EP1121118A1 - Agents therapeutiques a base de formamides - Google Patents

Agents therapeutiques a base de formamides

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Publication number
EP1121118A1
EP1121118A1 EP99942456A EP99942456A EP1121118A1 EP 1121118 A1 EP1121118 A1 EP 1121118A1 EP 99942456 A EP99942456 A EP 99942456A EP 99942456 A EP99942456 A EP 99942456A EP 1121118 A1 EP1121118 A1 EP 1121118A1
Authority
EP
European Patent Office
Prior art keywords
propyl
ethyl
phenyl
compound
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99942456A
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German (de)
English (en)
Other versions
EP1121118A4 (fr
Inventor
Robert Carl Glaxo Wellcome Inc. ANDREWS
Marc Werner Andersen
David John Glaxo Wellcome Inc. COWAN
David Norman Glaxo Wellcome Inc. DEATON
Scott Howard Glaxo Wellcome Inc. DICKERSON
David Harold Glaxo Wellcome Inc. DREWRY
Michael David Glaxo Wellcome Inc. GAUL
Michael Joseph Glaxo Wellcome Inc. LUZZIO
Brian Edward Glaxo Wellcome Inc. MARRON
Michael Howard Glaxo Wellcome Inc. RABINOWITZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
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Glaxo Group Ltd
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Publication date
Priority claimed from GBGB9818613.3A external-priority patent/GB9818613D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1121118A1 publication Critical patent/EP1121118A1/fr
Publication of EP1121118A4 publication Critical patent/EP1121118A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, such compounds generally pharmacologically useful as agents in those disease states alleviated by the inhibition or antagonism of matrix metalloproteases, metalloproteases, and/or tumor necrosis factor-alpha (TNF), which pathologically involve aberrant extracellular matrix degradation, shedding of cell surface protein ectodomains, and/or TNF synthesis, such disease states including arthritis, tumor metastasis and diabetes.
  • TNF tumor necrosis factor-alpha
  • the aforementioned pharmacologic activities are useful in the treatment of mammals.
  • the compounds of the present invention can be used in the treatment of osteoarthritis, rheumatoid arthritis, tumor invasion and metastasis, inflammatory bowel syndromes, periodontal disease, aberrant angiogenesis, corneal ulceration and the complications of diabetes.
  • rheumatology oncology, dentistry, opththalmology, gastroenterology, cardiology, neurology, nephrology, infectious disease and endocrinology therapy for such agents.
  • the matrix metalloprotease (MMP) family of zinc endoproteases includes fibroblast collagenase (MMP-1, collagenase- 1), neutrophil collagenase (MMP-8, collagenase-2), chondrocyte collagenase (MMP-13, collagenase-3), gelatinases A and B (MMP's 2 and 9), and members of the stromelysin family such as stromelysin-1 (MMP-3), stromelysin-3 (MMP-11), and mat ⁇ lysin (MMP-7). These enzymes accelerate breakdown of connective tissue by catalyzed resorption of the extracellular matrix.
  • MMP-1 fibroblast collagenase
  • MMP-8 neutrophil collagenase
  • MMP-13 chondrocyte collagenase
  • MMP's 2 and 9 gelatinases A and B
  • MMP's 2 and 9 members of the stromelysin family such as stromelysin-1 (MMP-3), stromely
  • inhibitors of one or more of the matrix metalloproteases would have utility m a wide range of disease states such as m abrogating the initiation of tumor metastasis and angiogenesis and m halting the pathogenesis of demyelmatmg diseases of the nervous system, multiple sclerosis being one example.
  • MMP inhibitors would also find utility in diseases involving connective tissue degradation m the joint, as occurs in osteoarthritis and rheumatoid arthritis.
  • MMP's-1 and -3 have been found in elevated levels in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis.
  • Collagenase-3 (MMP-13) is a member of the family of MMP's which preferentially digest collagen. Collagenase-3 is one of the more newly characterized MMP's; biochemical studies on the recombinant protein have demonstrated that it cleaves type II collagen, the predominant matrix component of articular cartilage, more efficiently than either MMP-1 or MMP-2 and that it is expressed by chondrocytes m osteoarthritic cartilage. These data would implicate collagenase-3 as a significant target rheumatoid arthritis and osteoarthritis for inhibition by MMP inhibitors.
  • inflammatory/autoimmune diseases which include, but not limited to rheumatoid arthritis, osteoarthritis, Crohn's disease and other inflammatory bowel diseases, pe ⁇ odontal disease, gingivitis, and corneal ulceration; n) diseases of cancer and malignancy, including but not limited to cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, colon, breast, cervix uteri, corpus endomet ⁇ um, ovary, prostate, testis, bladder, kidney and other urinary tissues, eye, bram and central nervous system, thyroid and other endoc ⁇ ne gland, leukemias (lymphocytic, granulocytic, monocytic), Hodgkin's disease, non-Hodgkm's lymphomas,
  • metabolic diseases including but not limited to complications of diabetes, osteoporosis, and other disorders involving resorption of bone
  • neurologic diseases including but not limited to multiple sclerosis and other demyehnation ailments
  • renal diseases including but not limited to nephrotic syndromes and glomerulonephritis
  • infectious diseases including but not limited to those mediated by viruses, bacteria, fungi
  • vin respiratory diseases, including but not limited to emphysema and COPD.
  • MMP inhibitors include some structure activity relationships for a series of carboxylalkylamine inhibitors. These molecules are exemplary for MMP inhibitors in general. They generally embody a functional group capable of tightly binding the zmc cofactor at the enzyme active site, which is contained within a peptidic or pseudopeptide structure. Zmc binding groups among the MMP inhibitor art have included hydroxamic acid, reverse hydroxamic acid, thiol, carboxylate, and phosphinate.
  • Hydroxamate metalloprotease inhibitors disclosed in the art usually have the following general structure (I)-
  • W is a zinc-chelating acyl derivative group of the formula -C(0)NHOH (which convention and in this application are referred to as "forward hydroxamates”) or a zinc- chelatmg substituted amme group of the formula -NH(OH)C(0)R (which by convention and in this application are referred to as "reverse hydroxamates”), where R is usually hydrogen or alkyl.
  • forward hydroxamates zinc-chelating acyl derivative group of the formula -C(0)NHOH
  • reverse hydroxamates zinc- chelatmg substituted amme group of the formula -NH(OH)C(0)R
  • MMP activity m conditions characterized by its overproduction w ould be of benefit, and compounds which inhibit MMP's would act m this manner at a specific target and be useful and of benefit.
  • the present invention fills this need by providing compounds that are potent, specific, orally active inhibitors of matrix metalloproteases.
  • Tumor necrosis factor- ⁇ (TNF ⁇ ), hereinafter called "TNF”
  • TNF Tumor necrosis factor- ⁇
  • TNF ⁇ Tumor necrosis factor- ⁇
  • Human TNF is produced as a larger pro-form of 26 kD which is processed to a secreted 17 kD mature form by proteolytic processing of the alamne-76 - vahne-77 peptide bond.
  • TNF convertase an intracellular or cell-associated specific enzyme or family of enzymes, which by convention is called a "TNF convertase", distinct from the matrix metalloproteases but related in that both contain a zmc cation at the active site.
  • TNF convertase enzymatic activity can be detected m monocyte membrane fractions, and the enzyme activity can be inhibited by certain matrix metalloprotease - inhibiting compounds.
  • a metalloprotease is thought to mediate the proteolysis of the cell surface-IgE receptor CD23.
  • Certain of the CD23 - derived peptides possess proinflammatory biological activities mimicking those of cytokmes, including TNF ⁇ .
  • Metalloprotease like activity is also thought to contribute to the shedding of certain cell surface protein ectodomains such as L-selectm, fibronectm, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density hpoprotem receptor, beta amyloid precursor protein, mterleukm-6 receptor alpha subunit, Fas hgand, CD40 hgand, epidermal growth factor receptor, macrophage colony stimulating factor, mterleukm-1 receptor type II, CD30, and tumor necrosis factor receptors type I and II.
  • cell surface protein ectodomains such as L-selectm, fibronectm, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density hpoprotem receptor, beta amyloid precursor protein, mterleukm-6 receptor alpha subunit, Fas hgand, CD40 hgand, epidermal growth factor receptor, macrophage colony stimulating factor, mterleukm-1 receptor type II
  • TNF is known to mediate many biological responses in vivo. Preclimcal and clinical studies in animals and humans with specific TNF neutralizing antibodies, soluble TNF receptor constructs, and TNF detection techniques have implicated TNF as a mediator in numerous pathologies.
  • the compounds of the present invention by virtue of their activity m inhibiting TNF production and/or their activity in preventing cell surface protein ectodomam shedding should show utility in the treatment of diverse pathologies such as: l) inflammatory/autoimmune diseases, including but not limited to rheumatoid arthritis, osteoarthritis, Crohn's disease and other inflammatory bowel diseases and inflammatory gastrointestinal diseases, and systemic lupus erythematosis, ⁇ ) reperfusion injuries, such as those caused by an initial lschemic event; in) systemic inflammatory response syndromes, including but not limited to sepsis, burn injury, pancreatitis, and adult respiratory distress syndrome, ⁇ v) allergic and dermatologic diseases, including but not limited to delayed type hypersensitivity
  • the present invention fills this need by providing potent, orally active inhibitors of shedding of cell surface protein ectodomains acting via inhibition of one or more specific enzymes which mediate this proteolytic event.
  • CD23 proteolysis in conditions characterized by an overabundance of CD23 proteolytic fragments would be of benefit, and compounds which inhibit CD23 proteolysis would be useful and of benefit.
  • the present invention fills this need by providing potent inhibitors of CD23 proteolysis acting via inhibition of one or more specific enzymes which mediate this proteolytic event.
  • a T* where A, is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond; where A 2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR 7 R 8 , OR 7 , SR 7 , or hydrogen, where R 7 and R 8 are as defined below; R, is
  • Di is alkylene, alkenylene, alkynylene, or a direct bond
  • D 2 is arylene, heteroarylene, or a direct bond
  • D 3 is aryl, heteroaryl, or heterocyclyl
  • Y is alkylene, alkenylene, alkynylene, O, S, S(O), S0 2 , NR 9 , Se, Si, C(O), P(O)OR 9 , P(O)R 9 , C(O)O, C(O)NR 9 , NR 9 C(0), OC(O), OC(0)0, NR 9 C(O)0, OC(0)NR 9 , NR 9 C(O)NR 10 , or
  • R 3 is hydrogen or lower alkyl
  • Ei is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond;
  • E 2 is hydrogen, NR,,Ri 2 , NR supplementSO 2 R, 2 , OR placed, SR,,, S(O)R, ⁇ , SO 2 R n , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where R n and R !2 are as defined below;
  • R 5 is hydrogen or lower alkyl; where Zi is lower alkylene, lower alkenylene, lower alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, or a direct bond;
  • Z 2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR ]3 Ri4, OR.3, SR 13 , NR 13 SO 2 R 14 , NR 13 C(O)R 14 , C(O)NR, 3 , C(O)R I3 , C(O)OR, 3 , OC(O)R 13 , S(O)R 13 , SO 2 R ]3 , SO 2 NR ]3 R 14 , (O(CH 2 ) q O) m R ⁇ or hydrogen, where m, q, R, 3 and R 1 are as defined below;
  • the present invention provides a family of compounds having the general structural formula:
  • W is a reverse hydroxamic acid group
  • Ri is a substituent other than hydrogen
  • R 2 is an alkylaryl or alkylheteroaryl substituent
  • R 4 is a hpophilic substituent preferably with ste ⁇ c bulk proximal to the peptide backbone.
  • R 2 , R 3 , R,, R 5 , and R show potent inhibition of MMP's, cell-free TNF convertase enzyme and TNF release from cells, and m some cases inhibit TNF convertase and TNF release from cells in preference to matrix metalloproteases.
  • the alkylaryl or alkylheteroaryl nature of R 2 in combination with an appropriate choice of R R 3 , R 4 , R 5 , and R 6 as described herein is beneficial m achieving selective inhibition of one or more of the matrix metalloproteases (for example, collagenase-3).
  • Such molecules can possess an improved therapeutic profile where inhibition of one or more of the matrix metalloproteases is associated with an adverse biological response or abnormal pathology.
  • the alkylaryl or alley lheteroaryl nature of R 2 m combination with an appropriate choice of R b R 3 , R 4 , R 5 , and R 6 as described herein is also beneficial in achieving selective inhibition of one or more of the matrix metalloproteases (for example, collagenase-3) in preference to TNF convertase inhibition and inhibition of TNF release from whole cells.
  • reverse hydroxamate compounds of the present invention include those of the formula (II):
  • alkylene alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond
  • a 2 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR 7 R 8 , OR 7 , SR 7 , or hydrogen, where R 7 and R 8 are as defined below;
  • R 2 ⁇ s
  • D ⁇ s alkylene, alkenylene, alkynylene, or a direct bond, D 2 ⁇ s arylene, heteroarylene, or a direct bond; D 3 ⁇ s aryl, heteroaryl, or heterocyclyl;
  • Y is alkylene, alkenylene, alkynylene, O, S, S(O), S0 2 , NR 9 , Se, Si, C(O), P(O)OR 9 , P(O)R 9 C(O)O, C(O)NR 9 , NR 9 C(0), OC(O), OC(0)0, NR 9 C(0)0, OC(0)NR 9 , NR 9 C(O)NR I0 , or
  • E] is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond;
  • E 2 is hydrogen, NR,,R 12 , NR,,SO 2 R, 2 , OR, , SR U , S(O)R réelle, SO 2 R,,, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where R), and R )2 are as defined below;
  • R 5 is hydrogen or lower alkyl
  • Z 2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR I3 R t4 ,
  • Preferred embodiments of the invention include compounds of general formula (II) where:
  • Ri is methyl, ethyl, n-propyl, isopropyl, 4-methyl-l-pentyl, 2- thiophenesulfanylmethyl, 3-aminophenoxymethyl, 2-(3-tetrazolyl)-l -ethyl, 2-(3-pyridyl)-l- ethyl, 2-(3-furyl)-l -ethyl, 2-(2-th ⁇ azolyl)-l -ethyl, 3,3,3-trifluoro-l -propyl, 2-(4- trifluorophenyl)-l -ethyl, thiophene-3-ethynyl, 2-nitrophenoxymethyl, 3-nitrophenoxymethyl, 2-phenylsulfanylmethyl, trifluoromethyl, trichloromethyl, or vinyl;
  • R 2 is 5-methylthiophene-2-methyl, 2-furanmethyl, thiophene-2-methyl, benzothiophene-2-methyl, benzofuran-2-methyl, 4-fluorobenzyl, 3-phenyl-l -propyl, 3- phenyl-2-methyl- 1 -propyl, 3-(2-pyridyl)-l-propyl, 3-(thiophene-2-yl)- 1 -propyl, 4-phenyl-l - butyl, 3-phenyl-2-propene-l-yl, 3-(benzofuran-3-yl)-l -propyl, 3-(benzothiophene-3-yl)-l- propyl, 3 -(furan-2-yl)-l -propyl, 3-(2-thiazolyl)-l -propyl, 3-(pyrimidin-2-yl)-l -propyl, 3-phenyl-2-ethyl-l -propyl, 3-
  • R 3 is hydrogen;
  • R 4 is tert-butyl, 1-phenyl-l -ethyl, 4-(benzyloxycarbonylam ⁇ no)-l -butyl, 2-(2- (benzyloxycarbonylam.no)- 1 -ethylsulfanyl)-2-propyl, 3-pyr ⁇ dylmethyl, 4-(2- naphthylacetylamino)- 1 -butyl, 3 -(benzyloxycarbonylammo)-l -propyl, 3-carbamoylammo-l- propyl, benzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-( ⁇ m ⁇ no-(2,3,6-t ⁇ methyl- 4-methoxybenzenesulfonylammo))-methylam ⁇ no-l -propyl, 4- benzyloxycarbonylammobenzyl, isopropyl,
  • R 5 is hydrogen
  • Re is methyl, 2-(l-pyrrol ⁇ d ⁇ no)-l -ethyl, 2-py ⁇ dylmethyl, 3-pyr ⁇ dylmethyl, 4- pyridylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-(4-mo ⁇ holmo)-l -ethyl, 3-(4- mo ⁇ hohno)-l -propyl, 3-(4-methylp ⁇ perazme)-l -propyl, 2-(4-methylp ⁇ peraz ⁇ ne)-l -ethyl, 2-(2- pyridyl)- 1 -ethyl, 2-(3-pyr ⁇ dyl)-l -ethyl, 2-(4-pyr ⁇ dyl)-l -ethyl, tetraethyleneglycolyl methyl ether, or 2,2,2-tr ⁇ fluoroethyl;
  • Other preferred embodiments of the invention include compounds of general formula (
  • R is 1-methylbenzyl, benzyl , 3- phenylcarbonylammo-1 -propyl, 2,2-d ⁇ methyl-l -propyl, 3-phenylcarbamoylam ⁇ no-l -propyl, 4-pyr ⁇ dylmethyl, 4-methoxybenzyl, 3-mdolemethyl, 2-mdolemethyl, 2-naphthylmethyl, 3- naphthylmethyl, or 2-phenyl-2-propyl; and R ⁇ ; is hydrogen, 2-(2-pyr ⁇ dyl)-l -ethyl, 2-(3- pyr ⁇ dyl)-l -ethyl, 2-(4-pyr ⁇ dyl)-l -ethyl, l-(2-am ⁇ noethyl)-p ⁇ peraz ⁇ ne, 2-(4- ⁇ m ⁇ dazolyl)
  • Particularly preferred embodiments of the invention include compounds of general formula II where: Ri is methyl, ethyl, n-propyl, isopropyl, 4-methyl-l-pentyl, 2- thiophenesulfanylmethyl, 2-(3-tetrazolyl)-l-ethyl, 2-(3 -pyridyl)- 1 -ethyl, 2-(3-furyl)-l -ethyl, 3,3,3-tr ⁇ fluoro-l -propyl, 2-(4-t ⁇ fluorophenyl)-l -ethyl, 2-phenylsulfanylmethyl, t ⁇ fluoromethyl, or t ⁇ chloromethyl;
  • R 2 is 5-methylth ⁇ ophene-2-methyl, 2-furanmethyl, th ⁇ ophene-2-methyl, 4- fluorobenzyl, 3-phenyl-l-propyl, 3-phenyl-2-methyl-l -propyl, 3-(2-pyr ⁇ dyl)-l -propyl, 3- (th ⁇ ophene-2-yl)-l -propyl, 4-phenyl-l -butyl, 3-phenyl-2-propene-l-yl, 3-(furan-2-yl)-l- propyl, 3-(2-th ⁇ azolyl)-l -propyl, 3-(3-pyr ⁇ dyl)-l -propyl, 2-phenyl-l -ethyl, 3-(furan-3-yl)-l- propyl, benzoth ⁇ ophene-3-methyl, benzoxazole-2-methyl, 3-(4-chlorophenyl)-l -propyl, 3-(4- fluorophen
  • R 3 is hydrogen
  • R is tert-butyl, 1-phenyl-l -ethyl, 4-(benzyloxycarbonylammo)-l -butyl, 2-(2- (benzyloxycarbonylammo)- 1 -ethylsulfanyl)-2-propyl, 3-pyr ⁇ dylmethyl, 4-(2- naphthylacetylammo)- 1 -butyl, 3 -(benzyloxycarbonylamino)- 1 -propyl, 3 -carbamoylammo- 1 - propyl, benzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, isopropyl, cyclohexyl, 4- cyclopentylacetylammo- 1 -butyl, 4-(3-methoxybenzoylammo)-l -butyl, 4- efhoxycarbonylammo- 1 -butyl, 2-(2-(
  • R5 is hydrogen
  • Ri is methyl, 2-(l-pyrrohdmo)-l -ethyl, 2-pyr ⁇ dylmethyl, 3-py ⁇ dylmethyl, 4- pyridylmethyl, cyclopropyl, cyclopentyl, 2-(4-mo ⁇ hohno)-l -ethyl, 3-(4-mo ⁇ holmo)-l- propyl, 3-(4-methylp ⁇ peraz ⁇ ne)-l -propyl, 2-(4-methylp ⁇ peraz ⁇ ne)-l -ethyl, 2-(2-pyr ⁇ dyl)- 1 - ethyl, 2-(3-pyr ⁇ dyl)-l -ethyl, 2-(4-pyr ⁇ dyl)-l -ethyl, tetraethyleneglycolyl methyl ether, or 2,2,2-tr ⁇ fluoroethyl;
  • Other particularly preferred embodiments of the invention include compounds of general formula (II) where
  • R is 1 -methylbenzyl, benzyl, 2,2-d ⁇ methyl-l -propyl, 4- pyridylmethyl, 4-methoxybenzyl, 3- ⁇ ndolemethyl, 2-mdolemethyl, 2-naphthylmethyl, 3- naphthylmethyl, or 2-phenyl-2-propyl; and R ⁇ is hydrogen, 2-(2-pyr ⁇ dyl)- 1 -ethyl, 2-(3- pyr ⁇ dyl)-l -ethyl, 2-(4-pyr ⁇ dyl)- -ethyl, or tetraethyleneglycolyl methyl ether; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
  • Ri is methyl, ethyl, n-propyl, isopropyl, or 3,3,3-tr ⁇ fluoro-l-propyl;
  • R 2 is 3-phenyl-l-propyl, 3 -(4-chlorophenyl)-l -propyl, 3-(4-fluorophenyl)-l -propyl, 3- (4-tr ⁇ fluoromethylphenyl)-l -propyl, or 3-(th ⁇ ophene-2-yl)-l -propyl;
  • R 3 is hydrogen;
  • R 4 is tert-butyl or 1-phenyl-l -ethyl; R 5 is hydrogen; and
  • R 6 is methyl, 2-(l-pyrrohdmo)-l -ethyl, 2-py ⁇ dylmethyl, 3-py ⁇ dylmethyl, or 4- py ⁇ dylmethyl; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
  • R 4 is benzyl, 4-fluorobenzyl, 2- butyl, cyclohexyl, or isopropyl
  • R 6 is 2-(4-mo ⁇ holmo)-l -ethyl, 3-(4-mo ⁇ holmo)-l- propyl, tetraethyleneglycolyl methyl ether, 2-(2-py ⁇ dyl)-l -ethyl, 2-(3-pyr ⁇ dyl)-l -ethyl, or 2- (4-pyr ⁇ dyl)-l -ethyl; and a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
  • the compounds of the present invention are inhibitors of matrix metalloproteases, TNF converting enzyme, and TNF activity from whole cells.
  • the compounds of the present invention may also inhibit shedding of pathologically significant cell surface protein ectodomains.
  • the invention described herein is additionally directed to pharmaceutical compositions and methods of inhibiting matrix metalloprotease and/or TNF activity in a mammal, which methods comprise administering, to a mammal in need of inhibition of matrix metalloprotease and/or TNF activity, a therapeutically defined amount of a compound of formula (I) or (II), defined above, as a single or polymo ⁇ hic crystalline form or forms, an amo ⁇ hous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer, a mixture of diastereoisomers, a solvate, a pharmaceutically acceptable salt, a solvate, a prodrug,
  • a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof for use in therapy is provided.
  • the present invention provides a method of inhibiting a matrix metalloprotease, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention.
  • the invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit a matrix metalloprotease.
  • a matrix metalloprotease- inhibiting amount can be an amount that reduces or inhibits a matrix metalloprotease activity in the subject.
  • the present invention further provides a method of inhibiting the intracellular release of tumor necrosis factor alpha, comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention.
  • the invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit cellular release of mature tumor necrosis factor.
  • An amount sufficient to inhibit cellular release of mature tumor necrosis factor can be an amount that reduces or inhibits cellular release of mature tumor necrosis factor in the subject.
  • a method of inhibition of shedding of cell surface protein ectodomains comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention.
  • the invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit shedding of cell surface protein ectodomains
  • An amount sufficient to inhibit shedding of cell surface protein ectodomains can be an amount that reduces or inhibits shedding of one or more cell surface protein ectodomains, such as L-selectin, fibronectm, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density hpoprotein receptor, beta amyloid precursor protein, ⁇ nterleuk ⁇ n-6 receptor alpha subunit, Fas hgand, CD40 hgand, epidermal growth factor receptor, macrophage colony stimulating factor, mterleukm- 1 receptor type II, CD30
  • Also provided is a method of inhibiting CD23 proteolysis comprising the step of administering to a mammal in need thereof a pharmacologically effective amount of a compound of the present invention.
  • the invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to inhibit CD23 proteolysis
  • An amount sufficient to inhibit CD23 proteolysis can be an amount that reduces or inhibits CD23 proteolysis in the subject.
  • a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof in the preparation of a medicament for inhibiting CD23 proteolysis Additionally provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to decrease, or inhibit, a malignant growth.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat arthritis.
  • Such an amount can be an amount that relieves, i.e., reduces or eliminates, one or more physiologic characteristic of arthritis
  • composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the present invention sufficient to treat diabetes.
  • an amount can be an amount that reduces or eliminates one or more of the complications associated with diabetes.
  • the present invention contemplates treating any of these diseases/conditions m a subject by administering to the subject the recited pharmaceutical composition.
  • the compounds of the present invention can be administered to any mammal in need of inhibition of matrix metalloprotease activity, CD23 proteolysis, shedding of cell surface protein ectodomains and/or TNF activity.
  • mammals can include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, most preferably humans.
  • Certain examples of the invention also are orally bioavailable in animals and possess oral activity in animal models of disease.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base.
  • Representative salts include the following salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochlo ⁇ de, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsamlate, Hexylresorcmate, Hydrabamine, Hydrobromide, Hydroclo ⁇ de, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamo
  • Phosphate/diphosphate Polygalacturonate, Potassium, Sahcylate, Sodium, Stearate, Subacetate, Succmate, Tannate, Tartrate, Teoclate, Tosylate, T ⁇ ethiodide, T ⁇ me hylammonium and Valerate.
  • the present invention also covers the individual enantiomers of the compounds represented by formula above as mixtures with diastereoisomers thereof in which one or more of the three stereocenters are inverted.
  • lower refers to a group having between one and six carbons.
  • alkyl refers to a straight or branched chain hydrocarbon having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbam
  • alkylene refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy
  • alkenyl refers to a hydrocarbon radical having from two to ten carbons and at least one carbon - carbon double bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • alkenylene refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon - carbon double bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • Examples of “alkenylene” as used herein include, but are not limited to, ethene-l,2-d ⁇ yl, propene-l,3-d ⁇ yl, methylene- 1,1-d ⁇ yl, and the like
  • alkynyl refers to a hydrocarbon radical having from two to ten carbons and at least one carbon - carbon triple bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • alkynylene refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon - carbon triple bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • alkynylene as used herein include, but are not limited to, ethyne-l,2-d ⁇ yl, propyne-l,3-d ⁇ yl, and the like.
  • cycloalkyl refers to a alicychc hydrocarbon group with one or more degrees of unsaturation, having from three to twelve carton atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed "Cycloalkyl” includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like.
  • cycloalkylene refers to an non-aromatic alicychc divalent hydrocarbon radical having from three to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • cycloalkylene examples include, but are not limited to, cyclopropyl- 1,1-d ⁇ yl, cyclopropyl- 1,2-d ⁇ yl, cyclobutyl- 1,2- diyl, cyclopentyl- 1, 3 -diyl, cyclohexyl- 1,4-d ⁇ yl, cycloheptyl-l ,4-dryl, or cyclooctyl- 1,5-d ⁇ yl, and the like.
  • cycloalkenyl refers to a substituted alicychc hydrocarbon radical having from three to twelve carbon atoms and at least one carbon-carbon double bond in the ring system, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • cycloalkenylene examples include, but are not limited to, 1- cyclopentene-3-yl, l-cyclohexene-3-yl, l-cycloheptene-4-yl, and the like.
  • cycloalkenylene refers to a substituted alicychc divalent hydrocarbon radical having from three to twelve carbon atoms and at least one carbon-carbon double bond in the ring system, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed
  • substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto
  • heterocyclic or the term “heterocyclyl” refers to a three to twelve-membered heterocyclic ring having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, S0 2 , O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • Such a ring may be optionally fused to one or more of another "heterocyclic” rmg(s) or cycloalkyl ⁇ ng(s).
  • heterocyclic include, but are not limited to, tetrahydrofuran, pyran, 1,4-d ⁇ oxane, 1,3- dioxane, pipe ⁇ dme, pyrrohdme, mo ⁇ holme, piperazine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
  • heterocyclylene refers to a three to twelve- membered heterocyclic ring diradical having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO 2 , O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • Such a ring may be optionally fused to one or more benzene rings or to one or more of another "heterocyclic" rings or cycloalkyl ⁇ ngs.
  • heterocyclylene include, but are not limited to, tetrahydrofuran-2,5-d ⁇ yl, mo ⁇ hohne-2,3-d ⁇ yl, pyran-2,4-d ⁇ yl, l,4-d ⁇ oxane-2,3-d ⁇ yl, l ,3-d ⁇ oxane-2,4-d ⁇ yl, pipe ⁇ dine- 2,4-d ⁇ yl, p ⁇ pe ⁇ d ⁇ ne-l,4-d ⁇ yl, pyrrohd ⁇ ne-l,3-d ⁇ yl, mo ⁇ hol ⁇ ne-2,4-d ⁇ yl, p ⁇ perazme-l,4-dy ⁇ l, and the like.
  • aryl refers to a benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • substituents selected from the group consisting of lower alkyl, lower alkoxy, lower
  • arylene refers to a benzene ring diradical or to a benzene ring system diradical fused to one or more optionally substituted benzene ⁇ ngs, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • substituents selected from the group consisting of lower alky
  • heteroaryl refers to a five - to seven - membered aromatic ring, or to a polycychc heterocyclic aromatic ring, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano
  • one or more of the rings may contain one or more heteroatoms.
  • heteroaryl used herein are furan, thiophene, pyrrole, lmidazole, pyrazole, t ⁇ azole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole.
  • heteroarylene refers to a five - to seven - membered aromatic ring diradical, or to a polycychc heterocyclic aromatic ring diradical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, ammo optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbony
  • heteroarylene used herein are furan-2,5-d ⁇ yl, th ⁇ ophene-2,4-d ⁇ yl, l,3,4-oxad ⁇ azole-2,5-d ⁇ yl, l,3,4-fh ⁇ ad ⁇ azole-2,5- diyl, l,3-th ⁇ azole-2,4-d ⁇ yl, l,3-th ⁇ azole-2,5-d ⁇ yl, py ⁇ d ⁇ ne-2,4-d ⁇ yl, py ⁇ d ⁇ ne-2,3-d ⁇ yl, py ⁇ d ⁇ ne-2,5-d ⁇ yl, py ⁇ m ⁇ d ⁇ ne-2,4-d ⁇ yl, qumohne-2,3-d ⁇ yl, and the like.
  • direct bond refers to the direct joining of the substituents flanking (preceding and succeeding) the variable taken as a "direct bond”. Where two or more consecutive variables are specified each as a "direct bond”, those substituents flanking (preceding and succeeding) those two or more consecutive specified "direct bonds" are directly joined.
  • alkoxy refers to the group R a O-, where R a is alkyl.
  • alkenyloxy refers to the group R a O-, where R a is alkenyl.
  • alkynyloxy refers to the group R a O-, where R a is alkynyl.
  • alkylsulfanyl refers to the group R a S-, where R a is alkyl.
  • alkenyl sulfanyl refers to the group R a S-, where R a is alkenyl.
  • alkynylsulfanyl refers to the group R a S-, where R a is alkynyl.
  • alkylsulfenyl refers to the group R a S(0)-, where R a is alkyl.
  • alkenylsulfenyl refers to the group R a S(0)-, where R a is alkenyl.
  • alkynylsulfenyl refers to the group R a S(0)-, where R a is alkynyl.
  • alkylsulfonyl refers to the group R a S0 2 -, where R a is alkyl.
  • alkenylsulfonyl refers to the group R a S0 2 -, where
  • R a is alkenyl
  • alkynylsulfonyl refers to the group R a S0 2 -, where R a is alkynyl.
  • acyl refers to the group R a C(O)- , where R a is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.
  • aroyl refers to the group R a C(0)- , where R a is aryl.
  • heteroaroyl refers to the group R a C(O)- , where R a is heteroaryl.
  • alkoxycarbonyl refers to the group R a OC(O)-, where R d is alkyl.
  • acyloxy refers to the group R a C(O)0- , where R a is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.
  • aroyloxy refers to the group R a C(O)0- , where R a is aryl.
  • heteroaroyloxy refers to the group R a C(O)O- , where R a is heteroaryl.
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
  • substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
  • the terms "contain” or “containing” can refer to in-line substitutions at any position along the above defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one or more of any of O, S, SO, SO 2 , N, or N-alkyl, including, for example, -CH 2 -O-CH 2 -, -CH 2 -SO 2 -CH 2 -, -CH 2 -NH-CH 3 and so forth.
  • solvate is a complex of variable stoichiometry formed by a solute (m this invention, a compound of formula (I) or (II)) and a solvent.
  • solvents for the pu ⁇ ose of the invention may not interfere with the biological activity of the solute.
  • Solvents may be, by way of example, water, ethanol, or acetic acid.
  • biohydrolyzable ester is an ester of a drug substance (in this invention, a compound of general formula (I) or (II)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle.
  • a drug substance in this invention, a compound of general formula (I) or (II)
  • b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle.
  • the advantage is that, for example, the biohydrolyzable ester is orally absorbed from the gut and is transformed to (I) or (II) in plasma.
  • biohydrolyzable amide is an amide of a drug substance (in this invention, a compound of general formula (I) or (II)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle.
  • the biohydrolyzable amide is orally absorbed from the gut and is transformed to (I) or (II) in plasma.
  • prodrug includes biohydrolyzable amides and biohydrolyzable esters and also encompasses a) compounds in which the biohydrolyzable functionality in such a prodrug is encompassed in the compound of formula (I) or (II): for example, the lactam formed by a carboxyhc group in R 2 and an amine in R 4 , and b) compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances of formula (I) or (II).
  • Examples of these functional groups include, but are not limited to, 1,4-d ⁇ hydropy ⁇ dme, N-alkylcarbonyl-l,4-d ⁇ hydropy ⁇ dme, 1,4- cyclohexadiene, tert-butyl, and the like.
  • affinity reagent is a group attached to the compound of formula (I) or (II) which does not affect its m vitro biological activity, allowing the compound to bind to a target, yet such a group binds strongly to a third component allowing a) characterization of the target as to localization within a cell or other organism component, perhaps by visualization by fluorescence or radiography, or b) facile separation of the target from an unknown mixture of targets, whether proteinaceous or not protemaceous.
  • An example of an affinity reagent according to b) would be biotin either directly attached to (I) or (II) or linked with a spacer of one to 50 atoms selected from the group consisting of C, H, O, N, S, or P m any combination.
  • An example of an affinity reagent according to a) above would be fluorescein, either directly attached to (I) or (II) or linked with a spacer of one to 50 atoms selected from the group consisting of C, H, O, N, S, or P in any combination.
  • pharmacologically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician This amount can be a therapeutically effective amount.
  • alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall be inte ⁇ reted as including those limitations given above for "alkyl” and "aryl”.
  • Alkyl or cycloalkyl substituents shall be recognized as being functionally equivalent to those having one or more degrees of unsaturation. Designated numbers of carbon atoms (e.g. Ci-io) shall refer independently to
  • alkyl the number of carbon atoms in an alkyl, alkenyl or alkynyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which the term "alkyl" appears as its prefix root.
  • halogen or halo shall include iodine, bromine, chlorine and fluorine.
  • mercapto shall refer to the substituent -SH.
  • cyano shall refer to the substituent -CN.
  • aminosulfonyl shall refer to the substituent -
  • sulfenyl shall refer to the substituent -S(O)-
  • sulfonyl shall refer to the substituent -S(O) 2 -.
  • the most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus.
  • the following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled m the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless noted otherwise.
  • DIEA d ⁇ sopropylethylamme
  • BOP ( 1 -benzot ⁇ azolyloxy)t ⁇ s(d ⁇ methylam ⁇ no)phosphon ⁇ um hexafluorophosphate
  • LAH lithium aluminum hydride
  • TFA t ⁇ fluoroacetic acid
  • EDC 1 -ethyl-3-(3-d ⁇ methylammopropyl)-carbod ⁇ m ⁇ de hydrochlo ⁇ de
  • HOBt 1 -hydroxybenzot ⁇ azole
  • SPA scintillation proximity assay
  • EDTA ethylenediamine tetraacetic acid
  • FBS fetal bovine serum
  • PBS phosphate buffered saline solution
  • ELISA enzyme - linked immunosorbent assay
  • Ri, R 2 , R 3 , R 4 , R 5 , and R(, are as defined as for formula (II).
  • RPGi is selected from the group consisting of benzyl or 2-tetrahydropyranyl
  • Rn is chosen from the group consisting of hydroxyl, 0-C 6 F 5 , or halogen.
  • the conversion of (V) to (VII) involves methods known in peptide chemistry; for example, the reaction may be conducted using HOBt in combination with a dehydrating agent such as dicyclohexylcarbod ⁇ mide in a suitable solvent, such as DMF.
  • a suitable solvent such as dichloromethane
  • pentafluorophenyl t ⁇ fluoroacetate m the presence of pyridme, or with EDC and pentafluorophenol in a suitable solvent such as dichloromethane.
  • the displacement reaction to produce (VII) is carried out in the presence of a suitable solvent such as dioxane, THF, dichloromethane, or DMF, at a temperature of 0 °C to 140 °C.
  • a suitable solvent such as dioxane, THF, dichloromethane, or DMF
  • the reaction is effected in the presence of an organic base such as NMM or t ⁇ ethylamine.
  • the removal of the RPGi group where RPGi is benzyl may be achieved by hydrogenation of (VII) with palladium on barium sulfate in a suitable solvent such as methanol or THF, or, where RPG, is 2-tetrahydropyranyl, by hydrolysis with aqueous acetic acid at a temperature of 20 °C to 100 °C.
  • Reaction Scheme 2 depicts the synthesis of a compound of formula (IV).
  • R ]6 O is a nucleofugal group such as methanesulfonate, trifluoromethanesulfonate, or p- toluenesulfonate.
  • RPG is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
  • the acid of formula (VIII) may be converted to the alcohol of formula (IX) by treatment with HOBt, O-benzylhydroxylamine hydrochlo ⁇ de or 2- tetrahydropyranyloxyamine, NMM, and a carbodnmide reagent such as EDC m a suitable solvent such as DMF.
  • the alcohol of formula (IX) may be converted to (X) by treatment with methanesulfonyl chloride, p-toluenesulfonyl chloride, or t ⁇ fluoromethanesulfonic anhydride and pyridine m a suitable solvent such as dichloromethane.
  • (X) to (XI) may be conducted by treatment with potassium carbonate in a suitable solvent such as acetone or 2-butanone, at temperature of 20 °C to 90 °C.
  • (IX) may be converted directly to (XI) by treatment with t ⁇ phenylphosphme and diethyl azodicarboxylate or another azodicarbonyl diester or diamide in a suitable solvent such as THF at a temperature of -78 °C to 50 °C.
  • the compound of formula (XI) may be converted to (XII) by treatment with an inorganic base such as sodium hydroxide in water or water in combination with a water soluble organic cosolvent such as methanol or dioxane, followed by acidification with an acidic solution such as aqueous citric acid or aqueous sodium bisulfate
  • an inorganic base such as sodium hydroxide in water or water in combination with a water soluble organic cosolvent such as methanol or dioxane
  • an acidic solution such as aqueous citric acid or aqueous sodium bisulfate
  • the compound of formula (XII) may be converted to (IV) by treatment with acetic anhydride and formic acid or by treatment with formic acetic anhydride in pyridine m the presence or absence of a suitable cosolvent such as dichloromethane.
  • Ri and R are as defined as for formula (II).
  • RPGi is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
  • R 17 is chosen from the group consisting of lower alkoxy or oxazohdinon-1-yl, where the 4 and 5 positions of an oxazol ⁇ d ⁇ non-1-yl group may be substituted with a lower alkyl, aryl, or lower alkylaryl group and where such an oxazol ⁇ dmon-1-yl substituent may exist as a single stereoisomer or as a mixture of stereoisomers.
  • a carbonyl compound of formula (XIII), where R ⁇ 7 is an alkoxy group such as methoxy or tert-butoxy, may be treated with a strong base such as LDA in a solvent such as THF at a temperature of from -78 °C to 0 °C, followed by treatment with the aldehyde (XIV) to provide (XV).
  • a strong base such as LDA
  • a solvent such as THF
  • R 17 is an oxazol ⁇ dmon-1-yl substituent
  • treatment of (XIII) with a Lewis acid such as d ⁇ (n-butyl)boron trifluoromethanesulfonate in the presence of N,N- diisopropylethylamine in a suitable solvent such as dichloromethane at a temperature of 0 °C followed by addition of the aldehyde (XIV) provides (XV).
  • Treatment of (XV) with aqueous base in the presence or absence of hydrogen peroxide affords (VIII) upon acidification.
  • the acid (VIII) may be converted directly to (IX) as m reaction Scheme 2, or may be treated with a dehydrating agent such a p-toluenesulfonyl chloride in pyridme or with friphenylphosphme and diethyl azodicarboxylate in a suitable solvent such as THF, to afford the lactone (XVI).
  • a dehydrating agent such as a p-toluenesulfonyl chloride in pyridme or with friphenylphosphme and diethyl azodicarboxylate in a suitable solvent such as THF
  • a suitable solvent such as THF
  • Reaction Scheme 4 depicts the preparation of compounds of general formula (VIII).
  • Ri and R 2 are as defined as for formula (II).
  • RPGi is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
  • Rig is selected from the group consisting of lower alkyl or benzyl.
  • Ri is selected from the group consisting of chloride, bromide, iodide, or t ⁇ fluoromethanesulfonate.
  • ketoester of general formula (XVII) may be formed by treating 2,2-d ⁇ methyl-l,3- d ⁇ oxane-4,6-d ⁇ one with an appropriate acid chloride Ri COCl in the presence of base, an
  • the ketoester of general formula (XVII) may be reduced with a reducing agent such as sodium borohydride to afford the hydroxyester (XVIII)
  • a reducing agent such as sodium borohydride
  • reduction of (XVII) with a chiral catalyst or chiral hgand in the presence of a reducing agent such as hydrogen or a metal hydride such as borane or lithium aluminum hydride may be employed to afford (XVIII) with chiral induction at the newly formed center
  • the alcohol (XVIII) may be converted to (XIX) by treatment with a strong base such as LDA in a suitable solvent such as THF, followed by the addition of R 2 -R ⁇ 9 in the presence or absence of a cosolvent such as DMPU Removal of the ester group by hydrolysis with aqueous hydroxide ion or, m the case where R 18 is tert-butyl, by treatment with a strong acid such as TFA, affords (VIII)
  • Ri and R 2 are as defined as for formula (II).
  • R 22 is selected from the group consisting of aryl or heteroaryl.
  • R ⁇ 9 ⁇ s selected from the group consisting of chloride, bromide, iodide, or t ⁇ fluoromethanesulfonate .
  • RPG is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
  • R 20 and R ] may be, independently, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, and alkynyl substituents may contain one or more O, S, SO, or S0 2 substituents.
  • the lactam of general formula (XX) may be treated with a metal catalyst such as tetrak ⁇ s(t ⁇ phenylphosphme)pallad ⁇ um or palladium chloride and R 2 -Ri 9 m a solvent such as acetonit ⁇ le at a temperature of from 20 °C to 200 °C to afford (XXI) Reduction of the olefinic group in (XXI) with hydrogen and a metal catalyst such as palladium on carbon and conversion of the lactam (XI) to the acid (IV) proceeds as outlined in reaction Scheme 2.
  • a metal catalyst such as tetrak ⁇ s(t ⁇ phenylphosphme)pallad ⁇ um or palladium chloride and R 2 -Ri 9 m a solvent such as acetonit ⁇ le at a temperature of from 20 °C to 200 °C to afford (XXI)
  • olefin in compounds of general formula (XXI) may be left in place and manipulation of the lactam (XXI) carried out as described in reaction Scheme 2 to afford (XXII).
  • Acid (XXII) may be converted to (IV) as described in reaction Scheme 2 with or without reduction of the olefin in (XXII), as appropriate
  • R] is selected from the group consisting of benzyl or 2-tetrahydropyranyl.
  • R] 8 is selected from the group consisting of lower alkyl or benzyl.
  • R] 9 is selected from the group consisting of chloride, bromide, iodide, or t ⁇ fluoromethanesulfonate.
  • R 20 , R 2 ⁇ and R 23 may be, independently, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, and alkynyl substituents may contain one or more O, S, SO, or S0 2 substituents.
  • R 22 is aryl or heteroaryl.
  • R 24 is a t ⁇ alkylstannyl group.
  • the alcohol (XVIII), prepared from (XVII) as outlined in reaction Scheme 4, may be converted to (XXIV) by treatment with a strong base such as LDA in a suitable solvent such as THF, followed by the addition of (XXIII), m the presence or absence of a cosolvent such as
  • the alkene (XXIV) may be converted to the acid (VIII) as described in reaction Scheme 2.
  • the alcohol (XVIII) may be converted to (XXVI) by treatment with a strong base such as LDA in a suitable solvent such as THF, followed by the addition of (XXV), in the presence or absence of a cosolvent such as DMPU.
  • Conversion of (XXVI) to (XXVII) proceeds as described in reaction Scheme 2.
  • the alkyne (XXVII) may be treated with R 24 -H and a radical initiator such as azob ⁇ s( ⁇ sobutyron ⁇ t ⁇ le) a solvent such as toluene to afford (XXVIII).
  • the alkenyltin compound (XXVIII) may be treated with a catalyst such as tetrak ⁇ s(t ⁇ phenylphosph ⁇ ne)pallad ⁇ um and R 22 -R ]9 m a solvent such as DMF at a temperature of from 20 °C to 180 °C to provide (XXIX).
  • a catalyst such as tetrak ⁇ s(t ⁇ phenylphosph ⁇ ne)pallad ⁇ um and R 22 -R ]9 m a solvent such as DMF at a temperature of from 20 °C to 180 °C to provide (XXIX).
  • the alkene (XXIX) may be transformed to the lactam (XI) by operations known in the art of organic chemistry such as catalytic hydrogenation.
  • Compound (XXXI) may be converted if desired to (XI) by operations known in the art of organic chemistry such as catalytic hydrogenation.
  • the preparation of compounds of general formula (VI) is shown in reaction Scheme
  • RPG 2 is selected from the group consisting of tert-butoxycarbonyl, allyloxycarbonyl, or benzyloxycarbonyl
  • R 25 is selected from the group consisting of 1 -benzot ⁇ azolyloxy, or bromine
  • the acid of formula (XXXII) may be converted in situ to (XXXIII), where R 25 is bromine, by treatment with bromo-t ⁇ s(pyrrol ⁇ d ⁇ no)phosphon ⁇ um hexafluorophosphate in a suitable solvent such as DMF in the presence of an organic base such as N,N- d ⁇ sopropylethylamme
  • the acid of formula (XXXII) may be converted in situ to (XXXIII), where R 2 5 is benzot ⁇ azolyloxy, by treatment with BOP in a suitable solvent such as DMF in the presence of an organic base such as NMM Addition of the amme (XXXIV) in the displacement step m the presence of a suitable solvent such as DMF and an organic base such as N,N-dnsopropylethylamine affords the amide (XXXV)
  • the compounds of the present invention can be administered in such oral
  • buccal and sublingual dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • they may also be administered in nasal, ophthalmic, otic, rectal, topical, intravenous (both bolus and infusion), intrape ⁇ toneal, mtraarticular, subcutaneous or intramuscular inhalation or insufflation form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the dosage regimen utilizing the compounds of the present invention is selected accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.1 to 2000 mg/kg of body weight per day, and particularly 1 to 1000 mg/kg of body weight per day. Oral dosage units will generally be administered in the range of from 1 to about 250 mg and more preferably from about 25 to 250 mg. The daily dosage for a 70 kg mammal will generally be in the range of about 10 mg to 5 grams of a compound of formula I or II.
  • While the dosage to be administered is based on the usual conditions such as the physical condition of the patient, age, body weight, past medical history, route of administrations, severity of the conditions and the like, it is generally preferred for oral administration to be used to administer to a human. In some cases, a lower dose is sufficient and, in some cases, a higher dose or more doses may be necessary. Topical application similarly may be once or more than once per day depending upon the usual medical considerations.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered m divided doses of two, three or four times daily.
  • preferred compounds for the present invention can be administered m lntranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skm patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen
  • the compounds herein described m detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "earner" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert earner such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert earner such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavonng, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Ghdants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubihzing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium algmate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used m these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, a gar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and dismtegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aligmate, gelatin, or poly vinyl pyrrohdone, a solution retardant such as paraffin, a reso ⁇ tion accelerator such as a quaternary salt and/or an abso ⁇ tion agent such as bentonite, kaolm or dicalcium phosphate
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stea ⁇ c acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound m a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound m a non-toxic vehicle.
  • Solubihzers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or saccharin, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of the present invention can also be administered m the form of hposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamme or phosphatidylchohnes.
  • the compounds of the present invention can also be administered in the form of hposome emulsion delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamme or phosphatidylchohnes.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrohdone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysme substituted with palmitoyl residues
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the present invention includes pharmaceutical compositions containing 0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula (II) in combination with a pharmaceutically acceptable carrier.
  • Parenteral administration can be effected by utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular, intrathecal, lntraarte ⁇ al or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound m a non-toxic liquid vehicle suitable for injection such as aqueous oleaginous medium and sterilizing the suspension or solution.
  • liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular, intrathecal, lntraarte ⁇ al or intravenous injection.
  • a measured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed.
  • An accompanying vial or vehicle can be provided for mixing prior to administration.
  • Non-toxic salts and salt solutions can be added to render the injection lsotonic.
  • Stabilizers, preservations and emulsifiers can also be added.
  • Rectal administration can be effected utilizing suppositories in which the compound is admixed with low-meltmg water-soluble or insoluble solids such as polyethylene glycol, cocoa butter, higher esters, my ⁇ styl palmitate or mixtures thereof.
  • Topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, t ⁇ chlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, t ⁇ chlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, t ⁇ chlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluor
  • compositions are those in a form suitable for oral administration, such as tablets and liquids and the like and topical formulations.
  • reaction mixture is quenched by addition 30 mL of saturated aqueous ammonium chloride solution, is poured into 400 mL of 1 M hydrochloric acid, and is extracted with two 500 mL portions of ethyl acetate.
  • the combined organic layers are dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 25% ethyl acetate - hexanes) to afford methyl (2R,3R)-2-[(2E)- 3-phenyl-2-propen-l-yl]-3-hydroxybutanoate as a yellow oil (42 g, 85% yield).
  • reaction mixture is quenched by addition 10 mL of saturated aqueous ammonium chloride solution, is poured into 100 mL of 1 M hydrochloric acid, and is extracted with two 100 mL portions of ethyl acetate.
  • the combined organic layers are dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 20% ethyl acetate - hexanes) to afford methyl (2R,3R)-2-(3-tnmethyls ⁇ lyl-2-propyne-l-yl)-3-hydroxybutanoate as a yellow oil (5.6 g, 58% yield).
  • 'H NMR 400 MHz, CDCI3 ⁇ 4.04 (m, IH), 3.72 (s, 3H), 2.62 (m, 3H), 1.23 (t, 3H), 0.09 (s,
  • reaction mixture is poured into ethyl acetate/hexanes (1 : 1, 200 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride.
  • Example 3a (3R,4S)-l-(2-Tetrahydropyranyloxy)-3-((2E)-3-(th ⁇ ophene-2-yl)-2-propene-l- yl)-4-methylazet ⁇ d ⁇ n-2-one
  • To a solution of (3R,4S)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-tnbutylstannyl-2- propene-l-yl)-4-mefhylazet ⁇ d ⁇ n-2-one (400 mg, 0.78 mmol) in 1 mL of dimethylformamide is added 2-bromoth ⁇ ophene (152 mg, 0.93 mmol) and tnphenyphosphine palladium (II) dichloride (27 mg, 0.04 mmol)
  • the resulting solution is heated at 80°C for 2 h, then 0.5 mL ammonium hydroxide is added.
  • reaction mixture is poured into saturated sodium chloride solution (20 mL) and extracted with 1 : 1 ethyl acetate/hexane (50 mL).
  • the combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3: 1 hexanes - ethyl acetate) to provide (3R,45)-l-(2-tetrahydropyranyloxy)-3-((2E)-3-(th ⁇ ophene-2-yl)-2-propene-l-yl)-4- methylazet ⁇ d ⁇ n-2-one as an oil (130 mg, 54% yield).
  • reaction mixture is poured into ethyl acetate/hexane (1.1, 20 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride.
  • the organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 1 : 1 ethyl acetate - hexane) to provide (2R,3S)-3-
  • Example 52a (3R,45)- 1 -(2-Tetrahydropyranyloxy)-3 -((2E)-3 -(4-methylphenyl)-2-propene- 1 - yl)-4-methylazet ⁇ d ⁇ n-2-one
  • Example 52c (2R,3S)-2-(3-(4-methylphenyl)-l-propyl)-3-(2- tetrahydropyranyloxyam ⁇ no)butano ⁇ c Acid
  • the solution is stirred at 23 °C for 20 h, then extracted with hexanes (10 mL).
  • the combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4- methylphenyl)-l-propyl)-3-(2-tetrahydropyranyloxyam ⁇ no)butano ⁇ c acid as an oil (114 mg, 67% yield).
  • ⁇ NMR (400 MHz, CDCI3) ⁇ 7.04 (m, 4H), 4.94 (m, 0.5H). 4.84 (m, 0.5H), 3.95 (m. 0.5H),
  • reaction mixture is poured into ethyl acetate (20 mL) and washed sequentially with 1 M hydrochlo ⁇ c acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride.
  • the organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 2: 1 ethyl acetate - hexane) to provide (2R,3S)-3-(Formyl-2- tetrahydropyranyloxyammo)-2-(3-(4-methylphenyl)- 1 -propyl)butano ⁇ c acid [( 15)-2,2- d ⁇ methyl-(l -methylcarbamoyl)- 1 -propyljamide as a white solid (55 mg, 68% yield).
  • Example 61a (3R,45)-l-(2-Tetrahydropyranyloxy)-3-((2E),(4E,Z)-3-phenyl-2,4-pentad ⁇ ene- 1 -yl)-4-methylazet ⁇ d ⁇ n-2-one
  • reaction mixture is poured into saturated sodium chloride solution (20 mL) and extracted wit 1 : 1 ethyl acetate/hexane (50 mL).
  • the combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3 : 1 hexanes - ethyl acetate) to provide (3R,45)-l-(2-tetrahydropyranyloxy)-3-((2E),(4E/Z)-3-phenyl-2,4-pentad ⁇ ene-l-yl)- 4-methylazet ⁇ d ⁇ n-2-one as an oil (140 mg, 49% yield).
  • ⁇ NMR 400 MHz, CDCI3
  • reaction mixture is poured into ethyl acetate (20 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride.
  • the organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 2: 1 ethyl acetate - hexane) to provide (2R,35)-3-(Formyl-2- tetrahydropyranyloxyammo)-2-(5-phenyl-l-pentyl)butano ⁇ c acid [(15)-2,2-d ⁇ methyl-(l- mefhylcarbamoyl)-l -propyljamide as a white solid (44 mg, 63% yield).
  • ESI-MS m/z 526.3 (M+Na) + .
  • MMP-1 Matrix Metalloprotease Inhibition Protocol
  • MMP- 13 20 kD truncated collagenase-3
  • MMP-3 stromelysin- 1
  • MMP-9 50 kD truncated gelatmase B
  • the potency of compounds of the invention as inhibitors of cell - free tumor necrosis factor ⁇ converting enzyme is determined as follows: Membrane preparation from MonoMac 6 cells (subfractionated extract from equivalent of 6x10 6 cells per 60 ⁇ l assay) is incubated for 1 hr with 200 nM radiolabeled substrate (B ⁇ ot ⁇ n-SPLAQAVRSSSRT-( 3 H)P-S-NH 2 , 4.1
  • the potency of compounds of the invention as inhibitors of release of soluble tumor necrosis factor ⁇ from stimulated monocytes m vitro is determined as follows: LPS/PMA solution for assay consisting of a) 4 ⁇ L of 5 mg/mL LPS stock and b) 6 ⁇ L of 10 mg/mL PMA stock are added to 500 ⁇ L of medium (RPMI 1640 (Gibco) + 10% FBS + penicillin/streptomycin + 1-glutam ⁇ ne). This solution is then diluted 1 : 1000 (40 ng/mL and 120 ng/mL) for use later in the assay. Compounds (10 mM) are serially diluted 1 :3 in DMSO.
  • MonoMac 6 cell suspension 130 ⁇ L, 1.5 xlO 6 cells/mL
  • LPS/PMA 50 ⁇ L
  • the plate is incubated at 37 °C for 2 hours then spun at 1 ,500 rpm for 3 minutes to pellet cells.
  • the supernatant 120 ⁇ L/well is removed to a new round bottom 96 well plate and diluted 1 : 10 m PBS. Then, 20 ⁇ L of the supernatant is transferred to a Cistron TNF ⁇ ELISA plate and processed according to the manufacturer's instructions to quantitate levels of TNF ⁇ . Percent inhibition of TNF ⁇ release is calculated at each inhibitor concentration and the data were plotted using standard curve fitting programs. Approximate IC ⁇ o values were determined from these curves.
  • mice with a weight of 21 ⁇ 2g are weighed and used.
  • Control and test animals are injected subcutaneously m the axillary region with a suspension of 2 X 10 6 viable tumor cells in 200 uL in PBS + mat ⁇ gel on day 0. Tumors are allowed to grow for 10 to 14 days prior to drug administration.
  • Doses of test drug are given on a mg/kg basis according to the mean body weight for each cage. For each drug, two doses are used, 30 mg/kg and 90 mg/kg and are administered by p.o. route once a day over a 14 day time span.
  • the criterion for antitumor activity is 25% inhibition of tumor growth after 2 weeks of dosmg (day 14).

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Abstract

La présente invention concerne une famille de composés représentés par la formule générale (I). Dans cette formule, W est un groupe acide hydroxamique inversé, et R1, R2, R3, R4, R5, et R6 sont, soit directement tels que décrits dans la spécification, soit indirectement certains de leurs sels, solvates, esters biohydrolysables, amides biohydrolysables, réactifs d'affinité ou promédicaments pharmaceutiquement admis. L'invention concerne également des procédés permettant d'élaborer ces produits, des compositions pharmaceutiques comprenant de tels composés et leur utilisation en médecine.
EP99942456A 1998-08-26 1999-08-25 Agents therapeutiques a base de formamides Withdrawn EP1121118A4 (fr)

Applications Claiming Priority (5)

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US9795698P 1998-08-26 1998-08-26
GBGB9818613.3A GB9818613D0 (en) 1998-08-26 1998-08-26 Formamides as therapeutic agents
GB9818613 1998-08-26
US97956P 1998-08-26
PCT/US1999/019303 WO2000012083A1 (fr) 1998-08-26 1999-08-25 Agents therapeutiques a base de formamides

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US5239078A (en) * 1990-11-21 1993-08-24 Glycomed Incorporated Matrix metalloprotease inhibitors
WO1994010990A1 (fr) * 1992-11-13 1994-05-26 British Biotech Pharmaceuticals Limited Inhibition de la production du facteur de necrose tumorale
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WO2000012082A1 (fr) * 1998-08-26 2000-03-09 Glaxo Group Limited Composes formamides utilises comme agents therapeutiques
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EP1121118A4 (fr) 2002-09-11
AU5582899A (en) 2000-03-21
WO2000012083A1 (fr) 2000-03-09

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