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  • 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
  • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• • 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
• • 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
  • 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
  • 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
  • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/44—Acylated amino or imino radicals
  • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
  • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
  • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
  • C07D285/135—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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 rheumatoid arthritis, osteoarthritis, inflammatory bowel syndromes, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, 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 matrilysin (MMP-7). These enzymes accelerate breakdown of connective tissue by catalyzed resorption of the extracellular matrix.
• inhibitors of one or more of the matrix metalloproteases would have utility in a wide range of disease states such as in abrogating the initiation of tumor metastasis and angiogenesis and in halting the pathogenesis of demyelinating diseases of the nervous system, multiple sclerosis being one example.
• MMP inhibitors would also find utility in diseases involving connective tissue degradation in 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 in osteoarthritic cartilage. These data would implicate collagenase-3 as a significant target in rheumatoid arthritis and osteoarthritis for inhibition by MMP inhibitors.
• inflammatory/autoimmune diseases which include rheumatoid arthritis, osteoarthritis, Crohn's disease and other inflammatory bowel diseases, periodontal disease, gingivitis, and corneal ulceration
• cardiovascular diseases which include atherosclerosis and restenosis
• metabolic diseases which includes complications of diabetes, osteoporosis, and other disorders involving resorption of bone
• neurologic diseases such as multiple sclerosis and other demyelination ailments
• diseases of cancer and malignancy including colorectal cancer and leukemias, tumor invasion, and metastatic and angiogenic events thereof
• renal diseases including nephrotic syndromes and glomerulonephritis
• infectious diseases including those mediated by viruses, bacteria, and fungi.
• 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 zinc co factor at the enzyme active site, which is contained within a peptidic or pseudopeptide structure. Zinc 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(O)NHOH (which by convention and in this application are referred to as "forward hydroxamates”) or a zinc-chelating substituted amine group of the formula -NH(OH)C(O)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(O)NHOH
• reverse hydroxamates zinc-chelating substituted amine group of the formula -NH(OH)C(O)R
• 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 alanine-76 - valine-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 zinc cation at the active site.
• TNF convertase enzymatic activity can be detected in monocyte membrane fractions, and the enzyme activity can be inhibited by certain matrix metalloprotease - inhibiting compounds.
• Metalloprotease - like activity is also thought to contribute to the shedding of certain cell surface protein ectodomains such as L-selectin, fibronectin, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density lipoprotein receptor, beta amyloid precursor protein, interleukin-6 receptor alpha subunit, Fas ligand, CD40 ligand, epidermal growth factor receptor, macrophage colony stimulating factor, interleukin- 1 receptor type II, CD30, and tumor necrosis factor receptors type I and II.
• cell surface protein ectodomains such as L-selectin, fibronectin, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density lipoprotein receptor, beta amyloid precursor protein, interleukin-6 receptor alpha subunit, Fas ligand, CD40 ligand, epidermal growth factor receptor, macrophage colony stimulating factor, interleukin- 1 receptor type II, CD30, and tumor necrosis factor receptors
• TNF is known to mediate many biological responses in vivo. Preclinical and clinical studies in animals and humans with specific TNF neutralizing antibodies, soluble TNF recept ⁇ r 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 in inhibiting TNF production and/or their activity in preventing cell surface protein ectodomain shedding should show utility in the treatment of diverse pathologies such as: i) 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; ii) reperfusion injuries, such as those caused by an initial ischemic event; iii) systemic inflammatory response syndromes, including but not limited to sepsis, burn injury, pancreatitis, and adult respiratory distress syndrome; iv) allergic and dermatologic diseases, including but not limited to delayed type hypersensitivity, psoriasis, asthma, eczema, allergic rhinitis, and allergic conjunctivitis; v) cardiovascular diseases, including but not limited to hyperlipidemia, myocardial infarction, atherosclerosis, and reste
• Epstein-Barr viral infection herpes viral infection, malaria, meningitis, leprosy, hepatitis (which includes hepatitis A, hepatitis B, and hepatitis C), infectious arthritis, leishmaniasis, Lyme disease, and viral encephalitis; xiii) effects of disease therapy, including but not limited to cytokine therapy, chemotherapy, radiation therapy and therapies using anti-T-cell antibodies or cytotoxin-antibody conjugates; and xiv) ocular diseases, including but not limited to macular degeneration.
• TNFc TNF-alpha converting enzyme
• the invention includes a family of compounds having the general structural formula:
• W is a reverse hydroxamic acid group
• Ri is a substituent other than hydrogen
• R 4 is a lipophilic substituent preferably with steric bulk proximal to the peptide backbone, and;
• R 6 is a heteroaryl substituent.
• Such compounds are novel and are unknown in the art and, given the appropriate choice of R 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 in some cases inhibit TNF convertase and TNF release from cells in preference to matrix metalloproteases.
• the heteroaryl nature of R in combination with an appropriate choice of R,, R 2 , R 3 , R , and R 5 is beneficial in achieving increased potency against TNF release firom cells relative to inhibition of MMP's.
• Such molecules are potentially selective for TNF inhibition over MMP's and may 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 heteroaryl nature of R $ in combination with an appropriate choice of R,, R 2 , R 3 , R 4 , and R 5 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.
• a more preferred group of compounds of the present invention include those of the formula (II):
• Ai is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond;
• a 2 is C(O)NR 7 , NR 7 C(O), SO 2 NR 7 , NR 7 SO 2 , NR 7 , S, SO, SO 2 , O, C(O), C(O)O,
• a 3 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond;
• a 4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl,
• is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, NR l0 (O)C, NR, 0 , S, SO, SO 2 , O, O(O)C, or a direct bond, where R, 0 is as defined below;
• D 2 is S, SO, SO 2 , O, C(O), C(O)O, OC(O), C(O)NR u , NR desireC(O), NR lake, or a direct bond, where R, ! is as defined below;
• D 3 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, S, SO, SO 2 , O, C(O), C(O)O, OC(O), C(O)NR, 2 , NR 12 C(O), SO 2 NR J2 , NR ⁇ 2 SO 2 , NR ⁇ 2 , or a direct bond, where R, 2 is as defined below;
• D 4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, OR, 3 , or hydrogen, where R 13 is as defined below;
• R 3 is hydrogen or lower alkyl
• Ej is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, C(O)NR, 4 , NR 14 C(O), C(O), C(O)O, OC(O), or a direct bond, where R 14 is as defined below;
• E 2 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR 15 , S, SO, SO 2 , O, C(O), C(O)O, OC(O), or a direct bond, where R 15 is as defined below;
• E 3 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR 16 , S, SO, SO 2 , O, C(O), C(O)O, OC(O),
• R 16 and R 17 are as defined below;
• E 4 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR 18 , S, SO, SO 2 , O, C(O), C(O)O, OC(O), or a direct bond, where R ⁇ 8 and R 19 are as defined below;
• E 5 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR 20 , S, SO, SO 2 , O, C(O), C(O)O, OC(O),
• R 20 and R 21 are as defined below;
• E 6 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, NR 22 , S, SO, SO 2 , O, C(O), C(O)O, OC(O), or a direct bond, where R 22 is as defined below;
• E 7 is hydrogen, NR 23 R 24 , OR 23 , SR 23 , SOR 23 , SO 2 R 23 , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, where R 23 and R 24 are as defined below;
• R 5 is hydrogen or lower alkyl
• Z 2 is lower alkylene, lower alkenylene, lower alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, C(O)NR 25 , NR 25 C(O),
• Z 3 is lower alkylene, lower alkenylene, lower alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, C(O)NR 26 , NR 26 C(O),
• Z 4 is lower alkylene, lower alkenylene, lower alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, C(O)NR 27 , NR 27 C(O), SO 2 NR 27 , NR 27 SO 2 , NR 27 , S, SO, SO 2 , O, C(O), C(O)O, OC(O), or a direct bond, where R 27 is as defined below;
• Z 5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR 28 R 29 , OR 28 , or hydrogen, where R 28 and R 29 are as defined below;
• R 29 are, independently, hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl;
• R 10 , R n , R, 2 , and R, 3 are, independently, hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, cycloalkenyl, or heterocyclyl;
• Preferred embodiments of the invention include compounds of general formula (II) as defined above or pharmaceutically acceptable salts, solvates, biohydrolyzable esters, biohydrolyzable amides, affinity reagents, or prodrugs thereof where
• R j is methyl, ethyl, isopropyl, benzyl, 2-benzyloxy-l -ethyl, benzyloxymethyi, 2- tetrahydrofuryl-1 -ethyl, 2-thiophenesulfanylmethyl, benzenesulfanylmethyl, 3- pyridyloxymethyl or n-propyl;
• R 2 is isobutyl, 3-methyl-l -butyl, sec-butyl, cyclohexylmethyl, cyclopentylmethyl, 2- methyl-1 -butyl, cyclohexyl, cyclopentylmethyl, or 2-(3-cyclopentenyl)-l -ethyl;
• R 3 is hydrogen
• R is tert-butyl, 2-thiophenemethyl, sec-butyl, 1-methoxy-l -ethyl, 4- (benzyloxycarbonylamino)- 1 -butyl, 4-(ethoxycarbonylamino)- 1 -butyl, 4-acetylamino- 1 -butyl, 4-cyclopentylacetylamino-l -butyl, 4-(3-methoxybenzoylamino)-l -butyl, 3- pyridylmethyl, 4-(2-pyridylmethoxycarbonylamino)-l -butyl, 2-(2-
• R 5 is hydrogen
• R ⁇ 5 is 2-thiazolyl, 2-pyridyl or 2-(l,3,4-thiadiazolyl).
• inventions include compounds of general formula (II) as defined above or pharmaceutically acceptable salts, solvates, biohydrolyzable esters, biohydrolyzable amides, affinity reagents, or prodrugs thereof where R, is 3,3,3-trifluoro-n-propyl, or cyclopropyl;
• R 2 is cyclobutylmethyl; R 3 is hydrogen;
• R 4 is isopropyl, 1-hydroxy-l -ethyl, 2-(2-pyridylcarbonylamino)-l -ethyl, l-(2- pyridylmethoxy)-l -ethyl, 2,2-dimethyl-l -propyl, 2-methylsulfenyl-2-propyl, 2- methylsulfanyl-2-propyl, 2-(4-mo holinesulfonyl)- 1 -ethyl, (4- ethoxycarbonylpiperazine- 1 -ylcarbonyl)methyl, 4-ethoxycarbonylamino- 1,1- dimethyl- 1 -butyl, 3 -(imino-(methanesulfonylamino))methylamino- 1 -propyl, 2-(4-(2- furyl)carbonylpiperazine- 1 -ylcarbonyl)ethyl, 2-ethoxycarbonylamino- 1
• R 5 is hydrogen
• Rg is 3-pyridyl, 4-pyridyl, 3-amino-2-pyridyl, 2-pyrimidinyl, 4-amino-2-pyrimidinyl, 2-pyrazinyl, 3-(5-methylisoxazolyl), or 2-(5-methyl-l,3,4-thiadiazolyl).
• R [ is methyl, ethyl, isopropyl, n-propyl or 3,3,3-trifluoro-n-propyl.
• R 2 is isobutyl or sec-butyl.
• R 3 is hydrogen
• R 4 is tert- butyl, sec-butyl, 1-methoxy-l -ethyl or 2-(2-pyridylcarbony lamino)-! -ethyl.
• R 5 is hydrogen.
• Rg is 2- thiazolyl or 2-pyridyl.
• a group of particularly preferred embodiments of the invention are those comprising Examples 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
• Another group of particularly preferred embodiments of the invention are those comprising Examples 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
• Another group of particularly preferred embodiments of the invention are those comprising Examples 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.
• Another group of particularly preferred embodiments of the invention are those comprising Examples 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40.
• Another group of particularly preferred embodiments of the invention are those comprising Examples 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50.
• Another group of particularly preferred embodiments of the invention are those comprising Examples 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60.
• Another group of particularly preferred embodiments of the invention are those comprising Examples 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70.
• Another group of particularly preferred embodiments of the invention are those comprising Examples 71, 72, 73, 74 or 75.
• Another group of particularly preferred embodiments of the invention are those comprising Examples 76, 77, 78, 79, 80, 81, 82 or 83.
• Another especially preferred embodiment of the invention is that comprising Example 35.
• Another especially preferred embodiment of the invention is that comprising Example 76.
• 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 a therapeutically defined amount of a compound of formula (I) or (II), defined above, as a single or polymorphic crystalline form or forms, an amorphous form, a solvate, a pharmaceutically acceptable salt, a solvate, a prodrug, a biohydrolyzable ester, or a biohydrolyzable amide thereof.
• Certain compounds of formula (I) or (II), defined above, may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formulae (I) or (II) may exist in tautomeric forms other than that shown in the formulae and these are also included within the scope of the present invention.
• 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, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate
• 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.
• 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.
• 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 the cellular release of tumour necrosis factor alpha.
• 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 a matrix metalloprotease.
• 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 the growth of tumour metastases, or for the treatment of diabetes, or for the treatment of arthritis.
• a method of inhibiting the cellular release of tumour necrosis factor alpha in a mammalian subject which comprises administering to said subject an effective amount of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
• a method of inhibiting a matrix metalloprotease in a mammalian subject which comprises administering to said subject an effective amount of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
• a method of inhibiting the shedding of cell surface protein ectodomains in a mammalian subject comprises administering to said subject an effective amount of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
• a method of inhibiting the growth of tumour metastases, or a method for the treatment of diabetes, or a method for the treatment of arthritis, in a mammalian subject which comprises administering to said subject an effective amount of a compound of formula (II) as defined above or a pharmaceutically acceptable salt; solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
• 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, 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, amino optionally substituted by alkyl, carboxy, carbamoyl optional
• 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, 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, amino optionally substituted by alkyl, carboxy, carbamo
• 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, 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.
• alkenylene refers to an 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, 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.
• alkenylene as used herein include, but are not limited to, ethene-l,2-diyl, propene- 1 ,3 -diyl, methylene- 1 1 , 1 -diy 1, 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, 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.
• 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, 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.
• alkynylene as used herein include, but are not limited to, ethyne-l,2-diyl, propyne- 1,3-diyl, and the like.
• cycloalkyl refers to a alicyclic 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, 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.
• Cycloalkyl includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like.
• cycloalkylene refers to an non-aromatic alicyclic 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-l,l-diyl, cyclopropyl-l,2-diyl, cyclobutyl-l,2-diyl, cyclopentyl-l,3-diyl, cyclohexyl-l,4-diyl, cycloheptyl-l,4-diyl, or cyclooctyl-l,5-diyl, and the like.
• cycloalkenyl refers to a substituted alicyclic 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, l-cyclopentene-3-yl, l-cyclohexene-3-yl, 1 -cycloheptene-4-yl, and the like.
• cycloalkenylene refers to a substituted alicyclic 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.
• cycloalkenylene examples include, but are not limited to, 4,5-cyclopentene-l,3- diyl, 3,4-cyclohexene-l,l-diyl, and the like.
• 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, 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,
• Such a ring may be optionally fused to one or more of another "heterocyclic" ring(s) or cycloalkyl ring(s).
• heterocyclic include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, 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 .
• Such a ring may be optionally fused to one or more of another "heterocyclic" rings or cycloalkyl rings.
• heterocyclylene examples include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1 ,4-dioxane-2,3-diyl, l,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-l,4-diyl, pyrrolidine-l,3-diyl, morpholine-2,4-diyl, 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, alkoxy carbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed.
• substituents selected from the group consisting of lower alky
• arylene refers to a benzene ring diradical or to a benzene ring system diradical 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, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed.
• arylene examples include, but are not limited to, benzene- 1,4-diyl, naphthalene- 1,8-diyl, anthracene- 1,4-diyl, and the like.
• heteroaryl refers to a five - to seven - membered aromatic ring, or to a polycyclic 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, amino
• heteroaryl used herein are furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, and indazole, and the like.
• heteroarylene refers to a five - to seven - membered aromatic ring diradical, or to a polycyclic 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, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
• heteroarylene used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole- 2,5-diyl, l,3,4-thiadiazole-2,5-diyl, l,3-thiazole-2,4-diyl, l,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline- 2,3-diyl, and the like.
• alkoxy refers to the group R a O-, where R a is alkyl.
• alkenyloxy refers to the group R a O-, where R ⁇ is alkenyl.
• alkynyloxy refers to the group R a O-, where R a is alkynyl.
• alkylsulfanyl refers to the group R g S-, where R a is alkyl.
• alkenylsulfanyl refers to the group R a S-, where R ⁇ is alkenyl.
• alkynylsulfanyl refers to the group R a S-, where R a is alkynyl.
• alkylsulfenyl refers to the group R a S(O)-, where R a is alkyl.
• alkenylsulfenyl refers to the group R a S(O)-, where R a is alkenyl.
• alkynylsulfenyl refers to the group R a S(O)-, where R a is alkynyl.
• alkylsulfonyl refers to the group R a SO 2 -, where R a is alkyl.
• alkenylsulfonyl refers to the group R a SO 2 -, where R a is alkenyl.
• alkynylsulfonyl refers to the group R a SO 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 RgC(O)- , 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 a is alkyl.
• acyloxy refers to the group R a C(O)O- , where R a is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.
• aroyloxy refers to the group R a C(O)O- , where R a is aryl.
• heteroaroyloxy refers to the group R a C(O)O- , where R a is heteroaryl.
• R a is heteroaryl.
• 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.
• 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 (in this invention, a compound of formula (I) or (II)) and a solvent.
• solvents for the purpose 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 carboxylic group in R 2 and an amine in j, 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 are, but are not limited to, 1 ,4-dihydropyridine, N- alkylcarbonyl-l,4-dihydropyridine, 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 in 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 proteinaceous.
• 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 in 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.
• pharmaceutically 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.
• alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall be interpreted 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
• halogen or halo shall include iodine, bromine, chlorine and fluorine.
• mercapto shall refer to the substituent -SH.
• carboxy shall refer to the substituent -COOH.
• cyano shall refer to the substituent -CN.
• aminosulfonyl shall refer to the substituent - SO 2 NH 2 .
• carbamoyl shall refer to the substituent -C(O)NH 2 .
• sulfanyl shall refer to the substituent -S-.
• 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 in 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.
• BOP (1 -benzotriazolyloxy)tris(dimethylamino)phosphonium hexafluorophosphate
• LAH lithium aluminum hydride
• HOBt 1 -hy droxybenzotriazole
• NMM N-methylmo ⁇ holine, 4-methylmo ⁇ holine
• HMPA hexamethylphosphoric triamide
• LPS lipopolysaccharide
• EDTA ethylenediamine tetraacetic acid
• FBS fetal bovine serum
• PBS phosphate buffered saline solution
• ELISA enzyme - linked immunosorbent assay
• Rj, R 2 , R 3 , R 4 , R 5 , and Rg are defined as for formula (II).
• RPG ! is a protecting group suitable for the hydro ylamine oxygen, such as benzyl or
• R 30 is chosen from the group consisting of hydroxyl, O-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 dicyclohexylcarbodiimide in suitable solvent, such as DMF.
• R 30 is O-C 6 F 5
• the conversion of (IV) to (V) is conducted by treating (IV) in a suitable solvent such as dichloromethane with pentafluorophenyl trifluoroacetate in the presence of pyridine, 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 triethylamine.
• the removal of the RPG ] group where RPG[ is benzyl may be achieved by hydrogenation of (VII) with palladium on barium sulfate in a suitable solvent such as ethanol 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).
• Ri and R 2 are as defined for formula (II).
• R 3 ) O is a nucleofugal group such as methanesulfonate or p-toluenesulfonate.
• RPG ! is as defined for reaction Scheme 1.
• the acid of formula (VIII) may be converted to the alcohol of formula (IX) by treatment with HOBt, O-benzylhydroxylamine hydrochloride or O-(2- tetrahydropyranyl)h droxylamine, NMM, and a carbodiimide reagent such as EDC in a suitable solvent such as DMF.
• the alcohol of formula (IX) may be converted to (X) by treatment with methanesulfonyl chloride or p-toluenesulfonyl chloride and pyridine in 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 triphenylphosphine 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 MeOH or THF, followed by acidification with 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 in the presence or absence of a suitable cosolvent such as dichloromethane.
• RPGi is as defined for reaction Scheme 1.
• Ri and R 2 are as defined as for formula (II).
• R 32 is lower alkoxy or 1-oxazolidinyl.
• a carbonyl compound of formula (XIII), where R 32 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).
• R 32 is a oxazolidinon-1-yl substituent
• treatment of (XIII) with a Lewis acid such as di(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 in reaction Scheme 2, or may be treated with a dehydrating agent such a p-toluenesulfonyl chloride in pyridine or with triphenylphosphine 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 pyridine or with triphenylphosphine and diethyl azodicarboxylate in a suitable solvent such as THF
• a suitable solvent such as THF
• Ri and R 2 are as defined for formula (II).
• RPG ! is as defined for reaction Scheme 1.
• R 33 is lower alkyl.
• L is bromide, iodide, or trifiuoromethanesulfonyloxy.
• R 34 , R 35 , R 36 , R 37 , and R 38 may be, independently, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, or hydrogen, where alkyl, alkenyl, alkynyl, and cycloalkyl substituents may contain one or more O, S, SO, or SO 2 substituents.
• the ketoester of general formula (XIX) may be prepared by reaction of ester (XVII) with a strong base such as LDA followed by treatment with the aldehyde (XIV).
• the resulting hydroxyester (XVIII) may be used directly or converted to the ketoester (XIX) by oxidation with, for example, pyridinium dichromate in a solvent such as dichloromethane.
• the ketoester of general formula (XIX) may be reduced with a reducing agent such as sodium borohydride to afford the hydroxyester (XVIII), where R 33 is a small alkyl group such as ethyl, methyl, or tert-butyl.
• a chiral catalyst or chiral ligand in the presence of a reducing agent such as hydrogen or a metal hydride such as borane or LAH may be employed to afford (XVIII) with chiral induction at the newly formed asymmetric center.
• the alcohol (XVIII) may be converted to (XX) by treatment with a strong base such as LDA in a suitable solvent such as THF, followed by the addition of R 2 -L in the presence or absence of a cosolvent such as DMPU. Removal of the ester group by hydrolysis with aqueous hydroxide ion or, in the case where R 33 is tert-butyl, by treatment with a strong acid such as TFA, affords (VIII).
• Hydroxy acid (XXI) is obtained by hydrolysis of the ester group of (XVIII) with aqueous alkali.
• (XXI) may be obtained by treatment of (XVIII) with TFA, where R 33 is tert-butyl.
• Coupling of the hydroxy acid (XXI) with an allylic alcohol (XXII) in the presence of a dehydrating agent such as EDC and a catalyst such as 4-dimethylaminopyridine provides the ester (XXIII).
• a dehydrating agent such as EDC
• a catalyst such as 4-dimethylaminopyridine
• protection of the alcohol functionality of ester (XVIII) with, for example, a tert-butyldimethylsilyl group may be required before processing of (XVIII) to the acid.
• R 3 , R 4 , Rj, and Rg are as defined for general formula (II).
• RPG 2 is a protecting group such as tert-butoxycarbonyl or benzy loxycarbony 1.
• R 39 is hydroxyl or halogen.
• the acid of formula (XXV) may be converted in situ to (XXVI), where R 39 is bromide, by treatment with bromo-tris(pyrrolidino)phosphonium hexafluorophosphate in a suitable solvent such as DMF in the presence of an organic base such as N, N- diisopropylethylamine.
• a suitable solvent such as DMF
• an organic base such as N, N- diisopropylethylamine
• the intermediate of formula (XXVI) where R 39 is hydroxyl may be treated with carbonyldiimidazole in a solvent such as dichloromethane, followed by treatment with the amine (XXVII) to afford (XXVIII).
• the intermediate of formula (XXV) may be treated with HOBt, the amine (XXVII), an organic base such as NMM, and a carbodiimide reagent such as EDC in a suitable solvent such as DMF, at a temperature of 0 °C to 80 °C to provide (XXVIII).
• the compound of formula (XXVIII) may be converted to (VI) by deprotection, conditions being particular to the nature of RPG 2 .
• conversion of (XXVIII) to (VI) may be accomplished by treatment of (XXVIII) with trifluoroacetic acid in the presence or 71 absence of a suitable solvent such as dichloromethane, at a temperature of 0 °C to 50 °C.
• a suitable solvent such as dichloromethane
• R 3 and R are as defined for general formula (II).
• RPG 2 is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl.
• R 40 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or
• R 41 is lower alkyl or hydrogen.
• R 42 is lower alkyl or hydrogen.
• R ⁇ is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, O, NH, N-alkyl, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or SO substituents.
• R 44 is alkyl- alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO 2 substituents.
• the compound (XXIX) may be treated with the reagent l ⁇ -R ⁇ -COCl in a solvent such as dichloromethane in the presence of tertiary base such as triethylamine to afford (XXX).
• (XXIX) may be treated with R 44 - 43 -COOH (where R_, 3 is not O, N, or N-alkyl) and a dehydrating agent such as EDC in a solvent such as DMF to afford (XXX).
• R 43 is NH
• R 44 -NCO a solvent such as dichloromethane.
• (XXXI) may be prepared by treating (XXIX) with R 44 -SO 2 .CI in the presence of a tertiary amine base such as NMM in a solvent such as dichloromethane. Removal of the alkyl group R 42 by saponification with aqueous base (or, if appropriate and where R_ j2 is tert-butyl, by treatment with trifluoroacetic acid) provides (XXV).
• Reaction scheme 7 depicts an alternate preparation of an intermediate of general formula (XXV).
• R 3 and R 4 are as defined for general formula (II).
• RPG 2 is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl.
• R ⁇ o is is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or
• R_u is lower alkyl or hydrogen.
• R 42 is lower alkyl or hydrogen.
• R 44 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO 2 substituents.
• R 45 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO 2 substituents.
• R_j 6 is is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO 2 substituents.
• 6 may be taken together to constitute three- to ten-membered ring.
• the amine compound (XXIX) is treated with (XXXII) in the presence of a tertiary base such as triethylamine or NMM to afford (XXXIII).
• a tertiary base such as triethylamine or NMM
• Reaction scheme 8 depicts an alternate preparation of an intermediate of general formula (XXV).
• R 3 and R are as defined for general formula (II).
• RPG 2 is a protecting group such as tert-butoxycarbonyl or benzy loxycarbony 1.
• R 40 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or
• R t2 is lower alkyl or hydrogen.
• R 3 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, O, NH, N-alkyl, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or SO 2 substituents.
• R 44 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO 2 substituents.
• R 47 is alkylene or heteroarylene.
• R t g is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO 2 substituents.
• the hydroxy compound (XXXV) may be treated with the reagent R 44 -R 43 - COC1 in a solvent such as dichloromethane in the presence of tertiary base such as triethylamine to afford (XXXVI).
• (XXXV) may be treated with - ⁇ - COOH (where R 43 is not O, N, or N-alkyl) and a dehydrating agent such as EDC and a catalyst such as DMAP in a solvent such as DMF or dichloromethane to afford (XXXVI).
• the compound (XXXVI) where R 43 is NH may be prepared by treating (XXXV) with R 44 -NCO in a solvent such as dichloromethane.
• the ether (XXXVII) may be prepared by treating (XXXV) with in the presence of a base such as potassium carbonate or sodium hydride in a solvent such as DMF. .
• Removal of the alkyl group R 42 by saponif ⁇ cation with aqueous base (or, if appropriate and where R 42 is tert-butyl, by treatment with trifluoroacetic acid) provides the acid (XXV).
• Reaction scheme 9 depicts an alternate preparation of an intermediate of general formula (XXV).
• R 3 and R are as defined for general formula (II).
• RPG 2 is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl.
• R 0 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or SO 2 substituents.
• R 42 is lower alkyl or hydrogen.
• R 47 is alkylene or heteroarylene.
• R 48 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO 2 substituents. n is 1 to 2.
• the thioether (XXXIX) may be prepared by treating (XXXVIII) with R 8 R 47 BT or R 4 ⁇ R 7 I and a base such as potassium carbonate or sodium hydride in a solvent such as DMF.
• the sulfur atom may be oxidized with a reagent such as m- chloroperoxybenzoic acid.
• Use of one molar equivalent of oxidant may be employed to provide (XL) where n is 1.
• Use of two molar equivalents of oxidant may be employed to provide (XL) where n is 2.
• R 3 and R 4 are as defined for general formula (II).
• RPG 2 is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl.
• R 40 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or
• R 42 i lower alkyl or hydrogen.
• R 49 is is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO 2 substituents.
• R 50 is is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO 2 substituents.
• R 49 and R 50 may be taken together to constitute a three- to ten-membered ring.
• the thiol (XXXVIII) may be oxidized to the disulfide (XLI) by treatment with a mild base such as TEA and oxygen or air.
• Either the thiol (XXXVIII) or the disulfide (XLI) may be converted to the sulfonyl chloride (XLII) by treatment with chlorine gas in tetrachloromethane.
• Treatment of the sulfonyl chloride (XLII) with an amine R 49 R 50 NH in the presence of a tertiary amine base such as TEA or NMM affords (XLIII).
• a tertiary amine base such as TEA or NMM
• Reaction scheme 11 depicts an alternate preparation of an intermediate of general formula (XXV).
• R 3 and R are as defined for general formula (II).
• RPG 2 is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl.
• R JO is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or
• R 42 is lower alkyl or hydrogen.
• R 49 is is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO 2 substituents.
• R 50 is is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one or more O, S, SO, or SO 2 substituents.
• R, 9 and R 50 may be taken together to constitute a three- to ten-membered ring.
• the acid (XLIV) may be converted to the amide (XLV) by treatment of
• Reaction scheme 12 depicts an alternate preparation of an intermediate of general formula (VI)-
• R 3 , R 4 , R 5 , and R ⁇ are as defined for general formula (II).
• R 5 ⁇ is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or
• R 52 is CO or SO 2 .
• R 53 is NH, N-alkyl, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, or heteroarylene, where alkylene, alkenylene, alkynylene, cycloalkylene, and cycloalkenylene substituents may contain one or more O, S, SO, or SO 2 substituents.
• R 5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, or hydrogen, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl substituents may contain one ormore O, S, SO, or SO 2 substituents.
• the amino alcohol (XLVI) is treated with phthalic anhydride in a solvent such as toluene at a temperature of from 25 °C to 120 °C, or with N- ethoxycarbonylphthalimide and sodium bicarbonate at a temperature of from - 20 °C to 45 °C, followed by oxidation of the resulting phthalimido alcohol with an oxidizing agent such as pyridinium chlorochromate to provide the aldehyde (XL VII).
• Treatment of (XLVII) with (R)-phenylglycinol in a solvent system such as chloroform - MeOH followed by addition of trimethylsilyl cyanide affords (XL VIII) with stereochemistry as depicted.
• (LI) may be treated with hydrazine in a solvent such as MeOH or ethanol, and the resulting amine may be treated with R 54 R 53 R 52 C1 to provide (LII) where R 53 is not NH.
• Use of R 54 NCO in this step provides (LII) where R 52 is CO and R 53 is NH.
• Treatment of (LII) with HCl in dioxane or trifluoroacetic acid affords (VI).
• the compounds of the present invention can be administered in such oral (including 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.
• oral 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), intraperitoneal, intraarticular, 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 in 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 300 mg/kg of body weight per day, and particularly 1 to 100 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 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 in divided doses of two, three or four times daily.
• preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin 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 in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” 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.
• carrier suitable pharmaceutical diluents, excipients or carriers
• the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
• an oral, non-toxic pharmaceutically acceptable inert carrier 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. Flavoring, 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.
• Glidants 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 solubilizing 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 alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
• Lubricants used in 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, agar, bentonite, xanthan gum and the like.
• Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant 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 aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
• a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
• a solution retardant such as paraffin
• a resorption accelerator such as a quaternary salt
• an absorption agent such as bentonite, kaolin 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.
• 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 stearic 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
• 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 in 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 in a non-toxic vehicle.
• Solubilizers 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 in the form of liposome 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, stearylamine or phosphatidylcholines.
• 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 polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine 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
• Parenteral administration can be effected by utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound in a non-toxic liquid vehicle suitable for injection such as aqueous oleaginous medium and sterilizing the suspension or solution. Alternatively, 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 isotonic. Stabilizers, preservations and emulsifiers can also be added.
• Rectal administration can be effected utilizing suppositories in which the compound is admixed with low-melting water-soluble or insoluble solids such as polyethylene glycol, cocoa butter, higher ester as for example flavored aqueous solution, while elixirs are prepared through myristyl 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.
• suitable 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, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
• a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
• a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropan
• compositions are those in a form suitable for oral administration, such as tablets and liquids and the like and topical formulations.
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof.
• the pharmacologically effective amount of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, solvate, biohydrolyzable ester, biohydrolyzable amide, affinity reagent, or prodrug thereof is sufficient to inhibit the cellular release of mature tumor necrosis factor alpha, to inhibit a matrix metalloprotease, to inhibit the shedding of cell surface protein ectodomains, to inhibit the growth of tumor metastases, to treat diabetes or to treat arthritis.
• Ethyl butyrylacetate (50.0 g, 316 mmol) is stirred in 75 mL of absolute ethanol as [RuCl 2 (BINAP)] 2 'NEt 3 (0.139 g, 0.158 mmol) is added along with 2 N hydrochloric acid (0.158 mL, 0.316 mmol).
• the mixture is placed on a pressure hydrogenation apparatus and degassed by evacuating and filling with nitrogen several times.
• the vessel is then pressurized with hydrogen to 65 psi.
• the reaction is heated to 70 °C for 36 h and then is allowed to cool to 25 °C.
• the resulting reddish brown solution is concentrated under reduced pressure and the product distilled (40-50 °C, 200 millitorr) to give a clear oil (50.0 g, 99% yield, >99% enantiomeric excess determined by chiral analytical HPLC).
• Methallyl bromide (6.14 g, 45.5 mmol) and HMPA (5 mL) are added and the reaction mixture is allowed to warm to -20 °C and stirred for 16 h.
• the reaction mixture is quenched by addition of a saturated ammonium chloride solution (5 mL), poured into 1 N hydrochloric acid (50 mL) and extracted with two 100 - mL portions of EtOAc.
• Example 1 k (2R,3S)-3 -(Formyl-2-tetrahydropyranyloxyamino)-2-(2-methyl- 1 - propyl)pentanoic Acid [( 1 S)-5-Benzyloxycarbonylamino- 1 -( 1 ,3 ,4-thiadiazol-2- ylcarbamoyl)- 1 -pentyljamide
• the reaction mixture is stirred 1 h, then treated with a solution of 3-bromo-2-methyl-l-propene (7.6 mL, 75.6 mmol) in 10 mL of HMPA and is allowed to stand at -20 °C overnight.
• the reaction mixture is poured into ice-cold 1 N hydrochloric acid (300 mL) and extracted with two 200 - mL portions of EtOAc.
• the combined organic layers are washed with two 100 - mL portions of saturated aqueous sodium chloride, dried over sodium sulfate, and filtered. The solvents are removed under reduced pressure.
• a mixture of powdered potassium carbonate (15.0 g, 109 mmol) in 200 mL of acetone is refluxed for 0.5 h then treated with a solution of the above methanesulfonate in 100 mL of acetone and refluxed for an additional 48 h.
• the resulting slurry is filtered to remove salts and the filtrate is concentrated under reduced pressure.
• the crude oil is dissolved in 200 mL of EtOAc and washed successively with 50 mL of water and 50 mL of saturated aqueous sodium chloride and the combined organic extracts are dried over sodium sulfate.
• the organic extracts are washed with two 10 - mL portions of 0.1 N hydrochloric acid, two 10 - mL portions of 1 M aqueous sodium carbonate, and one 10 - mL portion of saturated aqueous sodium chloride.
• the organic solution is dried over sodium sulfate and concentrated under reduced pressure followed by purification by flash chromatography on silica gel affording 0.150 g of the crude product which is dissolved in 10 mL of acetic acid and allowed to stand overnight.
• reaction mixture is acidified to pH 2 with 1 M sodium bisulfate and extracted with two 100 - mL portions of EtOAc.
• the combined organic extracts are washed with two 40 - mL portions of saturated aqueous sodium chloride and dried over sodium sulfate.
• Concentration under reduced pressure affords 2.80 g (80%) of (2R)-3 -(2 -benzy loxycarbony lamino- 1- ethylsulfanyl)-3-methyl-2-tert-butoxycarbonylaminobutanoic acid as a gum.
• the organic extracts are washed with two 10 - mL portions of 0.1 N hydrochloric acid, two 10 - mL portions of 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride. Drying over sodium sulfate and removal of the solvents under reduced pressure followed by purification by silica gel chromatography affords 0.100 g of the crude product which is dissolved in 10 mL of acetic acid and allowed to stand overnight.
• the organic extracts are washed with two 25 - mL portions of 0.1 N hydrochloric acid, two 25 - mL portions of 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride. Drying over sodium sulfate and concentration under reduced pressure is followed by purification by silica gel chromatography (elution with 50% EtOAc - hexanes followed by EtOAc) affording 0.100 g of the crude product which is dissolved in 10 mL of acetic acid and allowed to stand overnight.
• Diisopropylamine (3.92 mL, 30.0 mmol) is dissolved in 30 mL of anhydrous THF and cooled using an ice water bath.
• n-Butyllithium (16.5 mL, 2.0 M solution in cyclohexane, 27.5 mmol) is added dropwise over 10 min and the resulting pale yellow solution cooled to -78 °C.
• 2-Methyl-l -butyl iodide (3.70 g, 18.7 mmol) is dissolved in 10 mL of a 1 :1 THF - HMPA solution and added to the reaction mixture. The resulting solution is allowed to warm slowly to 0 °C over 3 h. After stirring overnight at 4 °C 250 mL of a 5% aqueous citric acid solution is added and the organics are extracted with two 250 - mL portions of ether and then washed with saturated aqueous sodium chloride. The organics are then dried over sodium sulfate and concentrated in vacuo.
• Potassium carbonate (0.87 g, 6.32 mmol) is added to 10 mL of acetone and the suspension is refluxed for 1 h.
• the above methanesulfonate (0.80 g, 2.11 mmol) is dissolved in 5 mL of acetone and then added to the refluxing mixture.
• the resulting thick slurry is refluxed for 16 h and is cooled to 25 °C and filtered.
• Pentafluorophenyl (2i.,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(2- methyl- 1 -butyl)hexanoate (0.10 g, 0.20 mmol) is dissolved in 2.5 mL of anhydrous DMF. To this solution is added HOBt (.003 g, 0.02 mmol) followed by (2S)-6- benzyloxycarbonylamino-2-aminohexanoic acid l,3-thiazol-2-ylamide (0.09 g, 0.24 mmol). The reaction is heated at 50 °C for 16 h.
• Example 6a (2E)-2-Buten-l-yl (3/?)-3-Hydroxybutyrate
• a mixture of ethyl (3- z -)-3-hydroxybutyrate (15 g, 0.127 mol), (E)-crotyl alcohol (100 g, 1.39 mol) and titanium tetraisopropoxide (3.5 g, 0.012 mol) are heated at 70 °C overnight under a stream of argon.
• the reaction mixture is cooled to 25 °C and treated with 5 mL of saturated aqueous sodium bicarbonate and stirred vigorously for 1 h to destroy catalyst.
• the resulting slurry is cooled to 25 °C, treated with 75 mL of 0.25 M aqueous sodium hydroxide, and extracted with two 50 - mL portions of ether.
• the aqueous layer is then acidified to pH 2 using concentrated hydrochloric acid (with ice cooling) and then is extracted with five 100 - mL portions of chloroform.
• the combined organic extracts are dried over sodium sulfate and filtered, and the solvents are removed under reduced pressure affording 1.50 g (75%) of
• a mixture of powdered potassium carbonate (5.0 g, 33 mmol) in 100 mL of acetone is refluxed for 0.5 h then treated with a solution of the above methanesulfonate in 10 mL of acetone and refluxed for an additional 48 h.
• the resulting slurry is allowed to cool to 25 °C, then is filtered and the filtrate is concentrated under reduced pressure.
• the crude oil is dissolved in 100 mL of EtOAc and washed successively with water and saturated aqueous sodium chloride. The combined organics are dried over sodium sulfate.
• reaction mixture is warmed to 50 °C overnight, poured into water (10 mL) and extracted with two 15 - mL portions of EtOAc.
• the organic extracts are washed with two 10 - mL portions of 0.1 N hydrochloric acid, two 10 - mL portions of 1 M aqueous sodium carbonate , and saturated aqueous sodium chloride. Drying over sodium sulfate and concentration under reduced pressure followed by purification by chromatography on silica gel
• Diisopropylamine (5.89 mL, 44.9 mmol) is dissolved in 30 mL of anhydrous THF and chilled to 0 °C.
• n-Butyllithium (16.5 mL of a 2.5 M solution in hexanes, 41.2 mmol) is added dropwise over 10 min and the resulting pale yellow solution cooled to -78 °C.
• Cyclohexylmethyl iodide (6.29 g, 28.05 mmol) is dissolved in 20 mL of a 1 : 1 THF/HMPA solution and added to the dianion at -78 °C dropwise. The resulting solution is allowed to warm slowly to 0 °C over 3 h. After stirring overnight at 4 °C 250 mL of a 5% aqueous citric acid solution is added and the mixture is extracted with two 250 - mL portions of ether. The combined organics are washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated in vacuo.
• the crude product is chromatographed on silica gel (elution with 25% EtOAc - hexanes) to provide ethyl (2 ⁇ ,3 .)-2-cyclohexylmethyl-3-hydroxyhexanoate (1.44 g, 30% yield) as an oil.
• Diisopropylamine (8.61 mL, 65.7 mmol) is dissolved in 40 mL of anhydrous THF and chilled to-0 °C.
• n-Butyllithium (30.1 mL of a 2.0M solution in hexanes, 60.2 mmol) is added dropwise over 10 min and the resulting pale yellow solution cooled to -78 °C.
• Benzyl bromide (3.60 mL, 30.1 mmol) is dissolved in 12 mL of a 1 :1 THF/HMPA solution and added at -78 °C dropwise. The resulting solution is allowed to warm slowly to 0 °C over 3h. Aqueous 5% citric acid solution (250 mL) is added and the organics are extracted with two 250 - mL portions of ether. The combined organics are washed with saturated aqueous sodium chloride.
• Methyl (2/?,3 ?)-2-benzyl-3-hydroxyhexanoate (3.35 g, 14.2 mmol) is dissolved in 35 mL of MeOH. Under an argon atmosphere 1.00 g of 5% rhodium on carbon is added. The reaction vessel is evacuated and refilled with hydrogen several times and then pressurized with hydrogen to 65 psi. After 8 h the reaction vessel is evacuated and refilled with nitrogen. The solution is filtered and the filtrate concentrated in vacuo giving methyl (2i?,3/?)-2-cyclohexylmethyl-3- hydroxyhexanoate as a clear oil (3.44 g, 99% yield).
• Potassium carbonate (4.09 g, 29.6 mmol) is added to 30 mL of acetone and the suspension is refluxed for 1 h.
• the above crude methanesulfonate (4.00 g, 9.86 mmol) is dissolved in 10 mL acetone and added.
• the resulting thick slurry continued to reflux for 16 h and is then cooled to 25 °C.
• the mixture is filtered and the filtrate is concentrated under reduced pressure giving (3i?,4S)-3-cyclohexylmethyl-4-propyl-l- (2-tetrahydropyranyloxy)azetidin-2-one as an oil (2.28 g, 75% yield).
• Pentafluorophenyl (2i?,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2- (cyclohexylmethyl)hexanoate (0.20 g, 0.38 mmol) is dissolved in 5 mL of anhydrous DMF. To this solution is added HOBt (.005 g, 0.04 mmol) followed by (2S)-6- benzyloxycarbonylamino-2-aminohexanoic acid l,3-thiazol-2-ylamide (0.17 g, 0.46 mmol). The reaction is heated at 50 °C for 16 h.
• Example 8a (2i-,3S)-3-(Formyl-2-tetrahydropyranyloxyamino)-2- (cyclohexylmethyl)hexanoic Acid [(lS)-5-Benzyloxycarbonylamino- 1 -(1 ,3,4- thiadiazol-2-ylcarbamoyl)- 1 -pentyljamide
• Example 8 (2R,3S)-3-(Formyl-hydroxyamino)-2-(cyclohexy lmethy l)hexanoic Acid [(lS)-5-Benzyloxycarbonylamino-l-(l, 3 ,4-thiadiazol-2-ylcarbamoyl)-l -pentyljamide (2 ⁇ ,3S)-3-(Formyl-2-tetrahydropyranyloxyamino)-2- (cyclohexylmethyl)hexanoic acid [(lS)-5-benzyloxycarbonylamino-l-(l,3,4- thiadiazol-2-y lcarbamoyl)- 1 -pentyljamide (0.19 g, 0.27 mmol) is dissolved in 2 mL of 80% aqueous acetic-acid and is stirred overnight at 45 °C.
• a solution of 37.7 g (372 mmol) of diisopropylamine in 300 mL of dry THF is cooled to -40 °C and treated with 186.2 mL (372 mmol) of 2.0 M n-butyllithium in hexanes. The mixture is stirred at 0 °C for 15 min. The solution is then cooled to -78 °C and treated dropwise with 20 g (170 mmol) of methyl (32-)-3-hydroxybutyrate. This solution is stirred at 0 °C for 45 min, followed by stirring at -78 °C for 15 min.
• Methyl (2i?,3i?)-2-(2-methyl-2-propen-l-yl)-3-hydroxybutanoate (8.1 g, 47.1 mmol) in 85 mL of EtOAc is treated with 800 mg of 10% palladium on carbon and the mixture is evacuated and purged with nitrogen. The heterogeneous solution is stirred under 52 psi of hydrogen for a period of 1.5 h. Filtration and concentration of the filtrate in vacuo affords 7.99 g (96%) of methyl (2i?,3i?)-2-(2-methyl-l-propyl)-3- hydroxybutanoate as an oil.
• Methyl (2/_,3i-)-2-(2-methyl- 1 -propyl)-3-hydroxybutanoate (7.99 g, 46 mmol) in 50 mL of THF is treated with 50 mL of water containing 3.9 g (92 mmol) of lithium hydroxide monohydrate.
• the reaction flask is treated with 5.0 mL of MeOH and allowed to stir for 17 h at 25 °C.
• the mixture is partitioned between water and ether followed by separation of the aqueous layer.
• the aqueous solution is brought to pH 3 with 6 N aqueous hydrochloric acid and the mixture is extracted with ether.
• the crude methanesulfonate is stirred in 150 mL of dry acetone and treated with 7.5 g (54.3 mmol) of potassium carbonate.
• the reaction is stirred at reflux for 17 h and the mixture is then allowed to cool to 25 °C.
• the mixture is filtered and the filtrate is concentrated to afford an oil (4.5 g) which is chromatographed on silica gel (elution with 4:1 hexanes - EtOAc) to give 3.5 g (65%) of (3i?,4S)-3-(2-methyl-l- propyl)-4-methyl-l-(2-tetrahydropyranyloxy)azetidin-2-one as an oil.
• THF is cooled to -45 °C.
• n-Butyllithium (32.4 mL, 2.5 M solution in hexanes) is added dropwise over 10 minutes.
• a solution of methyl (3 ?)-3-hydroxypentanoate (5.1 g, 38.6 mmol) in 5 mL of anhydrous THF is added dropwise and the mixture is stirred at -45 °C for 45 min.
• Benzyl bromide (7.90 g, 46.3 mmol) is dissolved in 5 mL of anhydrous THF - DMPU (1:1) and added to the reaction mixture. Stirring is continued at -45 °C for 1 h, then at -20 °C for 18 h.
• Methyl (2i_,3i?)-2-benzyl-3-hydroxypentanoate (4.60 g, 20.7 mmol) is dissolved in 8 mL of MeOH in a pressure vessel.
• 5% Rhodium on alumina (0.25 g) is added, and the system is evacuated and flushed with nitrogen, evacuated again and filled with 50 psi of hydrogen. After 5 d, the hydrogenation is 90 % complete by 1H NMR analysis.
• Example 35a (27?,3S)-3-(Formyl-2-tetrahydropyranyloxyamino)-2-(2-methyl-l- propyl)hexanoic Acid [( 1 S)-2,2-Dimethy 1- 1 -( 1 ,3 -thiazol-2-y lcarbamoyl)- 1 - propyl ljamide
• the resulting solution is heated to 50 °C and stirred for 20 h then poured into 50 mL of 1 :1 EtOAc - hexanes and washed sequentially with 1 M aqueous HCl, 1 M aqueous sodium carbonate solution and brine.
• Methyl isobutyrylacetate (135 g, 0.935 mol) in 135 mL of degassed MeOH is treated with 564 mg of [(RuCl 2 )(PhH)( ?-(+)-BINAP)j.
• the solution is purged with nitrogen and stirred under 62 psi of hydrogen while heating at 100 °C for 72 h.
• the reaction mixture is cooled to 25 °C and degassed followed by purging with nitrogen.
• the reaction mixture is concentrated to dryness and the residue is distilled (39 C, 0.52 mm Hg) to afford 106 g of methyl (3S)-3-hydroxy-4-methylpentanoate as an oil.
• the product is used without further purification.
• Methyl 6,6,6-trifluoro-3-oxohexanoate (23 g, 116 mmol), 46 mL of degassed MeOH and 231 mg of [(RuCl 2 (PhH)( ⁇ -(+)-BINAP)] are mixed in a pressure bottle and the mixture is stirred under 72 psi of hydrogen gas at 100 °C for 20 h. The reaction mixture is cooled to 25 °C and purged with nitrogen gas. The reaction mixture is concentrated to dryness and the residue distilled (39 C, 0.52 mm Hg) to afford 21.1g of methyl (3 ⁇ )-3-hydroxy-6,6,6-trifluorohexanoate as an oil.
• the reaction is stirred at 4 C for a total of 18 h followed by concentrating to dryness.
• the residue is treated with water and made acidic (pH 5) using 12 N HCl.
• the mixture is extracted with ether and the organic layer is washed with saturated aqueous sodium chloride.
• the organic phase is dried over magnesium sulfate, concentrated in vacuo, and the residue is chromatographed on silica gel (elution with 20% EtOAc - hexanes) to yield 10 g of methyl (2 ?,3/?)-2-(2-methyl-2-propen-l-yl)-3-hydroxy-6,6,6- trifluorohexanoate as an oil.
• Methyl (2i?,3 ?)-2-(2-methyl-2-propen-l-yl)-3-hydroxy-6,6,6- trifluorohexanoate (10 g, 39 mmol) is taken up in 100ml of EtOAc and 500 mg of Pd(OH) 2 is added.
• the reaction mixture is evacuated and purged with nitrogen gas followed by stirring under 62 psi of hydrogen for 16 h at 25 °C.
• the reaction mixture is filtered and the filtrate is concentrated in vacuo to afford 9.7 g of methyl 2R,3R)-2- (2-methyl- 1 -propyl)-3-hydroxy-6,6,6-trifluorohexanoate as an oil.
• Methyl (2 ?,3 ⁇ )-2-(2-methyl-l-propyl)-3-hydroxy-6,6,6-trifluorohexanoate (9.7 g, 40 mmol) in 100 mL of THF and 21 mL of MeOH is treated with 100 mL (250 mmol) of 2.5 N aqueous sodium hydroxide. The reaction is stirred at 25 °C for 17 h and is concentrated to half its volume. The mixture is extracted with ether. The aqueous phase is made acidic (pH 3) and is extracted with ether.
• reaction mixture is stirred at 25 °C for a total of 17 h and is concentrated to dryness.
• the reaction mixture is partitioned between saturated sodium bicarbonate and dichloromethane.
• the organic phase is dried over magnesium sulfate and concentrated to dryness to yield 4.9 g of (27?,37?)-2-(2-methyl-l-propyl)-3-hydroxy-
• 2- tetrahydropyranyloxyamide (4.9 g, 14 mmol) in 50 mL of pyridine is cooled to 0-5 °C and treated with 2.5 g (22 mmol) of methanesulfonyl chloride. After 4 h at " 25 °C the mixture is concentrated to dryness.
• (2i?,3S)-3-(2-Tetrahydropyranyloxyamino)-2-(2-methyl-l-propyl)-6,6,6- trifluorohexanoic acid (981 mg, 2.9 mmol) in 10 mL of pyridine is cooled to 0-5 °C and treated with 1.28 g (14.5 mmol) of formic acetic anhydride. After 2 h at 0 °C the mixture is concentrated in vacuo to afford 1.0 g of (2i?,3S)-3-(formyl-2- tetrahydropyranyloxyamino)-2-(2-methyl-l-propyl)-6,6,6-trifluorohexanoic acid.
• aqueous phase is extracted with dichloromethane and the dichloromethane extracts are washed with 10% aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and dried over magnesium sulfate.
• the solvent is removed under vacuum and the residue is purified by chromatography on silica gel (elution with 2:1 EtOAc - hexanes) to give 0.23 g of (2S,3i?)-2-tert-butoxycarbonylamino-3-methoxybutanoic acid l,3-thiazol-2-ylamide as a white solid.
• Example 80a (2R,3S)-3 -(Formy l-2-tetrahydropyranyloxyamino)-2-(2-methyl- 1 - propyl)-6,6,6-trifluorohexanoic Acid [(lS,2S)-2-Methyl-l-(pyridin-2-ylcarb--moyl)-l- butyljamide
• Example 80 (2 ⁇ ,3S)-3-(Formyl-hydroxyamino)-2-(2-methyl- 1 -propyl)-6,6,6- trifluorohexanoic Acid [(IS, S)-2-Methyl- 1 -(pyridin-2-ylcarbamoyl)- 1 -butyljamide
• Example 81a (2J.,3S)-3-Formyl-2-tetrahydropyranyloxyamino-2-(2-methyl-l- propyl)butanoic Acid [( 1 S,2 ⁇ )-2-Methoxy- 1 -( 1 ,3-thiazol-2-ylcarbamoyl)- 1 - propyljamide
• Example 82a (27?,3S)-3-(Formyl-hydroxyamino)-2-[(2i?)-2-butyl]butanoic Acid [( 1 S)-2,2-Dimethyl- 1 -( 1 ,3 -thiazol-2-y lcarbamoyl)- 1 -propyljamide
• HATU 4,5-bjpyridinium hexafluorophosphate
• the product formation is measured at Excitation343/Emission450 nm after 45-180 minutes using a Fluostar SLT fluorescence analyzer. Percent inhibition is calculated at each inhibitor concentration and the data are plotted using standard curve fitting programs. IC 50 values are determined from these curves. Assays are run at low substrate concentration ([Sj «K m ) such that the calculated IC 50 values are equivalent to K; within experimental error.
• 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 cells per 60 ⁇ l assay) is incubated for 1 hr with 200 nM radiolabeled substrate (Biotin-
• the potency of compounds of the invention as inhibitors of release of soluble tumor necrosis factor ⁇ from stimulated monocytes in 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 + 10% FBS + penicillin/streptomycin + 1-glutamine). 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.

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