WO2010093578A1 - Indolinyl-, benzofuranyl-, and benzothienyl- amides as modulators of chemokine receptors - Google Patents

Indolinyl-, benzofuranyl-, and benzothienyl- amides as modulators of chemokine receptors Download PDF

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Publication number
WO2010093578A1
WO2010093578A1 PCT/US2010/023459 US2010023459W WO2010093578A1 WO 2010093578 A1 WO2010093578 A1 WO 2010093578A1 US 2010023459 W US2010023459 W US 2010023459W WO 2010093578 A1 WO2010093578 A1 WO 2010093578A1
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pharmaceutically acceptable
compound
acceptable salt
hydroxy
methyl
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PCT/US2010/023459
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French (fr)
Inventor
Patrick Eidam
Pamela A. Haile
Terry Vincent Hughes
Tamara Ann Miskowski
Clark A. Sehon
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to a class of indolinyl-, benzofuranyl, and benzothienyl amides that are modulators of chemokine receptors, particularly as CCR2 antagonists and their methods of use.
  • CCR2 is a chemokine receptor that is expressed on a cell surface of monocytes and some other blood leukocytes. CCR2 binds to the monocyte chemotactic protein MCP-I, and other CC chemokines, which are produced at sites of inflammation and infection.
  • the present invention is a compound represented by the following formula (I):
  • Y is indolyl-(R 6 ) p , N-methylindolyl-(R 6 ) p , benzofuranyl-(R 6 ) p , or benzothienyl-(R 6 ) p ;
  • R 1 is H and R 2 is:
  • Z is N-R 8 , CH-R 9 , or O; each R 3 is independently halo, methyl, hydroxy, or hydroxymethyl; R 4 is H, hydroxy, CN, halo, hydroxymethyl, or COOH;
  • each R 5 is independently halo, methyl, hydroxy, or hydroxymethyl
  • R 6 and R 7 are each independently halo, CN, Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, hydroxy, hydroxymethyl, trifluoromethyl , trifluoromethoxy, SO 2 CH 3 , (R 10 ) r -phenoxy-, (R 10 ) r -benzyloxy-, C(O)N(R 1 %, or COOH;
  • R 8 is H, Ci-Ce-alkyl, or -CH 2 C(O)N(R 1 %;
  • each R 9 is H or, together with the carbon atoms to which they are attached form a double bond
  • each R 10 is independently halo, CN, Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, or SO 2 CH 3 ;
  • each R 11 is independently H or Ci-C ⁇ -alkyl or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group;
  • n, n, and q are each independently O, 1, or 2;
  • p and r are each independently O, 1, 2, or 3.
  • Compounds of the present invention are useful as modulators of CCR2 chemokine receptor.
  • the present invention is a compound represented by the following formula (I):
  • R ⁇ -R 5 , X, Y, m, and n are as previously defined.
  • R 1 is H and R 2 is:
  • the compound is represented by the following formula:
  • X is preferably .
  • Y is preferably indolyl-(R 6 ) p or N-methylindolyl-(R 6 ) p ; more preferably, Y is indol-2-yl-(R 6 ) p or N-methylindol-2-yl-(R 6 ) p .
  • Z is O.
  • Z is NH
  • Z is CH-R 9 where each R 9 is H.
  • each R together with the carbon atoms to which they are attached, form a double bond.
  • R 3 and R 5 are each independently methyl, hydroxy, or hydroxymethyl
  • R 6 and R 7 are each fluoro, chloro, Ci-C3-alkyl, Ci-C3-alkoxy, benzyloxy, phenoxy, or trifluoromethoxy;
  • p 0, 1, or 2.
  • the compound is represented by the following formula:
  • R 3 is methyl or hydroxy
  • R 7 is methyl, chloro, or CN
  • m 0 or 1.
  • the present invention is a composition
  • the present invention is a method of treating a disease comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease is atherosclerosis, inflammatory pain, influenza, metabolic syndrome, multiple sclerosis, asthma, kidney disease, congestive heart failure, Alzheimer's disease, stroke, Crohn's disease, inflammatory bowel disease, endometriosis, or diabetes.
  • the disease is atherosclerosis, inflammatory pain, influenza, metabolic syndrome, multiple sclerosis, asthma, kidney disease, congestive heart failure, Alzheimer's disease, stroke, Crohn's disease, inflammatory bowel disease, endometriosis, or diabetes.
  • Ci-C ⁇ -alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. Examples include methyl, ethyl, /? -propyl, n- butyl, isobutyl, isopropyl, t-butyl, and 1,1-dimethylpropyl.
  • Preferred Ci-C ⁇ -alkyl groups are Ci-C3-alkyl groups.
  • Preferred Ci-C ⁇ -alkoxy groups are Ci-C3-alkoxy groups.
  • halo refers to fluoro, chloro, or bromo.
  • the R 11 groups may, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group, representative examples of which include pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, morpholino, thiomorpholino, and 2-oxo-piperazinyl groups.
  • a compound or “the compound” refers to one or more compounds of the present invention.
  • Compounds may exist in crystalline or non-crystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may incorporate non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may incorporate water into the crystalline lattice. Water-incorporated crystalline forms are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. All such solvates and forms are considered to be within the scope of the present invention.
  • the present invention includes compounds as well as their pharmaceutically acceptable salts. Accordingly, the word “or” in the context of "a compound or a pharmaceutically acceptable salt thereof is understood to refer to either a compound or a pharmaceutically acceptable salt thereof (alternative), or a compound and a pharmaceutically acceptable salt thereof (in combination).
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication.
  • pharmaceutically acceptable salts of compounds according to the present invention may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Suitable acids include inorganic and organic acids; examples of suitable inorganic acids include hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids; examples of suitable organic acids include tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, methanesulfonic, ethanesulfonic, stearic, benzenesulfonic, bromobenzenesulfonic, and/?-toluenesulfonic acids.
  • Suitable bases include, for example, hydroxides, carbonates, hydrides, and alkoxides including NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaH, and potassium-t-butoxide.
  • compounds of the present invention may exist in stereoisomeric forms.
  • compounds of the present invention contain a hydroxy ethylene linker between piperidinyl groups that may be prepared as a racemic mixture or as individual enantiomers.
  • the enantiomers of a common epoxide intermediate may be resolved using a suitable agent such as (S,S)-Co(Salen) or (R,R)-Co(Salen). Accordingly, the individual stereoisomers and mixtures thereof are included within the scope of the present invention.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
  • the carrier(s), diluent(s) and/or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • Compounds of the present invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers, diluents, or excipients according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing, or dissolving the ingredients as appropriate to the desired preparation.
  • compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may contain conventional excipients including binding agents, fillers, lubricants, disintegrants, and wetting agents such as those well known in the art.
  • the tablets may be coated according to methods well known in the art.
  • chemokine receptors in particular the CCR2 receptor.
  • affinity is typically calculated from the IC50 as the concentration of a compound necessary to inhibit 50% of the stimulated response from the receptor in an appropriate assay, and is reported as a "K 1 " value calculated by the following equation: ⁇ IC 5 Q
  • pKi (corresponding to the antilogarithm of Ki) is used instead of Ki.
  • CHO cells expressing the human CCR-2 receptor were grown in DMEM F12 media supplemented with 10% foetal calf serum, 2 mM L-glutamine, G418 at 37 0 C 5% CO 2 .
  • Confluent cells were harvested using Hanks buffered salt solution (HBSS, Ca 2+ , Mg 2+ free) containing 0.6mM EDTA. The resulting cell suspension was centrifuged at 300 g at
  • the resulting cell pellet was resuspended in 50 mM HEPES containing 100 mM leupeptin, 25 ⁇ g/mL bacitracin, 1 mM EDTA, 1 mM PMSF and 2 ⁇ M pepstain A, at pH 7.4.
  • the suspension was homogenised using an ice cold blender and centrifuged at 500 g for 20 min. The supernatant is withdrawn and spun at 48000 g for 30 min. This cell pellet is resuspended in the above buffer minus the pepstatin A and PMSF and stored in aliquots at -70 0 C.
  • Assay Assay
  • membranes were thawed and re-suspended in assay buffer (20 mM HEPES, 10 mM MgCl 2 , 100 mM NaCl, pH 7.4, containing 1 mg/mL saponin, 10 mM GDP) to give a final concentration of 5 ⁇ g/well.
  • the membranes were pre-coupled with LEADseeker SPA beads (0.25 mg/well) for 30 min at room temperature while mixing.
  • Assay plates containing 0.5 ⁇ L of various test compounds (30 ⁇ M-30 pM) in 100% DMSO as 11 point, four fold dilutions across a 384-well plate were used in the assay which have been prepared on a Biomek FX.
  • the plate also contained 16 wells of DMSO and 16 wells of a high concentration of a standard antagonist to produce high and low controls in the experiment.
  • 15 ⁇ L of bead and membrane mix were added with, 15 ⁇ L [ 35 S] GTPgS (0.2 nM final assay concentration) and 15 ⁇ L of an EC 80 (40 nM) of MCP-I .
  • This concentration of MCP-I had been pre-determined from agonist curves run against this receptor. All additions were made using a multidrop. Plates were then sealed and centrifuged for 5 min at 300 rpm before they were left to incubate at room temperature for 3 hours. After this time they were read on a Viewlux imaging system. For data handling the high and low controls wells were used to normalize the data, which was then fitted using a 4 parameter kit in Excel.
  • the assay described above is believed to have an effective limit of detection of a pKi in the region of 5.0-5.5. Accordingly, a compound exhibiting a pKi value within this range from such an assay may indeed have a reasonable affinity for the receptor, but equally it may also have a lower affinity, including a considerably lower affinity. Using this assay, all of the exemplified compounds gave a of pKi > 6.
  • Pd(O 2 CCFs) 2 is palladium(II) trifluroracetate
  • DMA is N,N-dimethylacetamide
  • BINAP is 2,2'-bis(diphenylphosphino)-l,r-binaphthyl.
  • L is a suitable leaving group such as -OSO 2 -CH 3 or chloro
  • V0(acac) 2 is vanadyl(acetylacetonate) and ⁇ BuOOH is tert-butyl hydroperoxide Scheme 9
  • Example 1 ( ⁇ -( ⁇ -Chloro-l ⁇ -dihydro-rH-spirotindole-S ⁇ '-piperidi ⁇ -r-yO-l-ll- [(5,6-difluoro-lH-indol-2-yl)carbonyl]-4-piperidinyl ⁇ ethanol.
  • Example 2 (15)-l- ⁇ l-[(5,6-Difluoro-lH-indol-2-yl)carbonyl]-4-piperidinyl ⁇ -2-[(3 l S,3'5)- 3 ',6-dimethyl- 1 ,2-dihydro- 1 'H-spiro [indole-3 ,4'-piperidin]- 1 '-yl] ethanol
  • reaction was allowed to stir for 72 h after which time the reaction was filtered and purified by HPLC (Sunfire 30 x 150 mm C- 18 Column using a gradient of 15-55% H 2 O/MeCN (with 0.1 %TFA) over 16 min). The desired fractions were combined, basified with NaHCO 3 solution and extracted with DCM.
  • reaction stirred at room temperature for 16 h after which time the mixture was filtered and purified by HPLC (Sunfire 30 x 150 mm C- 18 Column using a gradient of 20-60% H 2 OMeCN (with 0.1 %TFA over 16 min). The desired fractions were combined, basified with NaHCO 3 solution and extracted with DCM.
  • Table 1 illustrates Examples 4-36 and the Schemes generally used to prepare them.

Abstract

The present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof; wherein R1-R5, X, Y, m, and n are as defined herein. Compounds of the present invention are useful for the treatment of a variety of diseases associated with overexpression of the CCR2 receptor.

Description

INDOLINYL-, BENZOFURANYL-, AND BENZOTHIENYL- AMIDES AS MODULATORS OF CHEMOKINE RECEPTORS
The present invention relates to a class of indolinyl-, benzofuranyl, and benzothienyl amides that are modulators of chemokine receptors, particularly as CCR2 antagonists and their methods of use.
CCR2 is a chemokine receptor that is expressed on a cell surface of monocytes and some other blood leukocytes. CCR2 binds to the monocyte chemotactic protein MCP-I, and other CC chemokines, which are produced at sites of inflammation and infection. Recruitment of monocytes to inflammatory sites by MCP-1/CCR2 interactions has been implicated in driving the pathogenesis of a number of diseases including multiple inflammatory disorders including rheumatoid arthritis, atherosclerosis, multiple sclerosis, bronchiolitis obliterans syndrome, asthma, allergic rhinitis, eczema, atopic dermatitis, kidney disease, alveolitis, nephritis, liver cirrhosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, Alzheimer's disease, stroke, acute nerve injury, HIV infection, AIDS, autoimmune diseases, cancer, sepsis, retinosis, inflammatory bowel disease, transplant arteriosclerosis, idiopathic pulmonary fibrosis, psoriasis, HIV-associated dementia, lupus, erthematosis, hepatitis, pancreatitis, Crohn's disease, endometriosis, and diabetes.
Accordingly, it would be an advance in the art to discover a class of compounds that bind to CCR2, thereby preventing or minimizing the formation of the undesirable MCPl- mediated recruitment of monocytes to inflammatory sites.
Summary of the Invention
The present invention is a compound represented by the following formula (I):
Figure imgf000003_0001
(i) or a pharmaceutically acceptable salt thereof; wherein
Figure imgf000003_0002
Y is indolyl-(R6)p, N-methylindolyl-(R6)p, benzofuranyl-(R6)p, or benzothienyl-(R6)p; R1 is H and R2 is:
Figure imgf000003_0003
or R and R , together with the carbon atom to which they are attached, form:
Figure imgf000003_0004
wherein Z is N-R8, CH-R9, or O; each R3 is independently halo, methyl, hydroxy, or hydroxymethyl; R4 is H, hydroxy, CN, halo, hydroxymethyl, or COOH;
each R5 is independently halo, methyl, hydroxy, or hydroxymethyl;
R6 and R7 are each independently halo, CN, Ci-Cβ-alkyl, Ci-Cβ-alkoxy, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, SO2CH3, (R10)r-phenoxy-, (R10)r-benzyloxy-, C(O)N(R1 %, or COOH;
R8 is H, Ci-Ce-alkyl, or -CH2C(O)N(R1 %;
each R9 is H or, together with the carbon atoms to which they are attached form a double bond;
each R10 is independently halo, CN, Ci-Cβ-alkyl, Ci-Cβ-alkoxy, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, or SO2CH3;
each R11 is independently H or Ci-Cβ-alkyl or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group;
m, n, and q are each independently O, 1, or 2; and
p and r are each independently O, 1, 2, or 3.
Compounds of the present invention are useful as modulators of CCR2 chemokine receptor.
Detailed Description of the Invention
The present invention is a compound represented by the following formula (I):
Figure imgf000005_0001
(I)
or a pharmaceutically acceptable salt thereof; wherein R^-R5, X, Y, m, and n are as previously defined.
In another aspect of the present invention is R1 is H and R2 is:
Figure imgf000005_0002
In another aspect of the present invention, the compound is represented by the following formula:
Figure imgf000005_0003
or a pharmaceutically acceptable salt thereof.
X is preferably
Figure imgf000005_0004
. Y is preferably indolyl-(R6)p or N-methylindolyl-(R6)p; more preferably, Y is indol-2-yl-(R6)p or N-methylindol-2-yl-(R6)p.
In another aspect, Z is O.
In another aspect, Z is NH.
In another aspect, Z is CH-R9 where each R9 is H.
In another aspect, each R , together with the carbon atoms to which they are attached, form a double bond.
In another aspect of the present invention, the compound of formula (I) is represented by the following structure:
Figure imgf000006_0001
where R3 and R5 are each independently methyl, hydroxy, or hydroxymethyl;
R6 and R7 are each fluoro, chloro, Ci-C3-alkyl, Ci-C3-alkoxy, benzyloxy, phenoxy, or trifluoromethoxy; and
p is 0, 1, or 2.
In another aspect of the present invention, the compound is represented by the following formula:
Figure imgf000007_0001
where R3 is methyl or hydroxy;
R7 is methyl, chloro, or CN; and
m is 0 or 1.
In another aspect, the present invention is a composition comprising a) the compound of the present invention, or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.
In another aspect, the present invention is a method of treating a disease comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease is atherosclerosis, inflammatory pain, influenza, metabolic syndrome, multiple sclerosis, asthma, kidney disease, congestive heart failure, Alzheimer's disease, stroke, Crohn's disease, inflammatory bowel disease, endometriosis, or diabetes.
As used herein, Ci-Cβ-alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. Examples include methyl, ethyl, /? -propyl, n- butyl, isobutyl, isopropyl, t-butyl, and 1,1-dimethylpropyl. Preferred Ci-Cβ-alkyl groups are Ci-C3-alkyl groups. Preferred Ci-Cβ-alkoxy groups are Ci-C3-alkoxy groups.
As used herein, "halo" refers to fluoro, chloro, or bromo.
The R11 groups may, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group, representative examples of which include pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, morpholino, thiomorpholino, and 2-oxo-piperazinyl groups.
As used herein, the term "a compound" or "the compound" refers to one or more compounds of the present invention. Compounds may exist in crystalline or non-crystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may incorporate non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may incorporate water into the crystalline lattice. Water-incorporated crystalline forms are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. All such solvates and forms are considered to be within the scope of the present invention.
The present invention includes compounds as well as their pharmaceutically acceptable salts. Accordingly, the word "or" in the context of "a compound or a pharmaceutically acceptable salt thereof is understood to refer to either a compound or a pharmaceutically acceptable salt thereof (alternative), or a compound and a pharmaceutically acceptable salt thereof (in combination).
As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication. The skilled artisan will appreciate that pharmaceutically acceptable salts of compounds according to the present invention may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
Compounds of the present invention can form pharmaceutically acceptable salts by reaction with a suitable acid or base. Suitable acids include inorganic and organic acids; examples of suitable inorganic acids include hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids; examples of suitable organic acids include tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, methanesulfonic, ethanesulfonic, stearic, benzenesulfonic, bromobenzenesulfonic, and/?-toluenesulfonic acids. Suitable bases include, for example, hydroxides, carbonates, hydrides, and alkoxides including NaOH, KOH, Na2CO3, K2CO3, NaH, and potassium-t-butoxide.
Compounds of the present invention may exist in stereoisomeric forms. For example, compounds of the present invention contain a hydroxy ethylene linker between piperidinyl groups that may be prepared as a racemic mixture or as individual enantiomers. The enantiomers of a common epoxide intermediate (see scheme 16) may be resolved using a suitable agent such as (S,S)-Co(Salen) or (R,R)-Co(Salen). Accordingly, the individual stereoisomers and mixtures thereof are included within the scope of the present invention.
While it is possible that a compound of the present invention may be administered as the pure chemical, it is generally preferable to present the active ingredient as a pharmaceutical formulation. Accordingly, in a further aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents. The carrier(s), diluent(s) and/or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
Compounds of the present invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers, diluents, or excipients according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing, or dissolving the ingredients as appropriate to the desired preparation.
The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Tablets and capsules for oral administration may contain conventional excipients including binding agents, fillers, lubricants, disintegrants, and wetting agents such as those well known in the art. The tablets may be coated according to methods well known in the art.
Affinity for CCR2 Receptor
Compounds of the present invention have been found to exhibit affinity for chemokine receptors, in particular the CCR2 receptor. Such affinity is typically calculated from the IC50 as the concentration of a compound necessary to inhibit 50% of the stimulated response from the receptor in an appropriate assay, and is reported as a "K1" value calculated by the following equation: κ IC5Q
1 1 + L / KD where L = radioligand and KD = affinity of radioligand for receptor (Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973).
In the context of the present invention pKi (corresponding to the antilogarithm of Ki) is used instead of Ki.
CCR-2 [35Sl GTPgS SPA binding assay
Membrane preparation
CHO cells expressing the human CCR-2 receptor were grown in DMEM F12 media supplemented with 10% foetal calf serum, 2 mM L-glutamine, G418 at 370C 5% CO2. Confluent cells were harvested using Hanks buffered salt solution (HBSS, Ca2+, Mg2+ free) containing 0.6mM EDTA. The resulting cell suspension was centrifuged at 300 g at
4 0C for 10 min, cell pellet resuspended in 100 mL HBSS+EDTA and respun at 30Og for
5 min. The resulting cell pellet was resuspended in 50 mM HEPES containing 100 mM leupeptin, 25 μg/mL bacitracin, 1 mM EDTA, 1 mM PMSF and 2 μM pepstain A, at pH 7.4. The suspension was homogenised using an ice cold blender and centrifuged at 500 g for 20 min. The supernatant is withdrawn and spun at 48000 g for 30 min. This cell pellet is resuspended in the above buffer minus the pepstatin A and PMSF and stored in aliquots at -70 0C. Assay
For the assay, membranes were thawed and re-suspended in assay buffer (20 mM HEPES, 10 mM MgCl2, 100 mM NaCl, pH 7.4, containing 1 mg/mL saponin, 10 mM GDP) to give a final concentration of 5 μg/well. The membranes were pre-coupled with LEADseeker SPA beads (0.25 mg/well) for 30 min at room temperature while mixing. Assay plates containing 0.5 μL of various test compounds (30 μM-30 pM) in 100% DMSO as 11 point, four fold dilutions across a 384-well plate were used in the assay which have been prepared on a Biomek FX. The plate also contained 16 wells of DMSO and 16 wells of a high concentration of a standard antagonist to produce high and low controls in the experiment. To this 15 μL of bead and membrane mix were added with, 15 μL [35S] GTPgS (0.2 nM final assay concentration) and 15 μL of an EC80 (40 nM) of MCP-I . This concentration of MCP-I had been pre-determined from agonist curves run against this receptor. All additions were made using a multidrop. Plates were then sealed and centrifuged for 5 min at 300 rpm before they were left to incubate at room temperature for 3 hours. After this time they were read on a Viewlux imaging system. For data handling the high and low controls wells were used to normalize the data, which was then fitted using a 4 parameter kit in Excel.
The assay described above is believed to have an effective limit of detection of a pKi in the region of 5.0-5.5. Accordingly, a compound exhibiting a pKi value within this range from such an assay may indeed have a reasonable affinity for the receptor, but equally it may also have a lower affinity, including a considerably lower affinity. Using this assay, all of the exemplified compounds gave a of pKi > 6.
Schemes
The following schemes illustrate how compounds of the present invention can be prepared. The specific solvents and reaction conditions referred to are also illustrative and are not intended to be limiting.
Scheme 1
Figure imgf000012_0001
Scheme 2
Figure imgf000012_0002
Scheme 3
Figure imgf000012_0003
Scheme 4
ZnCN2, BINAP, Zn, Pd(O2CCF3);,, DMA H2, Pd/C, MeOH
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
where Pd(O2CCFs)2 is palladium(II) trifluroracetate, DMA is N,N-dimethylacetamide, and BINAP is 2,2'-bis(diphenylphosphino)-l,r-binaphthyl.
Scheme 5
Figure imgf000013_0004
where L is a suitable leaving group such as -OSO2-CH3 or chloro
Scheme 6
HCI/Dioxane
Figure imgf000014_0001
Figure imgf000014_0002
Scheme 7
Figure imgf000014_0003
Scheme 8
Figure imgf000014_0004
where V0(acac)2 is vanadyl(acetylacetonate) and ^BuOOH is tert-butyl hydroperoxide Scheme 9
Figure imgf000015_0001
Scheme 10
Figure imgf000015_0002
Scheme 11 Base,
Figure imgf000015_0004
Figure imgf000015_0003
Scheme 12
Figure imgf000016_0001
1 ) Pd(OAc)2
2
Figure imgf000016_0002
3) deprotect
Examples
The following examples are for illustrative purposes and are not intended to limit the scope of the invention.
Example 1 : (^^-(β-Chloro-l^-dihydro-rH-spirotindole-S^'-piperidi^-r-yO-l-ll- [(5,6-difluoro-lH-indol-2-yl)carbonyl]-4-piperidinyl}ethanol.
Figure imgf000016_0003
To a magnetically stirred solution of 5,6-difluoro-lΗ-indole-2-carboxylic acid (22.54 mg, 0.114 mmol), Hunig's base (0.080 mL, 0.457 mmol), EDC (32.9 mg, 0.171 mmol) and HOBT (26.3 mg, 0.171 mmol) in JV,JV-Dimethylformamide (DMF) (2 mL) at room temperature was added (lS)-2-(6-chloro-l,2-dihydro-lΗ-spiro[indole-3,4'-piperidin]-r- yl)-l-(4-piperidinyl)ethanol (40 mg, 0.114 mmol) in one portion. The reaction was allowed to stir for 72 h after which time the reaction was filtered and purified by HPLC (Sunfire 30x150 mm C- 18 Column using a gradient of 15-55% H2O/MeCN (with 0.1 % TFA) over 16 min). The desired fractions were combined, basified with NaHCO3 solution and extracted with DCM. The mixture was poured through a hydrophobic frit to remove water and the organic filtrates were concentrated under reduced pressure to give ( 1 S)-2-(6-chloπ>- 1 ,2-dihydro- 1 Η-spiro [indole-3 ,4'-piperidin] - 1 ?-yl)- 1 - { 1 -[(5 ,6-difluoro- lH-indol-2-yl)carbonyl]-4-piperidinyl}ethanol (20 mg, 0.038 mmol, 33.1 % yield) as an off white solid. MS(ES) m/e 529 [M]+.
Example 2: (15)-l-{l-[(5,6-Difluoro-lH-indol-2-yl)carbonyl]-4-piperidinyl}-2-[(3lS,3'5)- 3 ',6-dimethyl- 1 ,2-dihydro- 1 'H-spiro [indole-3 ,4'-piperidin]- 1 '-yl] ethanol
Figure imgf000017_0001
To a magnetically stirred solution of 5,6-difluoro-lΗ-indole-2-carboxylic acid (22.96 mg, 0.116 mmol), Hunig's base (.1 mL, 0.573 mmol), EDC (33.5 mg, 0.175 mmol) and HOBT (26.7 mg, 0.175 mmol) in N,N-Dimethylformamide (DMF) (2 mL) at room temperature was added (lS)-2-[(3S,3>S)-3>,6-dimethyl-l,2-dihydro-lΗ-spiro[indole-3,4>-piperidin]-r- yl]-l-(4-piperidinyl)ethanol (40 mg, 0.116 mmol) in one portion. The reaction was allowed to stir for 72 h after which time the reaction was filtered and purified by HPLC (Sunfire 30 x 150 mm C- 18 Column using a gradient of 15-55% H2O/MeCN (with 0.1 %TFA) over 16 min). The desired fractions were combined, basified with NaHCO3 solution and extracted with DCM. The mixture was poured through a hydrophobic frit to remove water and the organic filtrates were concentrated under reduced pressure to give (lS)-l-{l-[(5,6-difluoro-lH-indol-2-yl)carbonyl]-4-piperidinyl}-2-[(3S,3'S)-3>,6- dimethyl-l,2-dihydro-l'H-spiro [indole-3, 4'-piperidin]-r-yl] ethanol (10.6 mg, 0.020 mmol, 17.42 % yield) as an off white solid. MS(ES) m/e 523 [M+H]+.
Example 3: (l^-l-CCS^S'^-S'^-Dimethyl-l^-dihydro-l'H-spiroCindole-S^'-piperidin]- 1 '-yl]-l -[ 1 -( {5-[(trifluoromethyl)oxy]- lH-indol-2-yl} carbonyl)-4-piperidinyl]ethanol
Figure imgf000018_0001
To a magnetically stirred solution of 5-[(trifluoromethyl)oxy]-lΗ-indole-2-carboxylic acid (18.7 mg, 0.076 mmol), EDC (21.93 mg, 0.114 mmol), HOBT (17.52 mg, 0.114 mmol) and Hunig's base (.1 mL, 0.573 mmol) in N,N-Dimethylformamide (DMF) (1 mL) was added (lS)-2-[(3S,3>S)-3>,6-dimethyl-l,2-dihydro-lΗ-spiro[indole-3,4>-piperidin]-r- yl]-l-(4-piperidinyl)ethanol (26.2 mg, 0.076 mmol). The reaction stirred at room temperature for 16 h after which time the mixture was filtered and purified by HPLC (Sunfire 30 x 150 mm C- 18 Column using a gradient of 20-60% H2OMeCN (with 0.1 %TFA over 16 min). The desired fractions were combined, basified with NaHCO3 solution and extracted with DCM. The mixture was poured through a hydrophobic frit to remove water and the organic filtrates were concentrated under reduced pressure to give (lS)-2-[(3S,3>S)-3>,6-dimethyl-l,2-dihydro-lΗ-spiro[indole-3,4>-piperidin]-r-yl]-l-[l- ({5-[(trifluoromethyl)oxy]-lH-indol-2-yl}carbonyl)-4-piperidinyl]ethanol (14 mg, 0.025 mmol, 32.2 % yield) as on off white solid. MS(ES) m/e 571 [M+H]+.
Table 1 illustrates Examples 4-36 and the Schemes generally used to prepare them.
Table 1
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001

Claims

WHAT IS CLAIMED IS:
1. A compound of the following formula:
Figure imgf000025_0001
(I) or a pharmaceutically acceptable salt thereof; wherein
Figure imgf000025_0002
Y is indolyl-(R6)p, N-methylindolyl-(R6)p, benzofuranyl-(R6)p, or benzothienyl-(R6)p; R1 is H and R2 is:
Figure imgf000025_0003
or R1 and R2, together with the carbon atom to which they are attached, form:
Figure imgf000025_0004
wherein Z is N-R8, CH-R9, or O; each R3 is independently halo, methyl, hydroxy, or hydroxymethyl; R4 is H, hydroxy, CN, halo, hydroxymethyl, or COOH;
each R5 is independently halo, methyl, hydroxy, or hydroxymethyl;
R6 and R7 are each independently halo, CN, Ci-Cβ-alkyl, Ci-Cβ-alkoxy, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, SO2CH3, (R10)r-phenoxy-, (R10)r-benzyloxy-, C(O)N(R1 %, or COOH;
R8 is H, Ci-Ce-alkyl, or -CH2C(O)N(R1 %;
each R9 is H or, together with the carbon atoms to which they are attached form a double bond;
each R10 is independently halo, CN, Ci-Cβ-alkyl, Ci-Cβ-alkoxy, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, or SO2CH3;
each R11 is independently H or Ci-Cβ-alkyl or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group;
m, n, q, and r are each independently O, 1, or 2; and
p is O, 1, 2, or 3.
2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1 is H; and R2 is:
Figure imgf000026_0001
R3 and R5 are each independently methyl, hydroxy, or hydroxymethyl;
each R6 and each R7 is fluoro, chloro, Ci-C3-alkyl, Ci-C3-alkoxy, benzyloxy, phenoxy, or trifluoromethoxy;
R8 is H or methyl; X is
OH
Y is indolyl-(R6)p or N-methylindolyl-(R6)p; and
m and n are each independently 0 or 1.
3. The compound of Claim 1 which is represented by the following formula:
Figure imgf000027_0001
or a pharmaceutically acceptable salt thereof.
4. The compound of either of Claims 1 or 3, or a pharmaceutically acceptable salt thereof, wherein Y is indolyl-(R6)p or N-methylindolyl-(R6)p.
5. The compound of any of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Y is indol-2-yl-(R6)p or N-methylindol-2yl-(R6)p.
6. The compound of any of Claims 1, 3, 4, or 5, or a pharmaceutically acceptable salt thereof, wherein Z is O.
7. The compound of any of Claims 1, 3, 4, or 5, or a pharmaceutically acceptable salt thereof, wherein Z is N-R8.
8. The compound of any of Claims 1, 3, 4, or 5, or a pharmaceutically acceptable salt thereof, wherein Z is CH-R9 wherein each R9 is H.
9. The compound of any of Claims 1, 3, 4, or 5, or a pharmaceutically acceptable salt tthheerreeooff,, wwhheerreeiinn ZZ iiss CCHH--RR99 aanndd eeach R9, together with the carbon atoms to which they are attached, form a double bond.
10. The compound of either of Claims 1 or 3 which is represented by the following structure:
Figure imgf000028_0001
or a pharmaceutically acceptable salt thereof, wherein:
R3 and R5 are each independently methyl, hydroxy, or hydroxymethyl;
R6 and R7 are each independently fluoro, chloro, Ci-C3-alkyl, Ci-C3-alkoxy, benzyloxy, phenoxy, or trifluoromethoxy; and
p is 0, 1, or 2.
11. The compound of any of Claims 1 or 10 which is represented by the following formula:
Figure imgf000028_0002
or a pharmaceutically acceptable salt thereof, wherein:
where R is methyl or hydroxy;
R is methyl, chloro, or CN; and
m is 0 or 1.
12. The compound of any of Claims 1, 3, or 10, or a pharmaceutically acceptable salt thereof, wherein:
Z is O or CH-R9;
R3 is methyl or hydroxy;
R7 is methyl, chloro, or CN; and
m is 0 or 1.
13. A composition comprising a) a compound of any of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, and b) a pharmaceutically acceptable excipient.
14. A method of treating a disease comprising administering the compound of any of Claims 1 to 12 or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease is atherosclerosis, inflammatory pain, influenza, metabolic syndrome, multiple sclerosis, asthma, kidney disease, congestive heart failure, Alzheimer's disease, stroke, Crohn's disease, inflammatory bowel disease, endometriosis, or diabetes.
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