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WO2008109238A1 - Substituted cyclopentyl piperidine ccr2 antagonists - Google Patents

Substituted cyclopentyl piperidine ccr2 antagonists Download PDF

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Publication number
WO2008109238A1
WO2008109238A1 PCT/US2008/053941 US2008053941W WO2008109238A1 WO 2008109238 A1 WO2008109238 A1 WO 2008109238A1 US 2008053941 W US2008053941 W US 2008053941W WO 2008109238 A1 WO2008109238 A1 WO 2008109238A1
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Prior art keywords
phenyl
cyclopentyl
piperidin
cis
acrylamide
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PCT/US2008/053941
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French (fr)
Inventor
Mingde Xia
Scott R. Pollack
Duane E. Demong
Michael P. Wachter
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Janssen Pharmaceutica N.V.
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Publication of WO2008109238A1 publication Critical patent/WO2008109238A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention is directed to substituted cyclopentyl piperidine compounds that are antagonists to the chemoattractant cytokine receptor 2 (CCR2), pharmaceutical compositions and methods for use thereof. More particularly, the substituted cyclopentyl piperidine compounds are useful antagonists for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
  • CCR2 chemoattractant cytokine receptor 2
  • CCR2 is a member of the GPCR family of receptors, as are all known chemokine receptors, and are expressed by monocytes and memory T-lymphocytes.
  • the CCR2 signaling cascade involves activation of phospho lipases (PLCp 2 ), protein kinases (PKC), and lipid kinases (PI-3 kinase).
  • Chemoattractant cytokines are relatively small proteins (8-10 kD), which stimulate the migration of cells.
  • the chemokine family is divided into four subfamilies based on the number of amino acid residues between the first and second highly-conserved cysteines.
  • Monocyte chemotactic protein- 1 is a member of the CC chemokine subfamily (wherein CC represents the subfamily having adjacent first and second cysteines) and binds to the cell-surface chemokine receptor 2 (CCR2).
  • MCP-I is a potent chemotactic factor, which, after binding to CCR2, mediates monocyte and lymphocyte migration (i.e., chemotaxis) toward a site of inflammation.
  • MCP-I is also expressed by cardiac muscle cells, blood vessel endothelial cells, fibroblasts, chondrocytes, smooth muscle cells, mesangial cells, alveolar cells, T-lymphocytes, marcophages, and the like.
  • monocyte differentiation provides a secondary source of several proinflammatory modulators, including tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukin-1 (IL-I), IL-8 (a member of the CXC chemokine subfamily, wherein CXC represents one amino acid residue between the first and second cysteines), IL-12, arachidonic acid metabolites (e.g., PGE 2 and LTB 4 ), oxygen-derived free radicals, matrix metalloproteinases, and complement components.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL-I interleukin-1
  • IL-8 a member of the CXC chemokine subfamily, wherein CXC represents one amino acid residue between the first and second cysteines
  • IL-12 e.g., arachidonic acid metabolites (e.g., PGE 2 and LTB 4 ), oxygen-derived free radicals, matrix metalloproteinases, and complement components.
  • PGE 2 and LTB 4 arachidonic acid metabolites
  • inflammatory disease pathologies such as psoriasis, uveitis, atherosclerosis, rheumatoid arthritis, multiple sclerosis, Crohn's Disease, nephritis, organ allograft rejection, fibroid lung, renal insufficiency, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, tuberculosis, sarcoidosis, invasive staphylococcia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, Chronic Obstructive Pulmonary Disease (COPD), allergic asthma, periodontal diseases, periodonitis, gingivitis, gum disease, diastolic cardiomyopathies, cardiac infarction, myocarditis, chronic heart failure, angiostenosis, restenosis, reperfusion disorders, glomerulone
  • COPD Chronic Obstructive Pulmonary Disease
  • MCP-I antagonists either antibodies or soluble, inactive fragments of MCP-I
  • monocyte infiltration into inflammatory lesions is significantly decreased.
  • KO mice are resistant to the development of experimental allergic encephalomyelitis (EAE, a model of human MS), cockroach allergen-induced asthma, atherosclerosis, and uveitis.
  • TNF- ⁇ antagonists e.g., monoclonal antibodies and soluble receptors
  • MCP-I has been implicated in the pathogenesis of seasonal and chronic allergic rhinitis, having been found in the nasal mucosa of most patients with dust mite allergies. MCP-I has also been found to induce histamine release from basophils in vitro. During allergic conditions, both allergens and histamines have been shown to trigger (i.e., to up- regulate) the expression of MCP-I and other chemokines in the nasal mucosa of people with allergic rhinitis, suggesting the presence of a positive feedback loop in such patients.
  • CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established (J. Clin. Invest., 2006, 116, 115-124).
  • CCR2 antagonists for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease resulting from MCP-I induced monocyte and lymphocyte migration to a site of inflammation.
  • the invention provides substituted cyclopentyl piperidine compounds of Formula (I):
  • the compounds of the present invention are CCR2 antagonists are useful in preventing, treating or ameliorating CCR2 mediated inflammatory syndromes, disorders or diseases in a subject in need thereof.
  • the present invention also provides a method for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form thereof.
  • the present invention is directed to a compound of Formula (I)
  • Ri is cycloalkyl, aryl-cycloalkyl, aryl, aryl-alkenyl, aryl-amino, aryloxy-alkyl, arylthio-alkyl, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, nitro, amino, alkylamino, aminoalkyl, alkylaminoalkyl, carboxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or alkylthio;
  • X is CH-R 2 or C, wherein C is a piperidine ring carbon atom in common with a cycloalkyl ring carbon atom, thus forming a spiro ring system;
  • R 2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, nitro, amino, alkylamino, aminoalkyl, alkylaminoalkyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonylamino, aminosulfonylalkyl, alkylaminosulfonylalkyl, carboxy, alkylcarbonyl or alkoxycarbonyl; R 3 is selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, aminoalkyl, cyano, carboxy or alkoxycarbonyl; and
  • R 4 is selected from hydrogen, hydroxy, hydroxyalkyl, haloalkyl, alkyl, aminoalkyl, cyano, alkoxy, carboxy or alkoxycarbonyl.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein
  • Ri is aryl-cycloalkyl, aryl, aryl-alkenyl, aryl-amino, aryloxy-alkyl, arylthio-alkyl, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen or haloalkyl;
  • X is CH-R 2 ;
  • R 2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen, haloalkyl, amino or alkylamino;
  • R3 is selected from hydrogen or carboxy;
  • R 4 is selected from hydrogen, hydroxy or carboxy.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein
  • Ri is aryl-alkenyl, aryl-amino, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or haloalkyl;
  • X is CH-R 2 ;
  • R 2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or alkylamino;
  • R 3 is hydrogen;
  • R 4 is selected from hydrogen or hydroxy.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein
  • Ri is aryl-alkenyl or heterocyclyl, wherein aryl and heterocyclyl are each optionally substituted with two or three substituents selected from halogen or haloalkyl;
  • X is CH-R 2 ;
  • R 2 is aryl or heterocyclyl each substituted with one substituent selected from alkoxy, halogen or alkylamino;
  • R 3 is hydrogen
  • R 4 is selected from hydrogen or hydroxy.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein
  • Ri is aryl-alkenyl, wherein aryl is substituted with three halogen substituents;
  • X is CH-R 2 ;
  • R 2 is aryl substituted with one alkoxy substituent; R3 is hydrogen; and R 4 is hydroxy.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein Ri is aryl-cycloalkyl, aryl, aryl-alkenyl, aryl-amino, aryloxy-alkyl, arylthio-alkyl, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen or haloalkyl.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein Ri is aryl-alkenyl, aryl-amino, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or haloalkyl.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein Ri is aryl-alkenyl or heterocyclyl, wherein aryl and heterocyclyl are each optionally substituted with two or three substituents selected from halogen or haloalkyl.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein Ri is aryl-alkenyl, wherein aryl is substituted with three halogen substituents.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein R 2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen, haloalkyl, amino or alkylamino.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein R 2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or alkylamino.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein R 2 is aryl or heterocyclyl each substituted with one substituent selected from alkoxy, halogen or alkylamino.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein R 2 is aryl substituted with one alkoxy substituent.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein R 3 is selected from hydrogen or carboxy.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein R 3 is hydrogen.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein R 4 is selected from hydrogen, hydroxy or carboxy.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein R 4 is selected from hydrogen or hydroxy.
  • An example of the invention is a compound of Formula (I) or a form thereof, wherein R 4 is hydroxy.
  • An example of the invention is a compound of Formula (I) or a form thereof represented as follows:
  • Bond lines drawn into a ring system from a substituent variable indicate that the substituent may be attached to any of the substitutable ring atoms.
  • alkyl means a saturated branched or straight-chain hydrocarbon radical or linking group substituent having from 1-8 carbon atoms, wherein the radical is derived by the removal of one hydrogen atom from a carbon atom and the linking group is derived by the removal of one hydrogen atom from each of two carbon atoms in the chain.
  • An alkyl radical or linking group includes, without limitation, methyl, methylene, ethyl, ethylene, propyl, propylene, isopropyl, isopropylene, n-butyl, n-butylene, t-butyl, t-butylene, pentyl, pentylene, hexyl, hexylene and the like.
  • alkyl radical may be attached to a core molecule and further substituted on any atom when allowed by available valences.
  • alkenyl means a partially unsaturated alkyl radical or linking group substituent having at least one double bond, wherein the double bond is derived by the removal of one hydrogen atom from each of two adjacent carbon atoms in the chain.
  • An alkenyl radical or linking group includes, without limitation, vinyl, propenyl, propenylene, isopropenyl, isopropenylene, n-butenyl (1-butenyl), n-butenylene, crotyl (2-butenyl) and the like.
  • An alkenyl radical may be attached to a core molecule and further substituted on any atom when allowed by available valences.
  • alkoxy means an alkyl radical or linking group substituent attached through an oxygen- linking atom, wherein a radical is of the formula -O-alkyl and a linking group is of the formula -O-alkyl, and includes, without limitation, methoxy, ethoxy, propoxy, butoxy and the like.
  • An alkoxy radical may be attached to a core molecule and further substituted on any atom when allowed by available valences.
  • cycloalkyl means a saturated or partially unsaturated hydrocarbon ring system radical or linking group such as a C 3 _ 8 Cycloalkyl, C 3 _iocycloalkyl, Cs-scycloalkyl, C 5 _i 2 cycloalkyl or C 9 _i 2 cycloalkyl ring system radical and the like, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, indanyl, indenyl, 1,2,3,4-tetrahydro-naphthalenyl, 5,6,7,8-tetrahydro- naphthalenyl, 6,7, ⁇ -tetrahydro-JH-benzocycloheptenyl, 5,6,7,8,9, 10- hexahydro-benzocyclooctenyl
  • heterocyclyl means a saturated, partially unsaturated (such as those named with the prefix dihydro, trihydro, tetrahydro, hexahydro and the like) or unsaturated ring system radical, wherein at least one ring carbon atom has been replaced with one or more heteroatoms independently selected from N, O, S, S(O) or SO 2 .
  • a heterocyclyl ring system further includes a ring system having 1, 2, 3, or 4 carbon atom members replaced by a nitrogen atom. Alternatively, a ring may have 0, 1, 2, or 3 nitrogen atom members and 1 oxygen or sulfur atom member.
  • up to two adjacent ring members may be heteroatoms, wherein one heteroatom is nitrogen and the other heteroatom is selected from N, O, S, S(O) or SO 2 .
  • a heterocyclyl radical is derived by the removal of one hydrogen atom from a single carbon or nitrogen ring atom.
  • a heterocyclyl linking group is derived by the removal of one hydrogen atom from two of either a carbon or nitrogen ring atom.
  • a heterocyclyl radical may be attached to a core molecule and further substituted on any ring atom when allowed by available valences.
  • heterocyclyl includes, without limitation, furanyl, thienyl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, pyrrolyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2-imidazolinyl (also referred to as 4,5-dihydro-lH-imidazolyl), imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, tetrazolinyl, tetrazolidinyl, 2H-pyranyl, 4H-pyranyl, thiopyranyl, pyridinyl, piperidinyl, 1 ,4-dioxanyl,
  • aryl means an unsaturated aromatic hydrocarbon ring system radical, and includes, without limitation, phenyl, naphthalenyl, azulenyl, anthracenyl and the like.
  • An aryl radical may be attached to a core molecule and further substituted on any ring atom when allowed by available valences.
  • aryl-cycloalkyl means an aryl ring system attached via a bond to a cycloalkyl ring system, wherein the cycloalkyl ring functions as a linking group, such as a radical of the formula, without limitation, -cyclopropyl-phenyl and the like.
  • An aryl- cycloalkyl radical may be attached to a core molecule and further substituted on any ring atom when allowed by available valences.
  • alkoxycarbonyl means a radical of the formula: -C(O)-O-alkyl.
  • alkylamino means a radical of the formula: -NH-alkyl or -N(alkyl)2.
  • alkylaminoalkyl means a radical of the formula: -alkyl-NH-alkyl or
  • alkylaminocarbonyl means a radical of the formula: -C(O)-NH-alkyl or -C(O)-N(alkyl) 2 .
  • alkylaminosulfonyl means a radical of the formula: -SO 2 -NH-alkyl or -SO 2 -N(alkyl) 2 .
  • alkylaminosulfonylalkyl means a radical of the formula: -alkyl-SO 2 -NH-alkyl or -alkyl-SO 2 -N(alkyl) 2 .
  • alkylcarbonyl means a radical of the formula: -C(O)-alkyl.
  • alkylsulfonylamino means a radical of the formula: -NH-SO 2 -alkyl.
  • alkylthio means a radical of the formula -S-alkyl.
  • amino means a radical of the formula: -NH 2 .
  • aminoalkyl means a radical of the formula: -alkyl-NH2.
  • aminocarbonyl means a radical of the formula: -C(O)-NH 2 .
  • aminosulfonyl means a radical of the formula: -SO 2 -NH 2 .
  • aminosulfonylalkyl means a radical of the formula: -alkyl-SO 2 -NH 2 .
  • aryl-alkenyl means a radical of the formula: -alkenyl-aryl.
  • aryl-amino means a radical of the formula: -NH-aryl.
  • aryloxy-alkyl means a radical of the formula: -alkyl-O-aryl.
  • arylthio-alkyl means a radical of the formula: -alkyl-S-aryl.
  • carboxy means a radical of the formula -C(O)-OH.
  • halogen or halo means the group chloro, bromo, fluoro or iodo.
  • haloalkoxy means a radical of the formula: -O-alkyl-(halo) n , wherein one or more halogen atoms may be substituted on alkyl when allowed by available valences (wherein n represents that amount of available valences based on the number of carbon atoms in the chain), and includes monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy and the like.
  • haloalkyl means a radical of the formula: -alkyl-(halo) n , wherein one or more halogen atoms may be substituted on alkyl when allowed by available valences (wherein n represents that amount of available valences based on the number of carbon atoms in the chain), and includes monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl and the like.
  • heterocyclyl-alkenyl means a radical of the formula: -alkenyl-heterocyclyl.
  • hydroxyalkoxy means a radical of the formula: -O-alkyl-hydroxy, wherein alkyl is substituted on one or more available carbon chain atoms with one or more hydroxy radicals.
  • hydroxyalkyl means a radical of the formula: -alkyl-hydroxy, wherein alkyl is substituted on one or more available carbon chain atoms with one or more hydroxy radicals.
  • substituted means the independent replacement of one or more hydrogen atoms within a radical with that amount of substituents allowed by available valences.
  • form means, in reference to compounds of the present invention, such may exist as, without limitation, a salt, stereoisomer, tautomer, crystalline, polymorph, amorphous, solvate, hydrate, ester, prodrug or metabolite form.
  • the present invention encompasses all such compound forms and mixtures thereof.
  • isolated form means, in reference to compounds of the present invention, such may exist in an essentially pure state such as, without limitation, an enantiomer, a racemic mixture, a geometric isomer (such as a cis or trans stereoisomer), a mixture of geometric isomers, and the like.
  • the present invention encompasses all such compound forms and mixtures thereof.
  • the compounds of the invention may be present in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts for use in medicines, refer to non-toxic acidic/anionic or basic/cationic salt forms.
  • Suitable salt forms include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of an acid such as acetic acid, adipic acid, benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid, hydrochloric acid, maleic acid, malonic acid, phosphoric acid, saccharinic acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid and the like.
  • an acid such as acetic acid, adipic acid, benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid, hydrochloric acid, maleic acid, malonic acid, phosphoric acid, saccharinic acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid and the like.
  • suitable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • alkali metal salts e.g. sodium or potassium salts
  • alkaline earth metal salts e.g. calcium or magnesium salts
  • suitable organic ligands e.g. quaternary ammonium salts.
  • representative salts include the following: acetate, adipate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate (or camphosulphonate), carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, fumarate, gluconate, glutamate, glyconate, hydrabamine, hydrobromine, hydrochloride, iodide, isothionate, lactate, malate, maleate, malonate, mandelate, mesylate, nitrate, oleate, pamoate, palmitate, phosphate/diphosphate, saccharinate, salicylate, stearate, sulfate, succinate, tartrate, tosylate, trichloroacetate, trifluoroacetate and the like.
  • prodrug means a compound of Formula (I) or a form thereof that is converted in vivo into a functional derivative form that may contribute to therapeutic biological activity, wherein the converted form may be: 1) a relatively active form; 2) a relatively inactive form; 3) a relatively less active form; or, 4) any form which results, directly or indirectly, from such in vivo conversions.
  • Prodrugs are useful when said compound may be either too toxic to administer systemically, absorbed poorly by the digestive tract or broken down by the body before it reaches its target. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in, for example, "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • metabolite means a prodrug form of a compound of Formula (I) or a form thereof converted by in vivo metabolism or a metabolic process to a relatively less active functional derivative of said compound.
  • the invention includes compounds of various isomers and mixtures thereof.
  • the term "isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. Such substances have the same number and kind of atoms but differ in structure. The structural difference may be in constitution (geometric isomers) or in an ability to rotate the plane of polarized light (optical isomers).
  • optical isomer means isomers of identical constitution that differ only in the spatial arrangement of their groups. Optical isomers rotate the plane of polarized light in different directions.
  • optical activity means the degree to which an optical isomer rotates the plane of polarized light.
  • racemate or “racemic mixture” means an equimolar mixture of two enantiomeric species, wherein each of isolated specie rotates the plane of polarized light in the opposite direction such that the mixture is devoid of optical activity.
  • enantiomer means an isomer having a nonsuperimposable mirror image.
  • diastereomer means stereoisomers that are not enantiomers.
  • chiral means a molecule, which in a given configuration, cannot be superimposed on its mirror image. This is in contrast to achiral molecules, which can be superimposed on their mirror images.
  • the two distinct mirror image versions of the chiral molecule are also known as levo (left-handed), abbreviated L, or dextro (right handed), abbreviated D, depending on which way they rotate polarized light.
  • L left-handed
  • D dextro
  • R and S represent the configuration of groups around a stereogenic carbon atom(s).
  • An example of an enantiomerically enriched form isolated from a racemic mixture includes a dextrorotatory enantiomer, wherein the mixture is substantially free of the levorotatory isomer.
  • substantially free means the levorotatory isomer may, in a range, comprise less than 25% of the mixture, less than 10%, less than 5%, less than 2% or less than 1% of the mixture according to the formula:
  • an example of an enantiomerically enriched form isolated from a racemic mixture includes a levorotatory enantiomer, wherein the mixture is substantially free of the dextrorotatory isomer.
  • substantially free means the dextrorotatory isomer may, in a range, comprise less than 25% of the mixture, less than 10%, less than 5%, less than 2% or less than 1% of the mixture according to the formula:
  • geometric isomer means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system.
  • Substituent atoms (other than hydrogen) on each side of a carbon-carbon double bond may be in an E or Z configuration. In the “E” configuration, the substituents are on opposite sides in relationship to the carbon- carbon double bond. In the "Z” configuration, the substituents are oriented on the same side in relationship to the carbon-carbon double bond.
  • Substituent atoms (other than hydrogen) attached to a ring system may be in a cis or trans configuration.
  • the substituents are on the same side in relationship to the plane of the ring; in the "trans” configuration, the substituents are on opposite sides in relationship to the plane of the ring.
  • Compounds having a mixture of "cis” and “trans” species are designated "cis/trans”.
  • the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include combining the free base (or free acid) of each isomer of an isomeric pair using an optically active acid (or base) to form an optically active salt (followed by fractional crystallization and regeneration of the free base), forming an ester or amide of each of the isomers of an isomeric pair by reaction with an appropriate chiral auxiliary (followed by fractional crystallization or chromatographic separation and removal of the chiral auxiliary), or separating an isomeric mixture of either an intermediate or a final product using various well known chromatographic methods.
  • a compound of the present invention may have at least one crystalline, polymorph or amorphous form.
  • the plurality of such forms is intended to be included in the scope of the invention.
  • a compound of the present invention may form a solvate with water (i.e., hydrates) or common organic solvents (e.g., organic esters such as ethanolate and the like). The plurality of such solvates is also intended to be encompassed within the scope of this invention.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known in the art.
  • the compounds of Formula (I) or a form thereof in accordance with the present invention are CCR2 antagonists.
  • a compound of Formula (I) or a form thereof may have a mean inhibition constant (IC 50 ) against MCP-I binding to CCR2 of between about 50 ⁇ M to about 0.01 nM; between about 25 ⁇ M to about 0.01 nM; between about 10 ⁇ M to about 0.01 nM; between about 5 ⁇ M to about 0.01 nM; between about 1 ⁇ M to about 0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM; or, between about 10 nM to about 0.01 nM.
  • IC 50 mean inhibition constant against MCP-I binding to CCR2 of between about 50 ⁇ M to about 0.01 nM; between about 25 ⁇ M to about 0.01 nM; between about 10 ⁇ M to about 0.01 nM; between about 5 ⁇ M to about 0.01 nM; between about 1 ⁇ M to about 0.01 nM; between about
  • a compound of Formula (I) or a form thereof reduces MCP-I induced monocyte chemotaxis.
  • a compound of Formula (I) or a form thereof may have an IC50 for reduction in MCP-I induced monocyte chemotaxis of between about 50 ⁇ M to about 0.01 nM; between about 25 ⁇ M to about 0.01 nM; between about 10 ⁇ M to about 0.01 nM; between about 5 ⁇ M to about 0.01 nM; between about 1 ⁇ M to about 0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM; or, between about 10 nM to about 0.01 nM.
  • a compound of Formula (I) or a form thereof reduces MCP-I intracellular calcium mobilization.
  • a compound of Formula (I) or a form thereof may have an IC 50 for reduction in MCP-I induced intracellular calcium mobilization of between about 50 ⁇ M to about 0.01 nM; between about 25 ⁇ M to about 0.01 nM; between about lO ⁇ M to about 0.01 nM; between about 5 ⁇ M to about 0.01 nM; between about 1 ⁇ M to about 0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM; or, between about 10 nM to about 0.01 nM.
  • the present invention includes use of a compound of Formula (I) or a form thereof as a CCR2 antagonist comprising contacting the receptor with the compound.
  • the use of the compound of Formula (I) or a form thereof further comprises use of the compound in a pharmaceutical composition, medicine or medicament for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
  • the compound of Formula (I) or a form thereof may also be used in the manufacture of a medicament for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
  • the present invention also includes a medicament comprising an effective amount of a compound of Formula (I) or a form thereof.
  • the present invention also includes the use of a compound of Formula (I) or a form thereof in a method for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease in a subject in need thereof comprising administering to the subject an effective amount of the compound of Formula (I) or form thereof.
  • the present invention is directed to a method for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form thereof.
  • administering means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of Formula (I) or a form thereof. Such methods include administering an effective amount of said compound, compound form, composition or medicament at different times during the course of a therapy or concurrently in a combination form.
  • the methods of the invention are to be understood as embracing all known therapeutic treatment regimens.
  • subject refers to a patient, which may be animal, typically a mammal, typically a human, which has been the object of treatment, observation or experiment and is at risk of (or susceptible to) developing a syndrome, disorder or disease that is associated with elevated MCP-I expression or MCP-I overexpression, or a patient with an inflammatory condition that accompanies syndromes, disorders or diseases associated with elevated MCP-I expression or MCP-I overexpression.
  • an effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated.
  • the effective amount of a compound of the invention in such a therapeutic method is from about 0.001 mg/kg/day to about 300 mg/kg/day.
  • An example of a compound of Formula (I) or a form thereof is selected from the group consisting of:
  • An example of a compound of Formula (I) or a form thereof is selected from the group consisting of:
  • the invention includes the use of an instant compound for the preparation of a composition or medicament for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease in a subject in need thereof, wherein the composition or medicament comprises a mixture one or more compounds of the invention and an optional pharmaceutically acceptable carrier.
  • composition means a product comprising at least a compound of the invention, such as a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from such combinations of the specified ingredients in the specified amounts and one or more pharmaceutically acceptable carriers or any such alternatives to a compound of the invention and a pharmaceutically acceptable carrier therefor.
  • the term “medicament” means a product for use in preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
  • a pharmaceutically acceptable formulation includes a compound of Formula (I) or a form, composition or medicament thereof for either human or veterinary use.
  • CCR2 mediated inflammatory syndrome, disorder or disease means, without limitation, syndromes, disorders or diseases associated with elevated MCP-I expression, MCP-I overexpression or inflammatory conditions that accompany syndromes, disorders or diseases associated with elevated MCP-I expression or MCP-I overexpression.
  • unregulated means unwanted CCR2 activation in a multicellular organism resulting in harm (such as discomfort or decreased life expectancy) to the multicellular organism.
  • up-regulated means: 1). increased or unregulated CCR2 activity or expression, or 2). increased CCR2 expression leading to unwanted monocyte and lymphocyte migration.
  • the existence of an inappropriate or abnormal level of MCP-I or activity of CCR2 is determined by procedures well known in the art.
  • CCR2 mediated inflammatory syndromes, disorders or diseases include, without limitation, ophthalmic disorders, uveitis, atherosclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn's Disease, ulcerative colitis, nephritis, organ allograft rejection, fibroid lung, renal insufficiency, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, obesity, tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, invasive staphyloccocia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, asthma, allergic asthma, periodontal diseases, periodonitis, gingivitis, gum disease, diastolic cardiomyopathies, cardiac infarction, myocarditis, chronic heart
  • Uveitis generically refers to any inflammatory disease involving the eye. Uveitis can be divided into clinically distinct subtypes based on the part of the eye in which the inflammation is present (percentages correspond to patients known to fit these categories): anterior (51%), intermediate (13%), posterior (20%), or panuveitis (16%) and, according to the course of the disease, as either acute (16%), recurring (26%), or chronic (58%). Those with anterior uveitis (-19%) eventually develop irreparable vision damage despite aggressive treatment such as unilateral blindness (9%), bilateral blindness (2%), or unilateral or bilateral vision impairment (8%).
  • uveitis Most cases of uveitis are idiopathic, but known causes include infection (e.g., toxoplasmosis, cytomegalovirus, and the like) or development as a component of a systemic inflammatory and/or autoimmune disorder (e.g., juvenile RA, HLA-B27-associated spondyloarthropathies, sarcoidosis, and the like).
  • infection e.g., toxoplasmosis, cytomegalovirus, and the like
  • development as a component of a systemic inflammatory and/or autoimmune disorder e.g., juvenile RA, HLA-B27-associated spondyloarthropathies, sarcoidosis, and the like.
  • MCP-I myeloma
  • Patients with anterior uveitis have MCP-I present in large quantities in the aqueous humor of the eye.
  • the amount of MCP-I correlates with the severity of the clinical symptoms and the large number of mononuclear cells present in the cellular infiltrate.
  • Uveitis is also a potential complication resulting from cataract surgery and prophylactic use of antibiotics and corticosteroids is common for such patients.
  • Currently, most patients with anterior uveitis are first treated with topical corticosteroids. Injected or oral steroids may be used in severe cases, or if the disease is recurrent or chronic.
  • immunosuppressive agents e.g., cyclosporine, methotrexate, azathioprine, cyclophosphamide, and the like
  • cyclosporine methotrexate
  • azathioprine azathioprine
  • cyclophosphamide and the like
  • All of these drugs have potentially severe side-effects, particularly in children, and there is general agreement that there is an unmet medical need for safe and effective steroid substitutes or steroid-sparing agents.
  • An example of the invention is a method for preventing, treating or ameliorating CCR2 mediated ophthalmic disorders (such as uveitis, allergic conjunctivitis and the like), rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, obesity, chronic obstructive pulmonary disease, allergic rhinitis, asthma, allergic asthma, periodontal diseases (such as periodonitis, gingivitis, gum disease and the like) in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form, composition or medicament thereof.
  • CCR2 mediated ophthalmic disorders such as uveitis, allergic conjunctivitis and the like
  • rheumatoid arthritis such as uveitis, allergic conjunctivitis and the like
  • psoriasis psoriatic arthritis
  • atopic dermatitis obesity
  • Another example of the invention is a method for preventing, treating or ameliorating CCR2 mediated uveitis, wherein uveitis includes, without limitation, acute, recurring or chronic uveitis (such as anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis and the like) in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form, composition or medicament thereof.
  • uveitis includes, without limitation, acute, recurring or chronic uveitis (such as anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis and the like) in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form, composition or medicament thereof.
  • An example of the invention is a method for preventing, treating or ameliorating
  • Another example of the invention is a method for preventing, treating or ameliorating CCR2 mediated obesity in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form, composition or medicament thereof.
  • the invention includes a method for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form, composition or medicament thereof in a combination product with one or more therapeutic agents.
  • combination product refers to a compound of Formula (I) or a form, composition or medicament thereof in admixture with a therapeutic agent and an optional carrier for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
  • therapeutic agent refers to one or more anti-inflammatory agents (such as a small molecule, antibiotic, corticosteroid, steroid, and the like), anti-infective agents or immunosuppressive agents.
  • anti-inflammatory agents such as a small molecule, antibiotic, corticosteroid, steroid, and the like
  • anti-infective agents such as a small molecule, antibiotic, corticosteroid, steroid, and the like
  • immunosuppressive agents such as a small molecule, antibiotic, corticosteroid, steroid, and the like
  • administering in the context of a combination product includes, without limitation, co-administration of the compound and the agent, sequential administration of the compound and the agent, administration of a composition containing of the compound and the agent or simultaneous administration of separate compositions containing of the compound and the agent.
  • the effective amounts of the components comprising the combination product may be independently optimized and combined to achieve a synergistic result whereby the pathology is reduced more than it would be if the components of the combination product were used alone.
  • the present invention includes a compound of Formula (I) or a form thereof, wherein the compound is labeled with a ligand for use as a marker, and wherein the ligand is a radioligand selected from deuterium, tritium and the like.
  • the present invention includes a pharmaceutical composition or medicament comprising one or more of the instant compounds and an optional pharmaceutically acceptable carrier.
  • the present invention further includes a process for making a pharmaceutical composition or medicament comprising mixing one or more of the instant compounds and an optional pharmaceutically acceptable carrier; and, includes those compositions or medicaments resulting from such a process.
  • Contemplated processes include both conventional and unconventional pharmaceutical techniques.
  • composition or medicament may take a wide variety of forms to effectuate mode of administration ocularly, intranasally (by inhalation or insufflation), sublingually, orally, parenterally or rectally including, without limitation, ocular (via a delivery device such as a contact lens and the like), intranasal (via a delivery device), transdermal, topical with or without occlusion, intravenous (both bolus and infusion), injection (intraperitoneally, subcutaneously, intramuscularly, intratumorally, or parenterally) and the like.
  • composition or medicament may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, biodegradable carrier, ion exchange resin, sterile solution and the like (facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto- injector device or suppository.
  • a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, biodegradable carrier, ion exchange resin, sterile solution and the like (facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto- injector device or suppository.
  • compositions or medicaments suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions.
  • Forms useful for nasal administration include sterile solutions or nasal delivery devices.
  • Forms useful for ocular administration include sterile solutions or ocular delivery devices.
  • Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
  • composition or medicament may be administered in a form suitable for once-weekly or once-monthly administration.
  • an insoluble salt of the active compound may be adapted to provide a depot preparation for intramuscular injection (e.g., a salt form) or to provide a solution for nasal or ocular administration (e.g., a quaternary ammonium salt).
  • the dosage form (tablet, capsule, powder, solution, contact lens, patch, liposome, ion exchange resin, suppository, teaspoonful, and the like) containing the composition or medicament thereof contains an effective amount of the active ingredient necessary to provide a therapeutic effect.
  • composition or medicament may contain an effective amount of from about 0.001 mg to about 5000 mg (preferably, from about 0.001 to about 500 mg) of a compound of the present invention or a pharmaceutically acceptable form thereof and may be constituted into any form suitable for the mode of administration selected for a subject in need.
  • a contemplated range of the effective amount includes from about 0.001 mg to about 300 mg/kg of body weight per day.
  • a contemplated range also includes from about 0.003 to about 100 mg/kg of body weight per day.
  • Another contemplated range includes from about 0.005 to about 15 mg/kg of body weight per day.
  • Another contemplated range includes from about 0.01 to about 15 mg/kg of body weight per day.
  • Another contemplated range includes from about 0.1 to about 10 mg/kg of body weight per day.
  • the composition or medicament may be administered according to a dosage regimen of from about 1 to about 5 times per day.
  • the composition or medicament is preferably in the form of a tablet containing, e.g., 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient's sex, age, weight, diet, time of administration and concomitant diseases, will result in the need to adjust dosages. The use of either daily administration or post-periodic dosing may be employed.
  • the composition is preferably in the form of an ophthalmic composition.
  • the ophthalmic compositions are preferably formulated as eye-drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette.
  • the composition is preferably in the form of an ophthalmic composition.
  • the ophthalmic compositions are preferably formulated as eye-drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette.
  • Representative compounds of the present invention can be synthesized in accordance with the general synthetic schemes described below and are illustrated more particularly in the specific examples that follow.
  • the general schemes and specific examples are offered by way of illustration; the invention should not be construed as being limited by the chemical reactions and conditions expressed.
  • the methods for preparing the various starting materials used in the schemes and examples are well within the skill of persons versed in the art.
  • Me 3 SiCHN 2 trimethylsilyl-diazomethane min/hr(s)/dy minute(s)/hour(s)/day(s)
  • Compound Al (wherein PG is a suitable protecting group such as tert- butoxycarbonyl and the like) is reacted with a solution of Compound A2 (wherein X is a halogen such as chlorine, R is a functional group such as methanesulfonyl and the like) in the presence of a suitable base (such as Et 3 N, DIPEA and the like) in a solvent (such as methylene chloride, tetrahydrofuran and the like or a mixture thereof) to give a Compound A3.
  • a suitable base such as Et 3 N, DIPEA and the like
  • solvent such as methylene chloride, tetrahydrofuran and the like or a mixture thereof
  • the Compound A5 protecting group may be removed at a suitable point using means known to those skilled in the art to provide a Compound A6 free base or salt form that is amendable for further substitution.
  • a solution of Compound A6 (in a suitable solvent such as CH 2 Cl 2 , CH3CN, DMF and the like or a mixture thereof) is reacted with a suitably substituted Compound A7 (wherein Compound A7 contains a suitable reaction group such as isocyanato, isothiocyanato, carboxy, acid chloride and the like) to provide a Compound A8 of Formula (I) (wherein certain portions of Compound A7 are incorporated into Compound A8 as a product of the reaction).
  • a suitable solvent such as CH 2 Cl 2 , CH3CN, DMF and the like or a mixture thereof
  • Compound A7 When the Compound A7 reaction group is carboxy, Compound A7 is reacted in conjunction with coupling reagents such as EDCI, HBTU and the like. When Compound A6 is a salt form, Compound A6 is reacted with Compound A7 in the presence of a suitable base such as Et 3 N, DIPEA and the like.
  • a suitable base such as Et 3 N, DIPEA and the like.
  • a solution of Compound Bl (wherein PG is a suitable protecting group such as tert-butoxycarbonyl and the like) is reacted with a reagent solution (such as LHMDS in a solvent such as THF and the like).
  • a second reagent such as TMSCl and the like
  • a halogen reagent solution is added (such as NBS, NCS, bromine and the like in a solvent such as THF and the like) to provide a Compound B2 (wherein Xc is a suitable leaving group such as halogen).
  • Compound B2 is reacted at reflux with Compound A4 (in a solvent such as acetonitrile and the like) to provide a compound B3.
  • the Compound B3 protecting group may be removed at a suitable point using means known to those skilled in the art to provide a Compound B4 free base or salt form that is amendable for further substitution.
  • a solution of Compound B4 (in a suitable solvent such as CH 2 Cl 2 , CH3CN, DMF and the like or a mixture thereof) is reacted with a suitably substituted Compound A7 (wherein Compound A7 contains a suitable reaction group such as isocyanato, isothiocyanato, carboxy, acid chloride and the like) to provide a Compound B5 (wherein certain portions of Compound A7 are incorporated into Compound B5 as a product of the reaction).
  • a suitable solvent such as CH 2 Cl 2 , CH3CN, DMF and the like or a mixture thereof
  • Compound B5 can be converted to Compound B6 using means known to those skilled in the art (such as hydrogenation or hydrolysis and the like).
  • Examples 4-8 are intended as prophetic examples and are expected to demonstrate that said compounds are useful in preventing, treating or ameliorating such examples of a CCR2 mediated inflammatory syndrome, disorder or disease.
  • THP-I cells were obtained from American Type Culture Collection (Manassas, VA, USA). The THP-I cells were grown in RPMI- 1640 supplemented with 10% fetal bovine serum in a humidified 5% CO 2 atmosphere at 37 0 C. The cell density was maintained between 0.5xl0 6 cells/ mL.
  • THP-I cells were incubated with 0.5 nM 125 I labeled MCP-I (Perkin-Elmer Life
  • Table 1 lists average IC 50 values for inhibition of MCP-I binding to CCR2 obtained for test compounds of the invention. Where an IC50 value was not obtained for a particular compound, the percent inhibition is provided at a test concentration of 25 ⁇ M.
  • THP-I cells were plated at a density of 8 x 10 ⁇ 5 cells/ mL (100 ⁇ L/well) into poly-D lysine coated clear bottom, black 96 well plates. The cells were loaded with 5 ⁇ M fluo-3 for 45 minutes. The fluo-3 was washed off and cells were incubated with varying concentrations of Compound 52 for 15 minutes. The change in calcium ion concentration upon addition of 0.2 ⁇ M MCP-I was determined using FLIPR and compared to vehicle.
  • Compound 52 gave an average IC50 value of 0.32 ⁇ M for inhibition of MCP-I induced calcium ion influx.
  • MCP-I induced chemotaxis was run in a 24-well chemotaxis chamber.
  • MCP-I (0.01 ⁇ g/mL) was added to the lower chamber and 100 ⁇ L of THP-I cells (1 x 10 7 cell/mL) was added to the top chamber. Varying concentrations of test compound were added to the top and bottom chambers. Cells were allowed to chemotax for 3 hours at 37 0 C and 5% CO 2 . An aliquot of the cells that had migrated to the bottom chamber was taken and counted then compared to vehicle.
  • Table 3 lists the average IC50 values for inhibition of MCP-I induced chemotaxis.

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Abstract

Substituted cyclopentyl piperidine compounds of Formula (I): or a form thereof, wherein X, R1, R3 and R4 are as defined herein, which are CCR2 antagonists useful in preventing, treating or ameliorating CCR2 mediated inflammatory syndromes, disorders or diseases in a subject in need thereof.

Description

SUBSTITUTED CYCLOPENTYL PIPERIDINE CCR2 ANTAGONISTS CROSS REFERENCE TO RELATED APPLICATION
The present application claims the benefit of U.S. Provisional Patent Application Serial No. 60/892,641, filed March 2, 2007, which is incorporated herein by reference in its entirety and for all purposes.
FIELD OF THE INVENTION
The invention is directed to substituted cyclopentyl piperidine compounds that are antagonists to the chemoattractant cytokine receptor 2 (CCR2), pharmaceutical compositions and methods for use thereof. More particularly, the substituted cyclopentyl piperidine compounds are useful antagonists for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
BACKGROUND OF THE INVENTION
CCR2 is a member of the GPCR family of receptors, as are all known chemokine receptors, and are expressed by monocytes and memory T-lymphocytes. The CCR2 signaling cascade involves activation of phospho lipases (PLCp2), protein kinases (PKC), and lipid kinases (PI-3 kinase).
Chemoattractant cytokines (i.e., chemokines) are relatively small proteins (8-10 kD), which stimulate the migration of cells. The chemokine family is divided into four subfamilies based on the number of amino acid residues between the first and second highly-conserved cysteines.
Monocyte chemotactic protein- 1 (MCP-I) is a member of the CC chemokine subfamily (wherein CC represents the subfamily having adjacent first and second cysteines) and binds to the cell-surface chemokine receptor 2 (CCR2). MCP-I is a potent chemotactic factor, which, after binding to CCR2, mediates monocyte and lymphocyte migration (i.e., chemotaxis) toward a site of inflammation. MCP-I is also expressed by cardiac muscle cells, blood vessel endothelial cells, fibroblasts, chondrocytes, smooth muscle cells, mesangial cells, alveolar cells, T-lymphocytes, marcophages, and the like. After monocytes enter the inflammatory tissue and differentiate into macrophages, monocyte differentiation provides a secondary source of several proinflammatory modulators, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-I), IL-8 (a member of the CXC chemokine subfamily, wherein CXC represents one amino acid residue between the first and second cysteines), IL-12, arachidonic acid metabolites (e.g., PGE2 and LTB4), oxygen-derived free radicals, matrix metalloproteinases, and complement components.
Animal model studies of chronic inflammatory diseases have demonstrated that inhibition of binding between MCP-I and CCR2 by an antagonist suppresses the inflammatory response. The interaction between MCP-I and CCR2 has been implicated (see Rollins BJ, Monocyte chemoattractant protein 1 : a potential regulator of monocyte recruitment in inflammatory disease, MoI. Med. Today, 1996, 2:198; and Dawson J, et ah, Targeting monocyte chemoattractant protein- 1 signaling in disease, Expert Opin. Ther. Targets, 2003 Feb, 7(l):35-48) in inflammatory disease pathologies such as psoriasis, uveitis, atherosclerosis, rheumatoid arthritis, multiple sclerosis, Crohn's Disease, nephritis, organ allograft rejection, fibroid lung, renal insufficiency, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, tuberculosis, sarcoidosis, invasive staphylococcia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, Chronic Obstructive Pulmonary Disease (COPD), allergic asthma, periodontal diseases, periodonitis, gingivitis, gum disease, diastolic cardiomyopathies, cardiac infarction, myocarditis, chronic heart failure, angiostenosis, restenosis, reperfusion disorders, glomerulonephritis, solid tumors and cancers, chronic lymphocytic leukemia, chronic myelocytic leukemia, multiple myeloma, malignant myeloma, Hodgkin's disease, and carcinomas of the bladder, breast, cervix, colon, lung, prostate, and stomach.
Monocyte migration is inhibited by MCP-I antagonists (either antibodies or soluble, inactive fragments of MCP-I), which have been shown to inhibit the development of arthritis, asthma, and uveitis. Both MCP-I and CCR2 knockout (KO) mice have demonstrated that monocyte infiltration into inflammatory lesions is significantly decreased. In addition, such KO mice are resistant to the development of experimental allergic encephalomyelitis (EAE, a model of human MS), cockroach allergen-induced asthma, atherosclerosis, and uveitis. Rheumatoid arthritis and Crohn's Disease patients have improved during treatment with TNF-α antagonists (e.g., monoclonal antibodies and soluble receptors) at dose levels correlated with decreases in MCP-I expression and the number of infiltrating macrophages.
MCP-I has been implicated in the pathogenesis of seasonal and chronic allergic rhinitis, having been found in the nasal mucosa of most patients with dust mite allergies. MCP-I has also been found to induce histamine release from basophils in vitro. During allergic conditions, both allergens and histamines have been shown to trigger (i.e., to up- regulate) the expression of MCP-I and other chemokines in the nasal mucosa of people with allergic rhinitis, suggesting the presence of a positive feedback loop in such patients.
CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established (J. Clin. Invest., 2006, 116, 115-124).
There remains a need for small molecule CCR2 antagonists for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease resulting from MCP-I induced monocyte and lymphocyte migration to a site of inflammation.
PCT Application WO 02/079190, published on October 10, 2002, describes 3 -substituted indoles as chemokine antagonists.
PCT Application WO 04/054974, published on July 1, 2004, describes substituted piperidine compounds as CCR5 antagonists.
United States Patent Publication 2004/0138226, published on July 15, 2004, describes substituted piperidine compounds as 17-beta hydroxysteroid dehydrogenase Type 3 inhibitors for the treatment of androgen related diseases. United States Patent Publication 2004/0147506, published on July 29, 2004 (Equivalent of PCT Application WO 02/085890, published on October 31, 2002), describes substituted benzimidazolone compounds as muscarinic acetylcholine antagonists.
All documents cited herein are incorporated by reference.
SUMMARY OF THE INVENTION
The invention provides substituted cyclopentyl piperidine compounds of Formula (I):
Figure imgf000005_0001
or a form thereof, wherein X, R1, R3 and R4 are as defined herein.
The compounds of the present invention are CCR2 antagonists are useful in preventing, treating or ameliorating CCR2 mediated inflammatory syndromes, disorders or diseases in a subject in need thereof.
The present invention also provides a method for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a compound of Formula (I)
Figure imgf000006_0001
or a form thereof, wherein Ri is cycloalkyl, aryl-cycloalkyl, aryl, aryl-alkenyl, aryl-amino, aryloxy-alkyl, arylthio-alkyl, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, nitro, amino, alkylamino, aminoalkyl, alkylaminoalkyl, carboxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or alkylthio;
X is CH-R2 or C, wherein C is a piperidine ring carbon atom in common with a cycloalkyl ring carbon atom, thus forming a spiro ring system;
R2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, nitro, amino, alkylamino, aminoalkyl, alkylaminoalkyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonylamino, aminosulfonylalkyl, alkylaminosulfonylalkyl, carboxy, alkylcarbonyl or alkoxycarbonyl; R3 is selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, aminoalkyl, cyano, carboxy or alkoxycarbonyl; and
R4 is selected from hydrogen, hydroxy, hydroxyalkyl, haloalkyl, alkyl, aminoalkyl, cyano, alkoxy, carboxy or alkoxycarbonyl. An example of the invention is a compound of Formula (I) or a form thereof, wherein
Ri is aryl-cycloalkyl, aryl, aryl-alkenyl, aryl-amino, aryloxy-alkyl, arylthio-alkyl, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen or haloalkyl;
X is CH-R2;
R2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen, haloalkyl, amino or alkylamino; R3 is selected from hydrogen or carboxy; and
R4 is selected from hydrogen, hydroxy or carboxy.
An example of the invention is a compound of Formula (I) or a form thereof, wherein
Ri is aryl-alkenyl, aryl-amino, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or haloalkyl;
X is CH-R2;
R2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or alkylamino; R3 is hydrogen; and
R4 is selected from hydrogen or hydroxy.
An example of the invention is a compound of Formula (I) or a form thereof, wherein
Ri is aryl-alkenyl or heterocyclyl, wherein aryl and heterocyclyl are each optionally substituted with two or three substituents selected from halogen or haloalkyl;
X is CH-R2; R2 is aryl or heterocyclyl each substituted with one substituent selected from alkoxy, halogen or alkylamino;
R3 is hydrogen; and
R4 is selected from hydrogen or hydroxy.
An example of the invention is a compound of Formula (I) or a form thereof, wherein
Ri is aryl-alkenyl, wherein aryl is substituted with three halogen substituents; X is CH-R2;
R2 is aryl substituted with one alkoxy substituent; R3 is hydrogen; and R4 is hydroxy.
An example of the invention is a compound of Formula (I) or a form thereof, wherein Ri is aryl-cycloalkyl, aryl, aryl-alkenyl, aryl-amino, aryloxy-alkyl, arylthio-alkyl, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen or haloalkyl.
An example of the invention is a compound of Formula (I) or a form thereof, wherein Ri is aryl-alkenyl, aryl-amino, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or haloalkyl.
An example of the invention is a compound of Formula (I) or a form thereof, wherein Ri is aryl-alkenyl or heterocyclyl, wherein aryl and heterocyclyl are each optionally substituted with two or three substituents selected from halogen or haloalkyl.
An example of the invention is a compound of Formula (I) or a form thereof, wherein Ri is aryl-alkenyl, wherein aryl is substituted with three halogen substituents. An example of the invention is a compound of Formula (I) or a form thereof, wherein R2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen, haloalkyl, amino or alkylamino.
An example of the invention is a compound of Formula (I) or a form thereof, wherein R2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or alkylamino.
An example of the invention is a compound of Formula (I) or a form thereof, wherein R2 is aryl or heterocyclyl each substituted with one substituent selected from alkoxy, halogen or alkylamino.
An example of the invention is a compound of Formula (I) or a form thereof, wherein R2 is aryl substituted with one alkoxy substituent.
An example of the invention is a compound of Formula (I) or a form thereof, wherein R3 is selected from hydrogen or carboxy.
An example of the invention is a compound of Formula (I) or a form thereof, wherein R3 is hydrogen.
An example of the invention is a compound of Formula (I) or a form thereof, wherein R4 is selected from hydrogen, hydroxy or carboxy.
An example of the invention is a compound of Formula (I) or a form thereof, wherein R4 is selected from hydrogen or hydroxy.
An example of the invention is a compound of Formula (I) or a form thereof, wherein R4 is hydroxy. An example of the invention is a compound of Formula (I) or a form thereof represented as follows:
Figure imgf000010_0001
Cpdl Cpd2 Cpd3 Cpd4
Figure imgf000010_0002
Cpd5 Cpd6 Cpd7 Cpd8
Figure imgf000011_0001
Figure imgf000012_0001
Cpd21 Cpd22 Cpd23
Figure imgf000013_0001
Cpd29 Cpd30 Cpd32
Figure imgf000014_0001
Figure imgf000015_0001
Cpd45 Cpd46 Cpd47 Cpd48
Figure imgf000016_0001
Figure imgf000017_0001
Cpd62 Cpd63 Cpd64
Figure imgf000018_0001
Figure imgf000019_0001
Chemical Definitions
Bond lines drawn into a ring system from a substituent variable indicate that the substituent may be attached to any of the substitutable ring atoms.
As used herein, the following terms are intended to have the following definitions. The definitions herein may specify that a chemical term has an indicated formula. The particular formula provided is not intended to limit the scope of the invention, but is provided as an illustration of the term.
The term "alkyl" means a saturated branched or straight-chain hydrocarbon radical or linking group substituent having from 1-8 carbon atoms, wherein the radical is derived by the removal of one hydrogen atom from a carbon atom and the linking group is derived by the removal of one hydrogen atom from each of two carbon atoms in the chain. An alkyl radical or linking group includes, without limitation, methyl, methylene, ethyl, ethylene, propyl, propylene, isopropyl, isopropylene, n-butyl, n-butylene, t-butyl, t-butylene, pentyl, pentylene, hexyl, hexylene and the like. An alkyl radical may be attached to a core molecule and further substituted on any atom when allowed by available valences. The term "alkenyl" means a partially unsaturated alkyl radical or linking group substituent having at least one double bond, wherein the double bond is derived by the removal of one hydrogen atom from each of two adjacent carbon atoms in the chain. An alkenyl radical or linking group includes, without limitation, vinyl, propenyl, propenylene, isopropenyl, isopropenylene, n-butenyl (1-butenyl), n-butenylene, crotyl (2-butenyl) and the like. An alkenyl radical may be attached to a core molecule and further substituted on any atom when allowed by available valences.
The term "alkoxy" means an alkyl radical or linking group substituent attached through an oxygen- linking atom, wherein a radical is of the formula -O-alkyl and a linking group is of the formula -O-alkyl, and includes, without limitation, methoxy, ethoxy, propoxy, butoxy and the like. An alkoxy radical may be attached to a core molecule and further substituted on any atom when allowed by available valences.
The term "cycloalkyl" means a saturated or partially unsaturated hydrocarbon ring system radical or linking group such as a C3_8Cycloalkyl, C3_iocycloalkyl, Cs-scycloalkyl, C5_i2cycloalkyl or C9_i2cycloalkyl ring system radical and the like, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, indanyl, indenyl, 1,2,3,4-tetrahydro-naphthalenyl, 5,6,7,8-tetrahydro- naphthalenyl, 6,7, δ^-tetrahydro-JH-benzocycloheptenyl, 5,6,7,8,9, 10- hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantanyl, octahydro-4,7-methano-lH-indenyl, octahydro-2,5- methano-pentalenyl (also referred to as hexahydro-2,5-methano-pentalenyl) and the like. A cycloalkyl radical may be attached to a core molecule and further substituted on any ring atom when allowed by available valences.
The term "heterocyclyl" means a saturated, partially unsaturated (such as those named with the prefix dihydro, trihydro, tetrahydro, hexahydro and the like) or unsaturated ring system radical, wherein at least one ring carbon atom has been replaced with one or more heteroatoms independently selected from N, O, S, S(O) or SO2. A heterocyclyl ring system further includes a ring system having 1, 2, 3, or 4 carbon atom members replaced by a nitrogen atom. Alternatively, a ring may have 0, 1, 2, or 3 nitrogen atom members and 1 oxygen or sulfur atom member. Alternatively, up to two adjacent ring members may be heteroatoms, wherein one heteroatom is nitrogen and the other heteroatom is selected from N, O, S, S(O) or SO2. A heterocyclyl radical is derived by the removal of one hydrogen atom from a single carbon or nitrogen ring atom. A heterocyclyl linking group is derived by the removal of one hydrogen atom from two of either a carbon or nitrogen ring atom. A heterocyclyl radical may be attached to a core molecule and further substituted on any ring atom when allowed by available valences.
The term heterocyclyl includes, without limitation, furanyl, thienyl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, pyrrolyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2-imidazolinyl (also referred to as 4,5-dihydro-lH-imidazolyl), imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, tetrazolinyl, tetrazolidinyl, 2H-pyranyl, 4H-pyranyl, thiopyranyl, pyridinyl, piperidinyl, 1 ,4-dioxanyl, morpholinyl, 1 ,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, azetidinyl, azepanyl, indolizinyl, indolyl, 4-aza-indolyl (also referred to as lΗ-pyrrolo[3,2-b]pyridinyl), 6-aza-indolyl (also referred to as lH-pyrrolo[2,3-c]pyridinyl), 7-aza-indolyl (also referred to as lH-pyrrolo[2,3- b]pyridinyl), isoindolyl, 3H-indolyl, indolinyl (also referred to as 2,3-dihydro-indolyl), benzo[δ] furanyl, furo[2,3-b]pyridinyl, benzo[δ]thienyl, indazolyl (also referred to as lH-indazolyl), benzoimidazolyl, benzothiazolyl, benzoxazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalzinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, quinuclidinyl, 2Η-chromenyl, 3H-benzo[f]chromenyl, tetrahydro-furanyl, tetrahydro-thienyl, tetrahydro-pyranyl, tetrahydro-thiopyranyl, tetrahydro-pyridazinyl, hexahydro-l,4-diazepinyl, hexahydro-l,4-oxazepanyl, 2,3-dihydro- benzo[b]oxepinyl, 1,3-benzodioxolyl (also known as 1,3-methylenedioxyphenyl or benzo[l,3]dioxolyl), 2,3-dihydro-l,4-benzodioxinyl (also known as 1 ,4-ethylenedioxyphenyl or benzo[l,4]dioxinyl), benzo-dihydro-furanyl (also known as 2,3-dihydro-benzofuranyl), benzo-tetrahydro-pyranyl, benzo-dihydro-thienyl, 5,6,7,8- tetrahydro-4H-cyclohepta[δ]thienyl, 5 ,6,7-trihydro-4H-cyclohexa[δ]thienyl, 5 ,6-dihydro- 4H-cyclopenta[δ]thienyl, 2-aza-bicyclo[2.2.1]heptyl, l-aza-bicyclo[2.2.2]octyl, 8-aza- bicyclo[3.2.1]octyl, 7-oxa-bicyclo[2.2.1]heptyl, pyrrolidinium, piperidinium, piperazinium, morpholinium and the like.
The term "aryl" means an unsaturated aromatic hydrocarbon ring system radical, and includes, without limitation, phenyl, naphthalenyl, azulenyl, anthracenyl and the like. An aryl radical may be attached to a core molecule and further substituted on any ring atom when allowed by available valences.
The term "aryl-cycloalkyl" means an aryl ring system attached via a bond to a cycloalkyl ring system, wherein the cycloalkyl ring functions as a linking group, such as a radical of the formula, without limitation, -cyclopropyl-phenyl and the like. An aryl- cycloalkyl radical may be attached to a core molecule and further substituted on any ring atom when allowed by available valences.
The term "acrylyl" means a radical of the formula -C(O)-CH=CH-.
The term "alkoxycarbonyl" means a radical of the formula: -C(O)-O-alkyl.
The term "alkylamino" means a radical of the formula: -NH-alkyl or -N(alkyl)2.
The term "alkylaminoalkyl" means a radical of the formula: -alkyl-NH-alkyl or
-alkyl-N(alkyl)2.
The term "alkylaminocarbonyl" means a radical of the formula: -C(O)-NH-alkyl or -C(O)-N(alkyl)2.
The term "alkylaminosulfonyl" means a radical of the formula: -SO2-NH-alkyl or -SO2-N(alkyl)2.
The term "alkylaminosulfonylalkyl" means a radical of the formula: -alkyl-SO2-NH-alkyl or -alkyl-SO2-N(alkyl)2.
The term "alkylcarbonyl" means a radical of the formula: -C(O)-alkyl.
The term "alkylsulfonylamino" means a radical of the formula: -NH-SO2-alkyl.
The term "alkylthio" means a radical of the formula -S-alkyl. The term "amino" means a radical of the formula: -NH2.
The term "aminoalkyl" means a radical of the formula: -alkyl-NH2.
The term "aminocarbonyl" means a radical of the formula: -C(O)-NH2.
The term "aminosulfonyl" means a radical of the formula: -SO2-NH2.
The term "aminosulfonylalkyl" means a radical of the formula: -alkyl-SO2-NH2.
The term "aryl-alkenyl" means a radical of the formula: -alkenyl-aryl.
The term "aryl-amino" means a radical of the formula: -NH-aryl.
The term "aryloxy-alkyl" means a radical of the formula: -alkyl-O-aryl.
The term "arylthio-alkyl" means a radical of the formula: -alkyl-S-aryl.
The term "carboxy" means a radical of the formula -C(O)-OH.
The term "halogen" or "halo" means the group chloro, bromo, fluoro or iodo.
The term "haloalkoxy" means a radical of the formula: -O-alkyl-(halo)n, wherein one or more halogen atoms may be substituted on alkyl when allowed by available valences (wherein n represents that amount of available valences based on the number of carbon atoms in the chain), and includes monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy and the like.
The term "haloalkyl" means a radical of the formula: -alkyl-(halo)n, wherein one or more halogen atoms may be substituted on alkyl when allowed by available valences (wherein n represents that amount of available valences based on the number of carbon atoms in the chain), and includes monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl and the like.
The term "heterocyclyl-alkenyl" means a radical of the formula: -alkenyl-heterocyclyl. The term "hydroxyalkoxy" means a radical of the formula: -O-alkyl-hydroxy, wherein alkyl is substituted on one or more available carbon chain atoms with one or more hydroxy radicals.
The term "hydroxyalkyl" means a radical of the formula: -alkyl-hydroxy, wherein alkyl is substituted on one or more available carbon chain atoms with one or more hydroxy radicals.
The term "substituted" means the independent replacement of one or more hydrogen atoms within a radical with that amount of substituents allowed by available valences.
In general, IUPAC nomenclature rules are used throughout this disclosure.
Compound Forms
The term "form" means, in reference to compounds of the present invention, such may exist as, without limitation, a salt, stereoisomer, tautomer, crystalline, polymorph, amorphous, solvate, hydrate, ester, prodrug or metabolite form. The present invention encompasses all such compound forms and mixtures thereof.
The term "isolated form" means, in reference to compounds of the present invention, such may exist in an essentially pure state such as, without limitation, an enantiomer, a racemic mixture, a geometric isomer (such as a cis or trans stereoisomer), a mixture of geometric isomers, and the like. The present invention encompasses all such compound forms and mixtures thereof.
The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the "pharmaceutically acceptable salts" of the compounds of this invention refer to non-toxic acidic/anionic or basic/cationic salt forms.
Suitable salt forms include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of an acid such as acetic acid, adipic acid, benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid, hydrochloric acid, maleic acid, malonic acid, phosphoric acid, saccharinic acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid and the like.
Furthermore when the compounds of the present invention carry an acidic moiety, suitable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
Thus, representative salts include the following: acetate, adipate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate (or camphosulphonate), carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, fumarate, gluconate, glutamate, glyconate, hydrabamine, hydrobromine, hydrochloride, iodide, isothionate, lactate, malate, maleate, malonate, mandelate, mesylate, nitrate, oleate, pamoate, palmitate, phosphate/diphosphate, saccharinate, salicylate, stearate, sulfate, succinate, tartrate, tosylate, trichloroacetate, trifluoroacetate and the like.
The term "prodrug" means a compound of Formula (I) or a form thereof that is converted in vivo into a functional derivative form that may contribute to therapeutic biological activity, wherein the converted form may be: 1) a relatively active form; 2) a relatively inactive form; 3) a relatively less active form; or, 4) any form which results, directly or indirectly, from such in vivo conversions.
Prodrugs are useful when said compound may be either too toxic to administer systemically, absorbed poorly by the digestive tract or broken down by the body before it reaches its target. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in, for example, "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
The term "metabolite" means a prodrug form of a compound of Formula (I) or a form thereof converted by in vivo metabolism or a metabolic process to a relatively less active functional derivative of said compound.
The invention includes compounds of various isomers and mixtures thereof. The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. Such substances have the same number and kind of atoms but differ in structure. The structural difference may be in constitution (geometric isomers) or in an ability to rotate the plane of polarized light (optical isomers).
The term "optical isomer" means isomers of identical constitution that differ only in the spatial arrangement of their groups. Optical isomers rotate the plane of polarized light in different directions. The term "optical activity" means the degree to which an optical isomer rotates the plane of polarized light.
The term "racemate" or "racemic mixture" means an equimolar mixture of two enantiomeric species, wherein each of isolated specie rotates the plane of polarized light in the opposite direction such that the mixture is devoid of optical activity.
The term "enantiomer" means an isomer having a nonsuperimposable mirror image. The term "diastereomer" means stereoisomers that are not enantiomers.
The term "chiral" means a molecule, which in a given configuration, cannot be superimposed on its mirror image. This is in contrast to achiral molecules, which can be superimposed on their mirror images.
The two distinct mirror image versions of the chiral molecule are also known as levo (left-handed), abbreviated L, or dextro (right handed), abbreviated D, depending on which way they rotate polarized light. The symbols "R" and "S" represent the configuration of groups around a stereogenic carbon atom(s).
An example of an enantiomerically enriched form isolated from a racemic mixture includes a dextrorotatory enantiomer, wherein the mixture is substantially free of the levorotatory isomer. In this context, substantially free means the levorotatory isomer may, in a range, comprise less than 25% of the mixture, less than 10%, less than 5%, less than 2% or less than 1% of the mixture according to the formula:
n/ i (mass levorotatory) % levorotatory = — x 100
(mass dextrorotatory) + (mass levorotatory) Similarly, an example of an enantiomerically enriched form isolated from a racemic mixture includes a levorotatory enantiomer, wherein the mixture is substantially free of the dextrorotatory isomer. In this context, substantially free means the dextrorotatory isomer may, in a range, comprise less than 25% of the mixture, less than 10%, less than 5%, less than 2% or less than 1% of the mixture according to the formula:
n / , (mass dextrorotatory)
% dextrorotatory = — x 100
(mass dextrorotatory) + (mass levorotatory)
The term "geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Substituent atoms (other than hydrogen) on each side of a carbon-carbon double bond may be in an E or Z configuration. In the "E" configuration, the substituents are on opposite sides in relationship to the carbon- carbon double bond. In the "Z" configuration, the substituents are oriented on the same side in relationship to the carbon-carbon double bond.
Substituent atoms (other than hydrogen) attached to a ring system may be in a cis or trans configuration. In the "cis" configuration, the substituents are on the same side in relationship to the plane of the ring; in the "trans" configuration, the substituents are on opposite sides in relationship to the plane of the ring. Compounds having a mixture of "cis" and "trans" species are designated "cis/trans".
The isomeric descriptors ("R," "S," "E," and "Z") indicate atom configurations and are intended to be used as defined in the literature.
The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include combining the free base (or free acid) of each isomer of an isomeric pair using an optically active acid (or base) to form an optically active salt (followed by fractional crystallization and regeneration of the free base), forming an ester or amide of each of the isomers of an isomeric pair by reaction with an appropriate chiral auxiliary (followed by fractional crystallization or chromatographic separation and removal of the chiral auxiliary), or separating an isomeric mixture of either an intermediate or a final product using various well known chromatographic methods.
Furthermore, a compound of the present invention may have at least one crystalline, polymorph or amorphous form. The plurality of such forms is intended to be included in the scope of the invention. In addition, a compound of the present invention may form a solvate with water (i.e., hydrates) or common organic solvents (e.g., organic esters such as ethanolate and the like). The plurality of such solvates is also intended to be encompassed within the scope of this invention.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.
Therapeutic Use
The compounds of Formula (I) or a form thereof in accordance with the present invention are CCR2 antagonists.
A compound of Formula (I) or a form thereof may have a mean inhibition constant (IC50) against MCP-I binding to CCR2 of between about 50 μM to about 0.01 nM; between about 25 μM to about 0.01 nM; between about 10 μM to about 0.01 nM; between about 5 μM to about 0.01 nM; between about 1 μM to about 0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM; or, between about 10 nM to about 0.01 nM.
A compound of Formula (I) or a form thereof reduces MCP-I induced monocyte chemotaxis. A compound of Formula (I) or a form thereof may have an IC50 for reduction in MCP-I induced monocyte chemotaxis of between about 50 μM to about 0.01 nM; between about 25 μM to about 0.01 nM; between about 10 μM to about 0.01 nM; between about 5 μM to about 0.01 nM; between about 1 μM to about 0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM; or, between about 10 nM to about 0.01 nM.
A compound of Formula (I) or a form thereof reduces MCP-I intracellular calcium mobilization. A compound of Formula (I) or a form thereof may have an IC50 for reduction in MCP-I induced intracellular calcium mobilization of between about 50 μM to about 0.01 nM; between about 25 μM to about 0.01 nM; between about lOμM to about 0.01 nM; between about 5 μM to about 0.01 nM; between about 1 μM to about 0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM; or, between about 10 nM to about 0.01 nM.
The present invention includes use of a compound of Formula (I) or a form thereof as a CCR2 antagonist comprising contacting the receptor with the compound.
The use of the compound of Formula (I) or a form thereof further comprises use of the compound in a pharmaceutical composition, medicine or medicament for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
The compound of Formula (I) or a form thereof may also be used in the manufacture of a medicament for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
The present invention also includes a medicament comprising an effective amount of a compound of Formula (I) or a form thereof.
The present invention also includes the use of a compound of Formula (I) or a form thereof in a method for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease in a subject in need thereof comprising administering to the subject an effective amount of the compound of Formula (I) or form thereof. The present invention is directed to a method for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form thereof.
The term "administering" with respect to the methods of the invention, means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of Formula (I) or a form thereof. Such methods include administering an effective amount of said compound, compound form, composition or medicament at different times during the course of a therapy or concurrently in a combination form. The methods of the invention are to be understood as embracing all known therapeutic treatment regimens.
The term "subject" refers to a patient, which may be animal, typically a mammal, typically a human, which has been the object of treatment, observation or experiment and is at risk of (or susceptible to) developing a syndrome, disorder or disease that is associated with elevated MCP-I expression or MCP-I overexpression, or a patient with an inflammatory condition that accompanies syndromes, disorders or diseases associated with elevated MCP-I expression or MCP-I overexpression.
The term "effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated.
The effective amount of a compound of the invention in such a therapeutic method is from about 0.001 mg/kg/day to about 300 mg/kg/day. An example of a compound of Formula (I) or a form thereof is selected from the group consisting of:
Cpd Name
1 (2E)-3-(3,4-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
2 (2E)-3-(3,5-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
3 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
4 (2£)-N-cis- {3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- (3,4,5-trifluoro-phenyl)-acrylamide,
5 (2E)-3-(3,5-dichloro-phenyl)-N-(li?,35)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
6 (2E)-3-(3,5-difluoro-phenyl)-N-(li?,35)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
7 (2E)-N-(li?,35)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}- 3-(3,4,5-trifluoro-phenyl)-acrylamide,
8 (2E)-3-(3,4-dichloro-phenyl)-N-(15',3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
9 (2E)-3-(3,5-dichloro-phenyl)-N-(15',3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
10 (2E)-3-(3,5-difluoro-phenyl)-N-(l^,3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yl]methyl} -cyclopentyl)-acrylamide,
11 (2E)-N-(\S,3R)-(3- {cis- [3 -hydroxy-4-(4-methoxy-phenyl)-piperidin- 1 - yl]methyl}-cyclopentyl)-3-(3,4,5-trifluoro-phenyl)-acrylamide,
12 (2E)-3-(3,5-bis-trifiuoromethyl-phenyl)-N-(llS,3i?)-(3-{cis-[3-hydroxy-4-(4- methoxy-phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
13 (i?)-[4-(4-methoxy-phenyl)-piperidin-l-yl]-(li?,35)-{3-[(2JE)-3-(3,4,5-trifluoro- phenyl)-acryloylamino]-cyclopentyl} -acetic acid,
14 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3,4-dimethoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
15 (2E)-3-(3,5-difiuoro-phenyl)-N-cis-[3-(3,4,5,6-tetrahydro-2H-[4,4']bipyridinyl- l-ylmethyl)-cyclopentyl]-acrylamide,
16 (2E)-N-cis-{3-[4-(3,4-dichloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- (3,5-difluoro-phenyl)-acrylamide,
17 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3,4-difluoro-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide, Cpd Name
18 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-dimethylamino-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide,
19 (2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l -ylmethylj-cyclopentyl} -3-(3, 5- difluoro-phenyl)-acrylamide,
20 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-trifluoromethyl-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide,
21 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-fluoro-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
22 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3-fluoro-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
23 (2E)-3-(3,5-difluoro-phenyl)-N-cis-[3-(4-phenyl-piperidin-l-ylmethyl)- cyclopentyl] -acrylamide,
24 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
25 (2E)-3-(3,5-difluoro-phenyl)-N-cis-[3-(4-p-tolyl-piperidin-l-ylmethyl)- cyclopentyl] -acrylamide,
26 (2E)-N-cis-[3-(4-benzofuran-3-yl-piperidin-l-ylmethyl)-cyclopentyl]-3-(3,5- difluoro-phenyl)-acrylamide,
27 1 - { [3 -cis-( { [2-(2E)-(3 ,5 -difluoro-phenyl)ethenyl]carbonyl} amino)- cyclopentyljmethyl} -spiro[piperidine-4,2'-indane] ,
28 1 - { [3 -cis-( { [2-(2E)-(3 ,5 -difluoro-phenyl)ethenyl]carbonyl} amino)- cyclopentyljmethyl} -spiro[piperidine-4, 1 '-indene] ,
29 1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3-(3,5- difluoro-phenyl)-urea,
30 N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l -ylmethylj-cyclopentyl} -3,5-difluoro- benzamide,
31 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(lH-indol-3-yl)-piperidin-l-ylmethylJ- cyclopentyl} -acrylamide,
32 1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3-phenyl- urea,
33 6-chloro-8-methyl-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy- phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
34 7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carboxylic acid cis-{3-[4-(4- methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
35 6-methyl-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide, Cpd Name
36 S-methyl-lH-chromene-S-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
37 6-chloro-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
38 (2E)-3-(3,5-difluoro-phenyl)-N-(15',3i?)-{3-[4-(2-methyl-benzoimidazol-l-yl)- piperidin- 1 -ylmethyl]-cyclopentyl} -acrylamide,
39 N-cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -2-phenoxy- acetamide,
40 N-cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -2- phenylsulfanyl-acetamide,
41 2-(4-chloro-phenoxy)-N-cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj- cyclopentyl} -acetamide,
42 (2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- pyridin-4-yl-acrylamide,
43 (2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3-flιran- 2-yl-acrylamide,
44 (2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3-flιran- 3-yl-acrylamide,
45 (2E)-N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- pyridin-3 -yl-acrylamide,
46 trans-2-phenyl-cyclopropanecarboxylic acid (i?,35)-{3-[4-(4-chloro-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
47 (2E)-N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- thiophen-2 -yl-acrylamide,
48 6-methoxy-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
49 6,8-dichloro-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
50 (2E)-N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- thiophen-3 -yl-acrylamide,
51 5-bromo-lH-indole-2-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
52 5-chloro-lH-indole-2-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
53 N-(li?,35)- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -2-(4- fluoro-phenoxy)-acetamide, Cpd Name
54 N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-2-(3,5- dichloro-phenoxy)-acetamide,
55 1 -(1R,3S)- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethyl]-cyclopentyl} -3-(4- cyano-phenyl)-urea,
56 6-fluoro-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
57 β-trifluoromethyl-lH-chromene-S-carboxylic acid cis-{3-[4-(4-methoxy- phenyl)-piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
58 S-fluoro^H-chromene-S-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
59 8-bromo-6-chloro-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy- phenyl)-piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
60 7-methyl-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
61 7-methoxy-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
62 6-tert-butyl-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
63 (li?,35)-{3-(2JE)-[3-(3,5-difluoro-phenyl)-acryloylamino]-cyclopentyl}-(i?5)-[4- ( 1 H-indol-3 -yl)-piperidin- 1 -yl] -acetic acid,
64 6,8-dichloro-2H-chromene-3-carboxylic acid (5',3i?)-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
65 6-chloro-2H-chromene-3-carboxylic acid (5',3i?)-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
66 (2E)-3-(3,5-dichloro-phenyl)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
67 (2E)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}- 3-(3,4,5-trifluoro-phenyl)-acrylamide,
68 (2E)-3-(3,5-difluoro-phenyl)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
69 1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethyl]-cyclopentyl} -3-(4- methoxy-phenyl)-urea,
70 1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethyl]-cyclopentyl} -3-(4-fluoro- benzyl)-urea,
71 5,7-dichloro-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide, Cpd Name
72 SH-benzoffJchromene^-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
73 (2E)-N-(IS,3R)- [3 -(4-benzoimidazol-l-yl-piperidin-l-ylmethyl)-cyclopentyl] -3- (3,5-difluoro-phenyl)-acrylamide,
74 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(2-fluoro-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide, and
75 (2£)-N-cis- {3-[4-(4-tert-butyl-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- (3 ,5 -difluoro-phenyl)-acrylamide .
An example of a compound of Formula (I) or a form thereof is selected from the group consisting of:
Cpd Name
1 (2E)-3-(3,4-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
2 (2E)-3-(3,5-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
3 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
4 (2E)-N-cis- {3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- (3,4,5-trifluoro-phenyl)-acrylamide,
8 (2E)-3-(3,4-dichloro-phenyl)-N-(15',3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
9 (2E)-3-(3,5-dichloro-phenyl)-N-(15',3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
10 (2E)-3-(3,5-difluoro-phenyl)-N-(l^,3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
11 (2E)-N-(\S,3R)-(3- {cis- [3 -hydroxy-4-(4-methoxy-phenyl)-piperidin- 1 - yl]methyl}-cyclopentyl)-3-(3,4,5-trifluoro-phenyl)-acrylamide,
12 (2E)-3-(3,5-bis-trifiuoromethyl-phenyl)-N-(llS,3i?)-(3-{cis-[3-hydroxy-4-(4- methoxy-phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
17 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3,4-difluoro-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
18 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-dimethylamino-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide,
19 (2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3-(3,5- difluoro-phenyl)-acrylamide, Cpd Name
25 (2E)-3-(3,5-difluoro-phenyl)-N-cis-[3-(4-p-tolyl-piperidin-l-ylmethyl)- cyclopentyl] -acrylamide,
31 (l^-S-CS^-difluoro-phenyO-N-cis-IS-^^lH-indol-S-yO-piperidin-l-ylmethyl]- cyclopentyl} -acrylamide,
33 6-chloro-8-methyl-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy- phenyl)-piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
37 6-chloro-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
44 (2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3-furan- 3-yl-acrylamide,
50 (2E)-N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- thiophen-3 -yl-acrylamide,
52 5-chloro-lH-indole-2-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
65 6-chloro-2H-chromene-3-carboxylic acid (5',3i?)-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
66 (2E)-3-(3,5-dichloro-phenyl)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
67 (2E)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}- 3-(3,4,5-trifluoro-phenyl)-acrylamide,
68 (2E)-3-(3,5-difluoro-phenyl)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
69 1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3-(4- methoxy-phenyl)-urea,
72 3H-benzo[f]chromene-2-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
73 (2E)-N-(IS,3R)- [3 -(4-benzoimidazol-l-yl-piperidin-l-ylmethyl)-cyclopentylJ -3- (3,5-difluoro-phenyl)-acrylamide,
74 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(2-fluoro-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide, and
75 (2E)-N-cis- {3-[4-(4-tert-butyl-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- (3 ,5 -difluoro-phenyl)-acrylamide . An example of a compound of Formula (I) or a form thereof is selected from the group consisting of:
Cpd Name
1 (2E)-3-(3,4-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
2 (2E)-3-(3,5-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
3 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
4 (2£)-N-cis- {3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- (3,4,5-trifluoro-phenyl)-acrylamide,
8 (2E)-3-(3,4-dichloro-phenyl)-N-(15',3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
9 (2E)-3-(3,5-dichloro-phenyl)-N-(15',3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
10 (2E)-3-(3,5-difluoro-phenyl)-N-(l^,3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
11 (2E)-N-(lS,3R)-(3- {cis- [3 -hydroxy-4-(4-methoxy-phenyl)-piperidin- 1 - yljmethyl} -cyclopentyl)-3-(3 ,4, 5-trifluoro-phenyl)-acrylamide,
12 (2E)-3-(3,5-bis-trifiuoromethyl-phenyl)-N-(llS,3i?)-(3-{cis-[3-hydroxy-4-(4- methoxy-phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
18 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-dimethylamino-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide,
19 (2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3-(3,5- difluoro-phenyl)-acrylamide,
31 (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(lH-indol-3-yl)-piperidin-l-ylmethylJ- cyclopentyl} -acrylamide,
52 5-chloro-lH-indole-2-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
66 (2E)-3-(3,5-dichloro-phenyl)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
67 (2E)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}- 3-(3,4,5-trifluoro-phenyl)-acrylamide, and
68 (2E)-3-(3,5-difluoro-phenyl)-N-(llS,3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide. An example of a compound of Formula (I) or a form thereof is selected from the group consisting of:
Cpd Name
11 (2E)-N-(\S,3R)-(3- {cis- [3 -hydroxy-4-(4-methoxy-phenyl)-piperidin- 1 - yl]methyl}-cyclopentyl)-3-(3,4,5-trifluoro-phenyl)-acrylamide, and
67 (2E)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}- 3-(3,4,5-trifluoro-phenyl)-acrylamide.
The invention includes the use of an instant compound for the preparation of a composition or medicament for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease in a subject in need thereof, wherein the composition or medicament comprises a mixture one or more compounds of the invention and an optional pharmaceutically acceptable carrier.
The term "composition" means a product comprising at least a compound of the invention, such as a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from such combinations of the specified ingredients in the specified amounts and one or more pharmaceutically acceptable carriers or any such alternatives to a compound of the invention and a pharmaceutically acceptable carrier therefor.
The term "medicament" means a product for use in preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
The term "pharmaceutically acceptable" means molecular entities and compositions that are of sufficient purity and quality for use in the formulation of a composition or medicament of the invention and that, when appropriately administered to an animal or a human, do not produce an adverse, allergic, or other untoward reaction. Since both human and veterinary use is included within the scope of the invention, a pharmaceutically acceptable formulation includes a compound of Formula (I) or a form, composition or medicament thereof for either human or veterinary use.
The term "CCR2 mediated inflammatory syndrome, disorder or disease" means, without limitation, syndromes, disorders or diseases associated with elevated MCP-I expression, MCP-I overexpression or inflammatory conditions that accompany syndromes, disorders or diseases associated with elevated MCP-I expression or MCP-I overexpression.
The terms "elevated MCP-I expression" or "MCP-I overexpression" mean unregulated or up-regulated CCR2 activation as a result of MCP-I binding.
The term "unregulated" means unwanted CCR2 activation in a multicellular organism resulting in harm (such as discomfort or decreased life expectancy) to the multicellular organism.
The term "up-regulated" means: 1). increased or unregulated CCR2 activity or expression, or 2). increased CCR2 expression leading to unwanted monocyte and lymphocyte migration. The existence of an inappropriate or abnormal level of MCP-I or activity of CCR2 is determined by procedures well known in the art.
CCR2 mediated inflammatory syndromes, disorders or diseases include, without limitation, ophthalmic disorders, uveitis, atherosclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn's Disease, ulcerative colitis, nephritis, organ allograft rejection, fibroid lung, renal insufficiency, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, obesity, tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, invasive staphyloccocia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, asthma, allergic asthma, periodontal diseases, periodonitis, gingivitis, gum disease, diastolic cardiomyopathies, cardiac infarction, myocarditis, chronic heart failure, angiostenosis, restenosis, reperfusion disorders, glomerulonephritis, solid tumors and cancers, chronic lymphocytic leukemia, chronic myelocytic leukemia, multiple myeloma, malignant myeloma, Hodgkin's disease, and carcinomas of the bladder, breast, cervix, colon, lung, prostate, or stomach.
The term "uveitis" generically refers to any inflammatory disease involving the eye. Uveitis can be divided into clinically distinct subtypes based on the part of the eye in which the inflammation is present (percentages correspond to patients known to fit these categories): anterior (51%), intermediate (13%), posterior (20%), or panuveitis (16%) and, according to the course of the disease, as either acute (16%), recurring (26%), or chronic (58%). Those with anterior uveitis (-19%) eventually develop irreparable vision damage despite aggressive treatment such as unilateral blindness (9%), bilateral blindness (2%), or unilateral or bilateral vision impairment (8%). Most cases of uveitis are idiopathic, but known causes include infection (e.g., toxoplasmosis, cytomegalovirus, and the like) or development as a component of a systemic inflammatory and/or autoimmune disorder (e.g., juvenile RA, HLA-B27-associated spondyloarthropathies, sarcoidosis, and the like).
Patients with anterior uveitis have MCP-I present in large quantities in the aqueous humor of the eye. The amount of MCP-I correlates with the severity of the clinical symptoms and the large number of mononuclear cells present in the cellular infiltrate. Uveitis is also a potential complication resulting from cataract surgery and prophylactic use of antibiotics and corticosteroids is common for such patients. Currently, most patients with anterior uveitis are first treated with topical corticosteroids. Injected or oral steroids may be used in severe cases, or if the disease is recurrent or chronic. If steroids are ineffective, immunosuppressive agents (e.g., cyclosporine, methotrexate, azathioprine, cyclophosphamide, and the like) are used, particularly if the patient's vision is in danger. All of these drugs have potentially severe side-effects, particularly in children, and there is general agreement that there is an unmet medical need for safe and effective steroid substitutes or steroid-sparing agents.
An example of the invention is a method for preventing, treating or ameliorating CCR2 mediated ophthalmic disorders (such as uveitis, allergic conjunctivitis and the like), rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, obesity, chronic obstructive pulmonary disease, allergic rhinitis, asthma, allergic asthma, periodontal diseases (such as periodonitis, gingivitis, gum disease and the like) in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form, composition or medicament thereof.
Another example of the invention is a method for preventing, treating or ameliorating CCR2 mediated uveitis, wherein uveitis includes, without limitation, acute, recurring or chronic uveitis (such as anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis and the like) in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form, composition or medicament thereof.
An example of the invention is a method for preventing, treating or ameliorating
CCR2 mediated acute uveitis, recurring uveitis, chronic uveitis, allergic conjunctivitis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, obesity, chronic obstructive pulmonary disease, allergic rhinitis, asthma, allergic asthma, periodonitis, gingivitis or gum disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form, composition or medicament thereof.
Another example of the invention is a method for preventing, treating or ameliorating CCR2 mediated obesity in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form, composition or medicament thereof.
The invention includes a method for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or a form, composition or medicament thereof in a combination product with one or more therapeutic agents.
The term "combination product" refers to a compound of Formula (I) or a form, composition or medicament thereof in admixture with a therapeutic agent and an optional carrier for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
The term "therapeutic agent" refers to one or more anti-inflammatory agents (such as a small molecule, antibiotic, corticosteroid, steroid, and the like), anti-infective agents or immunosuppressive agents. The term "administering," in the context of a combination product includes, without limitation, co-administration of the compound and the agent, sequential administration of the compound and the agent, administration of a composition containing of the compound and the agent or simultaneous administration of separate compositions containing of the compound and the agent.
As those skilled in the art will appreciate, the effective amounts of the components comprising the combination product may be independently optimized and combined to achieve a synergistic result whereby the pathology is reduced more than it would be if the components of the combination product were used alone.
The present invention includes a compound of Formula (I) or a form thereof, wherein the compound is labeled with a ligand for use as a marker, and wherein the ligand is a radioligand selected from deuterium, tritium and the like.
Pharmaceutical Compositions
The present invention includes a pharmaceutical composition or medicament comprising one or more of the instant compounds and an optional pharmaceutically acceptable carrier.
The present invention further includes a process for making a pharmaceutical composition or medicament comprising mixing one or more of the instant compounds and an optional pharmaceutically acceptable carrier; and, includes those compositions or medicaments resulting from such a process. Contemplated processes include both conventional and unconventional pharmaceutical techniques.
The composition or medicament may take a wide variety of forms to effectuate mode of administration ocularly, intranasally (by inhalation or insufflation), sublingually, orally, parenterally or rectally including, without limitation, ocular (via a delivery device such as a contact lens and the like), intranasal (via a delivery device), transdermal, topical with or without occlusion, intravenous (both bolus and infusion), injection (intraperitoneally, subcutaneously, intramuscularly, intratumorally, or parenterally) and the like. The composition or medicament may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, biodegradable carrier, ion exchange resin, sterile solution and the like (facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto- injector device or suppository.
Compositions or medicaments suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. Forms useful for nasal administration include sterile solutions or nasal delivery devices. Forms useful for ocular administration include sterile solutions or ocular delivery devices. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
Alternatively, the composition or medicament may be administered in a form suitable for once-weekly or once-monthly administration. For example, an insoluble salt of the active compound may be adapted to provide a depot preparation for intramuscular injection (e.g., a salt form) or to provide a solution for nasal or ocular administration (e.g., a quaternary ammonium salt).
The dosage form (tablet, capsule, powder, solution, contact lens, patch, liposome, ion exchange resin, suppository, teaspoonful, and the like) containing the composition or medicament thereof contains an effective amount of the active ingredient necessary to provide a therapeutic effect.
The composition or medicament may contain an effective amount of from about 0.001 mg to about 5000 mg (preferably, from about 0.001 to about 500 mg) of a compound of the present invention or a pharmaceutically acceptable form thereof and may be constituted into any form suitable for the mode of administration selected for a subject in need.
A contemplated range of the effective amount includes from about 0.001 mg to about 300 mg/kg of body weight per day. A contemplated range also includes from about 0.003 to about 100 mg/kg of body weight per day. Another contemplated range includes from about 0.005 to about 15 mg/kg of body weight per day. Another contemplated range includes from about 0.01 to about 15 mg/kg of body weight per day. Another contemplated range includes from about 0.1 to about 10 mg/kg of body weight per day. The composition or medicament may be administered according to a dosage regimen of from about 1 to about 5 times per day.
For oral administration, the composition or medicament is preferably in the form of a tablet containing, e.g., 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient's sex, age, weight, diet, time of administration and concomitant diseases, will result in the need to adjust dosages. The use of either daily administration or post-periodic dosing may be employed.
For ocular administration, the composition is preferably in the form of an ophthalmic composition. The ophthalmic compositions are preferably formulated as eye-drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette.
For ocular administration, the composition is preferably in the form of an ophthalmic composition. The ophthalmic compositions are preferably formulated as eye-drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette.
Synthetic Methods
Representative compounds of the present invention can be synthesized in accordance with the general synthetic schemes described below and are illustrated more particularly in the specific examples that follow. The general schemes and specific examples are offered by way of illustration; the invention should not be construed as being limited by the chemical reactions and conditions expressed. The methods for preparing the various starting materials used in the schemes and examples are well within the skill of persons versed in the art.
The following abbreviations and formulas have the indicated meanings: Abbreviations Meaning
HOAc or AcOH acetic acid
CH3COCl acetyl chloride atm atmosphere
Boc tert-butoxy carbonyl or t-butoxy carbonyl
(BoC)2O di-tert-buty\ dicarbonate
Cbz benzyloxycarbonyl
(CH2O)n paraformaldehyde
Cpd compound
DBU l,8-diazabicyclo[5.4.0]undec-7-ene
DCM or CH2Cl2 methylene chloride or dichloromethane
DIPEA or i-Pr2NEt diisopropylethylamine
DMAP 4-dimethylaminopyridine
DMF N,N-dimethyl formamide
EDCI 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride
Et2O diethyl ether
EtOAc or CH3CO2Et ethyl acetate
FLIPR fluorometric imaging plate reader
HBr hydrobromic acid
HOBt 1 -hydroxy-benzotriazole
HBTU 0-(7-benzotriazol- 1 -yl)-ΛWΛr,ΛT- tetramethyluronium hexafluorophosphate
K2CO3 potassium carbonate
KHMDS potassium bis(trimethylsilyl)amide
LiAlH4 lithium aluminum hydride
LHMDS lithium bis(trimethylsilyl)amide Abbreviations Meaning
LiOH lithium hydroxide
MeCN or CH3CN acetonitrile
MeOH or CH3OH methanol
Me3SiCHN2 trimethylsilyl-diazomethane min/hr(s)/dy minute(s)/hour(s)/day(s)
MS mass spectrum, refers to data shown as m/z (M+H)+
NBS N-bromo-succinimide
NCS N-chloro-succinimide
NH4Cl ammonium chloride
HCO2NH4 ammonium formate
NaBH4 sodium borohydride
NaB(OAc)3H sodium triacetoxyborohydride
NaCNBH3 sodium cyanoborohydride
NaHCO3 sodium bicarbonate
NaOH sodium hydroxide
Na2SO4 sodium sulfate
Pd(OH)2 palladium hydroxide psi pounds per square inch
PTLC preparative thin layer chromatography
RPMI Roswell Park Memorial Institute
RT/rt/r.t. room temperature
SOCl2 thionyl chloride t-BuOOH te/t-butyl-hydroxy-peroxide
TEA or Et3N triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMSCl chlorotrimethylsilane or trimethylsilyl chloride
VO(acac)2 vanadyl acetylacetonate Scheme A
Figure imgf000047_0001
Compound Al (wherein PG is a suitable protecting group such as tert- butoxycarbonyl and the like) is reacted with a solution of Compound A2 (wherein X is a halogen such as chlorine, R is a functional group such as methanesulfonyl and the like) in the presence of a suitable base (such as Et3N, DIPEA and the like) in a solvent (such as methylene chloride, tetrahydrofuran and the like or a mixture thereof) to give a Compound A3.
Figure imgf000047_0002
Compound A3 is reacted with a substituted piperidine Compound A4 in solution
(such as Hunig's base and the like in a solvent such as toluene, DCM, acetonitrile and the like or a mixture thereof) to give a Compound A5.
Figure imgf000048_0001
The Compound A5 protecting group may be removed at a suitable point using means known to those skilled in the art to provide a Compound A6 free base or salt form that is amendable for further substitution.
Figure imgf000048_0002
A solution of Compound A6 (in a suitable solvent such as CH2Cl2, CH3CN, DMF and the like or a mixture thereof) is reacted with a suitably substituted Compound A7 (wherein Compound A7 contains a suitable reaction group such as isocyanato, isothiocyanato, carboxy, acid chloride and the like) to provide a Compound A8 of Formula (I) (wherein certain portions of Compound A7 are incorporated into Compound A8 as a product of the reaction).
When the Compound A7 reaction group is carboxy, Compound A7 is reacted in conjunction with coupling reagents such as EDCI, HBTU and the like. When Compound A6 is a salt form, Compound A6 is reacted with Compound A7 in the presence of a suitable base such as Et3N, DIPEA and the like.
Scheme B
Figure imgf000049_0001
A solution of Compound Bl (wherein PG is a suitable protecting group such as tert-butoxycarbonyl and the like) is reacted with a reagent solution (such as LHMDS in a solvent such as THF and the like). A second reagent (such as TMSCl and the like) is added to the mixture and the mixture is stirred. Then a halogen reagent solution is added (such as NBS, NCS, bromine and the like in a solvent such as THF and the like) to provide a Compound B2 (wherein Xc is a suitable leaving group such as halogen).
Figure imgf000049_0002
Compound B2 is reacted at reflux with Compound A4 (in a solvent such as acetonitrile and the like) to provide a compound B3.
Figure imgf000050_0001
The Compound B3 protecting group may be removed at a suitable point using means known to those skilled in the art to provide a Compound B4 free base or salt form that is amendable for further substitution.
Figure imgf000050_0002
A solution of Compound B4 (in a suitable solvent such as CH2Cl2, CH3CN, DMF and the like or a mixture thereof) is reacted with a suitably substituted Compound A7 (wherein Compound A7 contains a suitable reaction group such as isocyanato, isothiocyanato, carboxy, acid chloride and the like) to provide a Compound B5 (wherein certain portions of Compound A7 are incorporated into Compound B5 as a product of the reaction).
Figure imgf000051_0001
Compound B5 can be converted to Compound B6 using means known to those skilled in the art (such as hydrogenation or hydrolysis and the like).
The invention is further defined by reference to the following examples, which are merely intended to be illustrative and not limiting.
Example 1
(2E)-3-(3,4-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy- phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
(Cpd 1)
Figure imgf000051_0002
To a solution of Compound Ia (1.955 g, 0.00905 mol, 1 eq) in CH2Cl2 (45 mL) was added triethlyamine (2.5 mL, 0.0176 mol, 2 eq). The solution was cooled to O0C and methansulfonyl chloride (0.91 mL, 0.0117 mol, 1.3 eq) was added. The reaction mixture was stirred an additional 18 hours at room temperature. The reaction was partitioned between NaHCO3 (saturated aqueous solution, 20 mL) and dichlormethane (20 mL). The aqueous phase was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were dried over anhydrous Na2SO4, then filtered and concentrated to give Compound Ib (2.54 g, 96%) as an orange-yellow oil. MS m/z 294(M+H)+.
Figure imgf000052_0001
To a solution of Compound Ib (1.0 g, 0.003398 mol, 1.3 eq) in CH3CN (26 mL) was added Hunig's base (2.3 mL, 0.013 mol, 5 eq) and 4-(4-methoxy-phenyl)-piperidine Compound Ic (0.5 g, 0.0026 mol, 1 eq). The mixture was heated at reflux for 18 hours and then loaded directly onto silica gel and chromatographed (gradient, 40 to 60% EtOAc/CH2Cl2) to give Compound Id (0.4889 g, 48%) as a yellow solid. MS m/z 389(M+H)+.
Figure imgf000052_0002
To a solution of Compound Id (0.4889 g, 0.00127 mol, 1 eq) in dichloromethane (12 mL) at O0C was added trifluoroacetic acid (2.5 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and dissolved in water (50 mL) and extracted with diethyl ether (2 x 25 mL). The aqueous layer was made basic with sodium hydroxide (15 mL, 15% aqueous solution) and extracted with CH2Cl2 (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, then filtered and concentrated to give Ie (0.2416 g, 67%) as an off-white solid. MS m/z 289 (M+H)+.
Figure imgf000053_0001
To a solution of Compound Ie (0.0604 g, 0.000209 mol, 1 eq) in dichloromethane (3 mL) was added 3-(3,4-dichloro-phenyl)-acrylic acid Compound If (0.068 g, 0.000314 mol, 1.5 eq), EDCI (0.06 g, 0.000314 mol, 1.5 eq) and DMAP (0.038 g, 0.000314 mol, 1.5 eq). The mixture was stirred for 18 hours at room temperature. The reaction mixture was then loaded directly onto silica and chromatographed (5% CH3OH-CH2Cl2 to give Compound 1 (0.0856 g, 85.6%) as an off-white solid. MS m/z 488(M+H)+.
Using the procedure of Example 1 and known appropriate reagents and starting materials, the following compounds of the invention were prepared:
Cpd Name MS
(2£)-3-(3,5-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)- 487 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide Cpd Name MS
3 (2£)-3-(3,5-difluσro-phenyl)-N-cis- (3-[4-(4-methoxy-phenyl)- 455 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
4 (2£)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]- 473 cyclopentyl}-3-(3,4,5-trifluoro-phenyl)-acrylamide
5 (2Je)-3-(3,5-dichloro-phenyl)-N-(li?,35)-{3-[4-(4-methoxy-phenyl)- 487 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
6 (2J£)-3-(3,5-difluoro-phenyl)-N-(li?,35)- (3-[4-(4-methoxy-phenyl)- 455 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
7 (2Je)-N-(li?,35)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethylJ- 473 cyclopentyl}-3-(3,4,5-trifluoro-phenyl)-acrylamide
8 (2£)-3-(3,4-dichloro-phenyl)-N-(l^,3i?)-(3- {cis-[3-hydroxy-4-(4- 503 methoxy-phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide
9 (2£>3-(3,5-dichloro-phenyl)-N-(lS,3i?)-(3- {cis-[3-hydroxy-4-(4- 503 methoxy-phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide
10 (2£)-3-(3,5-difluoro-phenyl)-N-(1^3i?)-(3-{cis-[3-hydroxy-4-(4- 471 methoxy-phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide
11 (2Je)-N-(llS,3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy-phenyl)-piperidin- 489 1 -yljmethyl} -cyclopentyl)-3-(3,4,5-trifluoro-phenyl)-acrylamide
12 (2Je)-3-(3,5-bis-trifluoromethyl-phenyl)-N-(llS,3i?)-(3-{cis-[3- 571 hydroxy-4-(4-methoxy-phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)- acrylamide
14 (2J£)-3-(3,5-difluoro-phenyl)-N-cis- (3-[4-(3,4-dimethoxy-phenyl)- 485 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
15 (2J£)-3-(3,5-difluoro-phenyl)-N-cis-[3-(3,4,5,6-tetrahydro-2H- 426 [4,4'Jbipyridinyl- 1 -ylmethy^-cyclopentylj-acrylamide
16 (2£)-N-cis- {3-[4-(3,4-dichloro-phenyl)-piperidin- 1 -ylmethylj- 493 cyclopentyl}-3-(3,5-difluoro-phenyl)-acrylamide
17 (2J£)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3,4-difluoro-phenyl)- 461 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
18 (2Je)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-dimethylamino-phenyl)- 468 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
19 (2J£)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l- 459 ylmethyl]cyclopentyl}-3-(3,5-difluoro-phenyl)-acrylamide
20 (2J£)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-trifluoromethyl-phenyl)- 493 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
21 (2J£)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-fluoro-phenyl)- 443 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide Cpd Name MS
22 (2£)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3-fluoro-phenyl)- 443 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
23 (2Je)-3-(3,5-difluoro-phenyl)-N-cis-[3-(4-phenyl-piperidin-l- 425 ylmethy^-cyclopentylj-acrylamide
24 (2J£)-3-(3,5-difluoro-phenyl)-N-cis- (3-[4-(3-methoxy-phenyl)- 455 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
25 (2Je)-3-(3,5-difluoro-phenyl)-N-cis-[3-(4-p-tolyl-piperidin-l- 439 ylmethyl)-cyclopentyl]-acrylamide
26 (2J£)-N-cis-[3-(4-benzofuran-3-yl-piperidin-l-ylmethyl)- 465 cyclopentyl] -3 -(3 ,5 -difluoro-phenyl)-acrylamide
27 l-{[3-cis-({[2-(2J£)-(3,5-difluoro-phenyl)ethenyl]carbonyl} amino)- 451 cyclopentyl]methyl}-spiro[piperidine-4,2'-indane]
28 1 - { [3 -cis-( { [2-(2£)-(3 ,5 -difluoro-phenyl)ethenyl]carbonyl} amino)- 449 cyclopentyl]methyl} -spiro[piperidine-4, 1 '-indene]
29 1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethyl]-cyclopentyl} -3- 448 (3,5-difluoro-phenyl)-urea
30 N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}- 433 3 ,5 -difluoro-benzamide
31 (2J£)-3-(3,5-difluoro-phenyl)-N-cis- {3-[4-(lH-indol-3-yl)-piperidin- 464 1 -ylmethylj-cyclopentyl} -acrylamide
32 1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- 412 phenyl-urea
33 6-chloro-8-methyl-2H-chromene-3-carboxylic acid cis- {3-[4-(4- 495 methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide
34 7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carboxylic acid cis- {3- 529 [4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide
35 6-methyl-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy- 461 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
36 8-methyl-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy- 461 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
37 6-chloro-2H-chromene-3-carboxylic acid cis- {3-[4-(4-methoxy- 481 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
38 (2£)-3-(3,5-difluoro-phenyl)-N-(1^3i?)-{3-[4-(2-methyl- 479 benzoimidazol- 1 -yl)-piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
39 N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l -ylmethylj-cyclopentyl} -2- 427 phenoxy-acetamide Cpd Name MS
40 N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-2- 443 phenylsulfanyl-acetamide
41 2-(4-chloro-phenoxy)-N-cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 - 461 ylmethylj-cyclopentyl} -acetamide
42 (2Je)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]- 424 cyclopentyl}-3-pyridin-4-yl-acrylamide
43 (2£)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]- 413 cyclopentyl}-3-furan-2-yl-acrylamide
44 (2Je)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]- 413 cyclopentyl}-3-furan-3-yl-acrylamide
45 (2Je)-N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]- 424 cyclopentyl}-3-pyridin-3-yl-acrylamide
46 trans-2-phenyl-cyclopropanecarboxylic acid (i?,35)-{3-[4-(4-chloro- 437 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
47 (2Je)-N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]- 429 cyclopentyl}-3-thiophen-2-yl-acrylamide
48 6-methoxy-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy- 477 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
49 6,8-dichloro-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy- 515 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
50 (2Je)-N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]- 429 cyclopentyl}-3-thiophen-3-yl-acrylamide
51 5-bromo-lH-indole-2-carboxylic acid cis-{3-[4-(4-methoxy -phenyl)- 510 piperidin- 1 -ylmethylj-cyclopentyl} -amide
52 5-chloro-lH-indole-2-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)- 466 piperidin- 1 -ylmethylj-cyclopentyl} -amide
53 N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethylJ- 445 cyclopentyl}-2-(4-fluoro-phenoxy)-acetamide
54 N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethylJ- 495 cyclopentyl}-2-(3,5-dichloro-phenoxy)-acetamide
55 l-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]- 437 cyclopentyl}-3-(4-cyano-phenyl)-urea
56 6-fluoro-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy- 465 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
57 6-trifluoromethyl-2H-chromene-3-carboxylic acid cis-{3-[4-(4- 515 methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide Cpd Name MS
58 S-fluoro-lH-chromene-S-carboxylic acid cis-{3-[4-(4-methoxy- 465 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
59 8-bromo-6-chloro-2H-chromene-3-carboxylic acid cis-{3-[4-(4- 559 methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide
60 7-methyl-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy- 461 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
61 7-methoxy-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy- 477 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
62 ό-tert-butyl-lH-chromene-S-carboxylic acid cis-{3-[4-(4-methoxy- 503 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
64 6,8-dichloro-2H-chromene-3-carboxylic acid (S,3R)-{3-[4-(4- 515 methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide
65 6-chloro-2H-chromene-3-carboxylic acid (5',3i?)-{3-[4-(4-methoxy- 481 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
66 (2£>3-(3,5-dichloro-phenyl)-N-(lS,3i?)- {3-[4-(4-methoxy-phenyl)- 487 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
67 (2£)-N-(1^3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]- 473 cyclopentyl}-3-(3,4,5-trifluoro-phenyl)-acrylamide
68 (2J£)-3-(3,5-difluoro-phenyl)-N-(llS,3i?)- (3-[4-(4-methoxy-phenyl)- 455 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
69 1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- 442 (4-methoxy-phenyl)-urea
70 1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- 444 (4-fluoro-benzyl)-urea
71 5,7-dichloro-2H-chromene-3-carboxylic acid cis-{3-[4-(4-methoxy- 515 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
72 3H-benzo[f]chromene-2-carboxylic acid cis- {3-[4-(4-methoxy- 497 phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-amide
73 (2E)-N-(IS,3R)- [3 -(4-benzoimidazol- 1 -yl-piperidin- 1 -ylmethyl)- 465 cyclopentyl] -3 -(3 ,5 -difluoro-phenyl)-acrylamide
74 (2J£)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(2-fluoro-phenyl)- 443 piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide
75 (2£)-N-cis- {3-[4-(4-tert-butyl-phenyl)-piperidin- 1 -ylmethyl]- 481 cyclopentyl}-3-(3,5-difluoro-phenyl)-acrylamide Example 2
(liU^-{3-(2£)-[3-(3,5-difluoro-phenyl)-acryloylamino]- cyclopentyl}-(i?S)-[4-(lH-indol-3-yl)-piperidin-l-yl]-acetic acid (Cpd 63)
Figure imgf000058_0001
To a solution of LHMDS in THF (1.0 M, 4.09 niL) at -780C was added dropwise a solution of Compound 2a (0.379g, 1.14 mmol) in THF (5 mL). The resulting reaction mixture was stirred at -780C for 30 min. TMSCl (0.52 mL, 4.09 mmol) was added dropwise to the reaction mixture at -780C, then the mixture was stirred for 1 hr and Br2 (0.07 mL, 1.37 mmol) was added dropwise at the same temperature. The reaction mixture was stirred at -780C for 2.5 hrs. The reaction mixture was poured into a mixture of EtOAc (100 mL) and NaHCO3 (100 mL). The organic layer was washed with water (1x100 mL) and brine (Ix 100 mL), then dried over Na2SO4, filtered and concentrated. The resulting crude product was purified on a silica gel column with 20% EtOAc/hexane to give Compound 2b (0.1 g). MS: m/z 412 (M+H)+.
Figure imgf000058_0002
To a solution of Compound 2b (O.lg, 0.243 mmol) in acetonitrile (8 mL) was added 3-piperidin-4-yl-lH-indole Compound 2c (0.05 g, 0.21 mmol) and Ηunig's base (0.13 mL). The resulting reaction mixture was refluxed for 2 days and then concentrated. The resulting crude product was purified on a silica gel column (3:1.5:1 CH2Cl2 : hexane EtOAc) to give Compound 2d (0.027 g). MS: m/z 532 (M+H)+.
Figure imgf000059_0001
TFA (0.5 ml) was added to a solution of Compound 2d (0.027 g, 0.051 mmol) in CH2Cl2 (1.5 mL). The reaction mixture was stirred for 3h. The solvent was removed in vacuo to provide a solid product (0.028 g). MS m/z 432 (M+H)+.
Figure imgf000059_0002
Compound 2e (0.028 g) was dissolved in CH2Cl2 (3 mL) and cooled to 00C. TEA (0.021 mL) was added, followed by slow addition of a solution of 3,5-difluoro-cinnamoyl chloride Compound 2f (0.01 g, 0.051 mmol). The reaction was allowed to warm to room temperature and diluted with ethyl acetate. The solution was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried with anhydrous Na2SO4 and filtered to remove the solid. The filtrate was evaporated and the resulting residue was chromatographed (3:1 CH2Cl2 : EtOAc) to provide Compound 2g (0.02 g). MS m/z 598 (M+H)+.
Figure imgf000060_0001
Compound 2g (0.020 g) was dissolved in MeOH (1.5 mL) and bubbled with N2. Pd/C (10%, 15 mg) was added, followed by addition of cyclohexa-l,4-diene (10 drops) and HCOONH4(0.04 g). The mixture was stirred for 2 h at r.t. then filtered through celite and concentrated. The crude product was purified with silica column (10% MeOH / CH2Cl2) to give Compound 63 (0.011 g). MS m/z 508 (M+H)+.
Using the procedure of Example 2 and known appropriate reagents and starting materials, the following compound of the invention was prepared:
Cpd Name MS
13 [4-(4-methoxy-phenyl)-piperidin-l-yl]-(li?,35)-{3-[(2E)-3-(3,4,5- 517 trifluoro-phenyl)-acryloylamino]-cyclopentyl} -acetic acid Biological Activity
Compounds of the present invention were subjected to various representative biological tests to demonstrate their usefulness for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease. The results of these tests are intended to illustrate the invention in a non-limiting fashion.
Examples 4-8 are intended as prophetic examples and are expected to demonstrate that said compounds are useful in preventing, treating or ameliorating such examples of a CCR2 mediated inflammatory syndrome, disorder or disease.
Example 1 MCP-I Receptor Binding Assay in THP-I Cells
THP-I cells were obtained from American Type Culture Collection (Manassas, VA, USA). The THP-I cells were grown in RPMI- 1640 supplemented with 10% fetal bovine serum in a humidified 5% CO2 atmosphere at 370C. The cell density was maintained between 0.5xl06 cells/ mL.
THP-I cells were incubated with 0.5 nM 125I labeled MCP-I (Perkin-Elmer Life
Sciences, Inc. Boston, MA) in the presence of varying concentrations of either unlabeled MCP-I (R & D Systems, Minneapolis, MN) or test compound for 2 hours at 30 0C in a 96 well plate. Cells were then harvested onto a filter plate, dried, and 20 μL of Microscint 20 was added to each well. Plates were counted in a TopCount NXT , Microplate Scintillation & Luminescence Counter (Perkin-Elmer Life Sciences, Inc. Boston, MA). Blank values (buffer only) were subtracted from all values and drug treated values were compared to vehicle treated values. 1 μM cold MCP-I was used for nonspecific binding.
Table 1 lists average IC50 values for inhibition of MCP-I binding to CCR2 obtained for test compounds of the invention. Where an IC50 value was not obtained for a particular compound, the percent inhibition is provided at a test concentration of 25 μM.
Table 1 Inhibition of MCP-I Binding IC50 (μM) Cpd IC 50 Cpd IC50 Cpd IC50
1 0.14 26 3.1 51 1.2
2 0.18 27 1.5 52 0.86
3 0.16 28 1.2 53 4.2
4 0.13 29 2.3 54 3.5
5 6.5 30 8.5 55 3.3
6 12 31 0.64 56 1.4
7 8.4 32 2 57 6.8
8 0.15 33 0.96 58 9.9
9 0.24 34 14.2 59 1.9
10 0.27 35 3.8 60 8.4
11 0.11 36 6.1 61 7.7
12 0.87 37 0.58 62 6.7
13 4.5 38 8.6 63 5.9
14 2.2 39 3.4 64 1.9
15 3.2 40 20.8 65 0.8
16 1.1 41 1.3 66 0.16
17 0.79 42 3.6 67 0.08
18 0.37 43 1.35 68 0.33
19 0.2 44 0.68 69 67%
20 2.2 45 2.3 70 43%
21 1.3 46 11.7 71 47.5%
22 6.9 47 2.9 72 55%
23 4.7 48 8 73 58%
24 15.9 49 2.8 74 53%
25 0.92 50 1 75 53%
Example 2
MCP-I Induced Calcium Mobilization in THP-I Cells
THP-I cells were plated at a density of 8 x 10 Λ5 cells/ mL (100 μL/well) into poly-D lysine coated clear bottom, black 96 well plates. The cells were loaded with 5 μM fluo-3 for 45 minutes. The fluo-3 was washed off and cells were incubated with varying concentrations of Compound 52 for 15 minutes. The change in calcium ion concentration upon addition of 0.2 μM MCP-I was determined using FLIPR and compared to vehicle.
Compound 52 gave an average IC50 value of 0.32 μM for inhibition of MCP-I induced calcium ion influx.
Example 3
MCP-I Induced Chemotaxis in THP-I Cells
MCP-I induced chemotaxis was run in a 24-well chemotaxis chamber. MCP-I (0.01 μg/mL) was added to the lower chamber and 100 μL of THP-I cells (1 x 10 7 cell/mL) was added to the top chamber. Varying concentrations of test compound were added to the top and bottom chambers. Cells were allowed to chemotax for 3 hours at 37 0C and 5% CO2. An aliquot of the cells that had migrated to the bottom chamber was taken and counted then compared to vehicle. Table 3 lists the average IC50 values for inhibition of MCP-I induced chemotaxis.
Table 3 Inhibition of MCP-I Induced Chemotaxis IC50 (μM)
Cpd IC50 Cpd IC50 Cpd IC50
2 4.1 17 0.74 43 1.7
3 0.64 18 0.12 44 1.2
4 3.6 19 0.21 52 1.2
8 0.15 31 0.38 67 0.13
11 0.07 33 1.1 68 0.19
12 0.25 37 0.87
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I):
Figure imgf000064_0001
or a form thereof, wherein
Ri is cycloalkyl, aryl-cycloalkyl, aryl, aryl-alkenyl, aryl-amino, aryloxy-alkyl, arylthio-alkyl, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, nitro, amino, alkylamino, aminoalkyl, alkylaminoalkyl, carboxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or alkylthio;
X is CH-R2 or C, wherein C is a piperidine ring carbon atom in common with a cycloalkyl ring carbon atom, thus forming a spiro ring system;
R2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, nitro, amino, alkylamino, aminoalkyl, alkylaminoalkyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonylamino, aminosulfonylalkyl, alkylaminosulfonylalkyl, carboxy, alkylcarbonyl or alkoxycarbonyl;
R3 is selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, aminoalkyl, cyano, carboxy or alkoxycarbonyl; and R4 is selected from hydrogen, hydroxy, hydroxyalkyl, haloalkyl, alkyl, aminoalkyl, cyano, alkoxy, carboxy or alkoxycarbonyl.
2. The compound of claim 1, wherein
Ri is aryl-cycloalkyl, aryl, aryl-alkenyl, aryl-amino, aryloxy-alkyl, arylthio-alkyl, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen or haloalkyl;
X is CH-R2;
R2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen, haloalkyl, amino or alkylamino;
R3 is selected from hydrogen or carboxy; and
R4 is selected from hydrogen, hydroxy or carboxy.
3. The compound of claim 1 , wherein
Ri is aryl-alkenyl, aryl-amino, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or haloalkyl;
X is CH-R2;
R2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or alkylamino;
R3 is hydrogen; and
R4 is selected from hydrogen or hydroxy.
4. The compound of claim 1, wherein
Ri is aryl-alkenyl or heterocyclyl, wherein aryl and heterocyclyl are each optionally substituted with two or three substituents selected from halogen or haloalkyl;
X is CH-R2;
R2 is aryl or heterocyclyl each substituted with one substituent selected from alkoxy, halogen or alkylamino;
R3 is hydrogen; and
R4 is selected from hydrogen or hydroxy.
5. The compound of claim 1 , wherein
Ri is aryl-alkenyl, wherein aryl is substituted with three halogen substituents;
X is CH-R2;
R2 is aryl substituted with one alkoxy substituent;
R3 is hydrogen; and
R4 is hydroxy.
6. The compound of claim 1, wherein Ri is aryl-cycloalkyl, aryl, aryl-alkenyl, aryl-amino, aryloxy-alkyl, arylthio-alkyl, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, cyano, halogen or haloalkyl.
7. The compound of claim 1, wherein Ri is aryl-alkenyl, aryl-amino, heterocyclyl or heterocyclyl-alkenyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or haloalkyl.
8. The compound of claim 1, wherein Ri is aryl-alkenyl or heterocyclyl, wherein aryl and heterocyclyl are each optionally substituted with two or three substituents selected from halogen or haloalkyl.
9. The compound of claim 1, wherein Ri is aryl-alkenyl, wherein aryl is substituted with three halogen substituents.
10. The compound of claim 1, wherein R2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen, haloalkyl, amino or alkylamino.
11. The compound of claim 1 , wherein R2 is aryl or heterocyclyl each optionally substituted with one, two or three substituents selected from alkyl, alkoxy, halogen or alkylamino.
12. The compound of claim 1, wherein R2 is aryl or heterocyclyl each substituted with one substituent selected from alkoxy, halogen or alkylamino.
13. The compound of claim 1, wherein R2 is aryl substituted with one alkoxy substituent.
14. The compound of claim 1, wherein R3 is selected from hydrogen or carboxy.
15. The compound of claim 1, wherein R3 is hydrogen.
16. The compound of claim 1, wherein R4 is selected from hydrogen, hydroxy or carboxy.
17. The compound of claim 1, wherein R4 is selected from hydrogen or hydroxy.
18. The compound of claim 1 , wherein R4 is hydroxy.
19. A compound selected from the group consisting of:
(2E)-3-(3,4-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
(2E)-3-(3,5-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide, (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
(2£)-N-cis- {3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- (3,4,5-trifluoro-phenyl)-acrylamide,
(2E)-3-(3,5-dichloro-phenyl)-N-(li?,35)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-(li?,35)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
(2E)-N-(li?,35)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}- 3-(3,4,5-trifluoro-phenyl)-acrylamide,
(2E)-3-(3,4-dichloro-phenyl)-N-(15',3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
(2E)-3-(3,5-dichloro-phenyl)-N-(llS,3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
(2E)-3 -(3 ,5 -difluoro-phenyl)-N-( 1 S,3R)-(3 - {cis- [3 -hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
(2E)-N-( 1 S,3R)-(3 - {cis- [3 -hydroxy-4-(4-methoxy-phenyl)-piperidin- 1 - yljmethyl} -cyclopentyl)-3-(3 ,4, 5-trifluoro-phenyl)-acrylamide,
(2E)-3 -(3 ,5 -bis-trifluoromethyl-phenyl)-N-( 1 S,3R)-(3 - {cis- [3 -hydroxy-4-(4- methoxy-phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
(i?)-[4-(4-methoxy-phenyl)-piperidin-l-yl]-(li?,35)-{3-[(2JE)-3-(3,4,5-trifluoro- phenyl)-acryloylamino]-cyclopentyl} -acetic acid,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3,4-dimethoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-[3-(3,4,5,6-tetrahydro-2H-[4,4']bipyridinyl- l-ylmethyl)-cyclopentyl]-acrylamide,
(2E)-N-cis-{3-[4-(3,4-dichloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- (3,5-difluoro-phenyl)-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3,4-difluoro-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-dimethylamino-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide,
(2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3-(3,5- difluoro-phenyl)-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-trifluoromethyl-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-fluoro-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide, (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3-fluoro-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
(2E)-3 -(3 ,5 -difluoro-phenyl)-N-cis- [3 -(4-phenyl-piperidin- 1 -ylmethyl)- cyclopentyl] -acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-[3-(4-p-tolyl-piperidin-l-ylmethyl)- cyclopentyl] -acrylamide,
(2E)-N-cis-[3-(4-benzofuran-3-yl-piperidin-l-ylmethyl)-cyclopentyl]-3-(3,5- difluoro-phenyl)-acrylamide,
1 - { [3 -cis-( { [2-(2E)-(3 ,5 -difluoro-phenyl)ethenyl]carbonyl} amino)- cyclopentyljmethyl} -spiro[piperidine-4,2'-indane] ,
1 - { [3 -cis-( { [2-(2E)-(3 ,5 -difluoro-phenyl)ethenyl]carbonyl} amino)- cyclopentyljmethyl} -spiro[piperidine-4, 1 '-indene] ,
1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3-(3,5- difluoro-phenyl)-urea,
N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l -ylmethylj-cyclopentyl} -3,5-difluoro- benzamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(lH-indol-3-yl)-piperidin-l-ylmethyl]- cyclopentyl} -acrylamide,
1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3-phenyl- urea,
6-chloro-8-methyl-2H-chromene-3-carboxylic acid cis- {3-[4-(4-methoxy- phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carboxylic acid cis- {3-[4-(4- methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
6-methyl-2H-chromene-3-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
8-methyl-2H-chromene-3-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
6-chloro-2H-chromene-3-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
(2E)-3-(3,5-difluoro-phenyl)-N-(l^,3i?)-{3-[4-(2-methyl-benzoimidazol-l-yl)- piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide,
N-cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -2-phenoxy- acetamide,
N-cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -2- phenylsulfanyl-acetamide, 2-(4-chloro-phenoxy)-N-cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj- cyclopentyl} -acetamide,
(2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- pyridin-4-yl-acrylamide,
(2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3-flιran- 2-yl-acrylamide,
(2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3-flιran- 3-yl-acrylamide,
(2E)-N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- pyridin-3 -yl-acrylamide, trans-2-phenyl-cyclopropanecarboxylic acid (R,3S)- (3-[4-(4-chloro-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
(2E)-N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- thiophen-2 -yl-acrylamide,
6-methoxy-2H-chromene-3-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
6,8-dichloro-2H-chromene-3-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
(2E)-N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- thiophen-3 -yl-acrylamide,
5-bromo-lH-indole-2-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
5-chloro-lH-indole-2-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
N-(1R,3<S)- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -2-(4- fluoro-phenoxy)-acetamide,
N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-2-(3,5- dichloro-phenoxy)-acetamide,
1 -(IR,3S)- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3-(4- cyano-phenyl)-urea,
6-fluoro-2H-chromene-3-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
6-trifluoromethyl-2H-chromene-3-carboxylic acid cis- {3-[4-(4-methoxy- phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
8-fluoro-2H-chromene-3-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
8-bromo-6-chloro-2H-chromene-3-carboxylic acid cis- {3-[4-(4-methoxy- phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide, V-methyl-lH-chromene-S-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
V-methoxy-lH-chromene-S-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide, β-tert-butyl-lH-chromene-S-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
(li?,35)-{3-(2JE)-[3-(3,5-difluoro-phenyl)-acryloylamino]-cyclopentyl}-(i?5)-[4- ( 1 H-indol-3 -yl)-piperidin- 1 -yl] -acetic acid,
6,8-dichloro-2H-chromene-3-carboxylic acid (S,3R)- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
6-chloro-2H-chromene-3-carboxylic acid (S,3R)- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
(2E)-3-(3,5-dichloro-phenyl)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
(2E)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}- 3-(3,4,5-trifluoro-phenyl)-acrylamide,
(2E)-3 -(3 ,5 -difluoro-phenyl)-N-( 1 S,3R)- {3 - [4-(4-methoxy-phenyl)-piperidin- 1 - ylmethylj-cyclopentyl} -acrylamide,
1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3-(4- methoxy-phenyl)-urea,
1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3-(4-fluoro- benzyl)-urea,
5,7-dichloro-2H-chromene-3-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
3H-benzo[f]chromene-2-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
(2E)-N-(15',3i?)-[3-(4-benzoimidazol-l-yl-piperidin-l-ylmethyl)-cyclopentyl]-3- (3,5-difluoro-phenyl)-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(2-fluoro-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide, and
(2E)-N-cis- {3-[4-(4-tert-butyl-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- (3 ,5 -difluoro-phenyl)-acrylamide .
20. The compound of claim 19 selected from the group consisting of:
(2E)-3-(3,4-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
(2E)-3-(3,5-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide, (2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
(2£)-N-cis- {3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- (3,4,5-trifluoro-phenyl)-acrylamide,
(2E)-3-(3,4-dichloro-phenyl)-N-(15',3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yl]methyl} -cyclopentyl)-acrylamide,
(2E)-3-(3,5-dichloro-phenyl)-N-(llS,3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yl]methyl} -cyclopentyl)-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-(l^,3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yl]methyl} -cyclopentyl)-acrylamide,
(2E)-N-( 1 S,3R)-0 - {cis- [3 -hydroxy-4-(4-methoxy-phenyl)-piperidin- 1 - yl]methyl}-cyclopentyl)-3-(3,4,5-trifluoro-phenyl)-acrylamide,
(2E)-3-(3,5-bis-trifluoromethyl-phenyl)-N-(llS,3i?)-(3-{cis-[3-hydroxy-4-(4- methoxy-phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(3,4-difluoro-phenyl)-piperidin-l- ylmethyl]-cyclopentyl}-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-dimethylamino-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide,
(2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l -ylmethylj-cyclopentyl} -3-(3, 5- difluoro-phenyl)-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-[3-(4-p-tolyl-piperidin-l-ylmethyl)- cyclopentyl] -acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(lH-indol-3-yl)-piperidin-l-ylmethyl]- cyclopentyl} -acrylamide,
6-chloro-8-methyl-2H-chromene-3-carboxylic acid cis- {3-[4-(4-methoxy- phenyl)-piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
6-chloro-2H-chromene-3-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
(2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l -ylmethylj-cyclopentyl} -3-furan- 3-yl-acrylamide,
(2E)-N-(li?,35)-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3- thiophen-3 -yl-acrylamide,
5-chloro-lH-indole-2-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
6-chloro-2H-chromene-3-carboxylic acid (S,3R)- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethylj-cyclopentyl} -amide,
(2E)-3-(3,5-dichloro-phenyl)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide, (2E)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}- 3-(3,4,5-trifluoro-phenyl)-acrylamide,
(2E)-3 -(3 ,5 -difluoro-phenyl)-N-( 1 S,3R)- {3 - [4-(4-methoxy-phenyl)-piperidin- 1 - ylmethylj-cyclopentyl} -acrylamide,
1 -cis- {3-[4-(4-chloro-phenyl)-piperidin- 1 -ylmethyl]-cyclopentyl} -3-(4- methoxy-phenyl)-urea,
3H-benzo[f]chromene-2-carboxylic acid cis- (3-[4-(4-methoxy-phenyl)- piperidin- 1 -ylmethyl]-cyclopentyl} -amide,
(2E)-N-( 1 S, 3R)- [3 -(4-benzoimidazol- 1 -yl-piperidin- 1 -ylmethyl)-cyclopentyl] -3 - (3,5-difluoro-phenyl)-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(2-fluoro-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide, and
(2£)-N-cis- {3-[4-(4-tert-butyl-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- (3 ,5 -difluoro-phenyl)-acrylamide .
21. The compound of claim 19 selected from the group consisting of:
(2E)-3-(3,4-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
(2E)-3-(3,5-dichloro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
(2E)-N-cis- {3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -3- (3,4,5-trifluoro-phenyl)-acrylamide,
(2E)-3-(3,4-dichloro-phenyl)-N-(15',3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
(2E)-3-(3,5-dichloro-phenyl)-N-(15',3i?)-(3-{cis-[3-hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yl]methyl} -cyclopentyl)-acrylamide,
(2E)-3 -(3 ,5 -difluoro-phenyl)-N-( 1 S,3R)-(3 - {cis- [3 -hydroxy-4-(4-methoxy- phenyl)-piperidin- 1 -yl]methyl} -cyclopentyl)-acrylamide,
(2E)-N-( 1 S,3R)-0 - {cis- [3 -hydroxy-4-(4-methoxy-phenyl)-piperidin- 1 - yl]methyl}-cyclopentyl)-3-(3,4,5-trifluoro-phenyl)-acrylamide,
(2E)-3-(3,5-bis-trifiuoromethyl-phenyl)-N-(llS,3i?)-(3-{cis-[3-hydroxy-4-(4- methoxy-phenyl)-piperidin- 1 -yljmethyl} -cyclopentyl)-acrylamide,
(2E)-3-(3,5-difluoro-phenyl)-N-cis-{3-[4-(4-dimethylamino-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -acrylamide,
(2E)-N-cis-{3-[4-(4-chloro-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}-3-(3,5- difluoro-phenyl)-acrylamide, (l^-S-CS^-difluoro-phenyO-N-cis-IS-^^lH-indol-S-yO-piperidin-l-ylmethyl]- cyclopentyl} -acrylamide,
S-chloro-lH-indole^-carboxylic acid cis-{3-[4-(4-methoxy-phenyl)-piperidin- 1 -ylmethylj-cyclopentyl} -amide,
(2E)-3-(3,5-dichloro-phenyl)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l- ylmethylj-cyclopentyl} -acrylamide,
(2E)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}- 3-(3,4,5-trifluoro-phenyl)-acrylamide, and
(2E)-3 -(3 ,5 -difluoro-phenyl)-N-( 1 S,3R)- {3 - [4-(4-methoxy-phenyl)-piperidin- 1 - ylmethylj-cyclopentyl} -acrylamide.
22. The compound of claim 19 selected from the group consisting of:
(2E)-N-( 1 S,3R)-(3 - {cis- [3 -hydroxy-4-(4-methoxy-phenyl)-piperidin- 1 - yl]methyl}-cyclopentyl)-3-(3,4,5-trifluoro-phenyl)-acrylamide, and
(2E)-N-(15',3i?)-{3-[4-(4-methoxy-phenyl)-piperidin-l-ylmethyl]-cyclopentyl}- 3-(3,4,5-trifluoro-phenyl)-acrylamide.
23. The compound of claim 1, wherein the compound is a CCR2 antagonist.
24. The compound of claim 23, wherein the compound is a prodrug form thereof.
25. The compound of claim 24, wherein the compound is a metabolite form thereof.
26. The compound of claim 23, wherein the compound is an isolated form thereof.
27. The compound of claim 26, wherein the compound is a metabolite form thereof.
28. The compound of claim 26, wherein the compound is labeled with a ligand for use as a marker, and wherein the ligand is a radioligand selected from deuterium or tritium.
29. A pharmaceutical composition comprising an effective amount of the compound of claim 26.
30. The pharmaceutical composition of claim 29, further comprising a pharmaceutically acceptable carrier.
31. The pharmaceutical composition of claim 29, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg to about 300 mg/kg of body weight per day.
32. A process for preparing a pharmaceutical composition comprising the step of admixing the compound of claim 1 and a pharmaceutically acceptable carrier.
33. A medicament comprising an effective amount of the compound of claim 26.
34. The medicament of claim 33, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg to about 300 mg/kg of body weight per day.
35. Use of the compound of claim 26 as a CCR2 antagonist comprising contacting the receptor with the compound.
36. The use of claim 35, wherein the use further comprises use of the compound in a pharmaceutical composition, medicine or medicament for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
37. Use of the compound of claim 26 in the manufacture of a medicament for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease.
38. A method for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease in a subject in need thereof comprising administering to the subject an effective amount of the compound of claim 1.
39. The method of claim 38, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg to about 300 mg/kg of body weight per day.
40. The method of claim 38, further comprising administering to the subject an effective amount of the compound as a pharmaceutical composition, medicine or medicament thereof.
41. The method of claim 38, wherein the syndrome, disorder or disease is associated with elevated MCP-I expression or MCP-I overexpression, or is an inflammatory condition that accompanies syndromes, disorders or diseases associated with elevated MCP-I expression or MCP-I overexpression.
42. The method of claim 38, wherein the syndrome, disorder or disease is selected from ophthalmic disorders, uveitis, atherosclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn's Disease, ulcerative colitis, nephritis, organ allograft rejection, fibroid lung, renal insufficiency, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, obesity, tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, invasive staphyloccocia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, asthma, allergic asthma, periodontal diseases, periodonitis, gingivitis, gum disease, diastolic cardiomyopathies, cardiac infarction, myocarditis, chronic heart failure, angiostenosis, restenosis, reperfusion disorders, glomerulonephritis, solid tumors and cancers, chronic lymphocytic leukemia, chronic myelocytic leukemia, multiple myeloma, malignant myeloma, Hodgkin's disease, or carcinomas of the bladder, breast, cervix, colon, lung, prostate, or stomach.
43. The method of claim 38, wherein the method further comprises preventing, treating or ameliorating CCR2 mediated ophthalmic disorders, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, obesity, chronic obstructive pulmonary disease, allergic rhinitis, asthma, allergic asthma, periodontal diseases in a subject in need thereof comprising administering to the subject an effective amount of the compound of claim 1.
44. The method of claim 43, wherein the ophthalmic disorder is selected from uveitis or allergic conjunctivitis and the periodontal disease is selected from periodonitis, gingivitis or gum disease.
45. The method of claim 44, wherein uveitis is selected from acute, recurring or chronic uveitis.
46. The method of claim 44, wherein uveitis is selected from anterior uveitis, intermediate uveitis, posterior uveitis or panuveitis.
47. The method of claim 43, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg to about 300 mg/kg of body weight per day.
48. The method of claim 43, further comprising administering to the subject an effective amount of the compound of claim 1 as a pharmaceutical composition, medicine or medicament thereof.
49. The method of claim 43, further comprising administering to the subject an effective amount of a combination product comprising the compound of claim 1 and one or more therapeutic agent.
50. The method of claim 49, wherein the therapeutic agent is selected from an anti- inflammatory agent, an anti-infective agent or an immunosuppressive agent.
51. A method for preventing, treating or ameliorating CCR2 mediated obesity in a subject in need thereof comprising administering to the subject an effective amount of the compound of claim 1.
52. The method of claim 51 , wherein obesity in the subject is prevented, treated or ameliorated by the inhibition of weight gain, the inducement of weight loss or, in the alternative, an improvement in insulin sensitivity.
53. The method of claim 51 , wherein the effective amount of the compound is in a range of from about 0.001 mg/kg to about 300 mg/kg of body weight per day.
54. The method of claim 51 , further comprising administering to the subject an effective amount of the compound of claim 1 as a pharmaceutical composition, medicine or medicament thereof.
PCT/US2008/053941 2007-03-02 2008-02-14 Substituted cyclopentyl piperidine ccr2 antagonists WO2008109238A1 (en)

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JP2016128401A (en) * 2009-10-22 2016-07-14 フィブロテック セラピューティクス プロプライエタリー リミテッド Anti-fibrotic agents of fused ring analogues
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