EP2211618A1 - Piperidinylhydroxyethylpiperidines as modulators of chemokine receptors - Google Patents

Piperidinylhydroxyethylpiperidines as modulators of chemokine receptors

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Publication number
EP2211618A1
EP2211618A1 EP08838205A EP08838205A EP2211618A1 EP 2211618 A1 EP2211618 A1 EP 2211618A1 EP 08838205 A EP08838205 A EP 08838205A EP 08838205 A EP08838205 A EP 08838205A EP 2211618 A1 EP2211618 A1 EP 2211618A1
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European Patent Office
Prior art keywords
alkyl
mmol
methyl
compound
pharmaceutically acceptable
Prior art date
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EP08838205A
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German (de)
French (fr)
Inventor
Clark A. Sehon
Gren Z. Wang
Andrew Q. Viet
Jing Zhang
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a class of piperidinylhydroxyethylpiperidines 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 chemo tactic protein MCP-I, and other CC chemokines, which are produced at sites of inflammation and infection.
  • each R 1 is independently -NR y -SO 2 -Ci-C 6 -alkyl, -NR -C(O)-N(R 1 1 ⁇ U X) 2 , -NR -C(O)-OR*, halo, Ci-Ce-alkyl, CF 3 , cyano, Ci-C 6 -alkoxy, OH, or -(Y) q -N(R 10 ) 2 ;
  • R 2 is H, Ci-C 6 -alkyl, -C(O)-C,-C 6 -alkyl, or -SO 2 R 11 ;
  • R 3 is H, halo, HO-C r C 6 -alkyl, C,-C 6 -alkyl, or CF 3 ;
  • R 4 and R 5 are each independently H, C r C 6 -alkyl, OH, HO-Ci-C 6 -alkyl, COOH, or Q-
  • R 6 is H, C,-C 6 -alkyl, OH, C t -C 6 -alkoxy, or HO-C r C 6 -a]kyl;
  • R 7 is H, OH, F, Cl, CN, CF 3 , Ci.C 6 -alkyl, hydroxy-C,-C 6 -alkyl, or Ci.C 6 -alkoxy;
  • each R 8 is independently halo, HO-Ci -C ⁇ -alkyl, Q-C ⁇ -alkyl, cyano, trifluoromethyl, Ci-C ⁇ -alkoxy, or Ci-C6-alkylthio;
  • each R 9 is independently H or Ci-C ⁇ -alkyl
  • each R 10 is independently H, -Ci-C ⁇ -alkyl, or acetyl, or, together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocycloalkyl ring;
  • R 1 ' is C , -C 6 -alkyl or phenyl-(R s ) n ; PU62673
  • Y is -SO 2 - or -C(O)-;
  • each m is independently O, 1, 2, or 3;
  • each n is independently 0, 1, 2, or 3;
  • q is 0 or 1 ;
  • the present invention is a composition that comprises a) the compound of Formula 1 or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.
  • the invention provides a method of treating a disease comprising administering the 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.
  • the present invention relates to a compound of the following formula:
  • R 1 is chloro, fluoro, methyl, trifluoromethyl, cyano, or methoxy;
  • R 2 and R 3 are each independently H or methyl; and
  • R 4 is H.
  • the compound of the present invention is represented by the following formula:
  • the compound of the present invention is represented by either of the following formulae:
  • the compound of the present invention is represented by either of the following formulae:
  • Ci-C ⁇ -alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. Examples include methyl, ethyl, n-propyl, n- butyl, rt-pentyl, w-hexyl, isobutyl, isopropyl, /-butyl, and 1,1-dimethylpropyl.
  • Ci-C 6 -alkoxy examples include methoxy, ethoxy, n-propoxy, prop-2-oxy, «-butoxy, but-2-oxy, 2-methylprop-l-oxy, 2-methylprop-2-oxy, «-pentoxy and n-hexyloxy.
  • Q-C ⁇ -alkylthio examples include methylthio, ethylthio, w-propylthio, prop-2-thio, w-butylthio, but-2-thio, 2-methylprop-l-thio, and 2-methylprop-2-thio.
  • R 10 and R 1 ' together with the nitrogen atom to which they are attached, may form a 5- to 6-membered heterocycloaliphatic ring, examples of which include pyrrolidinyl, morpholino, thiomorpholino, dihydropyridazinyl, piperidinyl, and piperazinyl.
  • PU62673
  • halo refers to fluoro, chloro, or bromo.
  • a compound of Formula (I) or “the compound of Formula (I)” refers to one or more compounds according to Formula (I).
  • the compound of Formula (I) may exist in crystalline or noncrystalline 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 involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the incorporated solvent are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • Compounds of the present invention contain at least one chiral center and therefore may be present as racemic mixtures or as enantiomers.
  • the present invention includes all such racemic mixtures and enantiomers.
  • 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 the compounds according to Formula (I) 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.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and m are as defined above.
  • the compound of Formula (II) is a racemate, even where R 6 and R 7 are H, due to the asymmetric carbon atom of the epoxide ring.
  • This racemate may be resolved with (S,S)- Co(Salen) or (R, R)-Co(Salen) prior to reaction with the compound of Formula (HI).
  • A is a protecting group such as Boc or Cbz, to form a compound of Formula VI:
  • Compounds of the Formula (VI) can be converted to compounds of the Formula (I) by those skilled in the art of synthetic chemistry using standard reaction conditions. For example, after the protecting group A is converted to H, the corresponding compound can be reacted with a suitable cinnamic acid or a phenyl isocyanate to form a compound of Formula (I).
  • Compounds of Formula (V) can be prepared, for example, by epoxidation of the corresponding aldehyde in the presence of (CFb ⁇ SOI and NaH in DMSO.
  • intermediate of Formula (IX) can be prepared by contacting indole of Formula (VII) with the protected piperidinone of Formula (VIII) in the presence of phosphoric acid and acetic acid to form a deprotected tetrahydropiperazinyl indole, followed by reprotection with (Boc) 2 ⁇ in a suitable solvent, such as THF or acetone.
  • a suitable solvent such as THF or acetone.
  • a 3' trans-hydroxylated piperidinyl intermediate can be prepared from the compound of Formula (IX) as shown in Scheme 2:
  • the indole of Formula (VII) can be prepared by a number of methods including those outlined in Schemes 5-8.
  • 3'-Alkoxylated piperidine intermediates can be prepared as shown in Scheme 12, where the alkyl group is methyl.
  • DMAP refers to A- dimethylaminopyridine.
  • Suitable protecting groups for amines include acyl type protecting groups such as formyl, trifluoroacetyl, acetyl groups; aromatic urethane type protecting groups such as benzyloxycarbonyl (Cbz) and substituted Cbz groups; aliphatic urethane protecting groups such as 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, and cyclohexyloxycarbonyl groups; and alkyl type protecting groups such as benzyl, trityl, and chlorotrityl groups.
  • acyl type protecting groups such as formyl, trifluoroacetyl, acetyl groups
  • aromatic urethane type protecting groups such as benzyloxycarbonyl (Cbz) and substituted Cbz groups
  • aliphatic urethane protecting groups such as 9-fluorenylmethoxycarbony
  • 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 /j-toluenesulfonic acids.
  • Suitable bases include NaH, potassiu ⁇ W-butoxide, sodium hydroxide, and potassium hydroxide.
  • the compounds of Formula (I) contain at least one asymmetric carbon atom. Racemates as well as individual stereoisomers (enantiomers and diastereomers) of the compounds of Formula (1) are included within the scope of the present invention. PU62673
  • the invention provides method of treating atherosclerosis comprising administering the compound of formula (I), or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • a compound of the invention may be administered as the pure chemical, it is generally preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further 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 recipient thereof.
  • the compounds of the 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.
  • pKi (corresponding to the antilogarithm of Ki) is used instead of Ki.
  • the present invention is a compound of Formula I having a pKi of at least 6.5 as derived from the assay method set out below.
  • CHO cells expressing the human CCR-2 receptor were grown in DMEM Fl 2 media supplemented with 10% foetal calf serum, 2mM L-glutamine, G418 at 37°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 30Og at 4°C for 10 min, cell pellet resuspended in 100ml HBSS+EDTA and respun at 30Og for 5 min.
  • HBSS Hanks buffered salt solution
  • the resulting cell pellet was resuspended in 5OmM HEPES containing 10OmM leupeptin, 25 ⁇ g/ml bacitracin, ImM EDTA, ImM PMSF and 2 ⁇ M pepstain A, at pH7.4.
  • the suspension was homogenised using an ice cold blender and centrifuged at 500g for 20mins. The supernatant is withdrawn and spun at 4800Og for 30mins. This cell pellet is PU62673
  • membranes are thawed and resuspended in assay buffer (2OmM HEPES, 10 mM MgCl 2 , 100 mM NaCl, pH7.4, containing lmg/ml saponin, 1OmM GDP) to give final concentration of 5 ⁇ g/well.
  • assay buffer 2OmM HEPES, 10 mM MgCl 2 , 100 mM NaCl, pH7.4, containing lmg/ml saponin, 1OmM GDP
  • LEADseeker SPA beads (0.25 mg/well) for 30 min at room temperature whilst mixing.
  • Assay plates containing 0.5 ⁇ L of various test compounds (30 ⁇ M-30pM) in 100% DMSO as 1 1 point, four fold dilutions across a 384 well plate are used in the assay which have been prepared on a Biomek FX.
  • the plate also contains 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 are 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 has been pre-determined from agonist curves run against this receptor. All additions are made using a multidrop. Plates are then sealed and centrifuged for 5 min at 300 rpm before they are left to incubate at room temperature for 3 h. After this time they are read on a Viewlux imaging system. For data handling the high and low controls wells are used to normalise the data which is 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.
  • Mass spectra were obtained using either a Waters ZQ mass spectrometer or Micromass Platform 2 mass spectrometer and use electro-spray ionisoation to observe either MH+ or
  • Table 1 is a table of substituted indoles that were prepared in accordance with the specified scheme. All other indoles used in the Examples were commercially available. PU62673
  • (S,S)-Co-salen catalyst (206 mg, 0.3 mmol) ((S,S)-(+)-N,N'-Bis(3,5-di-tert- butylsalicylidene)-l,2-cyclohexanediamino cobalt (II)) was dissolved in toluene (2 mL) in an open air flask. Glacial acetic acid (39 uL) was added and the reaction stirred at room temperature for 1 hour. The reaction was then concentrated to a brown solid which was placed under high vacuum overnight.
  • Trimethylsulfoxonium iodide (1.65 g, 7.5 mmol) was added in two portions to a solution of NaH (300 mg, 7.5 mmol) in anhydrous DMSO (10 mL) at room temperature. The resulting mixture was stirred for 1 hour, whereupon a solution of phenylmethyl 4-formyl- 1-piperidinecarboxylate (1.2 g, 5.0 mmol) in anhydrous DMSO (10 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then poured into cold water (100 mL), and extracted with Et 2 O (2 x 100 mL). The extracts were combined, washed with water, brine, and dried (Na 2 SO 4 ). The solvent was removed in vacuo to give the title compound (0.95 g, 3.6 mmol, 72%) as a colorless oil. MS (ES) m/e 262 [M+H] + .
  • the crude material was purified by reverse phase high pressure liquid chromatography ( ⁇ PLC, YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 20 to 55% over 10 minute, UV detection at 214 nm) to give a white solid material as a TFA salt (57 mg, 0.087 mmol, 15%). MS(ES) m/e 544 [M+ ⁇ ]+.
  • Table 2 illustrates other compounds prepared by methods as indicated. PU62673

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Abstract

The present invention relates to a compound of the formula (I), or a pharmaceutically acceptable salt thereof, wherein R1-R8 and X, m, and n are defined. Compounds and compositions of the present invention are useful the treatment of atherosclerosis.

Description

PU62673
PIPERIDINYLHYDROXYETHYLPIPERIDINES AS MODULATORS OF CHEMOKINE RECEPTORS
The present invention relates to a class of piperidinylhydroxyethylpiperidines 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 chemo tactic 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. PU62673
Summary of the Invention
In a first aspect of the invention, there is provided a compound of the following formula I:
(I)
or a pharmaceutically acceptable salt thereof, wherein
each R1 is independently -NRy-SO2-Ci-C6-alkyl, -NR -C(O)-N(R 11<UX)2, -NR -C(O)-OR*, halo, Ci-Ce-alkyl, CF3, cyano, Ci-C6-alkoxy, OH, or -(Y)q-N(R10)2;
R2 is H, Ci-C6-alkyl, -C(O)-C,-C6-alkyl, or -SO2R11;
R3 is H, halo, HO-CrC6-alkyl, C,-C6-alkyl, or CF3;
R4 and R5 are each independently H, CrC6-alkyl, OH, HO-Ci-C6-alkyl, COOH, or Q-
Cβ-alkoxy;
R6 is H, C,-C6-alkyl, OH, Ct-C6-alkoxy, or HO-CrC6-a]kyl;
R7 is H, OH, F, Cl, CN, CF3, Ci.C6-alkyl, hydroxy-C,-C6-alkyl, or Ci.C6-alkoxy;
each R8 is independently halo, HO-Ci -Cβ-alkyl, Q-Cβ-alkyl, cyano, trifluoromethyl, Ci-Cό-alkoxy, or Ci-C6-alkylthio;
each R9 is independently H or Ci-Cβ-alkyl;
each R10 is independently H, -Ci-Cβ-alkyl, or acetyl, or, together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocycloalkyl ring;
R1 ' is C , -C6-alkyl or phenyl-(Rs)n; PU62673
X is NH, -CH2O- or -HC=CH-;
Y is -SO2- or -C(O)-;
each m is independently O, 1, 2, or 3;
each n is independently 0, 1, 2, or 3; and
q is 0 or 1 ;
with the proviso that when R6 is H, at least one of R4 and R5 is not H.
In another aspect, the present invention is a composition that comprises a) the compound of Formula 1 or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.
In another aspect, the invention provides a method of treating a disease comprising administering the 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.
Detailed Description of the Invention
In a first aspect, the present invention relates to a compound of the following formula:
(I)
or a pharmaceutically acceptable salt thereof, wherein R'-RS and X, m, and n are defined. PU62673
In another embodiment, R1 is chloro, fluoro, methyl, trifluoromethyl, cyano, or methoxy; R2 and R3 are each independently H or methyl; and R4 is H.
In another embodiment, the compound of the present invention is represented by the following formula:
or a pharmaceutically acceptable salt thereof;
wherein m is 0, 1, or 2; n is 1 or 2; R5 is H, OH, methyl, ethyl, methoxy, or hydroxymethyl; R6 is H, methyl, OH, or hydroxymethyl; and R8 is methoxy, cyano, fluoro, or chloro; with the proviso that when R6 is H, R5 is OH, methyl, or hydroxymethyl.
In another embodiment, the compound of the present invention is represented by either of the following formulae:
or
or a pharmaceutically acceptable salt thereof. PU62673
In another embodiment, the compound of the present invention is represented by either of the following formulae:
or
or a pharmaceutically acceptable salt thereof, where R is OH or hydroxymethyl.
It has surprisingly been discovered that a substituent at the 3' position of the piperidine ring (R ) increases the selectivity of compounds of the present invention toward CCR2.
As used herein, Ci-Cό-alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. Examples include methyl, ethyl, n-propyl, n- butyl, rt-pentyl, w-hexyl, isobutyl, isopropyl, /-butyl, and 1,1-dimethylpropyl.
Examples of Ci-C6-alkoxy include methoxy, ethoxy, n-propoxy, prop-2-oxy, «-butoxy, but-2-oxy, 2-methylprop-l-oxy, 2-methylprop-2-oxy, «-pentoxy and n-hexyloxy.
Examples of Q-Cό-alkylthio include methylthio, ethylthio, w-propylthio, prop-2-thio, w-butylthio, but-2-thio, 2-methylprop-l-thio, and 2-methylprop-2-thio.
R10 and R1 ', together with the nitrogen atom to which they are attached, may form a 5- to 6-membered heterocycloaliphatic ring, examples of which include pyrrolidinyl, morpholino, thiomorpholino, dihydropyridazinyl, piperidinyl, and piperazinyl. PU62673
As used herein, "halo" refers to fluoro, chloro, or bromo.
As used herein, the term "a compound of Formula (I)" or "the compound of Formula (I)" refers to one or more compounds according to Formula (I). The compound of Formula (I) may exist in crystalline or noncrystalline 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 involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the incorporated solvent are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
Compounds of the present invention contain at least one chiral center and therefore may be present as racemic mixtures or as enantiomers. The present invention includes all such racemic mixtures and enantiomers.
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 the compounds according to Formula (I) 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. PU62673
Compounds of Formula (I) may be prepared by reacting a compound of formula (II)
asymmetric center
(H)
wherein R6, R7, R8, X, and n are as defined above, with a compound of formula (III)
(III)
wherein R1, R2, R3, R4, R5, and m are as defined above.
The compound of Formula (II) is a racemate, even where R6 and R7 are H, due to the asymmetric carbon atom of the epoxide ring. This racemate may be resolved with (S,S)- Co(Salen) or (R, R)-Co(Salen) prior to reaction with the compound of Formula (HI).
Compounds of Formula (I) can also be prepared by reacting a compound of Formula (III) with a compound of Formula (V):
(V) PU62673
where A is a protecting group such as Boc or Cbz, to form a compound of Formula VI:
(VI)
Compounds of the Formula (VI) can be converted to compounds of the Formula (I) by those skilled in the art of synthetic chemistry using standard reaction conditions. For example, after the protecting group A is converted to H, the corresponding compound can be reacted with a suitable cinnamic acid or a phenyl isocyanate to form a compound of Formula (I). Compounds of Formula (V) can be prepared, for example, by epoxidation of the corresponding aldehyde in the presence of (CFb^SOI and NaH in DMSO.
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. Compounds not described are either commercially available or are readily prepared by one skilled in the art using available starting materials.
Compounds of the Formula (I) where R5 is a hydroxyl group can be synthesized by reacting a hydroxylated intermediate with the Compound of Formula (II), as outlined in Scheme 1. PU62673
Scheme 1 :
IX
Alternatively, intermediate of Formula (IX) can be prepared by contacting indole of Formula (VII) with the protected piperidinone of Formula (VIII) in the presence of phosphoric acid and acetic acid to form a deprotected tetrahydropiperazinyl indole, followed by reprotection with (Boc)2θ in a suitable solvent, such as THF or acetone.
A 3' trans-hydroxylated piperidinyl intermediate can be prepared from the compound of Formula (IX) as shown in Scheme 2:
PU62673
Scheme 2:
K3Fe(CN)6, K2CO3,
where (DHQD)2PHAL is hydroquinidine 1,4-phthalazinediyl diether. 3'-Methyl piperidinyl intermediates can be prepared as described in Scheme 3.
Scheme 3:
Scheme 4 illustrates the preparation of a 3" piperidinyl carboxylic acid intermediate:
Scheme 4:
PU62673
The indole of Formula (VII) can be prepared by a number of methods including those outlined in Schemes 5-8.
Scheme 5:
Scheme 6:
Scheme 7:
Scheme 8:
Intermediate compounds containing epoxide groups such as compounds of Formula (II) can be resolved into specific enantiomers prior to ring opening, then reacted with compounds of Formula (III) as illustrated in Scheme 9. PU62673
Scheme 9:
(S.S)-Co(Salen), H2OJHF
The (S,S)-Co(Salen) creates one enantiomer while (R,R)-Co(Salen) creates the other enantiomer.
Intermediate of formula (V) and compound of formula (I), where R7 is OH can be prepared as illustrated in Scheme 10. The Grignard reaction can be conveniently carried out in diethyl ether, while the subsequent epoxidation step can be accomplished with a peroxide such as M)uty Hydroperoxide and a catalyst such as vanadyl acetylacetonate (VO(acac)2) in the presence of a suitable solvent such as toluene. If desired, the racemic epoxide group of the intermediate of formula (V) can be conveniently resolved into individual enantiomers, for example, using (R.R)-Co(Salen) or (S,S)-Co(Salen). The intermediate of formula (V) (resolved or unresolved) can then coupled, then reduced with a suitable reducing agent such as H2 over Pd/C, then be coupled with a cinnamic acid or a phenyl iscocyanate form a compound of formula (I): PU62673 Scheme 10:
bromide
1) nucleophilic πng opening
2) reduction
3'-Ethyl piperidinyl intermediates can be prepared as described in Scheme 1 1.
Scheme 11 :
PU62673
3'-Alkoxylated piperidine intermediates can be prepared as shown in Scheme 12, where the alkyl group is methyl. In the following scheme, DMAP refers to A- dimethylaminopyridine.
Scheme 12
3 '-Hydroxy methyl piperidine intermediates can be prepared as shown in Scheme 13.
Scheme 13
1 LiHMDS, CICOOBn, PhSeCI
Acid
3', 5'- Dihydroxypiperidine intermediates can be prepared as shown in Scheme 14. In the following scheme, (DHQD^PHAL refers to hydroquinidine 1,4-phthalazinediyl diether. PU62673
Scheme 14
KOH, MeOH
Those skilled in the art will appreciate that it may be desirable to protect one or more groups of intermediate compounds to prevent undesirable side reactions. Suitable protecting groups for amines include acyl type protecting groups such as formyl, trifluoroacetyl, acetyl groups; aromatic urethane type protecting groups such as benzyloxycarbonyl (Cbz) and substituted Cbz groups; aliphatic urethane protecting groups such as 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, and cyclohexyloxycarbonyl groups; and alkyl type protecting groups such as benzyl, trityl, and chlorotrityl groups.
Compounds of formula (I) can form a pharmaceutically acceptable salt 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 /j-toluenesulfonic acids. Suitable bases include NaH, potassiuπW-butoxide, sodium hydroxide, and potassium hydroxide.
The compounds of Formula (I) contain at least one asymmetric carbon atom. Racemates as well as individual stereoisomers (enantiomers and diastereomers) of the compounds of Formula (1) are included within the scope of the present invention. PU62673
According to a further aspect, the invention provides method of treating atherosclerosis comprising administering the compound of formula (I), or a pharmaceutically acceptable salt thereof to a patient in need thereof.
While it is possible that, for use in therapy, a compound of the invention may be administered as the pure chemical, it is generally preferable to present the active ingredient as a pharmaceutical formulation.
The invention thus further 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 recipient thereof.
The compounds of the 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. PU62673
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:
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.
In another aspect, the present invention is a compound of Formula I having a pKi of at least 6.5 as derived from the assay method set out below.
CCR-2 T35Sl GTPgS SPA Binding Assay
Membrane preparation
CHO cells expressing the human CCR-2 receptor were grown in DMEM Fl 2 media supplemented with 10% foetal calf serum, 2mM L-glutamine, G418 at 37°C 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 30Og at 4°C for 10 min, cell pellet resuspended in 100ml HBSS+EDTA and respun at 30Og for 5 min. The resulting cell pellet was resuspended in 5OmM HEPES containing 10OmM leupeptin, 25μg/ml bacitracin, ImM EDTA, ImM PMSF and 2μM pepstain A, at pH7.4. The suspension was homogenised using an ice cold blender and centrifuged at 500g for 20mins. The supernatant is withdrawn and spun at 4800Og for 30mins. This cell pellet is PU62673
resuspended in the above buffer minus the pepstatin A and PMSF and stored in aliquots at -700C.
Assay
For the assay, membranes are thawed and resuspended in assay buffer (2OmM HEPES, 10 mM MgCl2, 100 mM NaCl, pH7.4, containing lmg/ml saponin, 1OmM GDP) to give final concentration of 5 μg/well. These are pre-coupled with LEADseeker SPA beads (0.25 mg/well) for 30 min at room temperature whilst mixing. Assay plates containing 0.5 μL of various test compounds (30μM-30pM) in 100% DMSO as 1 1 point, four fold dilutions across a 384 well plate are used in the assay which have been prepared on a Biomek FX. The plate also contains 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 are 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 has been pre-determined from agonist curves run against this receptor. All additions are made using a multidrop. Plates are then sealed and centrifuged for 5 min at 300 rpm before they are left to incubate at room temperature for 3 h. After this time they are read on a Viewlux imaging system. For data handling the high and low controls wells are used to normalise the data which is 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 pKi at least 5.0.
Experimental
Mass spectra were obtained using either a Waters ZQ mass spectrometer or Micromass Platform 2 mass spectrometer and use electro-spray ionisoation to observe either MH+ or
M-. PU62673
The following examples are for illustrative purposes only and are not intended to limit the scope of the invention.
Intermediate 1 : Preparation of 4-fluoro-lH-indole
A: (£)-2-(2-Fluoro-6-nitrophenyl)-NrN-dimethylethenamine
A solution of l-fluoro-2-methyl-3-nitrobenzene (10 g, 64.5 mmol), dimethylformamide- dimethylacetal (DMF-DMA, 23 g, 193 mmol), Et3N (19.5 g, 197 mmol) in DMF (100 mL) was heated to 1 10 0C for 20 h. Dichloromethane (DCM) was added to the mixture which was washed with water, dried and concentrated to afford the crude product (17 g).
B: 4-Fluoro-lH-indole
A solution of (£)-2-(2-fluoro-6-nitrophenyl)-N,N-dimethylethenamine (87 mg, 64.5 mmol) in tetrahydrofuran (TΗF, 100 mL) was added Raney nickel (1 g). Next, hydrazine-Η2O (60 g, 258 mmol) was dropped into the solution at 0 0C. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was then allowed to stir overnight and then heated to 50 0C for 5 h. The mixture was filtered. Ethyl acetate (EtOAc) was added to the filtrate which was then washed with water, dried and concentrated. The concentrate was purified by normal phase silica gel chromatography to afford the desired product (2.3 g, 17 mmol, 26% yield). PU62673
Intermediate 2: Preparation of 2-methyl-4-(methyloxy)-lH-indole
A: N-[2-methyl-3-(methyIoxy)phenyl]acetamide
To a solution of 2-methyl-5-(methyloxy)aniline (5.0 g, 36 mmol) in DCM,(30 mL) was added acetic anhydride (4.7 g, 44 mmol) slowly. The mixture was stirred at 50 0C for 2 h, whereupon water (30 mL) was added; the resulting mixture was stirred at room temperature for 10 min. The mixture was separated and the aqueous solution was extracted with DCM (2 x 20 mL). The organic layer was washed with brine, dried over Na2SC^ and concentrated in vacuo to afford the product as a brown solid (6.5 g, 36 mmol, 100% yield).
B: 2-Methyl-4-(methyloxy)-lH-indole
To a solution of N-[2-methyl-5-(methyloxy)phenyl]acetamide (6.5 g, 36 mmol) in dry TΗF (100 mL) was added a solution of w-BuLi in hexanes (2.5 M, 73 mL, 182 mmol) at room temperature over 30 min. The mixture was then heated to reflux under nitrogen for 12 days. A solution of ammonium chloride was added slowly while cooling in an ice bath. The mixture was extracted with EtOAc dried and concentrated. The concentrate was purified by normal phase silica gel chromatography to afford the desired product as a yellow solid (700 mg, 4.34 mmol, 12% yield). MS(ES) m/e 162 [M+Η]+. PU62673
Intermediate 3: Preparation of 2-methyl-7-(methyloxy)-lH-indole
A solution of methyl 2-nitrophenyl ether (6 g, 39 mmol) in dry TΗF was dropped into the solution of isopropenylmagnesium bromide (0.5 M. 313.7 mL, 157 mmol) in TΗF at -55 0C. The resulting mixture was stirred at -55 0C for 1 hour. The reaction was quenched with the addition of ammonium chloride solution. The resulting mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried and concentrated. The crude product was purified by normal phase silica gel chromatography to afford the desired product (1.6 g, 9.92 mmol, 25% yield).
Intermediate 4: Preparation of 6-fluoro-2-methy I- lH-indole
A: (3£)-3-(4-Fluoro-2-nitrophenyl)-4-hydroxy-4-(methyloxy)-3-buten-2-one
A mixture of K2CO3 (138 mmol) and 1 ,4-difluoro-2-nitrobenzene (63 mmol) in DMF (50 mL) was warmed to 50 0C. To this was added methyl 3-oxobutanoate (72 mmol). The resulting mixture was stirred at 50 0C for 20 h. The mixture was then cooled and diluted with water. This solution was then extracted with EtOAc. The organic layer was washed with water, dried and concentrated to afford the product (15.6 g, 61 mmol, 97% yield) as a red oil. PU62673
B: 1 -(4-fluoro-2-nitrophenyl)-2-propanone
To a solution of (3£)-3-(4-fluoro-2-nitrophenyl)-4-hydroxy-4-(methyloxy)-3-buten-2-one (15.6 g, 65 mmol) in acetic acid (95 g) was added 50% H2SO4 (22.5 g) at room temperature. The reaction was then heated to reflux for 3 h. Solvent was evaporated, water added, and the product extracted with EtOAc. The organic layer was washed with water, dried, and concentrated to afford the product (10.1 g, 51 mmol, 78% yield) as a dark solid.
C: 6-Fluoro-2-methyl-lH-indole
To a solution of l-(4-fluoro-2-nitrophenyl)-2-propanone (200mg 1.0 mmol) in acetone (3 mL) was added aqueous NH4OAc (IM, 30 mL, 30 mmol). To the mixture was added TiCb (1 M, 7 mL, 7 mmol). The mixture was stirred for 1 hour, then extracted with EtOAc. The organic layer was dried and concentrated in vacuo. The residue was purified by normal phase silica gel chromatography to afford the desired product (20 mg, 0.13 mmol, 13 % yield).
Table 1 is a table of substituted indoles that were prepared in accordance with the specified scheme. All other indoles used in the Examples were commercially available. PU62673
Table 1
Intermediate 10: { l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}methanol
DCM
A mixture of 4-piperidinemethanol (17.7 g, 154 mmol), 3,5-difluorocinnamic acid (28.3 g, 154 mmol) and benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (78.2 g, 178 mmol) were dissolved in DCM (700 mL). Triethylamine (Et3N, 46.6 g, 461 mmol) was added and the resulting solution was stirred at room temperature overnight. LCMS showed 100% conversion. The reaction mixture was concentrated and purified via silica gel column eluting with 0-75% ethyl acetate in hexanes to afford the product as a white solid (35 g, 124 mmol, 81 %). MS (ES) m/e 282
[M+H]+. PU62673
Intermediate 11: l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinecarbaldehyde
A 2-L round bottom flask was charged with 900 mL DCM and oxalylchloride (25.4 g, 200 mmol) and cooled to -78 0C. Dimethylsulfoxide (DMSO) (31.2 g, 400 mmol) was added dropwise and the mixture was stirred at -78 0C for 10 min. Then, { l-[(2£)-3-(3,5- difluorophenyl)-2-propenoyl]-4-piperidinyl}methanol (43.2 g, 150 mmol, dissolved in 100 mL of DCM and a few mL of DMSO was added slowly. After stirring for another 30 min at -78 0C, Et3N (93.1 g, 920 mmol) was added slowly. The suspension was then stirred at -78 0C for 30 min, then warmed to room temperature over 2 h. The mixture was diluted with 300 mL DCM and washed with aqueous HCl (2M, 2 x 200 mL), saturated NaHCO3 (1 x 100 mL), dried over MgSO4, filtered and concentrated to afford l-[(2£)-3- (3,5-difluorophenyl)-2-propenoyl]-4-piperidinecarbaldehyde (35.4 g, 127 mmol, 85%) as a brown oil. The material was used in the next step without further purification. MS
(ES) m/e 280 [M+H]+. 1H NMR (CDCl3) δ(ppm): 9.72 (s, IH), 7.56 (d, IH), 7.04 (m, 2H), 6.90 (d, IH), 6.82 (m, IH), 4.40 (m, IH), 4.00 (m, IH), 3.36 (m, IH), 3.22 (m, IH), 2.56-2.64 (m, IH), 2.02 (m, 2H), 1.67 (m, 2H).
Intermediate 12: l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-(2-oxiranyl)piperidine
DMSO
An oven dried 1000-mL flask was charged with (CH3)3SOI (46.1 g, 210 mmol) and 250 mL dry DMSO. The solution was then cooled to 0 0C, whereupon 95% NaH (5.3 g, 210 mmol) was added in around 10 batches. The resulting mixture was stirred at 0 0C for 30 mins. The aldehyde (45 g, 161 mmol) in 150 mL dry DMSO solution was added dropwise and the resulting solution was stirred at 0 °C for 30 min. LCMS showed PU62673
completed reaction. The reaction was then quenched with 800 niL water and poured into 1500 mL diethyl ether. The organic layer was separated and washed with 2 x 150 mL water and dried over MgSO4 and concentrated. Crude LCMS showed >90% purity for the desired product as a light yellow oil (58% yield) which solidified to a yellow solid overnight. MS (ES) m/e 294 [M+H]+. 1H NMR (CDCl3) δ(ppm): 7.56 (d, IH), 7.04 (dd, 2H), 6.91 (d, I H), 6.80 (m, IH), 4.74 (m, IH), 4.11 (m, I H), 3.05 (m, IH), 2.77 (s, 2H), 2.61 (m, IH), 1.95 (m, IH), 1.70-1.80 (m, IH), 1.30-1.60 (m, 4H).
Intermediate 13: l -[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-(2S-oxiranyl)piperidine
(S,S)-Co-salen catalyst (206 mg, 0.3 mmol) ((S,S)-(+)-N,N'-Bis(3,5-di-tert- butylsalicylidene)-l,2-cyclohexanediamino cobalt (II)) was dissolved in toluene (2 mL) in an open air flask. Glacial acetic acid (39 uL) was added and the reaction stirred at room temperature for 1 hour. The reaction was then concentrated to a brown solid which was placed under high vacuum overnight. l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]- 4-(2-oxiranyl)piperidine (2 g, 7.7 mmol) was dissolved in THF (2 mL). The catalyst was dissolved in THF (0.5 mL) and added to the solution of epoxide in an open air flask. The mixture was cooled to 0 0C and H2O (69 uL) was added dropwise over 5 min. The reaction was warmed to room temperature and allowed to stir for 16 h. The reaction was then concentrated and purified by normal phase silica gel chromatography on a 120 g silica gel column (0 to 70% EtOAc/hexanes over 60 min.) to yield the desired epoxide as a yellow oil (805 mg, 2.74 mmol, 36%). MS (ES) m/e 294 [M+H]+ 1H NMR (400 MHz, DMSO-40 d ppm 7.55 (d, J = 16 Hz, IH), 7.03 (m, 2H), 6.91 (m, IH), 6.81 (m, IH), 4.74 (m, IH), 4.13 (m, IH), 3.15 (m, IH), 2.79 (m, 4H), 1.90 (m, IH), 1.47 (m, 4H). A PU62673
sample of l-[(2£T)-3-(3,5-difIuorophenyl)-2-propenoyl]-4-(2S-oxiranyl)piperidine from the above reaction was checked on a Chiralpac AD column with a 100% methanol mobile phase (0.9 mL/min) and found to have a retention time of 8.3 min, when compared to a racemic mixture (retention time 8.1 and 8.3 min) and found to be 99% ee.
Intermediate 14: Phenylmethyl 4-(2-oxiranyl)-l-piperidinecarboxylate
Trimethylsulfoxonium iodide (1.65 g, 7.5 mmol) was added in two portions to a solution of NaH (300 mg, 7.5 mmol) in anhydrous DMSO (10 mL) at room temperature. The resulting mixture was stirred for 1 hour, whereupon a solution of phenylmethyl 4-formyl- 1-piperidinecarboxylate (1.2 g, 5.0 mmol) in anhydrous DMSO (10 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then poured into cold water (100 mL), and extracted with Et2O (2 x 100 mL). The extracts were combined, washed with water, brine, and dried (Na2SO4). The solvent was removed in vacuo to give the title compound (0.95 g, 3.6 mmol, 72%) as a colorless oil. MS (ES) m/e 262 [M+H]+.
Intermediate 15: 1,1-DimethyIethyl 3-(l-{[(l,l-dimethylethyl)oxy]carbonyl}-l,2,3,6- tetrahydro-4-pyridinyl)-7-methyl-lH-indole-l-carboxylate
To a solution of indole (1.50 g, 4.80 mmol, 1 eq) and BOC anhydride (1.26 g, 4.76 mmol, 1.2 eq) in 25 mL TΗF was added DMAP (59 mg, 0.48 mmol, 0.1 eq). The resulting solution was stirred at room temperature for 2 h. LCMS showed complete reaction. The mixture was concentrated and purified via silica gel chromatography eluting with 10% PU62673
ethyl acetate in petroleum ether to give biscarbamate (1.80 g, 90%) as a pale yellow solid. MS(ES) m/e 425 [M+Na]+.
Intermediate 16: (i?αc-3,4-/r<ms-)- 1,1-dimethylethyl 3-(l -{[(l ,l - dimethylethyl)oxy]carbonyl}-3-hydroxy-4-piperidinyl)-7-rnethyl-lH-indole-l- carboxylate
To a -30 0C solution of 1,1-dimethylethyl 3-(l-{[(l,l-dimethylethyl)oxy]carbonyl}- l,2,3,6-tetrahydro-4-pyridinyl)-7-methyl-lH-indole-l -carboxylate (1.80 g, 4.30 mmol, 1.0 eq) in 15 mL dry TΗF was added borane dimethylsulfide complex (0.65 mL, 6.50 mmol, 1.5 eq). The solution was then warmed up to room temperature and stirred for 10 h. The mixture was then treated with 2.5 mL methanol for 3 min. After cooling down to -10 0C, the reaction was then treated with 30% Η2O2 (1.5 mL) and 2 M sodium hydroxide (6.5 mL, 3.0 eq) for Ih. Then it was warmed up to room temperature for 6 h. After diluting with 20 mL brine, the solution was extracted with 3 x 10 mL ethyl acetate. The combined organics were dried over sodium sulfate and concentrated. The crude material was purified via silica gel chromatography eluting with 20% ethyl acetate in petroleum ether to give the alcohol as a white solid (1.2 g, 64%). MS(ES) m/e 330 [M- Boc + H+]+.
Intermediate 17: (Rac-3,4-trans-)- 1,1-dimethylethyl 3-[l-{[(l,l- dimethylethyl)oxy]carbonyl}-3-(methyloxy)-4-piperidinyl]-7-methyl-lH-indole-l- carboxylate
PU62673
To a solution of (Rac-3,4-trans-)-\ ,\ -dimethy\ethy\ 3-(l-{[(l,l- d imethy lethy l)oxy]carbony I } -3 -hydroxy-4-piperidiny l)-7-methy 1- 1 H-indole- 1 - carboxylate (1.2 g, 2.79 mmol, 1.0 eq) in 20 mL dry DMF was added 60% NaH (130 mg, 3.34 mmol, 1.2 eq) at room temperature. After the solution was cooled to 0 0C, methyl iodide (0.60 g, 4.18 mmol, 1.5 eq) was added. The resulting mixture was stirred at room temperature for 4 h. The reaction was then quenched with 30 mL water and extracted with 3 x 20 mL ethyl acetate, dried over MgSθ4 and concentrated. The crude material was purified via silica gel column eluting with 10% ethyl acetate in petroleum ether to give the methyl ether (1.0 g, 80%) as a white solid. MS(ES) m/e 467 [M+Na+]+.
Intermediate 18: (Rαc-.3,4-/rø/7s-)-7-methyl-3-[3-(methyloxy)-4-piperidinyl]-lH-indole
To a solution of (Λαc-3, ^-/ran*-)-l,l-dimethylethyl 3-[l-{[(l,l- dimethylethyl)oxy]carbonyl}-3-(methyloxy)-4-piperidinyl]-7-methyI-lH-indole-l- carboxylate (1.0 g, 2.2 mol) in 10 mL dichloromethane was added 10 mL TFA. The mixture was stirred at room temperature for 6 h. Then the mixture was concentrated and dried over high vacuum pump to give the indolepiperidine (0.4 g, 44%) as a brown oil. MS(ES) m/e 245 [M+Η+]+.
Intermediate 19: l-(l,l-dimethylethyl) 3 -(pheny Imethy 1) 2-oxo-3-(phenylseleno)-l,3- piperidinedicarboxylate
To a -78 0C solution ofN-Boc-2-piperidone (5.0 g, 25 mmol, 1.0 eq) in 170 mL dry THF was added dropwise lithium hexamethyldisilazide (LIHMDS, IM in THF, 57 mL, 57 mmol, 2.3 eq). The resulting solution was stirred at -78 0C for lhr. Then benzyl PU62673
chloroformate (ClCOOBn, 5.14 g, 30 mmol, 1.2 eq) was added. After stirring for another 1 h, a solution of PhSeCl (6.25 g, 32.6 mmol, 1.3 eq) in 30 mL was added and stirred at - 78 0C for another 1 h. The mixture was allowed to warm up to room temperature for 2 h. The reaction was then quenched with 150 mL IM HCl and extracted with 3 x 100 mL ethyl acetate. The combined organics were washed with 1 x 100 mL saturated NaHCθ3 and 1 x 100 mL brine, dried over MgSO4 and concentrated. The crude material was purified via a silica gel column eluting with 10% ethyl acetate in petroleum ether to give the product (2.4 g, 19%). MS(ES) m/e 388 / 390 [M-Boc+H+]+.
Intermediate 20: l-(l,l-dimethylethyl) 3-(phenylmethyl) 2-oxo-5,6-dihydro-l,3(2H)- pyridined icarboxy late
To a 0 0C solution of 1 -( 1 , 1 -dimethylethyl) 3-(phenylmethyl) 2-oxo-3-(phenylseleno)- 1,3-piperidinedicarboxylate (4.8 g, 10 mmol, 1.0 eq) in 4 mL dichloromethane was added dropwise 30% H2O2 (4 mL, 40 mmol, 4.0 eq). The solution was stirred at 0 0C for 20 min, then quenched with 40 mL IM HCI and extracted with 3 x 30 mL ethyl acetate. The combined organics were dried over MgSO4 and concentrated to give the enone (2.7 g, 83%). MS(ES) m/e 232 [M-Boc+H+]+.
Intermediate 21 : (Rac-3,4-trans-)-l-(l,\-dimethy\Qthy\) 3-(phenylmethyl) -4-(7-methyl- lH-indol-3-yl)-2-oxo-l,3-piperidinedicarboxylate
Montmorillonite KSF PU62673
To a solution of l-(l,l-dimethylethyl) 3-(phenylmethyl) 2-oxo-5,6-dihydro-l,3(2H> pyridinedicarboxylate (2.7 g, 8.1 mmol, 1.0 eq) and montmorillonite (4.6 g) in 30 mL dichloromethane was added 7-methylindole (1.08 g, 8.1 mmol, l .Oeq). The resulting mixture was stirred at room temperature for 12 h. After filtration, the filtrate was concentrated and purified via silica gel chromatography to give the indolepiperidine (1.2 g, 58%) as a white solid. MS(ES) m/e 363 [M-Boc+Η+]+.
Intermediate 22: (Rac-3, ¥-/ram-)-phenylmethyl (3R,45)-4-(7-methy 1-1 H-indol-3-yl)-2- oxo-3-piperidinecarboxylate
To a solution of (Rac-3, 4-trans-)- 1 -( 1 , 1 -dimethylethyl) 3-(phenylmethyl) -4-(7-methyl- lH-indol-3-yl)-2-oxo-l,3-piperidinedicarboxylate (2.2 g, 4.7 mmol) in 2 mL dichloromethane solution was added 2 mL TFA. The mixture was stirred at room temperature for 4 h, then concentrated and dried over high vacuum pump to give the amine TFA salt (1.2 g, 53%) as a brown oil. MS(ES) m/e 363 [M+Η+]+
Intermediate 23: (i?αc-3,^-/rα«^-)-[4-(7-methyl-lH-indol-3-yl)-3-piperidinyl]methanol
LiAlH4
To a suspension of lithium aluminum hydride (0.53 g, 13.2 mmol, 4.0 eq) in 20 mL dry THF was added {rac-3, 4-/ra«5-)-phenylmethyl (3R,45)-4-(7-methyl-lH-indol-3-yl)-2- oxo-3-piperidinecarboxylate (1 ,2 g, 3.30 mmol, 1.0 eq) at room temperature. The mixture was stirred at room temperature for 1 h, then refluxed for 10 h. After cooling PU62673
down to 0 0C, 0.53 mL 10% NaOH was added to quench the reaction. After stirring for 30 min, the mixture was filtered. The filtrate was concentrated. The residue was taken up in diethyl ether and a few drops of TFA were added. The resulting precipitates were collected to give the amine TFA salt as a solid (0.5 g, 62%). MS(ES) m/e 245 [M+H+]+.
Intermediate 24: 1 , 1 -Dimethylethyl (3Λ)-3-hydroxy-4-(7-methyl-lH-indol-3-yl)-3,6- dihydro-l(2H)-pyridinecarboxylate
1 ,1 -Dimethylethyl (3Λ,4Λ)-3,4-dihydroxy-4-(7-methyl-lH-indol-3-yl)-l- piperidinecarboxylate (see Example 2B, 1.75 g, 5.05 mmol, 1.0 eq) in 15 mL methanol solution was treated with KOΗ (0.85 g, 15.15 mmol, 3.0 eq). The solution was heated at 70 0C overnight after which time the mixture was cooled down and concentrated. The residue was treated with 15 mL water and extracted with 2 x 40 mL EtOAc, dried over MgSO4 and concentrated. The crude product was purified via Isco silica gel column eluting with 10-50% EtOAc in hexanes to give two products. Product 1 , 7-methylindole, 320 mg, 48%. Product 2, the desired allylic alcohol, 600 mg, 36%. MS(ES) m/e 351 [M+Na+]+.
Intermediate 25: 1, 1 -Dimethylethyl (3Λ,5R)-3,5-dihydroxy-4-(7-methyl-lH-indol-3-yl)- 1 -piperidinecarboxy late
THF H2O2
1 , 1 -Dimethylethyl (3fl)-3-hydroxy-4-(7-methyl-lH-indol-3-yl)-3,6-dihydro-l (2H)- pyridinecarboxylate (600 mg, 1.83 mmol, 1.0 eq) was dissolved in 5 mL dry TΗF and cooled to 0 0C. BHs-Me2S (250 mg, 3.29 mmol, 1.5 eq) was added dropwise and stirred at 0 0C for 3 h, then warmed up to room temperature overnight. 30% H2O2 (1.68 mL) PU62673
was carefully added, followed by 18.2 mL 2 M NaOH. The mixture was stirred for another 1 h at 0 0C and warmed up to room temperature. LCMS showed complete conversion to the alcohol. The mixture was then extracted with 3 x 25 mL EtOAc. The combined organic was dried over MgSO4, concentrated. The crude product was purified via ISCO silica gel chromatography eluting with 25-50% EtOAc in hexanes to give final product as a light yellow solid, 420 mg, 66%. MS(ES) m/e 369 [M+Na+]+.
Intermediate 26: (3i?,5/?)-4-(7-methyl-lH-indol-3-yl)-3,5-piperidinediol
l,l-Dimethylethyl (3#,5i?)-3,5-dihydroxy-4<7-methyl-lH-indol-3-yl)-l- piperidinecarboxylate (400 mg, 1.16 mmol, 1.0 eq) was dissolved in 5 mL methanol. 1 M HCl in dioxane (prepared from 4 M HCl in dioxane, 4.62 mL, 4.62 mmol, 4.0 eq) was added to the solution. The resulting mixture was stirred at room temperature for around 10 h until LCMS showed complete consumption of the starting material. The solvent was then removed under vacuum. The residue was dried over high vacuum for a few hours to give the product as its HCl salt, 300 mg, 100% yield. MS(ES) m/e 247 [M+Η+]+.
Example 1 ; Preparation of 4-(7-chloro-lH-indol-3-yl)-l-(2-{ l-[(2E)-3-(3,5- difluorophenyl)-2-propenoyl]-4-piperidinyl}-2-hydroxyethyl)-3-piperidinol
PU62673
A: 1 , 1 -Dimethylethyl 4-(7-chloro-lH-indol-3-yl)-3,6-dihydro-l (2H)-pyridinecarboxylate
A mixture of 7-chloroindole (2.0 g, 13.2 mmol), 1,1 -dimethylethyl 4-oxo-l- piperidinecarboxylate (3.15 g, 15.8 mmol) and KOΗ (2.22 g, 39.6 mmol) was dissolved in methanol (MeOH, 50 mL) and heated at 600C for 5 h. The solvent was removed in vacuo and the residue was triturated with Η2O (200 mL). The precipitates were collected and dried to obtain a yellowish solid (4.19 g, 93 %). MS (ES): m/e 332/334 [M+H]+.
B: 1,1 -Dimethylethyl 4-(7-chloro-lH-indol-3-yl)-3-hydroxy-l-piperidinecarboxylate
rt, 3h
To a solution of 1,1 -dimethylethyl 4-(7-chloro-lH-indol-3-yl)-3,6-dihydro-l(2H)- pyridinecarboxylate (2.0 g, 6.0 mmol) in TΗF (20 mL) at room temperature was added a solution of IM BΗ3.TΗF complex (18 mL, 18 mmol). The reaction was stirred for 1 hour, whereupon a solution of 2N NaOH (4 mL) was added, followed by 30% H2O2 in H2O (6 mL). The resulting reaction mixture was continued to stir for an additional 3 h, then acidified with 2N HCl (pH= 3 -4), extracted with EtOAc (3x), washed with brine, dried over MgSθ4, concentrated to obtain a white solid. The crude material was purified by normal phase silica gel chromatography eluting with 0-30 % EtOAc in to afford the product (1.2 g, 3.42 mmol, 57%) as a white solid. MS(ES) m/e 350/352 [M+H]+.
C: 4-(7-Chloro-lH-indol-3-yl)-3-piperidinol
PU62673
To a solution of 1,1-dimethylethyl 4-(7-chloro-lH-indol-3-yl)-3-hydroxy-l- piperidinecarboxylate (0 .4 g, 1.14 mmol) in MeOH (2 mL) was added a solution of IN HCl in dioxane (2 mL). The mixture was stirred at room temperature for 10 hour, then concentrated to obtain a solid (0.32 g). MS(ES) m/e 250/252 [M+H]+.
D: 4-(7-Chloro-lH-indol-3-yl)-l-(2-{ l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4- piperidiny!}-2-hydroxyethyl)-3-piperidinol
A mixture of 4-(7-chloro-lH-indol-3-yl)-3-piperidinol (0.16 g, 0.56 mmol) and 1-[(2E)- 3-(3,5-difluorophenyl)-2-propenoyl]-4-(2-oxiranyl)piperidine (0.19 g, 0.64 mmol) in ethanol (EtOΗ 2 mL) was subjected to microwave irradiation at 125 0C for 1 hour. The crude material was purified by reverse phase high pressure liquid chromatography (ΗPLC, YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 20 to 55% over 10 minute, UV detection at 214 nm) to give a white solid material as a TFA salt (57 mg, 0.087 mmol, 15%). MS(ES) m/e 544 [M+Η]+.
Example 2: Preparation of (3S,4S)-l-((2S)-2-{l-[(2£)-3-(3,5-difluorophenyl)-2- propenoyl]-4-piperidinyl}-2-hydroxyethyl)-4-(7-methyl-lH-indol-3-yl)-3-piperidinol
PU62673
A: l ,l -Dimethylemyl 4-(7-methyl-lH-indol-3-yl)-3,6-dihydro-l(2H)- pyridinecarboxylate
A mixture of 7-methylindole (3.0 g, 22.9 mmol), 1,1-dimethylethyl 4-oxo-l- piperidinecarboxylate (5.4 g, 27.4 mmol) and KOΗ (3.9 g, 68.7 mmol) was dissolved in 30 mL of MeOH and heated at 60 0C for 5 h. The solvent was removed in vacuo and the residue was triturated with 200 mL Of H2O to obtain the crude product as a yellowish solid. MS (ES) m/e 313 [M+H]+.
B: l,l-Dimethylethyl (3R,4/?)-3,4-dihydroxy-4-(7-methyl-lH-indol-3-yl)-l- piperidinecarboxylate
Water (54 mL), K2Fe(CN)6 (19 g, 57.7 mol), K2CO3 (7.97 g, 57.7 mmol), MeSO2NH2 (1.83 g, 19.2 mmol), K2OsO4.2H2O (0.35 g, 0.96 mmol), hydroquinidine 1,4- phthalazinediyl diether ((DHQD)2PHAL, 0.15 g, 0.19 mmol), and /-butanol (36 mL) were added to a 250-mL round bottom flask in that order. The mixture was stirred at room temperature for 5 min, whereupon 1 ,1-dimethylethyl 4-(7-methyl-lH-indol-3-yl)- 3,6-dihydro-l (2H)-pyridinecarboxylate (6.0 g, 19.2 mmol) was slowly added. After 2 days, EtOAc (100 mL) was added and stirred vigorously for 2 h; the mixture was filtered over a pad of celite and the solid was washed with EtOAc (3x). The filtrates were combined and washed with 2N KOΗ then brine, and concentrated in vacuo. The crude product was purified by normal phase silica gel chromatography (40 g silica gel 60, 230- PU62673
400 mesh, 0 to 100% EtOAc in hexane) to give a white solid (2.6 g, 7.5 mmol, 39%). MS(ES) m/e 369 [M+Na]+.
C: Ul-DimethylethyKS^^-S-hydroxy^^T-methyl-lH-indoW-yO-l- piperidinecarboxylate
To a refluxing mixture of Raney Nickel (20 g wet weight) in H2O and EtOH (20 mL) was slowly added a solution of 1,1-dimethylethyl (3i?,4i?)-3,4-dihydroxy-4-(7-methyl-lH- indol-3-yl)-l-piperidinecarboxylate (1 g, 2.89 mmol) in EtOH (5 mL) via an addition funnel over a period of 30 min. The mixture was allowed to cool to room temperature before it was filtered through Celite, ensuring that the liquid level did not fall below the surface of the filter cake. A total of 1 L of EtOH was used to wash to filter cake. The filtrate was concentrated under reduced pressure to obtain the title compound (075 g, 2.7 mmol, 79%) plus some of the cis isomer in an 8: 1 ratio. MS (ES+): m/e 683 [2M + Na]+.
D : 4-(7-Methy 1- 1 H-indol-3 -yl)-3-piperidinol
To a solution of 1 ,1-dimethylethyl (3£,4S)-3-hydroxy-4-(7-methyl-lH-indol-3-yl)-l- piperidinecarboxylate (0 .9 g, 2.75 mmol) in MeOH (2 mL) was added a solution of 1 N HCl in dioxane (2 mL). The mixture was stirred at room temperature for 10 h, then diluted with EtOAc, treated with NaΗCθ3 and recrystalized from EtOAc to obtain an enantiomerically pure compound 99+ee (0.57 g, 2.5 mmol, 91%). MS(ES) m/e 231 [M+H]+. PU62673
E: (35,45)-l -((2-5)-2-{ l-[(2£)-3-(3,5-Difluorophenyl)-2-propenoyl]-4-piperidinyl}-2- hydroxyethyl)-4-(7-methyl-lH-indol-3-yl)-3-piperidinol
A mixture of 4-(7-methyl-lH-indol-3-yl)-3-piperidinol (50 mg, 0.22 mmol) and l-[(2£)- 3-(3,5-difluorophenyl)-2-propenoyl]-4-[(2S)-2-oxiranyl]piperidine (64 mg, 0.22 mmol) in EtOH (2 mL) was subjected to microwave irradiation at 160 0C for 45 min. The mixture was purified by reverse phase ΗPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 20 to 55% over 10 min, UV detection at 214 nm) to give the title compound (62 mg, 0.097 mmol, 44%). MS(ES) m/e 523 [M+Η]+.
Example 3: Preparation of l-{ l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4- piperidinyl}-2-[(35',41S)-4-(lH-indol-3-yl)-3-methyl-l -piperidinyl]ethanol
A: 3-[5-Methyl-l-(phenylmethyl)-l,2,3,6-tetrahydro-4-pyridinyl]-lH-indole
A mixture of lH-indole (1.17 g, 10 mmol), 3-methyl-l-(phenylmethyl)-4-piperidinone (4.06 g, 20 mmol), H3PO4 (2 M, 10 mL, 20 mmol), and HOAc (30 mL) was heated at 90 0C for 5 h. The mixture was cooled to room temperature and poured into a slurry of ice water with NH4OH added to make the solution basic. The resulting solution was PU62673
extracted with EtOAc (3 x 100 mL), washed with brine, dried over Na2SC>4 and concentrated. The concentrate was purified by reverse phase HPLC eluting with 10-50% acetonitrile in H2O with 0.1% TFA to afford the product as a yellow solid (2.24 g, 75%). MS (ES+): m/e 303 [M + H]+.
B: 3-[(31S,45)-3-methyl-4-piperidinyl]-lH-indole
To a solution of 3-[5-methyl-l-(phenylmethyl)-l,2,3,6-tetrahydro-4-pyridinyl]-lH-indole (1.0 g, 3.3 mmol) dissolved in EtOH (20 mL) was added ΗOAc (1 mL) followed by Pd/C (10% w/w, 200 mg). The mixture was stirred for 16 h at room temperature under 1 atm H2 gas. The reaction was filtered through a pad of celite, washed with EtOH (20 mL), and concentrated to give the crude product as a thick oil (0.9 g). MS (ES+): m/e 215 [M + H]+.
C: l-{ l-[(2^)-3-(3,5-Difluorophenyl)-2-propenoyl]-4-piperidinyl}-2-[(3,S',45)-4-(lH- indol-3-yl)-3-methyl-l-piperidinyl]ethanol
A mixture of 3-[(3S,4S)-3-methyl-4-piperidinyl]-lH-indole (107 mg, 0.5 mmol), l -[(2£> 3-(3,5-difluorophenyl)-2-propenoyl]-4-(2-oxiranyl)piperidine (147 mg, 0.5 mmol), and K2CO3 (207 mg, 1.5 mmol) in EtOΗ (2 mL) was heated at 85 0C for 20 h. The crude product was purified by reverse phase ΗPLC to afford the product as a TFA salt (170 mg, 55%). MS (ES+): m/e 508 [M + H]+. PU62673
Example 4: l -(2-{ l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}-2- hydroxyethyl)-4-(lH-indol-3-yl)-3-piperidinecarboxylic acid
A: l,l-Dimethylethyl 4-(lH-indol-3-yl)-3-[(methylsulfonyl)oxy]-l- piperidinecarboxylate
To a solution of 1,1-dimethylethyl 3-hydroxy-4-(lH-indol-3-yl)-l-piperidinecarboxylate (1.3 g, 4.11 mmol) in dry DCM, cooled to 0 0C was added Et3N (0.86 mL, 6.16 mmol) followed by methanesulfonyl chloride (0.44 mL, 5.35 mmol). The mixture was stirred at 0 °C for 1.5 h. The mixture was partitioned between ethyl acetate and water. The organic layer was dried and concentrated. The concentrate was purified by normal phase silica gel chromatography to afford the product (180 mg, 0.456 mmol, 11% yield).
B: 1,1-Dimethylethyl 3-cyano-4-(lH-indol-3-yl)-1 -piperidinecarboxylate
To a solution of 1,1-dimethylethyl 4-(lH-indol-3-yl)-3-[(methylsulfonyl)oxy]-l- piperidinecarboxylate (620 mg, 1.57 mmol) in DMSO was added KCN (439 mg, 2.85 mmol). The mixture was stirred at 60 0C for 24 h. The mixture was quenched with NaCI PU62673
solution and washed with brine. The organic layer was separated, dried and concentrated. The concentrate was purified by normal phase silica gel chromatography to afford the desired product (200 mg, 0.615 mmol, 39% yield).
C: 4-(lH-IndoI-3-yl)-3-piperidinecarboxylic acid
A solution of 1,1-dimethyIethyl 3-cyano-4-(lH-indol-3-yl)-l-piperidinecarboxylate (150 mg, 0.67 mmol) in concentrated ΗCI was stirred at 90 0C for 18 h. The mixture was concentrated and the residue purified by reverse phase ΗPLC to afford the desired product (18 mg, 0.074 mmol, 1 1% yield).
D: l-(2-{ l-[(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}-2-hydroxyethyl)-4- (lH-indol-3-yl)-3-piperidinecarboxylic acid
A mixture of 4-(lH-indol-3-yl)-3-piperidinecarboxylic acid (18 mg, 0.078 mmol) and 1- [(2£)-3-(3,5-difluorophenyl)-2-propenoyl]-4-(2-oxiranyl)piperidine (22 mg, 0.075 mmol) in EtOH (1 mL) was microwave irradiated at 125 0C for 1 hour. The crude mixture was purified by preparative ΗPLC to give a white solid material as a TFA salt (3.9 mg, 0.0059mmol, 13%). MS(ES) m/e 538 [M+Η]+. PU62673
Table 2 illustrates other compounds prepared by methods as indicated. PU62673
l-((2S)-2-{ l-[(2E)-3-(3,5- difluorophenyl)-2-propenoyl]-4-
22 524 piperidinyl } -2-hydroxyethy l)-4- 1, 9
(7-methyl-lH-indol-3-yl)-3- piperidinol
(3S,4S)- 1 -((2R)-2-{ 1 -[(2E)-3-
(3,5-difluorophenyl)-2-
23 524 propenoyl]-4-piperidinyl}-2- hydroxyethyl)-4-(7-methyl-l H- indol-3-yl)-3-piperidinol
(3S,4S)-1 -((25)-2-{ 1 -[(2£)-3-
(3,5-diftuorophenyl)-2-
24 538 propenoyl]-4-piperidinyl}-2- 1 , 5, 9 hydroxyethyl)-4-(2,7-dimethyl-
1 H-indol-3-y l)-3-piperidinol
(3Λ,4Λ)-l-((25)-2-{ l-[(2£)-3- (3,5-difluorophenyl)-2-
25 538 propenoyl]-4-piperidinyl }-2- 1, 5, 9 hydroxyethyl)-4-(2,7-dimethyl-
1 H-indol-3-yl)-3-piperidinol
(3S,4S)- l-((2Λ)-2-{ I-[(2£)-3-
(3 ,5-difluorophenyl)-2-
26 538 propenoy l]-4-piperidiny 1 } -2- 1, 5 hydroxyethyl)-4-(2,7-dimethyl-
1 H-indol-3-yl)-3-piperidinol
(3Λ,4Λ)-1 -((2Λ)-2-{ 1 -[(2£)-3-
W (3,5-difluorophenyl)-2-
27 538 propenoyl]-4-piperidinyl }-2- 1 , 5
) — ' hydroxyethyl)-4-(2,7-dimethyl- lH-indol-3-yl)-3-piperidinol
(3R,4R> 1 -((2S)-2-{ 1 -[(2E)-3-
(3,5-difluorophenyl)-2-
28 524 propenoyI]-4-piperidinyl}-2- 1, 2, 9 hydroxyethyl)-4-(7-methyI-lΗ- indol-3-yl)-3-piperidinol
(3R.4R)- 1 -((2R)-2-{ 1 -[(2E)-3-
(3,5-difIuorophenyl)-2-
29 524 propenoyl]-4-piperidinyl}-2- 1, 2 hydroxyethyl)-4-(7-methyl-l H- indol-3-yl)-3-piperidinol l-(2-{ l-[(2E)-3-(3,5- difluorophenyl)-2-propenoyl]-4-
30 540 piperidinyl} -2-hydroxyethy l)-4- [4-(methyloxy> 1 H-indol-3-yl]- 3-piperidinol l-(2-{ l-[(2E)-3-(3,5- difluoropheny l)-2-propenoy 1] -4-
524 piperidiny 1 } -2-hydroxyethy l)-4- (4-methyl-lH-indol-3-yl)-3- piperidinol l-(2-{ l-[(2E)-3-(3,5- difluorophenyl)-2-propenoyl]-4-
554 piperidinyl}-2-hydroxyethyl)-4- 1 , 6
[2-methyl-6-(methyloxy)- 1 H- indol-3-yl]-3-piperidinol l-(2-{ l-[(2E)-3-(3,5- difluorophenyl)-2-propenoyl]-4-
554 piperidinyl } -2-hydroxyethy l)-4- 1 , 6 [2-methyI-4-(methyloxy)- 1 H- indol-3-yl]-3-piperidinol l-(2-{ l-[(2E)-3-(3,5- difluorophenyl)-2-propenoyl]-4-
542 piperidiny 1 } -2-hydroxyethy l)-4- 1, 8
(6-fluoro-2-methyl-lH-indol-3- yl)-3-piperidinol l-(2-{ l-[(2E)-3-(3,5- difluorophenyl)-2-propenoyl]-4-
538 piperidinyl}-2-hydroxyethyl)-4-
(7-ethyl-lH-indol-3-yl)-3- piperidinol
(3S,4R)-l-(2-{ l-[(2E)-3-(3,5- difluoropheny l)-2-propenoy l]-4-
524 piperidinyl} -2-hydroxyethy l)-4- (7-methyI-lH-indol-3-yl)-3- piperidinol
4-(7-chloro- 1 H-indol-3-yl)- 1 -
((2S)-2-{ l-[(2E)-3-(3,5-
544 difluoroρhenyl)-2-propenoyl]-4- 1, 9 piperidinyl}-2-hydroxyethyl)-3- piperidinol
(3S,4S)-4-(7-chloro- 1 H-indol-3- yl)-l-((2S)-2-{ l-[(2E)-3-(3,5-
544 difluorophenyl)-2-propenoyl]-4- 1, 9 piperidinyl}-2-hydroxyethyl)-3- piperidinol
PU62673

Claims

PU62673CLAIMS:
1. A compound of the following formula:
(D or a pharmaceutically acceptable salt thereof, wherein
each R1 is independently -NR^SO2-C1 -C6-alkyl, -NR9-C(O)-N(R10)2, -NR9-C(O)-OR9, halo, Ci-Cβ-alkyl, CF3, cyano, CrU-alkoxy, OH, or -(Y)q-N(Rl0)2;
R2 is H, Ci-C6-alkyl, -C(O)-C ,-C6-alkyl, or -SO2R11;
R3 is H, halo, HO-Ci-C6-alkyl, Ci-C6-alkyl, or CF3;
R4 and R5 are each independently H, Ci-C6-alkyl, OH, HO-Ci-C6-alkyl, COOH, or C,- C6-alkoxy;
R6 is H, Ci-Cβ-alkyl, OH > C,-C6-alkoxy, or HO-d-C6-alkyl;
R7 is H, OH, F, Cl, CN, CF3, Ci.C6-alkyl, hydroxy-CrC6-alkyl, or CCe-alkoxy;
each R8 is independently halo, H0-C]-C6-alkyl, Cj-Cβ-alkyl, cyano, trifluoromethyl, Cj-Ce-alkoxy, or Ci-Ce-alkylthio;
each R9 is independently H or Ci-Cβ-alkyl;
each R10 is independently H, -Cj-Cό-alkyl, or acetyl, or, together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocycloalkyl ring;
R1 1 is Ci-Cβ-alkyl or phenyl-(R8)n; PU62673
X is NH, -CH2O- or -HC=CH-;
Y is -SO2- or -C(O)-;
each m is independently O, 1, 2, or 3;
each n is independently O, 1, 2, or 3; and
q is 0 or 1 ;
with the proviso that when R6 is H, at least one of R4 and R5 is not H.
2. The compound of Claim 1 or a pharmaceutically acceptable salt thereof; wherein R1 is chloro, fluoro, methyl, trifluoromethyl, cyano, or methoxy; R2 and R3 are each independently H or methyl; and R4 is H.
3. The compound of either of Claims 1 or 2 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof;
wherein m is 0, 1, or 2; n is 1 or 2; R5 is H, OH, methyl, ethyl, methoxy, or hydroxymethyl; R6 is H, methyl, OH, or hydroxymethyl; and R8 is methoxy, cyano, fluoro, or chloro; with the proviso that when R6 is H, R5 is OH, methyl, or hydroxymethyl. PU62673
4. The compound of any of Claims 1 to 3 which is represented by either of the following formulae:
or
or a pharmaceutically acceptable salt thereof, where R5 is HO or hydroxymethyl.
5. The compound of any of Claims 1 to 4 which is represented by either of the following formula:
or
or a pharmaceutically acceptable salt thereof, where R5 is HO or hydroxymethyl. PU62673
6. A composition that comprises a) the compound of any of Claims 1 to 5 or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.
7. A method of treating a disease comprising administering the compound of any of Claims 1 to 6 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.
EP08838205A 2007-10-11 2008-10-10 Piperidinylhydroxyethylpiperidines as modulators of chemokine receptors Withdrawn EP2211618A1 (en)

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CL2008001810A1 (en) 2007-06-20 2008-12-26 Glaxo Group Ltd Compounds derived from spiroindolines, chemokine receptor modulators; pharmaceutical composition comprising said compounds; and its use to treat atherosclerosis, inflammatory pain, influenza, metabolic syndrome, among other diseases.

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US7645771B2 (en) * 2002-12-13 2010-01-12 Smithkline Beecham Corp. CCR5 antagonists as therapeutic agents

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See references of WO2009049113A1 *

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