WO2008109238A1 - Cyclopentylpipéridines substituées antagonistes du ccr2 - Google Patents

Cyclopentylpipéridines substituées antagonistes du ccr2 Download PDF

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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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phenyl
cyclopentyl
piperidin
cis
acrylamide
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PCT/US2008/053941
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English (en)
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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/fr

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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

L'invention concerne des composés cyclopentylpipéridines substitués de formule (I), ou une forme de ceux-ci, dans lesquels X, R1, R3 et R4, définis dans l'invention, sont des antagonistes du CCR2 utiles pour prévenir, traiter ou atténuer des syndromes inflammatoires, des troubles ou des pathologies provoqués par le CCR2 chez un patient qui en a besoin.
PCT/US2008/053941 2007-03-02 2008-02-14 Cyclopentylpipéridines substituées antagonistes du ccr2 WO2008109238A1 (fr)

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Cited By (5)

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WO2013060865A1 (fr) 2011-10-28 2013-05-02 Galderma Research & Development Nouveaux marqueurs d'infiltrat leucocytaire de rosacée et utilisations de ceux-ci
JP2016128401A (ja) * 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 縮合環類似体の抗線維症剤
WO2020033791A1 (fr) 2018-08-09 2020-02-13 Verseau Therapeutics, Inc. Compositions oligonucléotidiques pour cibler ccr2 et csf1r et leurs utilisations
US11014873B2 (en) 2017-02-03 2021-05-25 Certa Therapeutics Pty Ltd. Anti-fibrotic compounds
JP2022537305A (ja) * 2019-06-20 2022-08-25 プレシジョン ナノシステムズ インコーポレーテッド 核酸送達のためのイオン化可能な脂質

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US20060004018A1 (en) * 2004-06-28 2006-01-05 Chu-Biao Xue 3-Aminocyclopentanecarboxamides as modulators of chemokine receptors
US20060069123A1 (en) * 2004-09-28 2006-03-30 Mingde Xia Substituted dipiperidine CCR2 antagonists

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016128401A (ja) * 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 縮合環類似体の抗線維症剤
US9951087B2 (en) 2009-10-22 2018-04-24 Fibrotech Therapeutics Pty Ltd Fused ring analogues of anti-fibrotic agents
WO2013060865A1 (fr) 2011-10-28 2013-05-02 Galderma Research & Development Nouveaux marqueurs d'infiltrat leucocytaire de rosacée et utilisations de ceux-ci
US11014873B2 (en) 2017-02-03 2021-05-25 Certa Therapeutics Pty Ltd. Anti-fibrotic compounds
US11603349B2 (en) 2017-02-03 2023-03-14 Certa Therapeutics Pty Ltd Anti-fibrotic compounds
WO2020033791A1 (fr) 2018-08-09 2020-02-13 Verseau Therapeutics, Inc. Compositions oligonucléotidiques pour cibler ccr2 et csf1r et leurs utilisations
JP2022537305A (ja) * 2019-06-20 2022-08-25 プレシジョン ナノシステムズ インコーポレーテッド 核酸送達のためのイオン化可能な脂質
JP7416096B2 (ja) 2019-06-20 2024-01-17 プレシジョン ナノシステムズ ユーエルシー 核酸送達のためのイオン化可能な脂質

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