncology, Inc. Treatment of acute myeloid leukemia (aml) with venetoclax failure
AU2020245437A1 (en) 2019-03-22 2021-09-30 Sumitomo Pharma Oncology, Inc. Compositions comprising PKM2 modulators and methods of treatment using the same
US11420966B2 (en) * 2019-05-02 2022-08-23 Aclaris Therapeutics, Inc. Substituted pyrrolopyridines as JAK inhibitors
EP3962951A1 (en) 2019-05-03 2022-03-09 Sutro Biopharma, Inc. Anti-bcma antibody conjugates
EP3738593A1 (en) 2019-05-14 2020-11-18 Amgen, Inc Dosing of kras inhibitor for treatment of cancers
NZ782284A (en) 2019-05-21 2024-11-29 Amgen Inc Solid state forms
AU2020300619A1 (en) 2019-07-03 2022-01-27 Sumitomo Pharma Oncology, Inc. Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof
JP7699100B2 (en) 2019-08-02 2025-06-26 アムジエン・インコーポレーテツド KIF18A inhibitor
JP7756070B2 (en) 2019-08-02 2025-10-17 アムジエン・インコーポレーテツド Pyridine derivatives as KIF18A inhibitors
CN114269731A (en) 2019-08-02 2022-04-01 美国安进公司 KIF18A inhibitor
WO2021026098A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021055728A1 (en) 2019-09-18 2021-03-25 Merck Sharp & Dohme Corp. Small molecule inhibitors of kras g12c mutant
TW202126636A (en) 2019-09-30 2021-07-16 美商阿吉歐斯製藥公司 Piperidine compounds as menin inhibitors
MX2022004656A (en) 2019-10-24 2022-05-25 Amgen Inc PYRIDOPYRIMIDINE DERIVATIVES USEFUL AS INHIBITORS OF KRAS G12C AND KRAS G12D IN THE TREATMENT OF CANCER.
CA3158793A1 (en) 2019-10-28 2021-05-06 Merck Sharp & Dohme Corp. Small molecule inhibitors of kras g12c mutant
JP2023515235A (en) 2019-10-31 2023-04-12 大鵬薬品工業株式会社 4-aminobut-2-enamide derivatives and salts thereof
CA3159561A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
EP4055028A1 (en) 2019-11-04 2022-09-14 Revolution Medicines, Inc. Ras inhibitors
KR20220109406A (en) 2019-11-04 2022-08-04 레볼루션 메디슨즈, 인크. RAS inhibitors
EP4620531A3 (en) 2019-11-08 2025-11-26 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
AR120457A1 (en) 2019-11-14 2022-02-16 Amgen Inc ENHANCED SYNTHESIS OF KRAS G12C INHIBITOR COMPOUND
JP2023501522A (en) 2019-11-14 2023-01-18 アムジエン・インコーポレーテツド Improved Synthesis of KRAS G12C Inhibitor Compounds
WO2021108683A1 (en) 2019-11-27 2021-06-03 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2021106231A1 (en) 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. A compound having inhibitory activity against kras g12d mutation
WO2021126799A1 (en) 2019-12-18 2021-06-24 Merck Sharp & Dohme Corp. Macrocyclic peptides as potent inhibitors of k-ras g12d mutant
TW202140011A (en) 2020-01-07 2021-11-01 美商銳新醫藥公司 Shp2 inhibitor dosing and methods of treating cancer
WO2021155006A1 (en) 2020-01-31 2021-08-05 Les Laboratoires Servier Sas Inhibitors of cyclin-dependent kinases and uses thereof
WO2021178597A1 (en) 2020-03-03 2021-09-10 Sutro Biopharma, Inc. Antibodies comprising site-specific glutamine tags, methods of their preparation and methods of their use
TW202204334A (en) 2020-04-08 2022-02-01 美商阿吉歐斯製藥公司 Menin inhibitors and methods of use for treating cancer
TW202204333A (en) 2020-04-08 2022-02-01 美商阿吉歐斯製藥公司 Menin inhibitors and methods of use for treating cancer
EP4139299B1 (en) 2020-04-24 2025-12-17 Taiho Pharmaceutical Co., Ltd. Kras g12d protein inhibitors
WO2021215545A1 (en) 2020-04-24 2021-10-28 Taiho Pharmaceutical Co., Ltd. Anticancer combination therapy with n-(1-acryloyl-azetidin-3-yl)-2-((1h-indazol-3-yl)amino)methyl)-1h-imidazole-5-carboxamide inhibitor of kras-g12c
AU2021293228A1 (en) 2020-06-18 2023-02-09 Revolution Medicines, Inc. Methods for delaying, preventing, and treating acquired resistance to RAS inhibitors
CN116113406B (en) 2020-07-10 2025-08-29 密歇根大学董事会 GAS41 inhibitors and methods of use
AU2021308045B2 (en) 2020-07-15 2024-06-20 Taiho Pharmaceutical Co., Ltd. Pyrimidine compound-containing combination to be used in tumor treatment
US20250195521A1 (en) 2020-09-03 2025-06-19 Revolution Medicines, Inc. Use of sos1 inhibitors to treat malignancies with shp2 mutations
IL301298A (en) 2020-09-15 2023-05-01 Revolution Medicines Inc Indole derivatives as ras inhibitors in the treatment of cancer
WO2022111793A1 (en) 2020-11-24 2022-06-02 Symrise Ag Medicament for accelerated wound healing
TW202237119A (en) 2020-12-10 2022-10-01 美商住友製藥腫瘤公司 Alk-5 inhibitors and uses thereof
JP2024501280A (en) 2020-12-22 2024-01-11 キル・レガー・セラピューティクス・インコーポレーテッド SOS1 inhibitors and their uses
WO2022161593A1 (en) 2021-01-26 2022-08-04 Symrise Ag Medicament for accelerated wound healing
MX2023012060A (en) 2021-04-13 2024-01-22 Nuvalent Inc Amino-substituted heterocycles for treating cancers with egfr mutations.
AR125490A1 (en) 2021-04-30 2023-07-19 Celgene Corp COMBINATION THERAPIES USING A DRUG-CONJUGATED ANTI-BCMA ANTIBODY (ADC) IN COMBINATION WITH A GAMMA SECRETase INHIBITOR (GSI)
WO2022235870A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
TW202309052A (en) 2021-05-05 2023-03-01 美商銳新醫藥公司 Ras inhibitors
EP4334324A1 (en) 2021-05-05 2024-03-13 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
EP4347041A1 (en) 2021-05-28 2024-04-10 Taiho Pharmaceutical Co., Ltd. Small molecule inhibitors of kras mutated proteins
WO2023056589A1 (en) 2021-10-08 2023-04-13 Servier Pharmaceuticals Llc Menin inhibitors and methods of use for treating cancer
AR127308A1 (en) 2021-10-08 2024-01-10 Revolution Medicines Inc RAS INHIBITORS
TW202340214A (en) 2021-12-17 2023-10-16 美商健臻公司 Pyrazolopyrazine compounds as shp2 inhibitors
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
JP2025509217A (en) 2022-03-07 2025-04-11 アムジエン・インコーポレーテツド Process for preparing 4-methyl-2-propan-2-yl-pyridine-3-carbonitrile
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
TW202412755A (en) 2022-04-25 2024-04-01 美商耐斯泰德醫療公司 Mitogen-activated protein kinase (mek) inhibitors
KR20250022133A (en) 2022-06-10 2025-02-14 레볼루션 메디슨즈, 인크. macrocyclic RAS inhibitors
EP4547284A1 (en) 2022-06-30 2025-05-07 Sutro Biopharma, Inc. Anti-ror1 antibodies and antibody conjugates, compositions comprising anti-ror1 antibodies or antibody conjugates, and methods of making and using anti-ror1 antibodies and antibody conjugates
JP2025521928A (en) 2022-07-08 2025-07-10 ネステッド・セラピューティクス・インコーポレイテッド Mitogen-activated protein kinase (MEK) inhibitors
AU2023358792A1 (en) 2022-10-14 2025-04-17 Black Diamond Therapeutics, Inc. Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives
KR20250164828A (en) 2023-03-30 2025-11-25 레볼루션 메디슨즈, 인크. Composition for inducing RAS GTP hydrolysis and use thereof
WO2024211663A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
AU2024243852A1 (en) 2023-04-07 2025-11-06 Revolution Medicines, Inc. Macrocyclic ras inhibitors
KR20250172857A (en) 2023-04-14 2025-12-09 레볼루션 메디슨즈, 인크. Crystalline form of RAS inhibitor
KR20250169290A (en) 2023-04-14 2025-12-02 레볼루션 메디슨즈, 인크. Crystalline form of RAS inhibitor, composition containing same and method of use thereof
AU2024262795A1 (en) 2023-04-24 2025-11-13 Nested Therapeutics, Inc. Heterocyclic derivative as mitogen-activated protein kinase (mek) inhibitor
AU2024265078A1 (en) 2023-05-04 2025-12-11 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
CN116640089A (en) * 2023-05-05 2023-08-25 深圳市茵诺圣生物科技有限公司 Synthesis method of N-BOC-4-amino-4-carboxylic acid piperidine
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
TW202515582A (en) 2023-08-24 2025-04-16 日商大塚製藥股份有限公司 Fixed dose combinations of cedazuridine
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025081117A2 (en) 2023-10-13 2025-04-17 Sutro Biopharma, Inc. Anti-tissue factor antibodies and antibody conjugates, compositions comprising anti-tissue factor antibodies or antibody conjugates, and methods of making and using anti-tissue factor antibodies and antibody conjugates
WO2025085748A1 (en) 2023-10-20 2025-04-24 Merck Sharp & Dohme Llc Small molecule inhibitors of kras proteins
WO2025090905A1 (en) 2023-10-26 2025-05-01 Nested Therapeutics, Inc. Crystalline forms of 3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-7-[(3-fluoro-2-pyridyl)oxy]-4-methyl-chromen-2-one
WO2025137507A1 (en) 2023-12-22 2025-06-26 Regor Pharmaceuticals, Inc. Sos1 inhibitors and uses thereof
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025250825A1 (en) 2024-05-30 2025-12-04 Sutro Biopharma, Inc. Anti-trop2 antibodies, compositions comprising anti-trop2 antibodies and methods of making and using anti-trop2 antibodies
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025259841A1 (en) 2024-06-13 2025-12-18 Nested Therapeutics, Inc. Crystalline forms of 3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]jmethyl]-7-[(3-fluoro-2-pyridyl)oxy]-4-methyl-chromen-2-one

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0606046A1 (en) * 1993-01-06 1994-07-13 Ciba-Geigy Ag Arylsulfonamido-substituted hydroxamic acids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0606046A1 (en) * 1993-01-06 1994-07-13 Ciba-Geigy Ag Arylsulfonamido-substituted hydroxamic acids

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