Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
  • C07C309/78—Halides of sulfonic acids
  • C07C309/86—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C309/87—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/50—Organo-phosphines
  • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/06—Antiabortive agents; Labour repressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
  • C07C309/01—Sulfonic acids
  • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C309/41—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
  • C07C309/42—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
  • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• This invention relates to acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acids which act as inhibitors of TNF- ⁇ converting enzyme
• TACE TNF- ⁇ mediated by TNF- ⁇ , such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss.
• TNF- ⁇ converting enzyme catalyzes the formation of TNF- ⁇ from membrane bound TNF- ⁇ precursor protein.
• TNF- ⁇ is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8(5), 531; Grossman, J. M.; Brahn, E. J. Women's Health 1997, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Med. 1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5), 613.] septic shock [Mathison, et. al.
• TACE inhibitors small molecule inhibitors of TACE would have the potential for treating a variety of disease states.
• TACE inhibitors are known, many of these molecules are peptidic and peptide-like which suffer from bioavailability and pharmacokinetic problems.
• many of these molecules are non-selective, being potent inhibitors of matrix metalloproteinases and, in particular, MMP-1. Inhibition of MMP-1 (collagenase 1) has been postulated to cause joint pain in clinical trials of MMP inhibitors [Scrip, 1998, 2349, 20]. Long acting, selective, orally bioavailable non-peptide inhibitors of TACE would thus be highly desirable for the treatment of the disease states discussed above.
• sulfonamide hydroxamic acid MMP/TACE inhibitors in which a 2 carbon chain separates the hydroxamic acid and the sulfonamide nitrogen, as shown below, are disclosed in WIPO international publications WO9816503, WO9816506, WO9816514 and WO9816520 and U. S. patent 5,776,961.
• Publications disclosing ⁇ -sulfonamide-hydroxamate inhibitors of MMPs and/or TACE in which the carbon alpha to the hydroxamic acid has been joined in a ring to the sulfonamide nitrogen include U. S. patent 5,753,653, WIPO international publications WO9633172, WO9720824, WO9827069, WO9808815, WO9808822, WO9808823, WO9808825, WO9834918, WO9808827, Levin, et. al. Bioorg. & Med. Chem. Letters 1998, 8, 2657 and Pikul, et. al. J. Med. Chem. 1998, 47, 3568.
• Sulfonamide MMP/TACE inhibitors in which a thiol is the zinc chelating group, as shown below, have been disclosed in WIPO international application 9803166.
• Y the sulfonyl or phosphinyl aryl
• These compounds provide enhanced levels of inhibition of the activity of TACE in vitro and in a cellular assay and/or selectivty over MMP-1. These compounds may therefore be used in the treatment of diseases mediated by TNF.
• TACE and MMP inhibiting ortho-sulfonamido hydroxamic acids of the present invention are represented by the formula:
• Y is 5-10 membered heteroaryl ring having from 1-3 heteroatoms selected from N, NR 9 , S and O, phenyl or naphthyl; with the proviso that X and Z may not be bonded to adjacent atoms of Y;
• Z is O, NH, CI ⁇ or S;
• R 5 is hydrogen or alkyl of 1-6 carbon atoms;
• R 6 and R. are each, independently, hydrogen or methyl
• R 8 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, a 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, NR 9 , S and O, a 5-7 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR 9 , S and O, or phenyl;
• R 9 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or phenyl;
• R 10 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, or 5-
• R ⁇ and R 12 are, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, a 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, NR 9 , S and O, a 5-7 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR,, S and O, or phenyl, and the optional double bond represented by the dotted line is present; or
• R n and R 12 together with the carbons to which they are attached, form a 5-10 membered saturated or unsaturated mono or bicyclic alkyl ring optionally fused to one of a 5 to 7 membered saturated or unsaturated cycloalkyl ring, a 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, NR 9 , S and O, a 5-7 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR,, S and O, phenyl or napthyl rings; or
• Preferred compounds of this invention include compounds of structure B wherein X is SO 2 .
• More preferred compounds of this invention include compounds of structure B wherein X is SO 2 and Y is a phenyl ring substituted at the 1- and 4-positions by X and Z, respectively.
• More preferred compounds of this invention include compounds of structure B wherein X is SO 2 N is a phenyl ring substituted at the 1- and 4-positions by X and Z, respectively, and Z is oxygen.
• More preferred compounds of this invention include compounds of structure B wherein X is SO 2 N is a phenyl ring substituted at the 1- and 4-positions by X and Z, respectively, Z is oxygen and R 6 and R, are hydrogen.
• More preferred compounds of this invention include compounds of structure B wherein X is SO 2 N is a phenyl ring substituted at the 1- and 4-positions by X and Z, respectively, Z is oxygen, R 6 andR, are hydrogen and R g is -CH 2 OH or methyl.
• Still more preferred compounds of the present invention are (lR,2R)-2-[ ⁇ [4- (2-Butynyloxy)phenyl]sulfonyl ⁇ (methyl)amino]-N-hydroxycyclohexanecarboxamide;
• Heteroaryl as used throughout, is a 5-10 membered mono- or bicyclic ring having from 1-3 heteroatoms selected from N, NR 9 , S and O. Heteroaryl is preferably
• K is NR,, O or S and R, is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or phenyl.
• Preferred heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole.
• Heteroaryl groups of the present invention may optionally be mono- or di- substituted.
• Heterocycloalkyl refers to a 5 to 10 membered saturated or unsaturated mono or bi-cyclic ring having 1 or 2 heteroatoms selected from N, NR 4 , S or O. Heterocycloalkyl rings of the present invention are preferably selected from
• M is NR 4 , O or S and R 4 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, heteroaryl, - SCO ⁇ R y -COOR 2 , -CONR 2 R 3 , -SO 2 NR 2 R 3 or -COR 2 .
• Preferred heterocycloalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine.
• Heterocycloalkyl groups of the present invention may optionally be mono- or di- substituted.
• Aryl refers to phenyl or naphthyl which may, optionally be mono-, di- or tri-substituted.
• Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both straight chain as well as branched moieties.
• Alkyl, alkenyl, alkynyl, and cycloalkyl groups may be unsubstituted (carbons bonded to hydrogen, or other carbons in the chain or ring) or may be mono- or poly-substituted.
• Cycloalkyl groups may be mono or bicyclic. Examples of monocyclic cycloalkyl groups include cyclopentyl and cyclohexyl.
• bicyclic cycloalkyl groups examples include bicycloheptane and adamantyl.
• Halogen means bromine, chlorine, fluorine, and iodine.
• Suitable substituents of aryl, heteroaryl, alkyl, alkenyl, alkynyl, and cycloalkyl include, but are not limited to halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cyclocalkyl of 3-6 carbon atoms, -OR ; ,, -CN, -CO-R-,, perfluoroalkyl of 1-4 carbon atoms, -O-perfluoroalkyl of 1-4 carbon atoms, -CONR..R 3 ,
• R 2 and 1 ⁇ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, heteroaryl or heterocycloalkyl;
• R 4 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, heteroaryl, -S O ⁇ R,, -COOR 2 , -CONR- ⁇ , -SO 2 NR 2 R 3 or -COR 2 ; and n is 0-2.
• Suitable substituents of heterocycloalkyl groups of the present invention include, but are not limited to alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, heteroaryl and heterocycloalkyl.
• salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety.
• Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains an acidic moiety.
• the compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. It is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
• the compounds of this invention are shown to inhibit the enzymes MMP-1, MMP-9, MMP- 13 and TNF- ⁇ converting enzyme (TACE) and are therefore useful in the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, graft rejection, insulin resistance, bone disease and HIV infection.
• TACE TNF- ⁇ converting enzyme
• the compounds of the invention provide enhanced levels of inhibition of the activity of TACE in vitro and in cellular assay and/or enhanced selectivity over MMP-1 and are thus particularly useful in the treatment of diseases mediated by TNF.
• this invention provides a process for preparing compounds of formula 1 , as defined above, which comprises one of the following: a) reacting a compound of formula V:
• reaction can be carried out by processes known in the art e.g. by reaction of the acid chloride reactive derivative with hydroxylamine.
• Removal of protecting groups as illustrated by process b) can be carried out by processes known in the art to provide the hydroxamic acid.
• a racemic mixture may be converted to a mixture of optically active diastereoisomers by reaction with a single enantiomer of a 'resolving agent' (for example by diastereomeric salt formation or formation of a covalent bond).
• the resulting mixture of optically active diastereoisomers may be separated by standard techniques (e.g. crystallisation or chromatography) and individual optically active diastereoisomers then treated to remove the 'resolving agent' thereby releasing the single enantiomer of the compound of the invention.
• Chiral chromatography using a chiral support, eluent or ion pairing agent
• the compounds of formula B may be isolated in the form of a salt of a pharmaceutically acceptable acid e.g. an organic or inorganic acid by treatment with an acid such as described above.
• a pharmaceutically acceptable acid e.g. an organic or inorganic acid by treatment with an acid such as described above.
• the invention is further directed to a process for making compounds of structure B involving one or more reactions as follows:
• the resultant sulfonyl chloride, fluoride or bromide may be further converted into triazolide, imidazolide or benzothiazolide derivatives, where J is 1,2,4-triazolyl, imidazol-yl or benzotriazolyl, by reacting the compound with 1,2,4-triazole, imidazole or benzotriazole, respectively.
• R 6 , R. and R g are as defined above.
• the invention is still further directed to a process for making compounds of structure B involving one or more reactions as follows:
• Particularly preferred intermediates are compounds of formulae II and -CQ, with the proviso that R s is not hydrogen.
• the invention compounds are prepared using conventional techniques known to those skilled in the art of organic synthesis.
• the starting materials used in preparing the compounds of the invention are known, made by known methods or are commercially available.
• those skilled in the art will recognize that certain reactions are best carried out when other potentially reactive functionality on the molecule is masked or protected, thus avoiding undesirable side reactions and/or increasing the yield of the reaction.
• those skilled in the art may use protecting groups. Examples of these protecting group moieties may be found in T. W. Greene, P. G. M. Wuts "Protective Groups in Organic Synthesis". 2"" Edition, 1991, Wiley & Sons, New York. Reactive side chain functionalities on amino acid starting materials are preferably protected.
• the need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxy, amino, carboxy, etc.), the structure and stability of the molecule of which the substituent is part and the reaction conditions.
• Compounds 3, wherein R ⁇ is a t-butyl, benzyl, trialkylsilyl or other suitable masking group may then be deprotected by known methods to provide the hydroxamic acid 1.
• Carboxylic acids 2 may be prepared as shown in Scheme 2.
• Amino acid derivative 4, in which R 40 is hydrogen or a suitable carboxylic acid protecting group may be sulfonylated or phosphorylated by reacting with compounds 5, in which J is a suitable leaving group including, but not limited to chlorine.
• the N-H compound 6 may then be alkylated with RJ and a base such as potassium carbonate or sodium hydride in a polar aprotic solvent such as acetone, N,N-dimethylformamide (DMF), or tetrahydrofuran (THF) to provide sulfonamide 7.
• Compound 7 is also available through direct reaction of 5 with an N-substituted amino acid derivative, 8. Conversion of 7 into the carboxylic acid is performed by acid, base hydrolysis, or other method consistent with the choice of protecting group R 40 and the presence of a carbon-carbon triple bond.
• Scheme 2 :
• sulfonic acid salts 9, where ZR 50 is a hydroxy, thiol or substituted amino moiety may be alkylated with acetylenes 10, where J is a suitable leaving group such as halogen mesylate, tosylate, or triflate to give 11.
• Acetylenes 10 are commercially available or known compounds, or they may be synthesized by known methods by those skilled in the art.
• the sulfonic acid salts 11 may be converted into the corresponding sulfonyl chloride or other sulfonylating agent 5 by known methods, such as reaction with oxalyl chloride or other reagent compatible with substituents R 6 , R, and R ⁇ and the acetylene.
• the disulfide 12 may be converted into di- acetylene 13 by reaction with compounds 10, followed by reduction of the disulfide bond to provide the analogous thiols which may be converted into 5 by known methods.
• the acetylenic side chain may also be appended after sulfonylation or phosphorylation of the amino acid derivative, as shown in Scheme 5.
• the amino acid derivatives 4 and 8 can be sulfonylated or phosphorylated with compounds 20, where ZR 50 is hydroxy or protected hydroxy, thiol or amine, and, if necessary, alkylated with R,J as in Scheme 2, to give 21. Removal of the R 50 masking group to give 22 and subsequent alkylation of the resulting phenol, thiol or amine with 10 provides 7. In the case where ZR 50 is equal to OH, no deprotection step is required to give 22.
• the propargylic amine analogs of 7 can be synthesized as shown in Scheme 6 starting from the amino acid derivatives 4 and/or 8.
• Sulfonylation or phosphorylation with para-nitro aryl compound 23, for example 4-nitrobenzenesulfonyl chloride, followed by alkylation with R 5 J (for 4) using a base such as potassium carbonate or sodium hydride in DMF provides 24.
• Reduction of the nitro moiety with hydrogen and palladium on carbon, tin chloride or other known method to give aniline 25 and subsequent alkylation with 10 then provides 7.
• Aniline 25 may be derivatized with a suitable nitrogen protecting group, such as t-butoxycarbonyl, to give 26 prior to alkylation with 10 subsequent deprotection after the alkylation step.
• Scheme 6 :
• Acetylenic derivatives 7 are also accessible via the fluoro compounds 27, readily prepared from the amino acid derivatives 4 and/or 8 by reaction with fluoraryl 26, as shown in Scheme 7.
• the fluorine of 27 can also be displaced in a polar aprotic solvent with the propargylic derivative 29, where Z is O, S or NH, in the presence of a base such as sodium hydride, to give 7 directly.
• Scheme 7 :
• Compounds of the invention can also be prepared by modifying substituents on the acetylenic side chain at any stage after sulfonylation or phosphorylation of the starting amino acid derivatives 4 or 8.
• Functional groups such as halogen, hydroxy, amino, aldehyde, ester, ketone, etc. may be manipulated by standard methods to form the moieties defined by R Rg of compounds 1. It is recognized by those skilled in the art of organic synthesis that the successful use of these methods is dependent upon the compatibility of substituents on other parts of the molecule. Protecting groups and/or changes in the order of steps described herein may be required.
• R 3 ,., R 45 , R 55 , R 65 and R. 5 are alkyl, e.g. methyl;
• Example 8 (cis)-2-[Benzyl-(4-methoxy-benzenesuIfonyI)-amino]-cyclohexanecarboxyIic acid
• 0.240 g (0.522 mmol) of the product from Example 6 provided 0.207 g (98%) of the desired carboxylic acid as a white solid.
• Example 24 3-( ⁇ [4-(2-Butynyloxy)phenyl]sulfonyl ⁇ (methyl) amino)-N-hydroxypropanamide N- ⁇ [4-(2-Butynyloxy)phenyl]sulfonyl ⁇ -N-methyl-beta-alanine (0.7 g, 2.25 mmol) was converted to 3-( ⁇ [4-(2-butynyloxy)phenyl]sulfonyl ⁇ (methyl) amino)-N- hydroxypropanamide (0.525 g white solid) as described in Example 21. Analysis for
• Example 25 to give a white solid (0.825 g), mp 172-175°C. Analysis for
• the thiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSO and the DTNB is dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature. Both the substrate and DTNB are diluted together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl2) before use. The stock of enzyme is diluted with buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij) to the desired final concentration.
• substrate buffer 50 mM HEPES pH 7.5, 5 mM CaCl2
• buffer 50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij
• the buffer, enzyme, vehicle or inhibitor, and DTNB/substrate are added in this order to a 96 well plate (total reaction volume of 200 ⁇ l) and the increase in color is monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader and the increase in color over time is plotted as a linear line.
• a fluorescent peptide substrate is used.
• the peptide substrate contains a fluorescent group and a quenching group.
• the fluorescence that is generated is quantitated on the fluorescence plate reader.
• the assay is run in HCBC assay buffer (50mM
• HEPES pH 7.0, 5 mM Ca+ 2 , 0.02% Brij, 0.5% Cysteine
• the substrate is dissolved in methanol and stored frozen in 1 mM aliquots.
• substrate and enzymes are diluted in HCBC buffer to the desired concentrations.
• Compounds are added to the 96 well plate containing enzyme and the reaction is started by the addition of substrate.
• the reaction is read (excitation 340 nm, emission 444 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line.
• the slope of the line is calculated and represents the reaction rate.
• the linearity of the reaction rate is confirmed (r 2 >0.85).
• the mean (x ⁇ sem) of the control rate is calculated and compared for statistical significance (p ⁇ 0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generated using multiple doses of drug and IC50 values with 95% CI are estimated using linear regression.
• each well receives a solution composed of 10 ⁇ L TACE (final concentration l ⁇ g/mL), 70 ⁇ L Tris buffer, pH 7.4 containing 10% glycerol (final concentration 10 mM), and 10 ⁇ L of test compound solution in DMSO (final concentration l ⁇ M, DMSO concentration ⁇ 1%) and incubated for 10 minutes at room temperature.
• the reaction is initiated by addition of a fluorescent peptidyl substrate (final concentration 100 ⁇ M) to each well and then shaking on a shaker for 5 sec.
• the reaction is read (excitation 340 nm, emission 420 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line. The slope of the line is calculated and represents the reaction rate.
• CI are estimated using linear regression.
• THP-1 Soluble Protein Assay Human Monocvtic THP-1 Cell Differentiation Assay For Soluble Proteins.
• Mitogenic stimulation of THP-1 cells cause differentiation into macrophage like cells with concomitant secretion of tumor necrosis factor (TNF- ⁇ and TNF receptor (TNF-R p75/80 and TNF-R p55/60) and Interleukin-8 (IL-8), among other proteins.
• TNF- ⁇ and TNF receptor TNF-R p75/80 and TNF-R p55/60
• IL-8 Interleukin-8
• TNF- ⁇ converting enzyme TACE
• THP-1 cells are a human monocytic cell line which were obtained from the peripheral blood of a one year old male with acute monocytic leukemia. They can be grown in culture and differentiated into macrophage like cells by stimulation with mitogens.
• THP-1 cells are seeded from an ATCC stock which was previously grown and frozen back at 5 x 106/ml/vial.
• One vial is seeded into a T25- flask with 16 mis of RPMI-1640 with glutamax (Gibco) media containing 10 % fetal bovine serum, 100 units/ml penicillin, 100 ⁇ g/ml streptomycin, and 5 x 10 "5 M 2- mercapto-ethanol (THP-1 media).
• Gibco glutamax
• THP-1 media 5 x 10 "5 M 2- mercapto-ethanol
• Each vial of cells are cultured for about two weeks prior to being used for an assay and then are used for only 4 to 6 weeks to screen compounds. Cells are subcultured on Mondays and Thursdays to a concentration of 1 x 105/ml.
• the THP-1 cells are co-incubated in a 24 well plate with
• Standard and test compounds are dissolved in DMSO at a concentration of 36 mM and diluted from here to the appropriate concentrations in THP-1 media and added to the wells at the beginning of the incubation period to give final concentrations of 100 mM, 30 mM, 10 mM, 3 mM, 1 mM, 300 nM, and 100 nM.
• Cell exposure to DMSO was limited to 0.1 % final concentration.
• Positive control wells were included in the experiment which had mitogen added but no drug.
• Vehicle control wells were included as well, which were identical to the positive control wells, except that DMSO was added to give a final concentration of 0.083%.
• Negative control wells were included in the experiment which had vehicle but no mitogen or drug added to the cells.
• Compounds can be evaluated for their effect on basal (non-stimulated) shedding of the receptors by replacing the LPS with 50 ml/well of THP-1 media. Plates are placed into an incubator set at 5% CO2 and at 37° C. After 4 hours of incubation, 300 ml/well of tissue culture supernatant (TCS) is removed for use in an TNF- ⁇ ELISA. Following 24 hours of incubation, 700 ml/well of TCS is removed and used for analysis in TNF-R p75/80, TNF-R p55/60 and IL-8 ELISAs.
• TCS tissue culture supernatant
• the cells for each treatment group are collected by resuspension in 500 ⁇ l/well of THP-1 media and transferred into a FACS tube.
• Two ml/tube of a 0.5 mg/ml stock of propidium iodide (PI) (Boerhinger Mannheim cat. # 1348639) is added.
• the samples are run on a Becton Dickinson FaxCaliber FLOW cytometry machine and the amount of dye taken up by each cell is measured in the high red wavelength (FL3). Only cells with compromised membranes (dead or dying) can take up PI.
• the percent of live cells is calculated by the number of cells not stained with PI, divided by the total number of cells in the sample.
• the viability values calculated for the drug treated groups were compared to the viability value calculated for the vehicle treated mitogen stimulated group ("vehicle positive control") to determine the "percent change from control".
• This "percent change from control" value is an indicator of drug toxicity.
• the quantity of soluble TNF- ⁇ , TNF-R p75/80 and TNF-R p55/60 and IL-8 in the TCS of the THP-1 cell cultures are obtained with commercially available ELISAs from R&D Systems, by extrapolation from a standard curve generated with kit standards.
• the number of cells that either take up or exclude PI are measured by the FLOW cytometry machine and visualized by histograms using commercially available Cytologic software for each treatment group including all controls.
• % Change pg/ml (compound) - pg/ml (veh pos control) x 100 pg/ml (veh pos control) - pg/ml (veh neg control)
• % Change pg/ml (compound neg control) - pg/ml (veh neg control x 100 pg/ml (veh neg control)
• IC 50 values for each compound are calculated by non-linear regression analysis using customized software utilizing the JUMP statistical package.
• the viabilities (PI exclusion) of pooled duplicate wells were determined and the results expressed as % change from "vehicle positive control".
• the viability values calculated for the compound treated groups were compared to the viability value calculated for the "vehicle positive control” to determine “percent change from control” as below. This value "percent change from control” is an indicator of drug toxicity.
• T suchiya, S., Yamabe, M., Yamagughi, Y., Kobayashi, Y., Konno, T., and Tada, K.
• TBP-1 human acute monocytic leukemia cell line
• the compounds of this invention are useful in the treatment of disorders such as arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, graft rejection, insulin resistance, bone disease and HIV infection.
• the compounds of this invention are also useful in treating or inhibiting pathological changes mediated by matrix metalloproteinases such as atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, infammatory bowel disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopafhy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's
• Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof.
• the pharmaceutical carrier may be solid or liquid.
• Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet- disintegrating agents or an encapsulating material.
• the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
• the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably contain up to 99% of the active ingredient.
• Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymefhyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
• Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
• the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
• a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
• the liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
• liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
• the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
• Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection.
• Sterile solutions can also be administered intravenously.
• Oral administration may be either liquid or solid composition form.
• the compounds of this invention may be administered rectally in the form of a conventional suppository.
• the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
• the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
• the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
• the creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type.
• Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
• a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
• the dosage to be used in the treatment of a specific patient suffering a MMP or TACE dependent condition must be subjectively determined by the attending physician.
• the variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient.
• Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached.
• Precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standard medical principles.
• the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules.
• the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
• the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids.
• the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

Applications Claiming Priority (3)

Publications (1)

Family

ID=22900530

Family Applications (1)

Country Status (16)

Families Citing this family (5)

Family Cites Families (5)

• 2000
  • 2000-01-26 AR ARP000100325A patent/AR035478A1/es not_active Application Discontinuation
  • 2000-01-27 KR KR1020017009153A patent/KR20010089617A/ko not_active Application Discontinuation
  • 2000-01-27 EA EA200100808A patent/EA200100808A1/ru unknown
  • 2000-01-27 JP JP2000595968A patent/JP2002535383A/ja active Pending
  • 2000-01-27 BR BR0007754-2A patent/BR0007754A/pt not_active IP Right Cessation
  • 2000-01-27 NZ NZ512025A patent/NZ512025A/en unknown
  • 2000-01-27 WO PCT/US2000/001865 patent/WO2000044711A1/en not_active Application Discontinuation
  • 2000-01-27 IL IL14432100A patent/IL144321A0/xx unknown
  • 2000-01-27 AU AU26306/00A patent/AU769410B2/en not_active Ceased
  • 2000-01-27 CA CA002356345A patent/CA2356345A1/en not_active Abandoned
  • 2000-01-27 CZ CZ20012709A patent/CZ20012709A3/cs unknown
  • 2000-01-27 CN CN00803031A patent/CN1337944A/zh active Pending
  • 2000-01-27 EP EP00904570A patent/EP1147078A1/en not_active Withdrawn
  • 2000-01-27 HU HU0200605A patent/HUP0200605A3/hu unknown
• 2001
  • 2001-05-31 ZA ZA200104508A patent/ZA200104508B/xx unknown
  • 2001-07-24 NO NO20013639A patent/NO20013639D0/no not_active Application Discontinuation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events